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The Psychopharmacology of Depression: Strategies, Formulations, and Future Implications

 

With well over two dozen traditional antidepressants available in the US, and an ever-growing list of other psychotropic compounds with apparent antidepressant properties, pharmacological options for treating clinical depression today are broad and vast. However, recent findings suggest that the magnitude of efficacy for most antidepressants compared with placebo may be more modest than previously thought.1Most depressed patients do not respond fully to a first antidepressant trial, and with each consequent trial, there is less chance of symptom remission.2 About one-third of patients receiving long-term treatment report persistent moderate-to-severe depression.3 Hence, there remains more than a little room for improvement.

Since the late 1950s, the traditional view of treating depression has focused on the role of monoamines (serotonin, norepinephrine, and dopamine) as the main targets for medications. Newer treatments are looking beyond effects on monoamines as potential strategies to leverage depressive symptoms.

A major challenge for progress in novel pharmacotherapies has been our lack of a full understanding about the causes of depression. Advances in functional neuroimaging and genetic markers have begun to shed new light on brain regions and pathways associated with aberrant neural functioning in depression, but not in ways that have led to treatments aimed at remedying its pathogenesis. This makes it hard to think of antidepressant medications as “treating” the pathophysiology of depression (as when antibiotics eliminate the cause of an infection); rather, antidepressant relieve symptoms by counteracting or compensating for depression’s consequences (as when diuretics alleviate peripheral edema regardless of its etiology).

Gone are the days of oversimplified theories that depression is caused by a “chemical imbalance.” More likely, depression involves changes in brain architecture and the interplay of complex circuits in which chemicals, or neurotransmitters, are the messengers of information, rather than the causes of faulty functioning. Table 1 summarizes some of the major conceptual shifts that have occurred in thinking about the probable causes of depression (or at least its neurobiological context), which sets the stage for new ways to consider innovative treatment strategies. Looking beyond the role of monoamines as treatment targets in depression, a number of novel therapeutic strategies have begun to receive growing interest in preclinical and clinical trials. Key points about emerging novel depression pharmacotherapies are summarized in Table 2, and described more fully below.

Subanesthetically dosed intravenous (IV) ketamine currently represents perhaps the most dramatic and innovative antidepressant pharmacotherapy to emerge in decades.4,5 It is pharmacodynamically unique in its rapid onset (hours rather than days to weeks) and its potential ability to reduce suicidal ideation after a single dose, independent of its antidepressant properties.6 (While both lithium and clozapine have been shown to reduce suicidal behaviors, neither has been shown to reduce ideation, much less in the same day after a single dose.) Meta-analyses suggest that 0.5 mg/kg IV ketamine produces nearly a 10-fold greater likelihood of response than placebo at day 1 and a 4- to 5-fold likelihood of sustained response after one week.7

The exact psychotropic mechanism of action of ketamine remains elusive. Initial work focused on blockade of ionotropic N-methyl-D-aspartate (NMDA) receptors as accounting broadly for its antidepressant effects. However, subsequent negative randomized trials with other NMDA receptor antagonists (such as riluzole8) redirected interest toward ketamine’s other, non-NMDA receptor-related mechanisms, such as sigma receptor agonism, mu opioid receptor antagonism, or midbrain monoaminergic inhibition. Other authors have suggested that at low doses, ketamine’s antidepressant effects may derive from an increase in glutamate transmission with increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression, leading to increased release of brain-derived neurotrophic factor (BDNF).9Murrough and colleagues10 recently observed the necessity of AMPA receptor activation for the antidepressant effects of ketamine. They reported that “directly targeting the NMDA [receptor] may not be required.” As noted by the American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments,11 future advances will depend on a better understanding of the many mechanisms of action relative to the antidepressant properties of ketamine.

Ketamine is currently not approved by the FDA as a treatment for depression. Uncertainty remains as to whether repeated dosing is safe, effective, and necessary to avoid relapse and, if so, when, at what frequency, and for how long. The aforementioned APA Council on Research Consensus Statement on ketamine treatment for depression11 stated that while some clinics already offer 2- to 3-week courses of ketamine delivered 2 to 3 times per week, “there remain no published data that clearly supports this practice, and . . . the relative benefit of each ketamine infusion [should] be considered in light of the potential risks associated with longer term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration.” 11 Thus far, studies of other pharmacotherapies to sustain an initial ketamine response (such as riluzole or lithium) have proven no better than placebo.

Enantiomeric esketamine remains investigational as a possible easier-to-administer intranasal (IN) antidepressant, although IN bioavailability is only about half that of IV ketamine’s 100%. Two randomized multi-site trials of IN esketamine added to antidepressants showed dose-related better efficacy than placebo: Daly and colleagues12 found that 28 mg to 84 mg of IN ketamine twice weekly over two weeks produced significant improvement in depressive symptoms as compared to placebo beginning after 1 week and continuing through week 9 for the majority of responders. A study by Canuso and colleagues13 demonstrated a significant reduction in depressive symptoms within 4 hours of administration (56 mg to 84 mg insufflated over 15 minutes) and a medium to large effect size, sustained after 25 days; suicidal ideation reduced significantly at 4 hours but not beyond that time. Another recent randomized pilot trial of IN racemic ketamine (the mixture of S- and R-ketamine) was prematurely discontinued due to poor tolerability (including cardiovascular and neurological adverse effects) and highly variable absorption across subjects.14

Modulation of the endogenous opioid system has long been a target of interest in the treatment of mood disorders, but it is limited by safety risks, tolerance, and addiction potential. Recent work has focused on a proprietary combination of the μ-opioid partial agonist/kappa antagonist buprenorphine plus the μ-opioid receptor antagonist samidorphan (ALKS 5461). The potent blockade of μ-opioid receptors in samidorphan, which prevents buprenorphine access to these receptors, effectively renders buprenorphine a selective kappa opiate receptor (KOR) antagonist, which is its putative antidepressant mechanism. After initial favorable Phase II trials, in 2013 the FDA granted ALKS 5461 fast track status for accelerated regulatory review as an antidepressant adjunct. Subsequent randomized trials in treatment-resistant major depression revealed statistically significant differences from placebo on some, but not all, depressive symptom outcome measures and at some, but not all, doses studied.15,16 The FDA initially refused to review the new drug application for ALKS 5461 as an adjunctive therapy for depression because of concerns about bioavailability and lack of evidence, but then reversed its position. ALKS 5461 is currently under regulatory review and a decision regarding its possible approval is expected by early 2019.

Antiinflammatories and immunomodulators

There has been growing recognition of complex interrelationships between depression and inflammation. Some but not all patients with clinically significant depression appear to have elevated serum markers of systemic inflammation, such as high sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines. While causal relationships between depression and inflammation are poorly understood and questions remain whether depression causes inflammation or vice versa, randomized trial data suggest potential antidepressant value of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the COX-2 inhibitor celecoxib. A pooled meta-analysis of 5447 participants from 10 NSAID trials and 4 cytokine inhibitors (as mono- or add-on therapy for depression) revealed statistically significant advantages over placebo, with small to medium effect sizes, for response (odds ratio = 6.6; 95% confidence interval=2.2-19.4) or remission (odds ratio = 7.9; 95% confidence interval=2.9-21.1)17It has not been established whether adding celecoxib or other NSAIDs to an antidepressant may be more useful only in the setting of elevated serum markers of inflammation. Elsewhere, preliminary studies reveal that inflammatory depressive subtypes (ie, high baseline hs-CRP) may respond better to a tricyclic than SSRI,18 adjunctive L-methylfolate,19 or the tumor necrosis factor (TNF) antagonist infliximab (admnistered IV at 5 mg/kg over 3 doses).20

The antimicrobial minocycline exerts anti-inflammatory and anti-oxidative properties and has been preliminarily studied mostly in small or open/nonrandomized trials. A meta-analysis of 3 randomized controlled trials found an overall significantly greater effect than placebo with a medium to large effect size and good tolerability, although the small number of well-designed studies and samples sizes (total N = 158) limits their generalizability.21

Anticholinergic muscarinic agents

Harkening back to the 1970s hypothesis that depression could reflect cholinergic-adrenergic dysregulation, interest has turned to the possible antidepressant effects of the muscarinic cholinergic antagonist scopolamine. Preliminary studies of intravenous scopolamine dosed at 4 µg/kg in both unipolar and bipolar depression have produced remission rates from 45% to 56% (Cohen’s d ranged from 1.2-3.4) typically within several days of administration, with persistence for 10 to 14 days.22Antimuscarinic adverse effects such as sedation, dry mouth, and blurry vision are common but transient. Neurocognitive measures reaction time during selective attention tasks reveal no significant delays following IV scopolamine infusion.23 Analogous to IV ketamine, questions remain about the optimal number of infusions to minimize relapse as well as the use of nonparenteral formulations.

Brexanolone (SAGE-547), also known as allopregnanolone, is a positive allosteric modulator of GABA-A receptors. It is a progesterone metabolite that exerts neuroprotective, pro-cognitive, and possible antidepressant/anxiolytic properties. Precipitous drops in progesterone and allopregnanolone after childbirth prompted interest in the use of allopregnanolone specifically in postpartum depression. A small (N = 21) initial trial of brexanolone (administered intravenously because of its short half-life and poor oral bioavailability) or placebo for severe postpartum depression yielded a substantial reduction in depressive symptom severity within 60 hours (effect size = 1.2).24 Further data remain pending. SAGE-217 is reformulated brexanolone that has good oral bioavailability, allowing for oral administration, as well as a longer half-life allowing once-a-day dosing. It is currently being studied as an adjunctive agent for treatment resistant depression.

PPAR-γ agonists and incretins

Thiazolidinediones are insulin sensitizers that also demonstrate antidepressant properties in animal studies and appear to possess anti-inflammatory, neuroprotective, antioxidant and anti-excitatory properties. Pioglitazone, a PPAR-γ agonist thiazolidinedione, has been studied versus placebo or metformin in major depression, both as monotherapy and in combination with antidepressants or lithium. A meta-analysis of 4 trials revealed significantly higher remission rates than controls (27% versus 10%, respectively; odds ratio of remission in major depression = 5.9 (95% confidence interval=1.6-22.4), p = .009), with an NNT = 6.25 Even though PPAR-γ agonists can decrease insulin resistance, weight gain can be an undesired adverse effect that is possibly a result of a combination of fat cell proliferation, fluid retention, and increased appetite. Pioglitazone also carries serious adverse risks for congestive heart failure and bladder cancer.

Glucagon-like peptide 1

Another class of antidiabetic drugs known as glucagon-like peptide 1 (GLP-1) agonists mimic the action of insulin (so-called incretins) and are of interest as a potential target for depression. GLP-1 agonists such as liraglutide possess neuroprotective and antiapoptotic properties, and animal studies suggest it has antidepressant and pro-cognitive effects, particularly involving reward and motivation. Human studies have thus far focused more on weight-reducing and possible cognitive benefits of liraglutide more than its potential antidepressant efficacy, but its mechanism represents a promising direction for further study.

Future directions

This brief overview has focused on emerging novel pharmacotherapies for depression. While the provisional nature of proof-of-concept studies may be encouraging, they are far from definitive. The aforementioned findings are largely preliminary and meant more to prompt larger randomized trials to establish efficacy, safety, and generalizability rather than inspire premature immediate uptake into clinical practice.

Given the focus on neuroprotection and enhanced neuroplasticity as proposed targets of treatment, it would seem remiss not to at least mention the neurobiological impact of depression-specific psychotherapies, mindfulness meditation, and related psychosocial interventions. Psychotherapy is, among other things, a behavioral learning paradigm, presumably rendering alterations in cognitive functions (memory, attention, and decision-making), fear extinction, and emotional processing. Evidence-based psychotherapies for depression have been shown to produce changes in brain network connectivity26 (recapitulating the idea of Hebbian synapses, where “neurons that fire together wire together”) and upregulation of intracellular transcription factors involved in neuronal plasticity.27Enhanced neuroplasticity may represent a common denominator target for effective biological or psychosocial treatments for depression.

Increasingly, drugs we call antidepressants are diversifying to include broader classes of molecules. A more neuroscience-based nomenclature for psychotropic drugs has already been proposed28 and will no doubt invoke more novel drug mechanisms, supplanting older concepts about depression as a chemical imbalance as perspectives continue to evolve about how antidepressants impact neuronal viability and brain microarchitecture.

References:

1. Cipriani A, Furukawa TA, Salanti G,et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; S0140-6736:32802-7. [Epub ahead of print]

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.

3. Cartwright C, Gibson K, Read J, et al. Long-term antidepressant use: patient perspectives of benefits and adverse effects. Patient Prefer Adher. 2016;10:1401-1407.

4. Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.

5. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134-1142.

6. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150-158.

7. Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950-966.

8. Mathew SJ, Gueorguieva R, Brandt C, et al. A randomized, double-blind, placebo-controlled, sequential parallel comparison design trial of adjunctive riluzole for treatment-resistant major depressive disorder. Neuropsychopharmacol 2017;42: 2567-2574.

9. Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacol. 2012;62:35-41.

10. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472-486.

11. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74:399-405.

12. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:139-148.

13. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. April 2018; Epub ahead of print.

14. Gálvez V, Li A, Huggins C, et al. Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial. J Clin Psychopharmacol. 2018;32:397-407.

15. Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacol. 2015;40:1448-1455.

16. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173:499-508.

17. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381-1391.

18. Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278-1286.

19. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014;75:855-863.

20. Raison CL, Rutheford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.

21. Rosenblat JD, McIntyre RS. Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord. 2018;227:219-225.

22. Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic antagonist scopolamine: a review. Biol Psychiatry. 2013;73:1156-1163.

23. Furey ML Pietrini P, Haxby JV, et al. Selective effects of cholinergic modulation on task performance during selective attention. Neuropsychopharmacol 2008; 33:913-923.

24. Kanes S, Colquohoun H, Grunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390:480-489.

25. Colle R, de Larminat D, Rotenberg S, et al. Pioglitazone could induce remission in major depression: a meta-analysis. Neuropsychiatr Dis Treat 2016;13: 9-16.

26.Yang CC, Barrós-Loscertales A, Pinazo D, et al. State and training effects of mindfulness meditation on brain networks reflect neuronal mechanisms of its antidepressant effect. Neural Plast. 2016;2016:9504642.

27. Koch JM, Hinze-Selch D, Stingele K, et al. Changes in CREB phosphorylation and BDNF plasma levels during psychotherapy of depression. Psychother Psychosom. 2009;78:187-192.

28. ECNP Neuroscience Applied. Neuroscience-based Nomenclature. https://www.ecnp.eu/research-innovation/nomenclature.aspx. Accessed June 6, 2018.

Ketamine for Depression | Articles and Links | 703-844-0184 | Springfield, Virginia |22306 | IV Ketamine Center | Ketamine Clinic | 22304| Ketamine Virginia

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Ketamine for Chronic Pain & Depression

Intravenous Ketamine is proving to be a tremendous treatment for intractable depression as well as chronic pain.  About half the patients treated respond positively with results lasting up to a week in most of the responders.

It has emerged as a treatment option for a variety of chronic pain conditions including fibromyalgia, small fiber neuropathy, Complex Regional Pain Syndrome (CRPS), Reflex Sympathetic Dystrophy (RSD) and psychiatric conditions including depression, Post Traumatic Stress Disorder (PTSD), suicidal ideation, and Obsessive-Compulsive Disorder (OCD).

Ketamine in the News

Remarkable secrets of ketamine’s antidepressant effect unlocked by scientists

Could Party Drug Ketamine Be a Treatment for Depression?

‘The fog is gone’: How ketamine could help lift hard-to-treat depression

Ketamine Research

Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action.

Ketamine safety and tolerability in clinical trials for treatment-resistant depression.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting.

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion.

How does ketamine elicit a rapid antidepressant response?

The use of ketamine as an antidepressant: a systematic review and meta-analysis.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.

KETAMINE FOR DEPRESSION | 703-844-0184 | FAIRFAX, VA | LOUDON, VA| LORTON, VA | |Ketamine For Geriatric Depression| 22308 |22304

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CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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Ketamine has ‘truly remarkable’ effect on depression and is effective in elderly patients, scientists say

Ketamine Infusions | 703-844-0184 | Fairfax, Va | 22304 | ketamine for depression

Ketamine can have a “truly remarkable” effect on people with depression, researchers have said after a new study showed promising results among elderly patients.

Colleen Loo, a professor at the University of New South Wales in Australia, led the world’s first randomised control trial into the drug’s effect on people over 60 with treatment-resistant depression.

“This trial has shown ketamine can be used safely in the elderly and it tends to be effective,” she told The Independent, adding that a similar effect was observed in this age group as in younger patients.

It is important to test how people of different ages respond to a new treatment before it can be offered by doctors, she said: “Sometimes depression in the elderly can be harder to treat, especially with medication.

“Also, they tend to have more medical problems, which can interfere with medication.”

Ketamine was discovered in 1962 and is licenced for medical use in the UK as an anaesthetic, but is also used illegally as a recreational drug.

Of the study’s 16 participants, 11 reported an improvement in their condition while being treated with the drug, according to the research published in the American Journal of Geriatric Psychiatry.

After six months, 43 per cent of the subjects said they had no significant symptoms of depression – a high rate given that the participants had not responded to previous treatment, said Professor Loo.

“It is truly remarkable the way ketamine can work,” she said. “Other people have also found you get a rapid and powerful effect after a single dose of ketamine.”

“Some people mistakenly think we are inducing a temporary, drug-induced euphoria and people are ‘out of it’, which is why they’re not depressed.

“But the effects take place in the first hour, and they’re not euphoric at all. In fact, all of our research participants disliked them. They considered them adverse effects.

“The antidepressant effect kicks in a few hours later and are maximised about 20 hours later, when you’re fully alert and in your usual state of mind.”

While research into the use of ketamine to treat mental health problems is still in its early stages, scientists at Oxford University have said their studies show the drug can provide relief to patients with severe depression “where nothing has helped before”.

Rupert McShane, the consultant psychiatrist who is leading Oxford’s ketamine treatment programme, told The Independent it was “good to see that, contrary to some reports, some older people do respond to ketamine.”

“This study highlights that ketamine can be given in a variety of ways (not just intravenous), that it’s a good idea to adjust the dose, and that the more resistant someone’s depression is, the higher the dose that they are likely to need,” he said.

Professor Loo and her colleagues delivered ketamine to the patients using a small injection under the skin – similar to the insulin jabs given to diabetes patients.

This makes the drug easier and quicker to administer than the intravenous infusions used in other trials, which require a machine pump to regulate the dose and takes up to an hour to complete.

Participants received increasing doses of ketamine over a period of five weeks, with the dose personalised for each patient.

However, she warned that while the research is one step closer to providing a model for how doctors could prescribe ketamine as a treatment for depression in future, it would still be “premature to jump into clinical practice”.

“There are ‘super-responders’, who after a single treatment can be well for several months,” said Professor Loo, giving the example of a subject who, in 2014, remained free of depressive symptoms for five months after just one dose of ketamine.

But “most people are well but then they relapse over around three to seven days,” she said. “That’s where repeated dosing comes in.”

Ketamine Injections May Help Older Adults With Depression

Repeated subcutaneous injections of ketamine significantly improved symptoms in a small group of older adults with treatment-resistant depression, researchers found in a pilot study published online in The American Journal of Geriatric Psychiatry.

The randomized controlled trial is the first to assess the efficacy and safety of ketamine in the geriatric patient population.

“These findings take us a big step forward as we begin to fully understand the potential and limitations of ketamine’s antidepressant qualities,” said lead author Colleen Loo, MD, a professor in the School of Psychiatry at the University of New South Wales, Sydney, Australia.

Psychiatrists Issue ‘Much-needed’ Consensus on Ketamine for Mood Disorders

“Not only was ketamine well-tolerated by participants, with none experiencing severe or problematic side effects, but giving the treatment by a simple subcutaneous injection (a small injection under the skin) was also shown to be an acceptable method for administering the drug in a safe and effective way.”

Overall, the response and remission rate for older adults receiving ketamine was 68.8%.

Australian researchers tested individualized dosing of ketamine using a dose-titration method in 16 adults age 60 and older. Participants received increasing doses over 5 weeks. The double-blind, placebo-controlled trial included 1 session in which participants received an active treatment substitute that, similar to ketamine, caused sedation.

Why Not Make Ketamine a First-line Treatment?

After the randomized controlled trial, participants received 12 ketamine doses in an open-label phase.

At a 6-month follow-up, 7 of 14 older adults who had completed the randomized controlled trial had depression remission — 5 of whom remitted at doses below the common ketamine dose of 0.5 mg/kg, researchers reported. Repeated treatments, they added, resulted in a higher likelihood of remission or a longer time to relapse.

“Elderly patients with severe depression face additional barriers when seeking treatment for the condition. Many medications may cause more side effects or have lower efficacy as the brain ages,” said researcher Duncan George, MBBS, School of Psychiatry, University of New South Wales. “Older people are also more likely to have comorbidities like neurodegenerative disorders and chronic pain, which can cause further complications due to ketamine’s reported side effects.

“Our results indicate a dose-titration method may be particularly useful for older patients, as the best dose was selected for each individual person to maximize ketamine’s benefits while minimizing its adverse side effects.”

—Jolynn Tumolo

References

George D, Gálvez V, Martin D, et al. Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression. The American Journal of Geriatric Psychiatry. 2017 June 13;[Epub ahead of print].

World-first ketamine trial shows promise for geriatric depression [press release]. Sydney, Australia: University of New South Wales; July 24, 2017.

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Poster Number: EI 5
Ketamine in Late Life Treatment-Resistant Depression
Erika Heard, MD1
; Yousuf Sohail, MD1
; Anusuiya Nagar, MD1
; Oliver M. Glass, MD2
; Adriana P. Hermida, MD1

Introduction: Ketamine is a dissociative anesthetic, which provides antagonism on the N-methyl-D-aspartate (NMDA)
receptor. Several studies have demonstrated rapid anti-depressant and anti-suicidal effects from the administration of ketamine
in adult patients but studies in late life patients are lacking. While ketamine may increase sympathetic stimulation and cause
decreased respiratory rate in geriatric patients, it is still nonetheless considered a safe agent. Low-dose intravenous infusion of
ketamine is gaining popularity in the treatment for treatment-resistant depression (TRD) in late life patients. We provide a case
report on a patient in late life who suffered from TRD and was treated with ketamine.
Methods: A case report of the use of intravenous ketamine to treat a geriatric patient with TRD along with a literature review
of the subject.
Results: A 76-year-old female with a history of hypertension and arthritis presented with worsening depressive symptoms for the
past two years. She endorsed neuro-vegetative symptoms of depressed mood, poor appetite, unintentional 25-pound weight loss,
and conflicted feelings about wanting to live. She also reported difficulties with concentration and memory, feelings of
worthlessness, and psychomotor retardation. Her daughter stated she was more vegetative and had a strong desire not to live alone.
QIDS (Quick Inventory of Depressive Symptomatology) baseline was 23. She had previous trials of multiple medications including
paroxetine, fluoxetine, sertraline, escitalopram, buproprion, and venlafaxine. This patient showed poor tolerance to all the
medications and at the time of assessment was taking mirtazapine 7.5 mg and duloxetine 60 mg. Electroconvulsive therapy (ECT)
was recommended; however, the patient was found to be not a good candidate as per anesthesiology due to multiple comorbidities.
As a result, mirtazapine was titrated to 15 mg nightly while duloxentine was continued at 60 mg daily. Patient was started on
intravenous ketamine infusions of 20 mg (0.5 mg/kg) over 40 minutes. Patient tolerated the acute course of ketamine, which was
administered twice per week. Patient and daughter reported clinicial improvement after the first infusion with noticeable
improvement in QIDS (23 to 12) after 6 acute sessions without adverse effects. Improved symptoms included brighter affect,
increased energy, decreased anhedonia, increased daily activity, improved appetite (gained 40lbs), and being more engaged in the
community. Additionally, she began to take care of herself again. She has received 17 ketamine treatments with latest QIDS score of
1. After 6 acute infusion sessions, she was tapered to once per week, then once per 10 days, once per 2 weeks and then to a once
every three week schedule before discontinuing. The patient continued to report improvements. The literature on intravenous
ketamine infusions has shown effectiveness in reducing depressive symptoms in cases of TRD. The patient presented in this study
demonstrates promise of the use of ketamine in late life depression patients. This case also highlights that ketamine can be an
alternative option for elderly patients with TRD who do not qualify for ECT. Within the geriatric population, comorbid medical
conditions and polypharmacy may increase the chance of morbidity and mortality. Ketamine infusions at a low dose must be
monitored closely over a course of time. Therefore, ketamine infusions should only be administered to TRD patients in facilities
where appropriate medical monitoring can occur. Geriatric patients who are given ketamine infusions should be assessed for the
development of dependency, and addiction given its abuse potential. Further research on this novel therapy will yield greater
knowledge of how to best utilize ketamine infusions in geriatric patients.
Conclusions: The literature on intravenous ketamine infusions has shown effectiveness in reducing depressive symptoms in cases of
TRD. Similarly, our patient had a decline in depressive symptoms and a positive outcome. The case highlights that ketamine can be
used as an alternative for the TRD population that may not qualify for ECT. Within the geriatric population, comorbid pathology
and poly-pharmacy increase the chance of morbidity and mortality. Ketamine infusions at a low dose can be a potential treatment if
monitored closely over a course of time. Therefore, ketamine infusions offer a safe and effective alternative option for TRD patients
in psychiatric facilities where close monitoring can occur. Patients on ketamine treatments should be continually monitored for
addiction potential and adverse effects to ketamine infusions, none of which were seen with our current patient. Further research on
this novel therapy will yield greater knowledge of how to best utilize ketamine infusions for the general population and more
specifically for the geriatric subset that encompasses the majority of TRD patients.

___________________________________________________________________________________

Exploring Ketamine Use in Geriatric Patients Suffering From Treatment-Resistant Depression

Introduction: Ketamine is a glutamate NMDA receptor antagonist and is commonly used as an anesthetic. Low-dose
subanesthetic intravenous ketamine is fairly new and an increasingly popular treatment for treatment-resistant depression
(TRD) in the adult population; however, there is a scarcity of evidence of ketamine’s use among geriatric patients. Previously,
psychotropics and electroconvulsive therapy (ECT) have been used in the geriatric TRD population. Ketamine provides a
possible new treatment modality for those patients concerned with ECT-induced cognitive effects and may also allow for use in
patients with significant cardiovascular co-morbidities, who would likely not quality for ECT.
Methods: We provide a literature review on the use of ketamine for TRD in the geriatric population.
Results: Studies and case series have shown the use of ketamine as a monotherapy and augmented therapy with
electroconvulsive therapy in the adult and geriatric population. Literature supports efficacy with monotherapy and questionable
benefit from augmentative therapy. Dosing ranges from 0.2 mg/kg to 0.5 mg/kg, with evidence showing remittance with
ketamine dosing less than 0.5 mg/kg. Some studies have shown cognitive protection as compared to other TRD treatment
modalities, while the majority of studies have not thoroughly analyzed systemic adverse risk profiles including cognitive and
cardiovascular effects.

Conclusions: There is evidence in the literature for the use of intravenous ketamine in the TRD geriatric population. Larger
randomized control trials are needed to provided guidance regarding dosing, cognitive and systemic effects, and treatment
response.

USe of Ketamine in agitated delirium in the ELderly:

Treatment of Behavior Disturbances with Ketamine in a Patient Diagnosed with Major Neurocognitive Disorder

Ketamine has been shown to be beneficial for some
depressed patients, but it is not known whether it could
be beneficial for agitated demented patients who are
not depressed.

_____________________________________________________

Augmentation of response and remission to serial intravenous ketamine in TRD

Background: Ketamine has been showing high efficacy and rapid antidepressant effect. However, studies of ketamine infusion wash subjects out from prior antidepressants, which may be impractical in routine practice. In this study, we determined antidepressant response and remission to six consecutive ketamine infusions while maintaining stable doses of antidepressant regimen. We also examined thetrajectory of response and remission, and the time to relapse among responders.

Methods: TRD subjects had at least 2-month period of stable dose of antidepressants. Subjects completed
six IV infusions of 0.5 mg/kg ketamine over 40 min on a Monday–Wednesday–Friday schedule during a
12-day period participants meeting response criteria were monitored for relapse for 4 weeks

.
Results: Fourteen subjects were enrolled. Out of twelve subjects who completed all six infusions, eleven(91.6%) achieved response criterion while eight (66.6%) remitted. After the first infusion, only three andone out of twelve subjects responded and remitted, respectively. Four achieved response and sixremitted after 3 or more infusions. Five out of eleven subjects remain in response status throughout the 4weeks of follow-up. The mean time for six subjects who relapsed was 16 days.Limitations: Small sample and lack of a placebo group limits the interpretation of efficacy.

Conclusions: Safety and efficacy of repeated ketamine infusions were attained without medication-free state in patients with TRD. Repeated infusions achieved superior antidepressant outcomes as compared to a single infusion with different trajectories of response and remission. Future studies are needed to elucidate neural circuits involved in treatment response to ketamine.

 

_____________________________________________________

Why Treat Depression besides feeling better? It is associated with increased risk of DEATH:

Anxiety, Depression Linked With Higher Cardiovascular Risk

Adults with mood disorders like anxiety and depression may be more likely to have a heart attack or stroke than people without mental illness, a new study suggests.

Researchers enrolled 221,677 people age 45 and older without any history of heart attack or stroke and tracked them for an average of nearly five years.

More than 90% of participants were ages 45 to 79. In this age group, compared to men without mental health issues at the start, men with moderate psychological distress were 28% more likely to have a heart attack during the study and 20% more likely to have a stroke. Men in this age group with high levels of distress were 60% more likely to have a heart attack and 44% more likely to have a stroke.

Women ages 45 to 79 with moderate psychological problems were 12% more likely to have a heart attack and 28% more likely to have a stroke than women without any mental distress. Women with high psychological distress were 24% more likely to have a heart attack and 68% more likely to have a stroke.

“The stronger association between psychological distress and heart attack in men compared to women could be due to women being more likely than men to seek primary care for mental and physical health problems, thus partly negating the possible physical effects of mental health problems,” said lead study author Caroline Jackson of the University of Edinburgh in the U.K.

“Alternatively, it could reflect the known hormonal protection against heart disease in women since the study population included a large number of younger women,” Jackson said by email. “We did however find a strong association between psychological distress and stroke in women, perhaps suggesting different mechanisms exist between psychological distress and different types of cardiovascular disease in women.”

Overall, the study participants suffered 4,573 heart attacks and 2,421 strokes.

The study wasn’t designed to prove whether or how depression or anxiety might directly cause heart attacks or strokes, researchers note in Circulation: Cardiovascular Quality Outcomes.

Another limitation is that researchers assessed psychological factors at a single point in time, making it impossible to know if worsening cardiovascular health contributed to mood disorders or if mental illness caused heart problems.

However, it’s possible that lifestyle factors like poor eating and exercise habits, smoking, or inactivity might independently influence both the risk of mental health problems and heart issues, the study authors note.

“It is also possible that symptoms of depression or anxiety directly affect the body’s physiology through mechanisms such as hormonal pathways, inflammatory processes in arteries and increased risk of blood clotting,” Jackson said. “It is vital that further research seeks to identify the underlying mechanisms so that we can better understand the link between mental health and subsequent physical health and inform intervention strategies.”

Researchers assessed psychological distress using a standard set of questions designed to reveal symptoms of mood disorders. The questions asked, for example, how often people felt tired for no reason, how often they felt restless or fidgety, and how frequently they felt so sad that nothing could cheer them up.

Overall, about 16% of the study participants had moderate psychological distress and roughly 7% had high or very high levels of mental distress.

SOURCE: http://bit.ly/2PfAJjd    Psychological Distress and Risk of Myocardial Infarction and Stroke in the 45 and Up Study

Psychological Distress and Risk of MI and stroke in the 45 and up study

 

Circulation: Cardiovascular Quality and Outcomes 2018.

________________________________________________

Psychological distress, physical illness, and risk of coronary heart disease 2005

depressed-patients-likely-experience-mi-stroke

 

Resistance Training Reduces Depressive Symptoms

Weightlifting and muscle training significantly reduced depressive symptoms among adults regardless of their age and health status, the amount of training, and whether they grew stronger, researchers found in a meta-analysis.

The study, published online in JAMA Psychiatry, spanned 33 randomized clinical trials with more than 1800 participants.

The best improvement appeared to be in participants with mild or moderate depression, suggesting resistance training could be an alternative or add-on treatment option.

Trivia: How Much Exercise Is Needed to Prevent Depression?

“For general feelings of depression and the beginning phases of major depression, antidepressants and medications may not be very effective. There also is a shift toward finding options that do not require someone to start a drug regimen they may be on for the rest of their lives,” said researcher Jacob Meyer, PhD, assistant professor of kinesiology at Iowa State University in Ames.

“Understanding that resistance training appears to have similar benefits to aerobic exercise may help those wading through daunting traditional medication treatment options.”

The meta-analysis did identify smaller reductions in depressive symptoms in randomized clinical trials with blinded allocation or assessment. Better quality trials that compare resistance training with other proven treatments for depression are needed, researchers advised.

—Jolynn Tumolo

References

Gordon BR, McDowell CP, Hallgren M, Meyer JD, Lyons M, Herring MP. Association of efficacy of resistance exercise training with depressive symptoms. JAMA Psychiatry. 2018 May 9;[Epub ahead of print].

Motivation to move may start with being mindful [press release]. Ames, Iowa: Iowa State University; May 14, 2018.

Resistance exercise training may reduce symptoms of depression. Psychiatric News Alert. May 15, 2018.

__________________________________

Neurologic Changes and Depression

KEY POINTS
 The assessment of late-life depression with comorbid cognitive impairment can be challenging and requires a clear clinical history and a thorough medical and cognitive assessment.

 There are several neuropsychological changes associated with late-life depression, ranging from subjective cognitive complaints to mild cognitive impairment to dementia.

 Changes on neuroimaging and in several biomarkers (eg, apolipoprotein E e4 allele, beta amyloid, tau, neurotrophins, and so forth) have been associated with late-life depression.

 Multiple psychotherapeutic techniques have been found effective in the treatment of late life depression as well as holistic/nontraditional, pharmacologic, and brain-stimulation
approaches.

______________________________________________________

Why Does Ketamine Work?

Ketamine and Ketamine Metabolite Pharmacology Insights into Therapeutic Mechanisms.

Abstract

Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

Mechanisms of ketamine action as an antidepressant.

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances.

Article Link::

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances

We find
that ketamine prevents the development of affective disturbances
when administered at the onset of forced abstinence, and not
shortly thereafter (2–6 days).Studies suggest that the GluN2B subunit of the N- methyl- Daspartate
(NMDA) receptor participates in regulating affect and in
the antidepressant actions of ketamine [9, 14, 16]. Chronic ethanol
administration and early withdrawal increase expression of
GluN2B in several brain areas, particularly within the central
nucleus of the amygdala and bed nucleus of the stria terminalis
(BNST) [17], both of which are heavily involved in regulating affect
[18–21]. Previously, we found that knockdown of GluN2B-within
the BNST produces antidepressant-like actions similar to ketamine
[22] and that GluN2B is necessary for long-term potentiation (LTP) within the BNST [23]. Furthermore, we have previously shown that
non-contingent chronic intermittent ethanol enhances LTP within
the BNST which is dependent on the GluN2B subunit [23].
However, no studies have looked at LTP within the BNST during
withdrawal after contingent 2-bottle choice ethanol drinking. Here
we show that withdrawal from 2BC ethanol drinking decreases the
early component of LTP within the BNST. Further, administration
of ketamine at the onset of forced abstinence, but not shortly
thereafter (2–6 days) facilitated later LTP induction.

Ketamine administered at the onset of
abstinence, but not 6 days later rescued the STP deficit and overall increased the capacity for plasticity within the BNST. Our results suggest, for the first time to our knowledge, that ketamine may need to be administered at a specific time point during abstinence in order to effectively treat and manage alcohol use dependent affective disturbances. These data thus suggest a “critical period” during which ketamine is effective in preventing the development of alcohol abstinence induced affective
disturbances.

_____________________________________________________________

Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking

Introduction: Ketamine has emerged as a safe and effective treatment option for treatment refractory depression (TRD) and
suicidal ideation. Electroconvulsive therapy (ECT) is a well established treatment for refractory depression, but this treatment is often deferred or terminated before response due tolerability or medical concerns.
Methods: We present a case series of TRD patients who were unable to receive ECT and offered intravenous ketamine at a dose
of 0.5 mg/kg infused over the course of forty minutes for up 3 treatment sessions within two weeks. Most of these patients
were hospitalized older patients with sufficient medical conditions that increased ECT risks.

Results: Ketamine appears to be a safe and effective alternative for these patients, leading to resolution of suicidality, adherence
to antidepressant treatment, and prompt hospital discharge.

Conclusions: In conclusion, for TRD patients unable to undergo ECT, availability of intravenous ketamine, as an adjunct to
an ECT service, can not only avert the prospect of a prolonged and costly course of hospitalization, but also quickly improve
patients’ quality of life.

___________________________________________

Why magnesium is important in treating depression:

Magnesium for treatment-resistant depression A review and hypothesis

Sixty percent of cases of clinical depression are considered to be treatment-resistant depression (TRD). Magnesium-deficiency causes N-methyl-D-aspartate (NMDA) coupled calcium channels to be biased towards opening, causing neuronal injury and neurological dysfunction, which may appear to humans as major depression. Oral administration of magnesium to animals led to anti-depressant-like effects that were comparable to those of strong anti-depressant drugs. Cerebral spinal fluid (CSF) magnesium has been found low in treatment-resistant suicidal depression and in patients that have attempted suicide. Brain magnesium has been found low in TRD using phosphorous nuclear magnetic resonance spectroscopy, an accurate means for measuring brain magnesium. Blood and CSF magnesium do not appear well correlated with major depression. Although the first report of magnesium treatment for agitated depression was published in 1921 showing success in 220 out of 250 cases, and there are modern case reports showing rapid terminating of TRD, only a few modern clinical trials were found. A 2008 randomized clinical trial showed that magnesium was as effective as the tricyclic anti-depressant imipramine in treating depression in diabetics and without any of the side effects of imipramine. Intravenous and oral magnesium in specific protocols have been reported to rapidly terminate TRD safely and without side effects. Magnesium has been largely removed from processed foods, potentially harming the brain. Calcium, glutamate and aspartate are common food additives that may worsen affective disorders. We hypothesize that – when taken together – there is more than sufficient evidence to implicate inadequate dietary magnesium as the main cause of TRD, and that physicians should prescribe magnesium for TRD. Since inadequate brain magnesium appears to reduce serotonin levels, and since anti-depressants have been shown to have the action of raising brain magnesium, we further hypothesize that magnesium treatment will be found beneficial for nearly all depressives, not only TRD.

___________________________________________________________________

Does oral administration of ketamine accelerate response to treatment in MDD

Conclusion:

Altogether, our results suggest that oral ketamine may be considered as suitable adjuvant to sertraline
in relieving depressive symptoms.

Patients received sertraline (150 mg a day). As an adjuvant, they
received either 50 mg/day ketamine or placebo. Formulation of ketamine capsules used in this study is delineated elsewhere. Different doses of oral ketamine have been used in previous studies; a number of studies have used a fixed dose 0.5 mg/kg or 150 mg/day (Irwin et al., 2013; Jafarinia et al., 2016) whereas others titrated the drug in a rangefrom 0.5 mg/kg to 0.7 mg/kg or 25–300 mg/day (Al Shirawi et al., 2017; Hartberg et al., 2017). The frequency of administration also varies from once daily usage to three times a day (Irwin et al., 2013;
Jafarinia et al., 2016). For IV administration, previous trials recommendan injection once every two or three days (Andrade, 2017).
Here, we used ketamine as an adjuvant and thus a fixed low dose was chosen to minimize adverse effects. Sertraline was initiated at 25 mg/day and increased by 25 mg every three days. The maximum dose reached 150 mg. Ketamine prescription started with initial dose ofsertraline and was prescribed at 25 mg twice daily. During the course of the trial, patients were not allowed to participate in psychotherapeutic sessions or receive any other medication, such as other antidepressants, anxiolytics or hypnotics. They were followed for six weeks and were asked to inform their therapist in case they experienced any adverse effects. Vital signs were recorded and physical examination was performed at the screening session and at each of the post-baseline visits. Upon high clinical suspicion for cardiovascular disease, electrocardiogram monitoring was performed and positive findings were excluded.

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Ketamine and Psychedelic Drugs Change Structure of Neurons

ummary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184
Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184

Ketamine and Psychedelic Drugs Change Structure of Neurons

Summary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

image shows neurons under psychedelics and ketamine

Psychedelic drugs such as LSD and ayahuasca change the structure of nerve cells, causing them to sprout more branches and spines, UC Davis researchers have found. This could help in “rewiring” the brain to treat depression and other disorders. In this false-colored image, the rainbow-colored cell was treated with LSD compared to a control cell in blue. NeuroscienceNews.com image is credited to Calvin and Joanne Ly.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder (PTSD), and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

 

Psychedelic drugs, ketamine change structure of neurons

Psychedelic drugs, ketamine change structure of neurons

Psychedelics as Possible Treatments for Depression and PTSD

A team of scientists at the University of California, Davis, is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders.

In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

Additional co-authors on the Cell Reports “Psychedelics Promote Structural and Functional Neural Plasticity.” study are Calvin Ly, Alexandra Greb, Sina Soltanzadeh Zarandi, Lindsay Cameron, Jonathon Wong, Eden Barragan, Paige Wilson, Michael Paddy, Kassandra Ori-McKinney, Kyle Burbach, Megan Dennis, Alexander Sood, Whitney Duim, Kimberley McAllister and John Gray.

Olson and Cameron were co-authors on the ACS Chemical Neuroscience paper along with Charlie Benson and Lee Dunlap.

The work was partly supported by grants from the National Institutes of Health.

Psychedelics Promote Structural and Functional
Neural Plasticity

Below is the Intro and Discussion for the article:

Psychedelics Promote Structural and Functional neural Plasticity

Authors:

Calvin Ly, Alexandra C. Greb,
Lindsay P. Cameron, …,
Kassandra M. Ori-McKenney,
John A. Gray, David E. Olson
Correspondence
deolson@ucdavis.edu

In Brief
Ly et al. demonstrate that psychedelic
compounds such as LSD, DMT, and DOI
increase dendritic arbor complexity,
promote dendritic spine growth, and
stimulate synapse formation. These
cellular effects are similar to those
produced by the fast-acting
antidepressant ketamine and highlight
the potential of psychedelics for treating
depression and related disorders.

  • Highlights
     Serotonergic psychedelics increase neuritogenesis,
    spinogenesis, and synaptogenesis
  •  Psychedelics promote plasticity via an evolutionarily
    conserved mechanism
  •  TrkB, mTOR, and 5-HT2A signaling underlie psychedelicinduced
    plasticity
  •  Noribogaine, but not ibogaine, is capable of promoting
    structural neural plasticity

SUMMARY
Atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression
and related disorders. The ability to promote
both structural and functional plasticity in the PFC
has been hypothesized to underlie the fast-acting
antidepressant properties of the dissociative anesthetic
ketamine. Here, we report that, like ketamine,
serotonergic psychedelics are capable of robustly
increasing neuritogenesis and/or spinogenesis both
in vitro and in vivo. These changes in neuronal structure
are accompanied by increased synapse number
and function, as measured by fluorescence microscopy
and electrophysiology. The structural changes
induced by psychedelics appear to result from stimulation
of the TrkB, mTOR, and 5-HT2A signaling
pathways and could possibly explain the clinical
effectiveness of these compounds. Our results underscore
the therapeutic potential of psychedelics
and, importantly, identify several lead scaffolds for
medicinal chemistry efforts focused on developing
plasticity-promoting compounds as safe, effective,
and fast-acting treatments for depression and
related disorders.

INTRODUCTION
Neuropsychiatric diseases, including mood and anxiety disorders,
are some of the leading causes of disability worldwide
and place an enormous economic burden on society (Gustavsson
et al., 2011; Whiteford et al., 2013). Approximately
one-third of patients will not respond to current antidepressant
drugs, and those who do will usually require at least 2–4 weeks
of treatment before they experience any beneficial effects
(Rush et al., 2006). Depression, post-traumatic stress disorder
(PTSD), and addiction share common neural circuitry (Arnsten,
2009; Russo et al., 2009; Peters et al., 2010; Russo and
Nestler, 2013) and have high comorbidity (Kelly and Daley,
2013). A preponderance of evidence from a combination of
human imaging, postmortem studies, and animal models suggests
that atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression and
related disorders and is precipitated and/or exacerbated by
stress (Arnsten, 2009; Autry and Monteggia, 2012; Christoffel
et al., 2011; Duman and Aghajanian, 2012; Duman et al.,
2016; Izquierdo et al., 2006; Pittenger and Duman, 2008;
Qiao et al., 2016; Russo and Nestler, 2013). These structural
changes, such as the retraction of neurites, loss of dendritic
spines, and elimination of synapses, can potentially be counteracted
by compounds capable of promoting structural and
functional neural plasticity in the PFC (Castre´ n and Antila,
2017; Cramer et al., 2011; Duman, 2002; Hayley and Litteljohn,
2013; Kolb and Muhammad, 2014; Krystal et al., 2009;
Mathew et al., 2008), providing a general solution to treating
all of these related diseases. However, only a relatively small
number of compounds capable of promoting plasticity in the
PFC have been identified so far, each with significant drawbacks
(Castre´ n and Antila, 2017). Of these, the dissociative
anesthetic ketamine has shown the most promise, revitalizing
the field of molecular psychiatry in recent years.
Ketamine has demonstrated remarkable clinical potential as a
fast-acting antidepressant (Berman et al., 2000; Ionescu et al.,
2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant
populations (DiazGranados et al., 2010; Murrough
et al., 2013; Zarate et al., 2006). Additionally, it has shown promise
for treating PTSD (Feder et al., 2014) and heroin addiction
(Krupitsky et al., 2002). Animal models suggest that its therapeutic
effects stem from its ability to promote the growth of dendritic
spines, increase the synthesis of synaptic proteins, and
strengthen synaptic responses (Autry et al., 2011; Browne and
Lucki, 2013; Li et al., 2010).

Like ketamine, serotonergic psychedelics and entactogens
have demonstrated rapid and long-lasting antidepressant and
anxiolytic effects in the clinic after a single dose (Bouso et al.,
2008; Carhart-Harris and Goodwin, 2017; Grob et al., 2011;
Mithoefer et al., 2013, 2016; Nichols et al., 2017; Sanches
et al., 2016; Oso´ rio et al., 2015), including in treatment-resistant
populations (Carhart-Harris et al., 2016, 2017; Mithoefer et al.,
2011; Oehen et al., 2013; Rucker et al., 2016). In fact, there
have been numerous clinical trials in the past 30 years examining
the therapeutic effects of these drugs (Dos Santos et al., 2016),
with 3,4-methylenedioxymethamphetamine (MDMA) recently
receiving the ‘‘breakthrough therapy’’ designation by the Food
and Drug Administration for treating PTSD. Furthermore, classical
psychedelics and entactogens produce antidepressant
and anxiolytic responses in rodent behavioral tests, such as
the forced swim test (Cameron et al., 2018) and fear extinction
learning (Cameron et al., 2018; Catlow et al., 2013; Young
et al., 2015), paradigms for which ketamine has also been shown
to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al.,
2010). Despite the promising antidepressant, anxiolytic, and
anti-addictive properties of serotonergic psychedelics, their
therapeutic mechanism of action remains poorly understood,
and concerns about safety have severely limited their clinical
usefulness.
Because of the similarities between classical serotonergic
psychedelics and ketamine in both preclinical models and clinical
studies, we reasoned that their therapeutic effects might
result from a shared ability to promote structural and functional
neural plasticity in cortical neurons. Here, we report that serotonergic
psychedelics and entactogens from a variety of chemical
classes (e.g., amphetamine, tryptamine, and ergoline) display
plasticity-promoting properties comparable to or greater than
ketamine. Like ketamine, these compounds stimulate structural
plasticity by activating the mammalian target of rapamycin
(mTOR). To classify the growing number of compounds capable
of rapidly promoting induced plasticity (Castre´ n and Antila,
2017), we introduce the term ‘‘psychoplastogen,’’ from the
Greek roots psych- (mind), -plast (molded), and -gen (producing).
Our work strengthens the growing body of literature indicating
that psychoplastogens capable of promoting plasticity
in the PFC might have value as fast-acting antidepressants
and anxiolytics with efficacy in treatment-resistant populations
and suggests that it may be possible to use classical psychedelics
as lead structures for identifying safer alternatives.

DISCUSSION
Classical serotonergic psychedelics are known to cause
changes in mood (Griffiths et al., 2006, 2008, 2011) and brain
function (Carhart-Harris et al., 2017) that persist long after the
acute effects of the drugs have subsided. Moreover, several
psychedelics elevate glutamate levels in the cortex (Nichols,
2004, 2016) and increase gene expression in vivo of the neurotrophin
BDNF as well as immediate-early genes associated with
plasticity (Martin et al., 2014; Nichols and Sanders-Bush, 2002;
Vaidya et al., 1997). This indirect evidence has led to the
reasonable hypothesis that psychedelics promote structural
and functional neural plasticity, although this assumption had
never been rigorously tested (Bogenschutz and Pommy,
2012; Vollenweider and Kometer, 2010). The data presented
here provide direct evidence for this hypothesis, demonstrating
that psychedelics cause both structural and functional changes
in cortical neurons.

Prior to this study, two reports suggested
that psychedelics might be able
to produce changes in neuronal structure.
Jones et al. (2009) demonstrated that DOI
was capable of transiently increasing the
size of dendritic spines on cortical neurons,
but no change in spine density was
observed. The second study showed
that DOI promoted neurite extension in a
cell line of neuronal lineage (Marinova
et al., 2017). Both of these reports utilized
DOI, a psychedelic of the amphetamine
class. Here we demonstrate that the ability
to change neuronal structure is not a
unique property of amphetamines like
DOI because psychedelics from the ergoline,
tryptamine, and iboga classes of compounds also promote
structural plasticity. Additionally, D-amphetamine does not increase
the complexity of cortical dendritic arbors in culture,
and therefore, these morphological changes cannot be simply
attributed to an increase in monoamine neurotransmission.
The identification of psychoplastogens belonging to distinct
chemical families is an important aspect of this work because
it suggests that ketamine is not unique in its ability to promote
structural and functional plasticity. In addition to ketamine, the
prototypical psychoplastogen, only a relatively small number of
plasticity-promoting small molecules have been identified previously.
Such compounds include the N-methyl-D-aspartate
(NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3
antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic
receptor antagonist scopolamine (Lepack et al., 2016; Castello
et al., 2014; Zeng et al., 2012; Voleti et al., 2013). We
observe that hallucinogens from four distinct structural classes
(i.e., tryptamine, amphetamine, ergoline, and iboga) are also
potent psychoplastogens, providing additional lead scaffolds
for medicinal chemistry efforts aimed at identifying neurotherapeutics.
Furthermore, our cellular assays revealed that several
of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting
properties of psychedelics and entactogens rivaled that
of BDNF (Figures 3A–3C and S3). The extreme potency of LSD
in particular might be due to slow off kinetics, as recently proposed
following the disclosure of the LSD-bound 5-HT2B crystal
structure (Wacker et al., 2017).
Importantly, the psychoplastogenic effects of psychedelics in
cortical cultures were also observed in vivo using both vertebrate
and invertebrate models, demonstrating that they act through an
evolutionarily conserved mechanism. Furthermore, the concentrations
of psychedelics utilized in our in vitro cell culture assays
were consistent with those reached in the brain following systemic
administration of therapeutic doses in rodents (Yang
et al., 2018; Cohen and Vogel, 1972). This suggests that neuritogenesis,
spinogenesis, and/or synaptogenesis assays performed
using cortical cultures might have value for identifying
psychoplastogens and fast-acting antidepressants. It should
be noted that our structural plasticity studies performed in vitro
utilized neurons exposed to psychedelics for extended periods
of time. Because brain exposure to these compounds is often
of short duration due to rapid metabolism, it will be interesting
to assess the kinetics of psychedelic-induced plasticity.
A key question in the field of psychedelic medicine has been
whether or not psychedelics promote changes in the density of
dendritic spines (Kyzar et al., 2017). Using super-resolution
SIM, we clearly demonstrate that psychedelics do, in fact, increase
the density of dendritic spines on cortical neurons, an effect
that is not restricted to a particular structural class of compounds.
Using DMT, we verified that cortical neuron spine
density increases in vivo and that these changes in structural
plasticity are accompanied by functional effects such as
increased amplitude and frequency of spontaneous EPSCs.

We specifically designed these experiments
to mimic previous studies of ketamine
(Li et al., 2010) so that we might
directly compare these two compounds,
and, to a first approximation, they appear
to be remarkably similar. Not only do they
both increase spine density and neuronal
excitability in the cortex, they seem to
have similar behavioral effects. We have
shown previously that, like ketamine,
DMT promotes fear extinction learning
and has antidepressant effects in the
forced swim test (Cameron et al., 2018). These results, coupled
with the fact that ayahuasca, a DMT-containing concoction, has
potent antidepressant effects in humans (Oso´ rio et al., 2015;
Sanches et al., 2016; Santos et al., 2007), suggests that classical
psychedelics and ketamine might share a related therapeutic
mechanism.
Although the molecular targets of ketamine and psychedelics
are different (NMDA and 5-HT2A receptors, respectively), they
appear to cause similar downstream effects on structural plasticity
by activating mTOR. This finding is significant because ketamine is
known to be addictive whereas many classical psychedelics are
not (Nutt et al., 2007, 2010). The exact mechanisms by which these
compounds stimulate mTOR is still not entirely understood, but
our data suggest that, at least for classical psychedelics, TrkB
and 5-HT2A receptors are involved. Although most classical psychedelics
are not considered to be addictive, there are still significant
safety concerns with their use in medicine because they
cause profound perceptual disturbances and still have the potential
to be abused. Therefore, the identification of non-hallucinogenic
analogs capable of promoting plasticity in the PFC could
facilitate a paradigm shift in our approach to treating neuropsychiatric
diseases. Moreover, such compounds could be critical to
resolving the long-standing debate in the field concerning whether
the subjective effects of psychedelics are necessary for their therapeutic
effects (Majic et al., 2015  ). Although our group is actively
investigating the psychoplastogenic properties of non-hallucinogenic
analogs of psychedelics, others have reported the therapeutic
potential of safer structural and functional analogs of ketamine
(Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016).
Our data demonstrate that classical psychedelics from several
distinct chemical classes are capable of robustly promoting the
growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities
between the effects of ketamine and those of classical serotonergic
psychedelics, supporting the hypothesis that the clinical
antidepressant and anxiolytic effects of these molecules might
result from their ability to promote structural and functional plasticity
in prefrontal cortical neurons. We have demonstrated that
the plasticity-promoting properties of psychedelics require
TrkB, mTOR, and 5-HT2A signaling, suggesting that these key
signaling hubs may serve as potential targets for the development
of psychoplastogens, fast-acting antidepressants, and anxiolytics.
Taken together, our results suggest that psychedelics
may be used as lead structures to identify next-generation neurotherapeutics
with improved efficacy and safety profiles.

Also below is a great article on DMT and neuroplasticity:

 

Dark Classics in Chemical Neuroscience N,N-Dimethyltryptamine DMT

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Ketamine Consultants Blog

Ketamine is a dissociative anesthetic that acts on the central nervous system by antagonizing the n-methyl-d-aspartate (NMDA) receptors. It is a rapid acting anti-depressant, but there is a lot more attention being paid to it’s efficacy in alcohol and drug abuse treatment.

Ketamine has been shown in some studies to prolong abstinence from alcohol and drug use disorders. It also has been found to reduce cocaine craving and self-administration in untreated patients.

The mechanisms by which this works has been through the disruption of relevant neural networks which blocks reconciliation of drug-related memories, neuroplasticity and neurogenesis, and enhancing psychological therapy.

We know that addiction is a chronic relapsing disorder with cravings, drug seeking, and unpleasant withdrawal symptoms upon cessation of the drug. Relapse rates with current therapies are between 40-80%.

Pre-clinical research on Ketamine has shown effectiveness in alcohol intake in a rat model:

Alcohol-preferring rats could self-administer
0.08% weight/volume saccharin, 10% weight/volume ethanol or
water. After intraperitoneal administration of either ketamine or
memantine, operant responding and motor activity were assessed.
A dose of 20 mg/kg of ketamine reduced ethanol administration
significantly (33.3% less than vehicle-treated rats) without affecting
motor activity and water consumption. Importantly, coadministration
of rapamycin blocked ketamine-mediated reduction
of alcohol intake, but not that of memantine (Sabino et al.,
2013). Similarly, ketamine’s antidepressant effects are suppressed
by rapamycin. mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

Also:

Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats.

The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD.

Addiction is characterised by disruptions in learning and memory. Addicts develop cue-specific responses to drug-related
cues. One preclinical study examined the effects of ketamine administration on reconsolidation
where memories are rendered more labile following reactivation. After morphine CPP ( conditioned place preference) was induced, rats were intraperitoneally administered 60 mg/kg of ketamine after being reexposed to the conditioned context or while they were in their home cages. After ketamine administration, preference for morphine decreased significantly in the first retest.  This has been interpreted as evidence that ketamine successfully disrupted reconsolidation of the environment-drug memory.

Effects of scopolamine and ketamine on reconsolidation of morphine conditioned place preference in rats

Persistent memory associated with addictive drugs contributes to the relapse of drug abuse. The current study was conducted to examine the effects of scopolamine and ketamine on reconsolidation of morphine-induced conditioned place preference (CPP). In experiment 1, after morphine CPP was acquired, rats were injected with ketamine (60 mg/kg, intraperitoneally) and scopolamine (2 mg/kg, intraperitoneally), respectively, after reexposure to an earlier morphine-paired context or in their home cages. The CPP was reassessed 24 and 48 h after reexposure. An additional group of rats received saline following reexposure to the earlier morphine-paired context. In experiment 2, two groups of rats were only given saline during the CPP training and subsequent administration of ketamine or scopolamine during the reexposure. In experiment 1, rats failed to exhibit morphine CPP when ketamine and scopolamine were administered only after reexposure to a morphine-paired context. CPP was not abolished by ketamine or scopolamine administration in the animals’ home cages. Also, the animals receiving only saline injections showed strong morphine CPP 24 h after a short exposure to the morphine-paired context. In experiment 2, ketamine or scopolamine treatment alone did not induce CPP or aversion. Administration of scopolamine and ketamine, after reexposure to a drug-paired context, resulted in the disruption of morphine CPP, suggesting the potential effects of scopolamine and ketamine in disrupting memory associated with environmental cues and addictive drugs.

The capacity of ketamine to treat addiction was not investigated scientifically until decades later when Krupitsky and
Grinenko (1997), published work that reported the use of ketamineto reduce relapse in recently detoxified alcoholics. These
published results were a review of 10 years of previous research.The procedure that was investigated was referred to as Ketamine Psychedelic Therapy (KPT) and had been applied since the mid-80sin the former Soviet Union, until ketamine was banned in Russia 1998.  Ten Year Study of Ketamine Psychedelic Therapy (KPT) of Alcohol Dependence [

KPT consisted of three stages. The first step was the preparation,during which patients underwent a preliminary psychotherapy session where a psychotherapist discussed with them the content of the psychedelic experience. They were told that under the influence of ketamine, they would view the world symbolically, realise about the negative aspects of alcohol dependence and see the positive sides of sobriety. They were also told that they would become aware of unconscious mental concepts about the negative aspects of their addiction, such as their personal problems and their self-identity. These insights would help them to accept new life values, purposes and meaning of life and in turn e to overcome
their alcoholism. The second stage was the ketamine session in which ketamine was intramuscularly injected and the psychotherapist interacted with the patient. The psychotherapist verbally guided the patient, with the aim of creating new meaning and purpose in life. At moments of highly intense psychedelic experience, the smell of alcohol was introduced to the individuals. The idea was to enhance the negative emotional valence of the thoughts related to alcohol during the session. Finally, group psychotherapy was performed after the session. The aim of this session was to help patients integrate
insights of psychedelic experience into their lives. It is reported that this procedure was used in
over 1000 alcoholics with no reported complications.In Krupitsky and Grinenko, 1997 report, relapse rates in a group
of recently detoxified alcohol dependent patients undergoing KPT (n ¼ 111) were compared with another group of alcohol dependent patients who were treated with treatment as usual (n ¼ 100). Both groups underwent alcohol detoxification before treatment. After these sessions, the KPT group received an intramuscular injection of ketamine (2.5 mg/kg) along with the corresponding preparation. The control group received ‘conventional, standard methods of treatment’ in the same hospital. Only 24% of the control group remained abstinent after a year, whereas 66% of the KPT group did not relapse during the same period (p < .01).

In a further study, 70 detoxified heroin-dependent patients were randomised into two KPT groups, who were injected different doses of ketamine, in a double-blind manner (Krupitsky et al., 2002). One group (n ¼ 35) received 0.2 mg/kg i.m. of ketamine, which was considered an active placebo, whereas the experimental group (n ¼ 35) received 2.0 mg/kg i.m. After two years, the higher dose of ketamine resulted in a greater rate of abstinence (17% vs 2% abstinent subjects, p < .05). Additionally, the experimental group had a larger positive change in nonverbal unconscious emotional attitudes and a greater and longer-lasting reduction in craving for heroin. The authors therefore concluded that effectiveness of ketamine
was dose dependent. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

In 2007, Krupitsky’s lab compared the impact of a single vs three KPT sessions (dose: 2.0 mg/kg, i.m.) (Krupitsky et al., 2007). Fifty nine detoxified heroin dependent patients first received a KPT session. After this, 6 participants relapsed and abandoned the treatment. The remaining participants were randomised into two groups: one received a further two KPT sessions (n ¼ 26) in monthly intervals, whereas the other underwent two counseling sessions (n ¼ 27) also in monthly intervals. After a year, 50% in the 3-session KPT group remained abstinent compared to 22% in the single KPT (p < .05) (Krupitsky et al., 2007). This clearly demonstrates the superior efficacy of three KPT sessions in comparison to
one KPT session, which indicates that the KPT sessions are beneficial.  Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence 

In a private psychiatric practice in the US, another psychiatrist has successfully conducted KPT since 1994. He has not only treated patients with drug addiction, but also individuals with other types of addictions (e.g. food addiction) and other psychological disorders. His reported anecdotal, clinical findings are positive, having adhered strictly to the original protocol.  Ketamine Enhanced Psychotherapy: Preliminary Clinical Observations on Its Effectiveness in Treating Alcoholism. Kolp, Eli,Friedman, Harris L.,Young, M. Scott,Krupitsky, Evgeny The Humanistic Psychologist, Vol 34(4), 2006, 399-422

Abstract:

Ketamine is a dissociative anesthetic widely used by physicians in the United States and also a psychedelic drug that physicians can legally prescribe off-label within the United States for other therapeutic purposes. It has been used in Russia and elsewhere to successfully treat alcoholism and other psychological or psychiatric problems, but has not been researched for this purpose in the United States. Results of a series of clinical trials using ketamine for treating alcoholism in the United States are retrospectively reported, along with 2 case studies of how psychotherapy facilitated by this substance helped two individuals achieve abstinence through ketamine’s transpersonal effects. Considering the massive problems caused by alcoholism, the need to begin formal research studies on ketamine psychotherapy for alcoholism is emphasized.

In 2014, 8 cocaine dependent males disinterested in treatment received 3 infusions in a double-blind, cross-over design: 0.41 mg/ kg ketamine, 0.71 mg/kg ketamine, and 2 mg lorazepam (an active benzodiazepine control, which induces mild subjective and anxiolytic effects) (Dakwar et al., 2014b). Infusions lasted 52 min and were separated by 48 h. Before and after each infusion, motivation to quit cocaine and cue-induced craving were assessed. Relative to the lorazepam, motivation to quit cocaine was enhanced and cueinduced craving for cocaine was reduced by the 0.4 mg/kg ketamine (both ps ¼ 0.012), and this latter effect was augmented by the 0.71 mg/kg ketamine dose. During the psychedelic experience,
dissociation and mystical-type effects were assessed. As predicted, the higher dose of ketamine led to greater mystical experiences. Strikingly, these mystical-type experiences, but not the dissociative effects, were found to mediate motivation to quit. However, the small non-treatment-seeking sample, the absence of an inactive placebo and the cross-over design, limit the results.Having said that, the participants showed a significant reduction in the frequency and amount of cocaine
consumed in normal life in the 4 weeks following the experiment, compared to baseline. Dakwar, E., Levin, F., Foltin, R.W., Nunes, E.V., Hart, C.L., 2014b. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol. Psychiatry 76, 40e46. https://doi. org/10.1016/j.biopsych.2013.08.009.

Also, more cocaine research from the same group is here:

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial E DakwarMolecular Psychiatry volume22pages76–81 (2017) |

Abstract:

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

Neural plasticity is defined as the cellular and structural reorganisation
of the brain. Synaptogenesis is a crucial mechanism for
plasticity, since for change to happen within brain circuitry new
synapses between neurons must be formed. Surface expression of
AMPARs and upregulation of other synaptic proteins are involved in
the process of synaptogenesis. Diminished glutamatergic synaptic
transmission and reduced plasticity are thought to be associated
with addiction. Existing models suggest that ketamine’s blockade of NMDA receptors
increases synaptogenesis by stimulating protein synthesis
and the insertion of AMPA receptors. Hence, ketamine’s
effects help to reverse the glutamatergic changes associated
with depression and addiction. 

Animal models of addiction, depression and other psychiatric disorders
have been linked to a reduction in adult neurogenesis . It has been suggested that in addiction
the loss of neurogenesis, especially in cortical and hippocampal
regions, may contribute to levels of self-administration and the
vulnerability of relapsing. The reduction of neurogenesis in addiction is supported in
humans by the reduction in BDNF serum levels. In a study, 37
subjects with diagnosis of alcohol dependence showed significantly
reduced BDNF serum levels compared to healthy individuals
. Similarly, cocaine- and heroin-dependentpatients have significantly lower serum BDNF levels and these
seem to recover during withdrawal. Rapid and transient up-regulation of the neuroplasticity marker
BDNF is implicated as a critical component of the antidepressant
mechanism of ketamine . BDNF knock-out mice do not show anti-depressant response to
ketamine in animal models of depression.

Recent research has
demonstrated that ketamine increases peripheral plasma BDNF in
depressed people who respond to treatment but not in treatment
non-responders or patients receiving an active placebo. These BDNF increases in depressed people given ketamine
are robustly correlated with the drug’s antidepressant effects.

It has been found there is a dispersion in normal brain connectivity and the disruption of the usual pattern of communication  in depression and addictions. . The integrity of functional networks decreased, being the
change maximal in functional hubs such as the thalamus, putamen
and high-level association cortices. In particular, connectivity
within the Default Mode Network was reduced between the posterior
cingulate cortex and the mPFC .
The connectivity between the parahippocampal and the retrosplenial
cortex also decreased as well as the segregation between
other major functional networks such as the salience, attention and
different visual networks Infusions of ketamine have shown to decrease connectivity
between and within resting-state consciousness networks.
Connectivity between the mPFC and the rest of the Default
Mode Network (via the posterior cingulate cortex) has been found
to be reduced, along with the integrity and activity of the salience
and visual networks are also affected. Since it is known
that connectivity with the mPFC is elevated in depression , the reduction of connectivity in the Default Mode
Network observed during the psychedelic experience might be a
mechanism that helps treat depressive states, which are very
common in addicts and predictive of relapse.

Given addiction is highly co-morbid with depression   and ketamine’s role within psychiatry changed
dramatically when it was discovered to be an anti-depressant, we
now briefly describe the research concerning ketamine and
depression. In 2000, the first clinical trial hinted at the potential of
ketamine as a treatment for depression. Four subjects diagnosed
with depression were intravenously administered 0.5 mg/kg of
ketamine in a randomised, double-blind design. The results were
compared to the injection of saline solutions in 3 subjects with an
equivalent diagnosis. Comparison on the Hamilton Rating Scale for
Depression (HAM-D) showed moderate evidence for a greater
reduction in scores after ketamine infusion compared to saline
(Berman et al., 2000). The reduction was rapid and outlasted the
subjective effects of ketamine, lasting for 3 days after infusion.
Despite the small sample size and the limited follow-up, this result
and anti-depressant effects observed in animal models of depression
encouraged researchers in the field to perform more studies in humans . Since then, over 30 studies have
examined the antidepressants effects of ketamine in patients with
treatment-resistant major depressive and bipolar disorders.

Ketamine has shown a 65-70% response rate in treating
depression within 24 h, which contrasts with the ~47% response
rate of conventional monoaminergic antidepressants after weeks
or months . Furthermore,
ketamine’s antidepressant actions are almost immediate and last
for approximately a week ,
whereas conventional antidepressive medications take weeks to
have an effect, are given daily and most of them fail to exert long lasting
effects . Furthermore, studies
have consistently shown that after a ketamine infusion there is a
significant reduction in suicidal ideation which also lasts for several
days.Depression and addiction’s co-expression is almost ubiquitous
People with alcohol, opioids, cannabis and
cocaine use disorders show notably higher rates of depression than
the average of the general population. Furthermore, high levels of depression and anxiety
may predispose relapse to: heroin, alcohol, cannabis and cocaine.

Memories and their creation and alteration is felt to be at the heart of cues and triggers and relapse in addiction. Once consolidated, memories are thought to be stored in a
stabilised state after initial acquisition. Shortly after reactivation
(i.e. remembered) of consolidated memories, these are rendered
transiently unstable and labile, before they then re-stabilise. This
process has been named reconsolidation . After reconsolidation,
the memories are stored again, but they may have been slightly
altered or updated. Each time memories are reactivated the latest
version is retrieved and they are again susceptible to change. During reconsolidation memories may be vulnerable to
manipulation and disruption. This was first demonstrated in animals
using fear conditioning. Rodents were trained to associate a
neutral stimulus with a shock such that the neutral stimulus elicited
a fear response. Researchers eliminated this fear response by
pharmacologically disrupting the reconsolidation process . Reward memories can also be disrupted such that a
neutral stimulus that once elicited appetitive behaviour no longer
does so. Therefore, non-pharmacological and drug therapies that
aim at weakening drug-cue memories via manipulation of reconsolidation
are of interest. Preclinical studies have shown that ketamine affects reconsolidation
of drug memories. . A recent review has suggested that ketamine (along with other psychedelics)
may be able to disrupt maladaptive appetitive memories
(Fattore et al., 2017).  Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Article ABSTRACT:

Rationale

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.

Objective

Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.

Results

We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.

Furthermore, a meta-analysis of pre-clinical
studies found evidence suggesting that NMDAR antagonists can
be used to target reward memory reconsolidation, and more successfully
than adrenergic antagonists such as propranolol (Das
et al., 2013)  Das, R.K., Freeman, T.P., Kamboj, S.K., 2013. The effects of N-methyl d-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis. Neurosci. Biobehav. Rev. 37, 240-255.:

Abstract

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-d-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR = 30, B-AR = 22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.

Highlights

► Meta-analysis of NMDAR and B-adrenergic antagonists in preclinical reward reconsolidation. ► Larger effects of NMDAR (r = .613) than B-adrenergic (r = .24) antagonists were found. ► ‘Relapse process’, trace type, reinforcer and drug dose moderated effect sizes. ► NMDAR antagonists particularly might be of clinical use in treating addiction.

 

.

                           Mystical experiences and psychedelic effects

Mystical experiences and psychedelic effects provoked by
classic psychedelic drugs have been shown to be psychologically
beneficial in long-term studies.They have not only been linked with positive
outcomes in various treatments, but also to ‘life-changing’,
‘spiritually meaningful’ and ‘eye opening’ events.In the ketamine studies described
above, anecdotal and qualitative reports suggest that the subjective
psychedelic experience seemed to help patients. For example, to
help them: undergo a cathartic process, improve relationships with
the world and other people, maintain positive psychological
changes and enhance self-awareness and personal growth.During KPT, patients reported a feeling of ‘resolution’ and
‘catharsis’ of some psychological problems, mainly those related to
alcohol. Furthermore, the degree of mystical experience was also
linked to the insight and impact of KPT reported by patients
. Interestingly, the intensity of the negative experiences (experiences associated
with negative emotions, fear and horror) during the
ketamine session was associated with longer remission. This was
blindly and quantitatively assessed by analysing patient’s selfreports.
Moreover, spirituality, self-concept, emotional attitudes
to other people and positive changes in life values and purposes
were improved after the ketamine experience.

Notably, ketamine’s mystical experiences, but not dissociative
effects, were found to mediate ketamine’s increase motivation to
quit 24 h after the infusion in cocaine addicts .
Moreover, consistent with previous studies, it was also observed
that mystical experiences were positively dose-dependent. This
study therefore provides evidence that the mystical experience
induced by ketamine is important in its therapeutic mechanism
. Speculatively, mystical experiences may help
to rapidly shift patients’ mindsets towards the integration and
acceptance of a sober lifestyle.

The acute disruptions of the functional networks, especially the
alterations to the default mode network, are related to the psychedelic
experience. In fact, the degree of network dissolution in
LSD and psilocybin is correlated with the intensity of the psychedelic
experience . The disruption to the default mode network may engender a reduction
in rumination and maladaptive repetitive thoughts. Psychological
therapies for addiction often aim to help the patient consider
different ways of life, especially those without the drug, and a
pharmacological agent such as ketamine which expedites that
process may be useful in treating addiction.

Speculatively, ketamine can
provide a unique mental state during and after acute drug effects
that facilitates and enriches therapeutic experiences, which in turn
may improve efficacy and lengthen treatment effects. Furthermore, synaptogenesis
and neurogenesis are putatively critical in learning new
information . The uptake of psychological therapy may
therefore be facilitated after ketamine infusions due increases in
synaptogenesis and neurogenesis, and thus improved learning of
relapse-reducing strategies, such as those used in relapseprevention
based cognitive behavioural therapy (CBT). In fact, the
idea that neurogenesis and synaptogenesis work synergistically
with psychological therapies is becoming recognised as a new
approach in the treatment of mental disorders . Theoretically, the administration of ketamine (which can
produce a ‘psychedelic’ experience) may open people’s minds so
they are more able to embrace what is presented during therapy as
well as enhancing the uptake of new therapeutic content.

The promise of ketamine in the treatment of addiction is supported
by research with large treatment effect sizes, especially in
comparison to existing treatments. In recently detoxified alcoholics,
ketamine treatment increased one-year abstinence rates in
alcoholics from 24% in the control to 66% in the ketamine group
(Krupitsky and Grinenko, 1997) and reduced cocaine self administration
by 67% relative to baseline in non-treatment
seeking cocaine users (Dakwar et al., 2016). These results clearly
demonstrate profound effects of ketamine administration (with
and without therapy) on drug and alcohol use, of an order of
magnitude which is 2 or 3 times more effective than existing
pharmacotherapies.

Ketamine for the treatment of addiction Evidence and potential mechanisms

 

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Maryland (MD): Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902 Washington DC: Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016 Northern Virginia: McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304 Fairfax – 20191 – Reston – 22009 – Springfield – 22152 22015 Lorton 22199 Fairfax, Va 2303 – 22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312 22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 – 20124 22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043 22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101 22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153 22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 – 22182 Woodbridge – 22191 – 22192 -22193 -22194 – 22195 Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160

 

 

 

 

 

 

 

 

 

 

 

Ketamine IV reduces depression in Adolescents |703-844-0184 | Ketamine therapy for Anxiety and Depression| IV Ketamine for depression, PTSD, bipolar disorder, and others | Ketamine therapy for depression | 703-844-0184 | Fairfax, Va 22304 |

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

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Ketamine doctors in Fairfax, Va | 703-844-0184

Below is a recent study regarding the treatment of adolescents with Ketamine for refractory depression. There seems to be good success and longer lasting results:

Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study

The average response rate in published studies testing ketamine for adult TRD is 67% (Wan et al. 2015), which is considerably higher than TRD interventions (e.g., the average response rate for transcranial magnetic stimulation is 45%
(Conelea et al. 2017).

Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.

Methods: Adolescents, 12–18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children’s Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).

Results: Thirteen participants (mean age 16.9 years, range 14.5–18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.

Conclusions: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.

Intravenous Ketamine for Adolescents – PDF

___________________________________________

Area Codes Near Us::
Maryland (MD): Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902 Washington DC: Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016 Northern Virginia: McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304 Fairfax – 20191 – Reston – 22009 – Springfield – 22152 22015 Lorton 22199 Fairfax, Va 2303 – 22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312 22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 – 20124 22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043 22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101 22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153 22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 – 22182 Woodbridge – 22191 – 22192 -22193 -22194 – 22195 Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161 Front Royal 22630

Ketamine IV reduces suicidal thinking in depressed patients |703-844-0184 | Ketamine therapy for Anxiety and Depression| IV Ketamine for depression, PTSD, bipolar disorder, and others | Ketamine therapy for depression | 703-844-0184 | Fairfax, Va 22304 |

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog

Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

NOVA Health Recovery | 703-844-0184 | Fairfax, Virginia 22304
NOVA Health Recovery | 703-844-0184 | Fairfax, Virginia 22304

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients << Article link 

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

 

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study  << Article in Clinical Psychiatry

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial Article link for below:

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”

Ketamine for Rapid Reduction of Suicidal Thoughts in major depression – A midazolam controlled trial PDF article

Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304
Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304

______________________________________________________________________

Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

Abstract
Objective To review the published literature on the efficacy
of ketamine for the treatment of suicidal ideation (SI).
Methods The PubMed and Cochrane databases were
searched up to January 2015 for clinical trials and case
reports describing therapeutic ketamine administration to
patients presenting with SI/suicidality. Searches were also
conducted for relevant background material regarding the
pharmacological function of ketamine.
Results Nine publications (six studies and three case
reports) met the search criteria for assessing SI after
administration of subanesthetic ketamine. There were no
studies examining the effect on suicide attempts or death
by suicide. Each study demonstrated a rapid and clinically
significant reduction in SI, with results similar to previously
described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been
reported in the literature as receiving therapeutic ketamine.
Seven studies delivered a dose of 0.5 mg/kg intravenously
over 40 min, while one study administered a 0.2 mg/kg
intravenous bolus and another study administered a liquid
suspension. The earliest significant results were seen after
40 min, and the longest results were observed up to
10 days postinfusion.
Conclusion Consistent with clinical research on ketamine
as a rapid and effective treatment for depression, ketamine
has shown early preliminary evidence of a reduction in
depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to
further investigate its mechanism of action, long-term
outcomes, and long-term adverse effects (including abuse)
and benefits. In addition, ketamine could potentially be
used as a prototype for further development of rapid-acting
antisuicidal medication with a practical route of administration
and the most favorable risk/benefit ratio.
Key Points
Preliminary data from randomized controlled trials
have demonstrated that ketamine may rapidly and
effectively control treatment-resistant depression,
though the effects are transient.
A small subset of studies has demonstrated similar
results in the effects of ketamine on suicidal ideation.
Ketamine has potential as a rapid treatment for
suicidal ideation and/or a possible model compound
for future drug development.

4 Discussion
With an estimated prevalence of mood disorders ranging
from 3.3 to 21.4 % and the substantially increased risk of
suicide among patients with mood disorders, treatment is
certainly warranted [19]. Current treatment options for
suicidality are limited. They include brain stimulation
therapeutics, such as ECT, and pharmacological intervention
(lithium, clozapine). The efficacy of lithium in treating
suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48
studies [22]. Clozapine has also been shown to reduce
suicide risk in patients with schizophrenia [23, 24]. The
limitations of both lithium and clozapine include a longer
time to efficacy in this psychiatric emergency/urgency,
compared with the early response to ketamine [25]. Ketamine
seems to be gaining substantial evidence as a pharmacological
option for depression with a fast onset of
action, but its long-term effects need further investigation.
In addition, ketamine probably offers a faster onset of
action in terms of SI, but further work is certainly needed
in this area. Given the risk of suicide and even the
increasing rates of suicide in certain subgroups, such as
soldiers and veterans [26, 27], there is an urgent need for
faster therapeutics for SI and TRD. Importantly, suicidality
and suicide pose a high global burden of patient suffering
to families and society. Although several small-to-moderate
sized studies, in addition to several reviews, have been
published that have examined the efficacy of ketamine in
TRD, there are considerably fewer published data
specifically examining ketamine in patients presenting with
SI. Notably, only three studies have directly examined SI
as the primary outcome [11, 16, 17], while the rest
examined SI as the secondary outcome [4, 15, 18], not
including case reports. This review summarizes the current
published literature regarding ketamine as a treatment for
SI. The data so far show promising trends of ketamine
being an effective and rapid treatment with minimal side
effects.
Pharmacologically, ketamine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It has been used for anesthesia
in the USA since the 1970s. At subanesthetic doses,
ketamine has been shown to increase glutamate levels [3].
This mechanism is relevant, as glutamate regulation and
expression are altered in patients with major depressive
disorder (MDD). Studies have also demonstrated an
abnormal glutamate–glutamine–gamma-aminobutyric acid
cycle in patients with suicidality [28]. Furthermore, ketamine
has also been shown to work on nicotinic and opioid
receptors [29]. No other class of antidepressant medication
works to modulate the glutamatergic system, and research
continues into this, with the goal of characterizing the full
mechanism of action of ketamine and perhaps developing
other compounds that would have similar effects. Thus,
even if the approval and marketing of ketamine as a rapidacting
antisuicidal and antidepressant medication is not
realized, it could well be a prototype for development of
other medication(s) that retain the mechanism of action
with more favorable qualities and a lesser adverse effect
profile (such as a longer duration of action or less or no
addictive potential). Although the mechanisms explaining
the antisuicidal effect and the NMDA receptor antagonism
of ketamine are still unclear, some of the initial evidence
points to an anti-inflammatory action via the kynurenic
acid pathway. Strong suggestions as to the causal relationship
between inflammation and depression/suicidality
has come from studies demonstrating that cytokines [30,
31] and interferon-b [32] induce depression and suicidality.
Other recent studies have added to the notion of implicating
brain immune activation in the pathogenesis of suicidality.
For instance, one study showed microglial
activation of postmortem brain tissue in suicide victims
[33]. Another study found increased levels of the cytokine
interleukin-6 in cerebrospinal fluid from patients who had
attempted suicide [34]. Higher levels of inflammatory
markers have been shown in suicidal patients than in nonsuicidal
depressed patients [33, 35]. Inflammation leads to
production of both quinolinic acid (an NMDA agonist) and
kynurenic acid (a NMDA antagonist). An increased
quinolinic acid to kynurenic acid ratio leads to NMDA
receptor stimulation. The correlation between quinolinic
acid and Suicide Intent Scale scores indicates that changes
in glutamatergic neurotransmission could be specifically
linked to suicidality [36].
Small randomized controlled trials have demonstrated
the efficacy of ketamine in rapidly treating patients with
both TRD and/or bipolar depression [4, 8, 9, 11, 16–18].
Some studies have also examined suicide items as a secondary
measure in their depression rating scales [4, 7]. In
total, the studies examining ketamine and TRD have nearly
consistently demonstrated that ketamine provides relief
from depressive and suicidal symptoms, starting at 40 min
and lasting for as long as 5 days. Questions still remain as
to the long-term effects of this treatment, how much should
be administered and how often, any serious adverse effects,
and the mechanism of action.
Pharmacologically, ketamine has poor bioavailability
and is best administered via injection [37]. In their landmark
study, Berman et al. [4] found that a subanesthetic
dose (0.5 mg/kg) rapidly improved depressive symptoms.
Most of the subsequent studies have delivered ketamine as
a constant infusion for 40 min at a rate of 0.5 mg/kg.
Others have examined its efficacy after multiple infusions
and observed similar results [8, 13, 16, 38]. Currently, it is
recommended that ketamine be administered in a hospital
setting [39].

______________________________________

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:

 

Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic
modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after
ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI
response to ketamine.
Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with
DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic
(0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture
modeling to generate SI response classes, and class membership predictors were evaluated using multinomial
logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.
Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders
(44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1.
Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for
Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated
with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to
Remitters rather than Responders.
Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma,
rather than CSF, markers were used.
Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence
from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic
SI were less likely to respond or remit post-ketamine.

1. Introduction
Suicide poses a serious threat to public health. Worldwide, suicide
accounts for approximately 1 million deaths, and 10 million suicide
attempts are reported annually (World Health Organization, 2014). In
the United States, the national suicide rate has increased by approximately
28% over the last 15 years (Curtin et al., 2016). At the same
time, relatively few interventions for suicide risk exist. While treatments
such as clozapine and lithium have demonstrated effects on
suicidal behavior over weeks to months, these effects may be limited to
specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently,
no FDA-approved medications exist to treat suicidal ideation
(SI), leaving those who experience a suicidal crisis with limited options
for a reprieve of symptoms. Consequently, a critical need exists for
rapid-acting treatments that can be used in emergency settings.
A promising off-label agent for this purpose is the rapid-acting antidepressant
ketamine, which past studies have suggested reduces suicidal
thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price
et al., 2009). A recent meta-analysis of 167 patients with a range of
mood disorder diagnoses found that ketamine reduced suicidal
thoughts compared to placebo as rapidly as within a few hours, with
effects lasting as long as seven days (Wilkinson et al., 2017). These
results are reinforced by newer findings of reduced active suicidal
ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era
of personalized medicine, two important issues must be addressed.
First, little is known about the acute course of SI following ketamine.
The speed with which antidepressant response occurs, and how much
improvement can be expected on average, has been documented for
single administrations of ketamine (Mathew et al., 2012; Sanacora
et al., 2017); in the limited available literature, researchers have
emulated previous studies examining antidepressant effect, where a
cutoff of 50% improvement demarcated response (Nierenberg and
DeCecco, 2001). Nevertheless, it remains unknown whether this categorization
accurately reflects the phenomenon of suicidal thoughts.
Empirically-derived approaches to the description of SI trajectory after
ketamine may be useful in operationalizing “response” in future clinical
trials.
Second, identifying demographic, clinical, or biological predictors
of SI response to ketamine would allow researchers and clinicians to
determine who is most likely to exhibit an SI response to ketamine. A
broad literature describes clinical and demographic predictors for suicide
risk (Franklin et al., 2017), and a smaller literature connects suicidal
thoughts and behaviors to plasma markers such as brain-derived
neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015;
Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini
et al., 2013). However, no biomarkers have been shown to predict SI/
behavior response to intervention, a finding reinforced by the National
Action Alliance for Suicide Prevention’s Research Prioritization Task
Force’s Portfolio Analysis (National Action Alliance for Suicide
Prevention: Research Prioritization Task Force, 2015). Notably, predictor
analyses have the potential to reveal insights into personalized
treatments for suicidal individuals, as well as the neurobiology of SI
response. With respect to antidepressant response, for example, this
approach yielded the observation that individuals with a family history
of alcohol dependence may be more likely to exhibit an antidepressant
response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip
et al., 2014).
The goals of this study were to elucidate trajectories of SI response
and identify predictors of that response, with the ultimate goal of
adding to the growing literature surrounding ketamine’s specific effects
on SI. In particular, we sought to determine whether the heterogeneous
patterns of change in SI after ketamine administration were better explained
by a model with two or more latent groups of trajectories rather
than a single average trajectory, using secondary analyses from previously
published clinical trials. These classes were then used to evaluate
potential clinical, demographic, and plasma biomarker predictors
of SI response to ketamine in order to generate hypotheses.. Discussion
This analysis used a data-driven approach to characterize SI response
to ketamine. The data were best explained by three trajectory
classes: one with severe average baseline SI and little to no response to
ketamine (Non-Responders), one with moderate average baseline levels
of SI and significant response to ketamine (Responders), and a third
with moderate average baseline levels of SI and complete remission of
SI by two days post-ketamine (Remitters). These findings suggest a
diversity of post-ketamine changes in SI that may not be captured under
traditional methods of categorizing response to treatment.
Furthermore, we found evidence that SI response and antidepressant
response could be distinguished from each other; one subset of participants
experienced improvement in SI that was partially explained by
improvements in Depressed Mood, while the other group’s improvements
in SI occurred independently of antidepressant response. With
regard to predictors of SI response trajectory, preliminary results suggest
the individuals least likely to experience improvement in SI postketamine
were those with the most severe SI and a history of self-injury.
Few plasma markers emerged as predictors of SI response in this study,
highlighting the limitations of connecting SI ratings of response with
biological markers.
The growth mixture modeling approach used here underscored the
heterogeneity of SI response to ketamine, which would not have been
captured by simply calculating the average trajectory. The class assignment
from this approach also differed from the definition of response
(50% reduction in symptoms) traditionally used in the antidepressant
literature, which often focuses on a specific timepoint rather
than the entire symptom trajectory. In comparing classification using a
50% response at Day 1 and Day 3 with the latent trajectory classes, we
found representation of almost every SI class across each responder
group, highlighting the potential limitations of the 50% response approach.
Further study is needed to determine which of these approaches
will prove more fruitful. Complete remission of SI has previously been
used as an outcome measure in clinical trials and in a meta-analysis of
ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018;
Wilkinson et al., 2017), as well as in a study examining the relationship
between SI response to ketamine and changes in nocturnal wakefulness
(Vande Voort et al., 2017). One strength of the present study is that this
data-driven approach provides classifications that directly reflect the
phenomena under study as they are, as opposed to what they should be.
Especially when used in larger samples than the current study, this
approach is particularly promising in its ability to provide a more
nuanced understanding of the nature of SI response to ketamine.
Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable
by baseline Depressed Mood scores; patients with the most
severe SI did not differ meaningfully in Depressed Mood scores from
those with the mildest SI. Second, while previous analyses of these data
documented that BMI and family history of alcohol dependence predicted
antidepressant response (Niciu et al., 2014), SI response was not
associated with these variables in the current analysis. Third, the antidepressant
response profiles of the SI classes suggest that SI response
and antidepressant response are not wholly redundant. This aligns with
previous clinical trials and meta-analytic reviews of the literature suggesting
that SI response to ketamine occurs partially independently of
antidepressant response (Grunebaum et al., 2018; Wilkinson et al.,
2017). Nevertheless, this independence did not hold true across both SI
response groups. Specifically, antidepressant and SI response were
clearly linked in Remitters, with depression accounting for half of the
changes in SI; however, in Responders, improvements in SI occurred
independently from improvements in Depressed Mood. These discrepancies
could be related to ketamine’s complex neurobiological
mechanisms or to the potentially low levels of clinical severity observed
in the Remitters.
Interestingly, the current analyses found no baseline demographic
variables that reliably distinguished Responders from Remitters. Some
phenotypic characteristics were uniquely associated with belonging to
the Non-Responder group, suggesting that a long-standing history of
self-injury or SI may indicate resistance to rapid changes in SI.
Relatedly, a recent, randomized clinical trial of repeat-dose ketamine
compared to placebo found that ketamine had no effect on SI in a
sample of patients selected for their longstanding, chronic history of SI
(Ionescu, 2017). These results highlight the importance of patient selection,
particularly for suicide risk. It should be stressed, however, that
SI does not necessarily translate to suicidal attempts or deaths; to our
knowledge, no study has yet linked ketamine with reduced risk of
suicidal behavior. Indeed, in the present study the SI Non-Responders
experienced limited antidepressant effects in response to ketamine, but
may nevertheless have improved on other, unmeasured symptoms that
could provide important benefit and relief. As the ketamine literature
develops, it will be important to identify which clinical symptom profiles
are most likely to have a robust anti-SI and anti-suicidal behavior
response to ketamine and which ones may benefit from other interventions.
While we evaluated a range of potential plasma markers previously
linked to suicidal ideation and behavior, in the present analysis only IL5
was associated with the SI Responder subgroup. Ketamine is known to
have anti-inflammatory effects (Zunszain et al., 2013), but the relationship
between antidepressant response and change in cytokine
levels remains unclear (Park et al., 2017). Cytokines have been linked
to suicidal behavior in the past; a recent meta-analysis found that lower
levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated
with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large
number of comparisons and lack of precedent in the literature, this
result may have been spurious and should be interpreted with caution.
A number of other results may reflect meaningful relationships, but the
high degree of variability—and the associated wide confidence intervals—suggests
that larger sample sizes are needed to better elucidate
the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13,
p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly,
plasma BDNF levels were not associated with responder class.
Previous studies of bipolar, but not MDD, samples found that plasma
BDNF levels were associated with SI response after ketamine
(Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed
diagnostic composition of this study may explain differences from
previous work. Studies exploring the relationship between BDNF and
antidepressant response to ketamine have also yielded mixed findings
(Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven
approaches have considered both biological and behavioral variables in
characterizing depression (Drysdale et al., 2017); a similar approach
might prove useful for predicting SI response.
The present study is associated with several strengths as well as
limitations. Strengths include the relatively large sample size of participants
who received ketamine, the use of composite SI scores from
previous exploratory factor analyses as opposed to individual items,
and the combination of clinical and biological markers as potential
predictors of class membership. Limitations include patient selection
methods, as these patients were part of an antidepressant trial and were
not selected for active suicidal thoughts, as well as the exploratory
nature of the analysis. As stated above, suicidal thoughts do not necessarily
equate to suicidal behavior, and class membership would thus
not necessarily correspond with an overall reduction in suicide risk.
Another limitation is that results were collapsed across several clinical
trials with slight variations in study design, and findings were thus only
extended to Day 3 rather than a week after ketamine administration. As
a result, only a subset of the sample could be used for predictive analyses.
In addition, plasma—rather than CSF—markers were used, and
the latter might better indicate underlying biology due to proximity to
the brain, though certain markers such as plasma BDNF may be related
to platelet storage, rather than the brain (Chacón-Fernández et al.,
2016). Comparison of results to trajectories of suicide-specific measures,
such as the Scale for Suicide Ideation (Beck et al., 1979), may also
give further insight into specific SI content. Finally, many clinical
predictors were collected upon hospital admission; future analyses
could use formal assessments, such as the Childhood Traumatic Questionnaire
(Bernstein et al., 1994), assessment of personality disorders,
or diagnoses such as post-traumatic stress disorder (PTSD) as potential
indicators of response.
Despite these limitations, the study demonstrates the utility of a
data-driven approach for characterizing the heterogeneity of SI response
to a rapid-acting intervention. This allows for a more finegrained
analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at
50% reduction in symptoms. This study identified several findings of
note. These included distinguishing at least three patterns of SI response
to ketamine and finding that subjects who exhibited more severe SI at
baseline were not likely to experience an SI response to ketamine.

Ketamine | Rapid antidepressant | 703-844-0184 | Ketamine therapy in Fairfax, Va 22304

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

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Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog

 

Ketamine for Depression | NOVA Health Recovery 703-844-0184 | Ketamine treatment for Bipolar, PTSD, Anxiety disorders

Ketamine | Rapid antidepressant | 703-844-0184 | Ketamine therapy in Fairfax, Va 22304

_________________________________________________________________________

Ketamine offers a rapid solution for many when their other treatments for depression have failed. Most patients studied for Ketamine treatment have failed standard therapies. Sanjay Gupta discusses this below in the link:

 

KETAMINE as a rapid antidepressant – CNN article Sanjay Gupta

Suicide in the United States

 

Ketamine for Depression | NOVA Health Recovery 703-844-0184 | Ketamine treatment for Bipolar, PTSD, Anxiety disorders

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog

 

 

__________________________________________________________________________________________________________

Ketamine has been around for a long time and offers successful opportunities to treat individuals with very resistant depression, PTSD and anxiety. It is also rapid acting. Look at the following links below,

Useful in depression,anxiety, Bipolar, PTSD, pain, migraines, Bipolar, post partum depression, fibromyalgia, and multiple other hard-to-treat disorders. Here are some links and information below to popular press articles on Ketamine!

 

Ketamine For Severe Depression: ‘How Do You Not Offer This Drug To People?’

and

 

ketamine-a-miracle-drug-for-depression/   <<< Link to article

 

Ketamine Relieves Depression By Restoring Brain Connections

Chris Stephens, 28, has been battling depression all of his life. At times he wouldn’t get out of bed for weeks. In January, he said his depression hadn’t returned since he started taking ketamine.

Lianne Milton/For NPR

Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.

Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.

The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.

“It’s exciting,” says Ron Duman, a a psychiatarist and neurobiologist at Yale University. “The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression.”

Ketamine is an FDA-approved anesthetic. It’s also a popular club drug that can produce out-of-body experiences. Not exactly the resume you’d expect for a depression drug.

But a few years ago, researchers discovered that ketamine could help people with major depression who hadn’t responded to other treatments. What’s more, the relief came almost instantly.

The discovery “represents maybe one of the biggest findings in the field over the last 50 years,” Duman says.

A rat neuron before (top) and after (bottom) ketamine treatment. The increased number of orange nodes are restored connections in the rat’s brain.

Ronald Duman/Yale University

Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.

The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to “rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress,” Duman says.

A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.

It’s possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. “What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”

And there’s also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.

His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.

Preliminary results suggest that “some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine,” Zarate says.

One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

From Chaos To Calm: A Life Changed By Ketamine

 

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

 2018 Jan 1;225:545-551. doi: 10.1016/j.jad.2017.08.081. Epub 2017 Aug 30.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Abstract

OBJECTIVES:

Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author.

METHODS:

As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration.

RESULTS:

Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were “much” to “very much” improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration.

LIMITATIONS:

Retrospective review from a single practice without placebo control with potential for response and recall bias.

CONCLUSIONS:

InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted.

___________________________________________________________________________________

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. <<< ARTICLE link

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

NOVA Health Recovery

Call 703-844-0184 if you are interested in options for Ketamine treatment for Depression, Anxiety, PTSD, fibromyalgia, Lyme disease, CRPS, or other disorders.

Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications    << ARTICLE LINK

Population scale data reveals the antidepressant effects of Ketamine  << PDF copy

 

This article looked at the adverse event reporting system, evaluating the ‘side effects’ of Ketamine, which demonstrated LOWER depression rates in patients using Ketamine for pain. These same patients had fewer side effects from those pain medicines as well when they used Ketamine. In numerous settings, we have utilized Ketamine as an adjunct to control pain when opioids have failed (i.e.morphine) with excellent results.

Depression affects 8-12 % of the population at any one time and steals away quality of life as well as productivity. Depression is listed as the 4th leading cause of disease burden on the population by the World Health Organization.
Standard medications, such as SSRI antidepressants, may be ineffective or take several weeks to begin to have any effect. Ketamine has been shown to result in immediate (12-24 hours) improvement of depressive symptoms in a large percentage of patients. We see the same in many of our office infusions.

There is an inflammatory component to depression. This same article points out that Diclofenac, minocycline (an antibiotic), and Botox, also have some antidepressant effect as a result of their anti-inflammatory effects.

The bottom line is that Ketamine showed effectiveness for treatment-resistant depression in this article.

Has anyone had Botox with a Ketamine infusion? Just curious…

FACEBOOK NOVAKetamine LINK

Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications

  • Scientific Reportsvolume 7, Article number: 1450

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine’s potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.

 

The World Health Organization estimates depression as the 4th highest disease burden in the world1. In majority of the countries lifetime depression prevalence ranges 8–12%2,3,4. Current standard of practice of depression treatment consists of five main classes of antidepressants, serotonin reuptake inhibitors (SSRIs) being the most common. Nearly half of psychiatric and primary care patients discontinue their antidepressant therapy prematurely5. The main reasons for the discontinuation of therapy include late onset of beneficial outcomes, lack of efficacy for a fraction of patients, adverse reactions, fear of drug dependence, and lack of mechanisms to enforce adherence5. The initial therapeutic effect of antidepressants is delayed by 2–3 weeks after the first dose and the optimal effect is delayed by 6–10 weeks6. The long lag period renders the standard of care antidepressants ineffective for suicidal patients who can’t afford to wait 2–6 weeks. Aside from the lag in antidepressant effects, there is insufficient evidence that antidepressants prevent suicide during long-term treatment7, and in many cases the antidepressant increases the risk of suicidal thoughts and actions8. Efficacy is another issue affecting depression treatment. In the STAR*D protocol study depression remission is 67% after every drug class and drug class combination is tried9.

Because of these problems, some clinicians have been driven to utilize other drugs, such as ketamine, for treatment resistant depression (TRD) patients10,11,12. Ketamine is a drug used illicitly as a hallucinogen and clinically as an anesthetic since 1970’s. It is given intravenously, almost exclusively, due to a lack of an approved oral formulation. There have been some clinical trials where ketamine shows acute efficacy in treating TRD10,11, bipolar depression12 and major depressive disorder with suicidal ideation13, but the number of subjects in these trials ranges from 20 to 57 patients. There are financial and ethical obstacles for a larger scale clinical trial. Here we sought larger scale statistical evidence of ketamine antidepressant action in the FDA Adverse Event Reporting System (FAERS) postmarketing database containing over eight million patient records. Although FAERS was originally intended to track frequent adverse events, with sufficient amount of data, it can also be used to track the beneficial outcomes indirectly through monitoring reductions of related complaint frequencies. Here we apply Inverse-Frequency Analysis (IFA), which looks for statistically significant values of the negative log odds ratio (LogOR).

We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain (LogOR −0.67 ± 0.034) (Fig. 1c). This reduction in depression is specific to ketamine and is known to be much more rapid than current antidepressants, making this observed effect very promising for treatment of patients with acute depressive or suicidal episodes11. These patients cannot afford to wait up to six weeks for reductions in their depressive symptoms. Pain reports were also significantly lower for ketamine patients (LogOR −0.41 ± 0.019) (Fig. 1c)

Figure 1

Legend: (a) Frequencies of adverse events in patients on FAERS who took ketamine. Adverse events above 2.5% were reported. (b) Odds ratios were calculated comparing adverse event rates of ketamine patients (n = 41,337) and pain patients (n = 238,516). (c) LogOR of pain and depression event rates were calculated from the ketamine and pain patient cohorts. Negative values showing protective effect of ketamine. (d) LogOR of constipation, vomiting, and nausea were calculated from the ketamine and pain patient cohorts. Negative values showing protective effect of ketamine.

The analysis of the whole FAERS database revealed several other unintentional depression reducing drugs among antibiotics, cosmeceuticals and NSAIDS (Fig. 2). Our data supported previous studies that observed the psychiatric polypharmacology of minocycline, a tetracycline antibiotic14 (Fig. 2). The NSAID, diclofenac, was also observed to have some antidepressant properties (Fig. 2). It is theorized that both of these drugs may accomplish antidepressant effects through an anti-inflammatory mechanism15. Because of the antidepressant activity of several NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression event rates remained low (LogOR −0.56 ± 0.035) (Fig. 2).

Figure 2

LogOR of psychiatric events were calculated from FAERS patients who used botox, diclofenac or minocycline. FAERS patients who took any drugs for the indication of depression were used as the control cohort. Negative values showing protective effect

The reduction of depression rates in ketamine patient records makes a case for study of ketamine as a psychiatric drug. These results imply that ketamine may be further explored as a monotherapy or adjunct therapy for depression. It should also be noted that FAERS data revealed that ketamine use lead to renal side effects and awareness and caution in patients with renal or hepatic impairment may be warranted (Fig. 1a and b).

As an important side note, we also evaluated efficacy and side effects with the use of ketamine for pain management. We found that patients who were on ketamine had reduced opioid induced side effects including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) than patients who received any other combination of drugs for pain indications (Fig. 1d). Our data supports ketamine’s opioid-sparing properties and alludes to the fact that patients may receive benefits of improved pain, reduced requirement of opioids, and ultimately less opioid reduced side effects.

The results of this study support previous small scale studies’ conclusions that ketamine is a good monotherapy or adjunct therapy for depression. In clinical practice ketamine would be especially useful for depression because of the quick onset of its action compared to existing first line therapies10,11,12,13. Regardless of the causative mechanism ketamine appears to have therapeutic potential for TRD. Further, the potential to reduce many of the most complained side effects of opioid treatment makes ketamine adjunct therapy for pain seem desirable.

Overall, this study demonstrates that the therapeutic potential of ketamine can be derived from appropriate statistical analysis of existing population scale data. This study also outlines a methodology for discovering off label pharmacology of existing approved drugs. This method can be applied to other indications and may reveal new important uses of already approved drugs, providing reliable justification for new indications without large investments in additional clinical trials.

 

The rest of the article can be easily accessed from the above Link.

 

Botox and ketamine could help treat depression, study finds

Call 703-844-0184 to schedule a Ketamine evaluation or infusion.

 

The ketamine infusion for depression experience is not as scary as some people think. Read on to learn about what the ketamine infusion protocol feels like.
Ketamine Fairfax, Va |22308|703-844-0184 | Alexandria, Va | Ketamine for depression

Before getting ketamine infusions for depression, you’ll likely want to know what a ketamine infusion experience is like. While the ketamine infusion experience is different from person to person, the protocol for ketamine infusions for depression is similar for everyone. Read on to learn what it’s really like to receive intravenous ketamine infusions.

What Is a Ketamine Infusion?

A ketamine infusion is a dose of ketamine that is given via the intravenous (IV) route of administration. Ketamine infusions are typically used to treat major depression or depression in bipolar disorder but can be used to treat chronic pain conditions as well.

Before Getting a Ketamine Infusion

Before getting a ketamine infusion, you should expect thorough medical and psychiatric evaluations as well as medical tests to make sure you are healthy enough for the treatment. These assessments and tests are very important as ketamine infusions can be challenging both mentally and physically and only a doctor who is well-acquainted with your health can make good decisions for you.

Ketamine Infusion Procedure

You will likely be shown to a room with a comfortable reclining chair or bed. You will not need to disrobe or wear a hospital gown for treatment. The Ketamine Advocacy Network suggests that you always request a single-person room as a ketamine infusion is a very personal experience. A loved one is usually allowed to stay with you during the ketamine infusion treatment if you want. You’ll then be connected to vital sign monitors such as pulse and oxygen saturation monitors.

It is at this point that you’ll have an IV inserted. A tiny needle is used to insert a tube into a vein in your hand or arm and many find this to be painless. The tube will be connected to a bag held a couple of feet above you. The bag contains the specific dose of ketamine you will require and it will be delivered directly into your bloodstream at a controlled rate. The rate may be adjusted during your treatment to maximize its benefit. It takes approximately 45 minutes for a ketamine infusion and you may need to be under observation after that for an hour or occasionally more. You cannot drive yourself home after an infusion.

People, typically, initially receive six infusions over the course of two-three weeks.

What Does Getting an IV Ketamine Infusion for Depression Feel Like?

Once the ketamine enters your system, it will reach your brain within seconds and you will quickly be able to feel its effects. You won’t be able to stand or converse normally and you’ll feel extremely relaxed but you will still be awake. While others may view a person that seems almost asleep, your brain will still fully be engaged. While this sensation is often found to be “weird”, most people do find it pleasant.

Experience of Side Effects of the Ketamine Infusion

During the infusion, you may experience dissociation, where the mind and body seem to separate. This side effect of the ketamine infusion can often be minimized simply by opening your eyes.

As stated, your mind will be very active during the IV infusion so it may wander to thoughts of trauma or anxiety, but unlike your usual feelings around those thoughts, you will view it matter-of-factly. One patient described his ketamine infusion experience like this:

“. . . you start disassociating with everything, like you’re observing, not participating in anything. It’s really weird . . . As far as the mind goes, you start going through these weird levels, kind of like in the movies Inception or The Matrix, where you don’t know what’s real.

“You start thinking about all kinds of stuff. Whatever races through your mind—and usually when you’re depressed it’s negative sh*t—when you’re on ketamine, it’s just like: ‘Well, nothing I can do about that.’ You feel like, ‘I’m not in control, and that’s fine; you’re going to die someday and that’s just life.’ You kind of learn to just accept it, I guess.”

Although most patients do experience relaxation during a ketamine infusion, there can be moments of fright, particularly if you go into the experience with very high anxiety. Listening to calming music or watching a calming image may help with this, however.

Feeling Better After the Ketamine Infusion Procedure

It varies as to how long it will take for the ketamine to kick in. Some find relief within only an hour or two while others need multiple infusions to feel the benefit. Unfortunately, 20-40% of people do not experience a positive response to ketamine treatment (Reviews on Ketamine for Depression).

What’s important to remember is that no matter what you experience during a ketamine infusion, it’s the changes that the ketamine makes to your brain that relieve depression and not the infusion experience itself.

 

 

Ketamine treatment for depression reviews are scant but some are available. Read about ketamine for depression reviews from patients and doctors.

Ketamine is a relatively new treatment for depression so people are often looking for ketamine treatment for depression reviews to help guide their choices. This is understandable as ketamine treatment cost falls between $400-800 per intravenous (IV) infusion and more than six infusions may be needed. Read on for real patients’ ketamine for depression reviews.

Ketamine Treatment for Depression Reviews

It’s important to note that reviews for any type of treatment are personal and individual. This means that any one person may or may not have the same experience as you. This is why it’s important to work with your doctor to decide if ketamine is a good treatment option for your depression.

That being said, there are ketamine treatment for depression reviews available.

A site like PatientsLikeMe can be valuable as individual patients can report their experiences with a treatment. As of August 2017, four patients who took ketamine for major depressive disorder and two patients who took ketamine for bipolar depression have left reviews. Of the six, three indicated that ketamine had “major effectiveness” on their condition. Two patients noted moderate effectiveness and one noted no effectiveness. Side effects to ketamine included: dissociation, dizziness, nausea, memory problems, cognition problems and drowsiness. Two of the patients noted no side effects although one of those also reported no useful effect either.

When looking at these ketamine infusion reviews, most people were happy with the treatment, with one patient saying, “Very effective. I would do it again in a heartbeat.”

However, most patients noted the cost of ketamine infusions as being burdensome.

When looking at the reviews that all patients left, regardless as to the reason the ketamine was prescribed, two out of 24 noted severe side effects and nine out of 24 noted no side effects.

Ketamine Review Article

In 2015, Vice.com published a ketamine review article called, I Used Ketamine to Treat My Depression. In it, one person with bipolar depression discusses his experience with receiving ketamine infusion for depression. Brent Miles, a 41-year-old songwriter and journalist from Phoenix, Arizona, regularly got ketamine infusion treatments at a clinic in North Scottsdale in 2013 and shares his story.

Miles’ experiences are quite positive although he notes that he could not continue the ketamine depression treatment due to cost.

You can read Miles’ experience here.

 

Ketamine Treatment for Depression Reviews by Doctors

As with many treatments, some doctors are wary of this new depression treatment while others forge ahead with cautious optimism.

“A really important part of these recommendations is to make sure people fully understand what the risks and benefits are to treatment so that they are able to make an informed decision based on knowing what the risk-benefit ratio is,” said Gerard Sanacora, MD, PhD, professor of psychiatry and director of the Yale Depression Research Program.

Dr. Sanacora also added:

“The reality is that this is a unique situation where we have a tremendously promising treatment. We use it a lot, and I believe this really is a transformative change in the field, but we do have to appreciate the limits of the knowledge that we are working with right now.”

Ketamine side effects range from mild to severe. Get complete details on side effects of ketamine for depression on HealthyPlace.

The side effects of ketamine for depression are typically mild but can range in severity. Understanding the ketamine infusion therapy for depression side effects before starting treatment is a good idea so that you know what to look for and aren’t surprised by the more common ketamine side effects.

Side Effects of Ketamine

It’s important to remember that the doses of ketamine for depression treatment are far smaller than any dose that would be used recreationally or as an anesthetic (Can You Get Addicted to Ketamine?). Thus, if you read about the side effects of ketamine in general, you will likely see more severe and different side effects listed than those experienced by those being treated for depression.

Some of the common side effects experienced when larger dosages are used include:

  • High blood pressure
  • Increased cardiac output
  • Pressure inside the skull (intracranial pressure)
  • Irregular heart rhythm
  • Seizure-type movements (tonic-clonic movements)
  • Hallucinations
  • Vivid dreams

Side Effects of Ketamine for Depression

As mentioned, dosages of ketamine when used to treat depression are very small. However, ketamine infusion therapy side effects still exist.

According to a small 2012 study wherein patients received up to six ketamine infusion treatments for treatment-resistant depression, the following were the commonly-reported side effects:

  • The presence of psychotic symptoms (delusions and/or experiences of things that don’t exist such as hallucinations)
  • Dissociative symptoms (feeling “out of body,” disconnected, etc.)
  • Feeling “strange” or “unreal”
  • Abnormal sensations
  • Blurred vision
  • Feeling drowsy or sleepy
  • Elevated heart rate or blood pressure

Notably, only four people in the study (16.7%) reported any side effect that impaired functioning at any time.

That said, the majority of people who were given ketamine infusion therapy for depression did experience some side effects, most remitting within two hours after the infusion.

Those who responded positively to the ketamine treatment experienced the same level and type of side effects that those who did not respond experienced.

Positive Effects of Ketamine for Depression

In a small, recent study, it was found that within two hours of the first dose of ketamine, each individual item on a depression scale known as the Montgomery– Asberg Depression Rating Scale (MADRS), was reduced with the exception of appetite and sleep items which couldn’t be assessed at that time.

The following positive effects of ketamine for depression were seen as reductions in:

  • Suicidal thoughts
  • Pessimistic thoughts
  • Inability to feel
  • Feelings of weariness, diminished energy or listlessness (lassitude)
  • Concentration difficulties
  • Inner tension
  • Reported sadness
  • Apparent sadness

The largest positive changes were seen in lassitude, concentration difficulties, and apparent sadness.

It’s important to remember that while these positive ketamine health effects will be seen by many, not everyone responds to ketamine treatment in this way. In the above-mentioned study, 71% of people had a positive response to ketamine treatment for depression and it is known that those receiving more treatments have a better chance at a positive response.

Ketamine is both a legitimate medical treatment as well as a street drug. But can you get addicted to ketamine? Find out on HealthyPlace.

Ketamine isn’t just a drug used to treat depression, chronic pain or as an anesthesia, ketamine is also a street drug of abuse. Often called “special k,” ketamine is used in large doses by some in the party scene. It’s important to remember, however, that recreationally, people take much larger doses of ketamine than are used in depression treatment (How Does Ketamine Work for Depression?). This means that recreational users are more likely to experience increasing tolerance to the drug’s effects, seek greater doses and become addicted.

Ketamine Addiction

Ketamine is the number one drug of abuse in Asia, particularly Hong Kong. Some of the ketamine found on the street is diverted from pharmaceutical supplies but there is also increasing evidence of ketamine production specifically for street use, particularly in India and China. Ketamine may also be found in ecstasy in Asia.

Ketamine is also a drug of abuse in the United States. The reason why people abuse ketamine is its desirable acute effects on the person. If a person takes a street dose of ketamine, he or she may experience:

  • Reduced sensations in the body / a lack of pain
  • A floating or detached feeling
  • A feeling of being incapable of moving
  • A change in how the person sees and hears things, possibly causing hallucinations

Some people find these effects desirable. However, ketamine can also cause:

  • Confusion
  • Agitation
  • Panic attacks
  • Impairment in short- and long-term memory impairment
  • Attention problems
  • Difficulty in cognition
  • Impaired reaction time

Death from acute ketamine use is rare but does occur.

If a person continues to abuse ketamine, over time even worse effects can be felt. Someone who is addicted to ketamine or who consistently abuses ketamine may experience:

  • Depression
  • Very serious bladder problems possibly leading to the bladder needing removal
  • Serious damage to the urinary tract
  • Liver dysfunction
  • Impaired gallbladder activity
  • Kidney failure
  • Extreme pain, particularly during urination

You may not experience a physical addiction to ketamine but you can become addicted to ketamine psychologically. Being addicted to ketamine is no joke and anyone who abuses ketamine or who is addicted to ketamine needs to seek help immediately.

How to Get Off Ketamine

Getting off ketamine involves the same thing as getting off of other drugs: going through withdrawal. Withdrawal effects make it difficult for someone trying to get off ketamine to stay sober, but withdrawal effects can be managed.
If you’re trying to get off of ketamine, symptoms of withdrawal that you might experience include:

  • Double vision
  • Hearing loss
  • Increased heart beat
  • Rapid breathing
  • Loss of motor skills
  • Loss of coordination
  • Depression

These effects are not typically medically dangerous although if they get out of hand, medical intervention may be needed in the short-term. While these withdrawal effects may sound awful, it’s important to remember that these effects are short-lived and day-by-day, you will start to feel better.

 

I attached a youtube video on SAD – seasonal Affective Disorder

www.ubcsad.ca   <<  SAD website
https://youtu.be/pUYOxnuzRHU?t=1

 

 

 

https://www.healthyplace.com/depression/depression-treatment/can-you-get-addicted-to-ketamine/

Ketamine in the NEWS April 2018

http://sltbr.org/ Biological rhythms – depression  << Website

Medical Express Article regarding Ketamine for Depression <<<<

Ketamine, notorious club drug, shows promise as a treatment for depression, studies indicate

April 20, 2018 by John Keilman, Chicago Tribune

Sabrina Misra suffered from depression for most of her life, but last summer, it became almost too heavy to bear.

Despite years of therapy and many medications, Misra, 36, had become so despondent that she started planning her suicide. But then her psychiatrist introduced her to a new treatment with an unusual back story.

The treatment was ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high.

But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression—particularly those who, like Misra, have found little relief from other medications.

“After the first couple of treatments it didn’t seem to work, but after I hit my fourth one, everything started to change,” said Misra, a therapist and college instructor who lives in Lisle, Ill. “I went from actively wanting to kill myself to being fine.”

Though some researchers have found that ketamine can be a valuable antidepressant, no one has performed the large-scale clinical trials necessary to get U.S. Food and Drug Administration approval to use it a psychiatric medication.

Consequently, most insurance plans won’t pay for it, leaving patients to pay thousands of dollars out of pocket for a series of intravenous infusions.

Some warn that questions remain about ketamine’s long-term safety and effectiveness. Dr. James Murrough, a psychiatrist at the Icahn School of Medicine at Mount Sinai in New York, said people who misuse the drug have developed cognitive problems, and high doses have proved toxic in rats.

And because ketamine has a history of abuse, he said, doctors and patients must consider the threat of addiction.

“We think the risk is low, but it’s probably not zero, particularly if it gets scaled up,” he said. “There’s excitement but also a justified caution.”

Nonetheless, demand for the drug is so great that dozens of specialty clinics are popping up around the country. The doctors who run them say ketamine has helped most of their patients.

“It’s much better than anything we’ve had before,” said Dr. Abid Nazeer, the psychiatrist who treated Misra at his Oak Brook clinic, Advanced Psychiatric Solutions. “I’ve seen it work so quickly that one infusion gets rid of suicidal thoughts that had been there for 20 years.”

Ketamine was created as an anesthetic, and doctors including veterinarians and battlefield medics embraced it for its fast-acting properties and relative safety. But because it produces strong out-of-body sensations in high doses, it became a club drug, potent enough to send hundreds of people to emergency rooms each year.

In the 1990s, researchers discovered another use for ketamine: A small dose, they found, limits the concentration of a neurotransmitter called glutamate in the brain, and with startling speed, lifts the mood of many depression sufferers who haven’t been helped by medications like Prozac or Lexapro.

“Our standard antidepressants can take six to eight weeks to be effective—ketamine can take just one hour,” said Dr. Carlos Zarate of the National Institute of Mental Health, whose studies in the 2000s accelerated interest in the drug.

Over the past few years, doctors have opened specialty clinics that offer ketamine to patients who have depression or, to a lesser extent, chronic pain. Though the FDA has not approved those uses, the agency allows doctors to dispense drugs for “off-label” purposes if they believe it is medically appropriate.

The basic regimen calls for the intravenous infusion of a small dose—0.5 mg per kilogram of body weight, far less than someone would use to get high—six times over two weeks. After that, patients return every few weeks or months for booster doses.

Clinic operators say they screen clients to focus on those who have not improved with standard antidepressants.

“This is a last resort for those that are treatment-resistant,” said Dr. June Lee of Lombard’s Optimum Ketamine Center. “Most of the patients we’ve seen here have tried everything.”

Zarate said research has shown ketamine to be effective for about 60 percent of people with treatment-resistant depression, though some local clinics say their results have been better.

“We’ve had about a 70 percent response rate, but it really works for them,” said Dr. Vikas Patel, an emergency room physician who runs the Midwest Ketamine Center in Arlington Heights. “For the 30 percent it doesn’t work for, there’s no benefit at all. I would say there isn’t a big in-between.”

He charges $500 per infusion. Insurance typically won’t cover ketamine treatments, though Patel said he expects that to change. A pharmaceutical company is seeking FDA approval for a nasal spray, he said, and other companies are testing their own versions.

But for now, the out-of-pocket cost limits the number of people who can afford the treatment. Misra said that while she put the infusions on her credit card, seeing them as a life-or-death investment, others aren’t so fortunate.

“I have patients who are struggling right now, and they actually can’t swing it,” she said. “I think that’s a horrible thing. No one should have to die because they can’t pay for treatment.”

Dominic Sisti, who directs the Scattergood Program for Applied Ethics of Behavioral Health Care at the University of Pennsylvania, co-wrote a paper three years ago warning about the possible risks of using for depression.

The research that has come out since then has persuaded him that it is appropriate for many people, he said, but he still believes doctors should share data on their results to further knowledge of the drug and improve the protocols for using it.

“In a sense, each patient they treat is an experiment of one,” he said. “It would be really helpful if all these clinics got together and figured out a way to report those outcomes. Without those data, I worry that someone’s going to get hurt.”

Antidepressant response within hours? Experts weigh evidence on ketamine as fast-acting treatment for depression

antidepressant-response-hours-experts-evidence << Article

Recent studies suggest that ketamine, a widely used anesthetic agent, could offer a wholly new approach to treating severe depression—producing an antidepressant response in hours rather than weeks. Two reviews of recent evidence on ketamine and related drugs for treating depression appear in the Harvard Review of Psychiatry.

Ketamine and related drugs may represent a “paradigm shift” in the treatment of  (MDD) and bipolar depression—especially in patients who do not respond to other treatments, according to a review by Carlos A. Zarate, Jr, MD and colleagues at the National Institute of Mental Health. A second article explores evidence on the mechanisms behind ‘s rapid antidepressant effects.

Growing Evidence, Clinical Caution about Ketamine for Severe Depression

Current treatments for MDD and bipolar depression have major limitations. Many patients with severe depressive symptoms don’t respond to available antidepressant drugs. Even for those who do respond, it may take several weeks before symptoms improve.

Ketamine, an anesthetic, is one of several glutamatergic drugs affecting neurotransmitters in the central nervous system. Over the past decade, several studies have reported “rapid, robust, and relatively sustained antidepressant response” to ketamine, injected intravenously at low, subanesthetic doses.

Dr. Zarate and colleagues review the research on ketamine and other glutamatergic drugs for depression. Ketamine, by far the best-studied of these medications, is notable for its very rapid antidepressant effects. In patients with treatment-resistant MDD, ketamine has produced initial reductions in depressive symptoms within two hours, with peak effects at 24 hours.

Ketamine may also rapidly reduce suicidal thoughts. Combined with other medications, ketamine has also produced rapid antidepressant effects in patients with treatment-resistant bipolar depression.

Prompted by these studies, some doctors are already using ketamine in patients with severe or treatment-resistant depression. However, since it is FDA-approved only as an anesthetic, use of ketamine in depressive disorders is “off-label,” unregulated, and not standardized. Many questions remain about its short- and long-term side effects and potential for abuse.

“Efforts are underway to bring ketamine to market, standardize its use, and determine its real-world effectiveness,” Dr. Zarate and coauthors write. They also present evidence on several other glutamatergic drugs. One , esketamine, has been given “breakthrough therapy” status by the FDA for  at imminent risk of suicide.

Cristina Cusin, MD of Massachusetts General Hospital and colleagues review neuroimaging studies evaluating ketamine’s effects in the brain. The studies show ketamine-induced changes in several brain areas involved in the development of depression. Ketamine may exert its antidepressant effects by “acutely disabl[ing] the emotional resources required to perpetuate the symptoms of depression,” as well as by increasing emotional blunting and increasing activity in reward processing.

Independent of how ketamine works or its ultimate role in clinical treatment, antidepressant response to glutamatergic drugs points to an exciting conclusion: “that rapid antidepressant effects are indeed achievable in humans,” Dr. Zarate and coauthors write. “This paradigm shift lends additional urgency to the development of novel treatments for MDD and bipolar , particularly for patient subgroups that do not respond to currently available therapies.”

Glutamatergic Modulators in Depression

Ketamine-Associated Brain Changes A Review of the Neuroimaging Literature bb

Brain-Derived Neurotrophic Factor and Major Depressive Disorder Evidence from Meta-Analyses

Suicidal thoughts rapidly reduced with ketamine, finds study

Suicidal thoughts rapidly reduced with ketamine, finds study

December 14, 2017, Columbia University Medical Center
Ketamine
3-D model of Ketamine. Credit: Wikipedia

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

“There is a critical window in which  who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing  in with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

“This study shows that ketamine offers promise as a rapidly acting  for reducing suicidal thoughts in patients with ,” said Dr. Grunebaum. “Additional research to evaluate ‘s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”

The study is titled, “Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial.”

https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060720

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of , when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking—including lithium and clozapine—can have serious , requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period—about five times less than a typical anesthetic dose—and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits—one dropped out because of ketamine side effects and one had a scheduling conflict—most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of  at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for  in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and  may help us discover areas of the brain to target with new, even better therapeutic drugs.”

Dawn F. Ionescu et al, Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine, The Journal of Clinical Psychiatry (2016). DOI: 10.4088/JCP.15m10056

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study

Background: Ketamine rapidly reduces thoughts of suicide in patients with treatment-resistant depression who are at low risk for suicide. However, the extent to which ketamine reduces thoughts of suicide in depressed patients with current suicidal ideation remains unknown.

Methods: Between April 2012 and October 2013, 14 outpatients with DSM-IV–diagnosed major depressive disorder were recruited for the presence of current, stable (≥ 3 months) suicidal thoughts. They received open-label ketamine infusions over 3 weeks (0.5 mg/kg over 45 minutes for the first 3 infusions; 0.75 mg/kg over 45 minutes for the last 3). In this secondary analysis, the primary outcome measures of suicidal ideation (Columbia-Suicide Severity Rating Scale [C-SSRS] and the Suicide Item of the 28-item Hamilton Depression Rating Scale [HDRS28-SI]) were assessed at 240 minutes postinfusion and for 3 months thereafter in a naturalistic follow-up.

Results: Over the course of the infusions (acute treatment phase), 7 of 14 patients (50%) showed remission of suicidal ideation on the C-SSRS Ideation scale (even among patients whose depression did not remit). There was a significant linear decrease in this score over time (P < .001), which approached significance even after controlling for severity of 6-item Hamilton Depression Rating Scale (HDRS6) core depression items (P = .05). Similarly, there were significant decreases in the C-SSRS Intensity (P < .01) and HDRS28-SI (P < .001) scores during the acute treatment phase. Two of the 7 patients who achieved remission during the acute treatment phase (29%) maintained their remission throughout a 3-month naturalistic follow-up.

Conclusions: In this preliminary study, repeated doses of open-label ketamine rapidly and robustly decreased suicidal ideation in pharmacologically treated outpatients with treatment-resistant depression with stable suicidal thoughts; this decrease was maintained for at least 3 months following the final ketamine infusion in 2 patients.

Ketamine improved bipolar depression within minutes

May 30, 2012, Elsevier

Bipolar disorder is a serious and debilitating condition where individuals experience severe swings in mood between mania and depression. The episodes of low or elevated mood can last days or months, and the risk of suicide is high.

Antidepressants are commonly prescribed to treat or prevent the , but they are not universally effective. Many patients still continue to experience periods of depression even while being treated, and many patients must try several different types of  before finding one that works for them. In addition, it may take several weeks of treatment before a patient begins to feel relief from the drug’s effects.

For these reasons, better treatments for depression are desperately needed. A new study in  this week confirms that scientists may have found one in a drug called ketamine.

A group of researchers at the National Institute of Mental Health, led by Dr. Carlos Zarate, previously found that a single dose of ketamine produced rapid antidepressant effects in  with . They have now replicated that finding in an independent group of depressed patients, also with bipolar disorder. Replication is an important component of the scientific method, as it helps ensure that the initial finding wasn’t accidental and can be repeated.

In this new study, they administered a single dose of ketamine and a single dose of placebo to a group of patients on two different days, two weeks apart. The patients were then carefully monitored and repeatedly completed ratings to ‘score’ their  and suicidal thoughts.

When the patients received ketamine, their  significantly improved within 40 minutes, and remained improved over 3 days. Overall, 79% of the patients improved with ketamine, but 0% reported improvement when they received placebo.

Importantly, and for the first time in a group of patients with bipolar depression, they also found that ketamine significantly reduced . These antisuicidal effects also occurred within one hour. Considering that bipolar disorder is one of the most lethal of all psychiatric disorders, these study findings could have a major impact on public health.

“Our finding that a single infusion of ketamine produces rapid antidepressant and antisuicidal effects within one hour and that is fairly sustained is truly exciting,” Dr. Zarate commented. “We think that these findings are of true importance given that we only have a few treatments approved for acute bipolar depression, and none of them have this rapid onset of action; they usually take weeks or longer to have comparable antidepressant effects as ketamine does.”

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which means that it works by blocking the actions of NMDA. Dr. Zarate added, “Importantly, confirmation that blocking the NMDA receptor complex is involved in generating rapid antidepressant and antisuicidal effects offers an avenue for developing the next generation of treatments for depression that are radically different than existing ones.”

The article is “Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial” by Carlos A. Zarate Jr., Nancy E. Brutsche, Lobna Ibrahim, Jose Franco-Chaves, Nancy Diazgranados, Anibal Cravchik, Jessica Selter, Craig A. Marquardt, Victoria Liberty, and David A. Luckenbaugh (doi: 10.1016/j.biopsych.2011.12.010). The article appears in Biological Psychiatry, Volume 71, Issue 11 (June 1, 2012)

Replication of Ketamine’s Antidepressant Efficacy in bipolar depression

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Areas served by NOVA Health Recovery:

Maryland (MD):
Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902

Washington DC:
Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016

Northern Virginia:
McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304 Fairfax – 20191 – Reston – 22009 – Springfield – 22152 22015 Lorton 22199
Fairfax, Va
2303 – 22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312
22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 – 20124
22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043
22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101
22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153
22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 – 22182
Woodbridge – 22191 – 22192 -22193 -22194 – 22195
Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161
Front Royal 22630
Warren County 22610 22630 22642 22649
Fredericksburg Va 22401 22402 – 22403 – 22404 -22405 -22406 -22407 -22408 – 22412
Zip Code City County Zip Code Map 20101 Dulles Loudoun – 20102 Dulles Loudoun – 20103 Dulles Loudoun – 20104 Dulles Loudoun – 20105 Aldie Loudoun – 20106 Amissville Culpeper – 20107 Arcola Loudoun – 20108 Manassas Manassas City – 20109 Manassas Prince William – 20110 Manassas Manassas City – 20111 Manassas Prince William – 20112 Manassas Prince William – 20113 Manassas Manassas Park City – 20115 Marshall Fauquier – 20116 Marshall Fauquier – 20117 Middleburg Loudoun – 20118 Middleburg Loudoun – 20119 Catlett Fauquier View
Map 20120 Centreville Fairfax – 20121 Centreville Fairfax – 20122 Centreville Fairfax – 20124 Clifton Fairfax – 20128 Orlean Fauquier – 20129 Paeonian Springs Loudoun – 20130 Paris Clarke – 20131 Philomont Loudoun – 20132 Purcellville Loudoun – 20134 Purcellville Loudoun – 20135 Bluemont Clarke – 20136 Bristow Prince William – 20137 Broad Run Fauquier – 20138 Calverton Fauquier – 20139 Casanova Fauquier – 20140 Rectortown Fauquier – 20141 Round Hill Loudoun – 20142 Round Hill Loudoun – 20143 Catharpin Prince William View
Map 20144 Delaplane Fauquier – 20146 Ashburn Loudoun – 20147 Ashburn Loudoun – 20148 Ashburn Loudoun – 20149 Ashburn Loudoun – 20151 Chantilly Fairfax – 20152 Chantilly Loudoun – 20153 Chantilly Fairfax – 20155 Gainesville Prince William – 20156 Gainesville Prince William – 20158 Hamilton Loudoun – 20159 Hamilton Loudoun – 20160 Lincoln Loudoun – 20163 Sterling Loudoun – 20164 Sterling Loudoun – 20165 Sterling Loudoun – 20166 Sterling Loudoun – 20167 Sterling Loudoun – 20168 Haymarket Prince William View
Map 20169 Haymarket Prince William – 20170 Herndon Fairfax – 20171 Herndon Fairfax – 20172 Herndon Fairfax – 20175 Leesburg Loudoun – 20176 Leesburg Loudoun – 20177 Leesburg Loudoun – 20178 Leesburg Loudoun – 20180 Lovettsville Loudoun – 20181 Nokesville Prince William – 20182 Nokesville Prince William – 20184 Upperville Fauquier – 20185 Upperville Fauquier – 20186 Warrenton Fauquier – 20187 Warrenton Fauquier – 20188 Warrenton Fauquier – 20189 Dulles Loudoun – 20190 Reston Fairfax – 20191 Reston Fairfax View
Map 20192 Herndon Fairfax – 20193 Reston Fairfax – 20194 Reston Fairfax – 20195 Reston Fairfax – 20196 Reston Fairfax – 20197 Waterford Loudoun – 20198 The Plains Fauquier – 20199 Dulles Loudoun – 22003 Annandale Fairfax – 22009 Burke Fairfax – 22015 Burke Fairfax – 22025 Dumfries Prince William – 22026 Dumfries Prince William – 22027 Dunn Loring Fairfax – 22030 Fairfax Fairfax City – 22031 Fairfax Fairfax – 22032 Fairfax Fairfax – 22033 Fairfax Fairfax – 22034 Fairfax Fairfax View
Map 22035 Fairfax Fairfax – 22036 Fairfax Fairfax – 22037 Fairfax Fairfax – 22038 Fairfax Fairfax City – 22039 Fairfax Station Fairfax – 22040 Falls Church Falls Church City – 22041 Falls Church Fairfax – 22042 Falls Church Fairfax – 22043 Falls Church Fairfax – 22044 Falls Church Fairfax – 22046 Falls Church Falls Church City – 22047 Falls Church Fairfax – 22060 Fort Belvoir Fairfax – 22066 Great Falls Fairfax – 22067 Greenway Fairfax – 22079 Lorton Fairfax – 22081 Merrifield Fairfax – 22082 Merrifield Fairfax – 22092 Herndon Fairfax View
Map 22093 Ashburn Loudoun – 22095 Herndon Fairfax – 22096 Reston Fairfax – 22101 Mc Lean Fairfax – 22102 Mc Lean Fairfax – 22103 West Mclean Fairfax – 22106 Mc Lean Fairfax – 22107 Mc Lean Fairfax – 22108 Mc Lean Fairfax – 22109 Mc Lean Fairfax – 22116 Merrifield Fairfax – 22118 Merrifield Fairfax – 22119 Merrifield Fairfax – 22120 Merrifield Fairfax – 22121 Mount Vernon Fairfax – 22122 Newington Fairfax – 22124 Oakton Fairfax – 22125 Occoquan Prince William – 22134 Quantico Prince William View
Map 22135 Quantico Stafford – 22150 Springfield Fairfax – 22151 Springfield Fairfax – 22152 Springfield Fairfax – 22153 Springfield Fairfax – 22156 Springfield Fairfax – 22158 Springfield Fairfax – 22159 Springfield Fairfax – 22160 Springfield Fairfax – 22161 Springfield Fairfax – 22172 Triangle Prince William – 22180 Vienna Fairfax – 22181 Vienna Fairfax – 22182 Vienna Fairfax – 22183 Vienna Fairfax – 22184 Vienna Fairfax – 22185 Vienna Fairfax – 22191 Woodbridge Prince William – 22192 Woodbridge Prince William View
Map 22193 Woodbridge Prince William – 22194 Woodbridge Prince William – 22195 Woodbridge Prince William – 22199 Lorton Fairfax – 22201 Arlington Arlington – 22202 Arlington Arlington – 22203 Arlington Arlington – 22204 Arlington Arlington – 22205 Arlington Arlington – 22206 Arlington Arlington – 22207 Arlington Arlington – 22209 Arlington Arlington – 22210 Arlington Arlington – 22211 Ft Myer Arlington – 22212 Arlington Arlington – 22213 Arlington Arlington – 22214 Arlington Arlington – 22215 Arlington Arlington – 22216 Arlington Arlington View
Map 22217 Arlington Arlington – 22218 Arlington Arlington – 22219 Arlington Arlington – 22222 Arlington Arlington – 22223 Arlington Arlington – 22225 Arlington Arlington – 22226 Arlington Arlington – 22227 Arlington Arlington – 22229 Arlington Arlington – 22230 Arlington Arlington – 22234 Arlington Arlington – 22240 Arlington Arlington – 22241 Arlington Arlington – 22242 Arlington Arlington – 22243 Arlington Arlington – 22244 Arlington Arlington – 22245 Arlington Arlington – 22246 Arlington Arlington – 22301 Alexandria Alexandria City View
Map 22302 Alexandria Alexandria City – 22303 Alexandria Fairfax – 22304 Alexandria Alexandria City – 22305 Alexandria Alexandria City – 22306 Alexandria Fairfax – 22307 Alexandria Fairfax – 22308 Alexandria Fairfax – 22309 Alexandria Fairfax – 22310 Alexandria Fairfax – 22311 Alexandria Alexandria City – 22312 Alexandria Fairfax – 22313 Alexandria Alexandria City – 22314 Alexandria Alexandria City – 22315 Alexandria Fairfax – 22320 Alexandria Alexandria City – 22321 Alexandria Fairfax – 22331 Alexandria Alexandria City – 22332 Alexandria Alexandria City – 22333 Alexandria Alexandria City View
Map 22334 Alexandria Alexandria City – 22336 Alexandria Alexandria City – 22401 Fredericksburg Fredericksburg City – 22402 Fredericksburg Fredericksburg City – 22403 Fredericksburg Stafford – 22404 Fredericksburg Fredericksburg City – 22405 Fredericksburg Stafford – 22406 Fredericksburg Stafford – 22407 Fredericksburg Spotsylvania – 22408 Fredericksburg Spotsylvania – 22412 Fredericksburg Stafford – 22427 Bowling Green Caroline – 22428 Bowling Green Caroline – 22430 Brooke Stafford – 22432 Burgess Northumberland – 22433 Burr Hill Orange – 22435 Callao Northumberland – 22436 Caret Essex – 22437 Center Cross Essex View
Map 22438 Champlain Essex – 22442 Coles Point Westmoreland – 22443 Colonial Beach Westmoreland – 22446 Corbin Caroline – 22448 Dahlgren King George – 22451 Dogue King George – 22454 Dunnsville Essex – 22456 Edwardsville Northumberland – 22460 Farnham Richmond – 22463 Garrisonville Stafford – 22469 Hague Westmoreland – 22471 Hartwood Stafford – 22472 Haynesville Richmond – 22473 Heathsville Northumberland – 22476 Hustle Essex – 22480 Irvington Lancaster – 22481 Jersey King George – 22482 Kilmarnock Lancaster – 22485 King George King George View
Map 22488 Kinsale Westmoreland – 22501 Ladysmith Caroline – 22503 Lancaster Lancaster – 22504 Laneview Essex – 22507 Lively Lancaster – 22508 Locust Grove Orange – 22509 Loretto Essex – 22511 Lottsburg Northumberland – 22513 Merry Point Lancaster – 22514 Milford Caroline – 22517 Mollusk Lancaster – 22520 Montross Westmoreland – 22523 Morattico Lancaster – 22524 Mount Holly Westmoreland – 22526 Ninde King George – 22528 Nuttsville Lancaster – 22529 Oldhams Westmoreland – 22530 Ophelia Northumberland – 22534 Partlow Spotsylvania View
Map 22535 Port Royal Caroline – 22538 Rappahannock Academy Caroline – 22539 Reedville Northumberland – 22542 Rhoadesville Orange – 22544 Rollins Fork King George – 22545 Ruby Stafford – 22546 Ruther Glen Caroline – 22547 Sealston King George – 22548 Sharps Richmond – 22552 Sparta Caroline – 22553 Spotsylvania Spotsylvania – 22554 Stafford Stafford – 22555 Stafford Stafford – 22556 Stafford Stafford – 22558 Stratford Westmoreland – 22560 Tappahannock Essex – 22565 Thornburg Spotsylvania – 22567 Unionville Orange – 22570 Village Richmond View
Map 22572 Warsaw Richmond – 22576 Weems Lancaster – 22577 Sandy Point Westmoreland – 22578 White Stone Lancaster – 22579 Wicomico Church Northumberland – 22580 Woodford Caroline – 22581 Zacata Westmoreland – 22601 Winchester Winchester City – 22602 Winchester Frederick – 22603 Winchester Frederick – 22604 Winchester Winchester City – 22610 Bentonville Warren – 22611 Berryville Clarke – 22620 Boyce Clarke – 22622 Brucetown Frederick – 22623 Chester Gap Rappahannock – 22624 Clear Brook Frederick – 22625 Cross Junction Frederick – 22626 Fishers Hill Shenandoah View
Map 22627 Flint Hill Rappahannock – 22630 Front Royal Warren – 22637 Gore Frederick – 22638 Winchester Frederick – 22639 Hume Fauquier – 22640 Huntly Rappahannock – 22641 Strasburg Shenandoah – 22642 Linden Warren – 22643 Markham Fauquier – 22644 Maurertown Shenandoah – 22645 Middletown Frederick – 22646 Millwood Clarke – 22649 Middletown Warren – 22650 Rileyville Page – 22652 Fort Valley Shenandoah – 22654 Star Tannery Frederick – 22655 Stephens City Frederick – 22656 Stephenson Frederick – 22657 Strasburg Shenandoah View
Map 22660 Toms Brook Shenandoah – 22663 White Post Clarke – 22664 Woodstock Shenandoah – 22701 Culpeper Culpeper – 22709 Aroda Madison – 22711 Banco Madison – 22712 Bealeton Fauquier – 22713 Boston Culpeper – 22714 Brandy Station Culpeper – 22715 Brightwood Madison – 22716 Castleton Rappahannock – 22718 Elkwood Culpeper – 22719 Etlan Madison – 22720 Goldvein Fauquier – 22721 Graves Mill Madison – 22722 Haywood Madison – 22723 Hood Madison – 22724 Jeffersonton Culpeper – 22725 Leon Madison View
Map 22726 Lignum Culpeper – 22727 Madison Madison – 22728 Midland Fauquier – 22729 Mitchells Culpeper – 22730 Oakpark Madison – 22731 Pratts Madison – 22732 Radiant Madison – 22733 Rapidan Culpeper – 22734 Remington Fauquier – 22735 Reva Madison – 22736 Richardsville Culpeper – 22737 Rixeyville Culpeper – 22738 Rochelle Madison – 22739 Somerville Fauquier – 22740 Sperryville Rappahannock – 22741 Stevensburg Culpeper – 22742 Sumerduck Fauquier – 22743 Syria Madison – 22746 Viewtown Culpeper View
Map 22747 Washington Rappahannock – 22748 Wolftown Madison – 22749 Woodville Rappahannock – 22801 Harrisonburg Harrisonburg City – 22802 Harrisonburg Harrisonburg City – 22803 Harrisonburg Harrisonburg City – 22807 Harrisonburg Harrisonburg City – 22810 Basye Shenandoah – 22811 Bergton Rockingham – 22812 Bridgewater Rockingham – 22815 Broadway Rockingham – 22820 Criders Rockingham – 22821 Dayton Rockingham – 22824 Edinburg Shenandoah – 22827 Elkton Rockingham – 22830 Fulks Run Rockingham – 22831 Hinton Rockingham – 22832 Keezletown Rockingham – 22833 Lacey Spring Rockingham View
Map 22834 Linville Rockingham – 22835 Luray Page – 22840 Mc Gaheysville Rockingham – 22841 Mount Crawford Rockingham – 22842 Mount Jackson Shenandoah – 22843 Mount Solon Augusta – 22844 New Market Shenandoah – 22845 Orkney Springs Shenandoah – 22846 Penn Laird Rockingham – 22847 Quicksburg Shenandoah – 22848 Pleasant Valley Rockingham – 22849 Shenandoah Page – 22850 Singers Glen Rockingham – 22851 Stanley Page – 22853 Timberville Rockingham – 22901 Charlottesville Albemarle – 22902 Charlottesville Charlottesville City – 22903 Charlottesville Charlottesville City – 22904 Charlottesville Charlottesville City View
Map 22905 Charlottesville Charlottesville City – 22906 Charlottesville Charlottesville City – 22907 Charlottesville Charlottesville City – 22908 Charlottesville Charlottesville City – 22909 Charlottesville Albemarle – 22910 Charlottesville Charlottesville City – 22911 Charlottesville Albemarle – 22920 Afton Nelson – 22922 Arrington Nelson – 22923 Barboursville Orange – 22924 Batesville Albemarle – 22931 Covesville Albemarle – 22932 Crozet Albemarle – 22935 Dyke Greene – 22936 Earlysville Albemarle – 22937 Esmont Albemarle – 22938 Faber Nelson – 22939 Fishersville Augusta – 22940 Free Union Albemarle View
Map 22942 Gordonsville Orange – 22943 Greenwood Albemarle – 22945 Ivy Albemarle – 22946 Keene Albemarle – 22947 Keswick Albemarle – 22948 Locust Dale Madison – 22949 Lovingston Nelson – 22952 Lyndhurst Augusta – 22957 Montpelier Station Orange – 22958 Nellysford Nelson – 22959 North Garden Albemarle – 22960 Orange Orange – 22963 Palmyra Fluvanna – 22964 Piney River Nelson – 22965 Quinque Greene – 22967 Roseland Nelson – 22968 Ruckersville Greene – 22969 Schuyler Nelson – 22971 Shipman Nelson View
Map 22972 Somerset Orange – 22973 Stanardsville Greene – 22974 Troy Fluvanna – 22976 Tyro Nelson – 22980 Waynesboro Waynesboro City – 22987 White Hall Albemarle – 22989 Woodberry Forest Madison – 23001 Achilles Gloucester – 23002 Amelia Court House Amelia – 23003 Ark Gloucester – 23004 Arvonia Buckingham – 23005 Ashland Hanover – 23009 Aylett King William – 23011 Barhamsville New Kent – 23014 Beaumont Goochland – 23015 Beaverdam Hanover – 23018 Bena Gloucester – 23021 Bohannon Mathews – 23022 Bremo Bluff Fluvanna View
Map 23023 Bruington King And Queen – 23024 Bumpass Louisa – 23025 Cardinal Mathews – 23027 Cartersville Cumberland – 23030 Charles City Charles City – 23031 Christchurch Middlesex – 23032 Church View Middlesex – 23035 Cobbs Creek Mathews – 23038 Columbia Goochland – 23039 Crozier Goochland – 23040 Cumberland Cumberland – 23043 Deltaville Middlesex – 23045 Diggs Mathews – 23047 Doswell Hanover – 23050 Dutton Gloucester – 23055 Fork Union Fluvanna – 23056 Foster Mathews – 23058 Glen Allen Henrico – 23059 Glen Allen Henrico View
Map 23060 Glen Allen Henrico – 23061 Gloucester Gloucester – 23062 Gloucester Point Gloucester – 23063 Goochland Goochland – 23064 Grimstead Mathews – 23065 Gum Spring Goochland – 23066 Gwynn Mathews – 23067 Hadensville Goochland – 23068 Hallieford Mathews – 23069 Hanover Hanover – 23070 Hardyville Middlesex – 23071 Hartfield Middlesex – 23072 Hayes Gloucester – 23075 Highland Springs Henrico – 23076 Hudgins Mathews – 23079 Jamaica Middlesex – 23081 Jamestown James City – 23083 Jetersville Amelia – 23084 Kents Store Fluvanna View
Map 23085 King And Queen Court House King And Queen – 23086 King William King William – 23089 Lanexa New Kent – 23090 Lightfoot York – 23091 Little Plymouth King And Queen – 23092 Locust Hill Middlesex – 23093 Louisa Louisa – 23101 Macon Powhatan – 23102 Maidens Goochland – 23103 Manakin Sabot Goochland – 23105 Mannboro Amelia – 23106 Manquin King William – 23107 Maryus Gloucester – 23108 Mascot King And Queen – 23109 Mathews Mathews – 23110 Mattaponi King And Queen – 23111 Mechanicsville Hanover – 23112 Midlothian Chesterfield – 23113 Midlothian Chesterfield View
Map 23114 Midlothian Chesterfield – 23115 Millers Tavern Essex – 23116 Mechanicsville Hanover – 23117 Mineral Louisa – 23119 Moon Mathews – 23120 Moseley Chesterfield – 23123 New Canton Buckingham – 23124 New Kent New Kent – 23125 New Point Mathews – 23126 Newtown King And Queen – 23127 Norge James City – 23128 North Mathews – 23129 Oilville Goochland – 23130 Onemo Mathews – 23131 Ordinary Gloucester – 23138 Port Haywood Mathews – 23139 Powhatan Powhatan – 23140 Providence Forge New Kent – 23141 Quinton New Kent View
Map 23146 Rockville Hanover – 23147 Ruthville Charles City – 23148 Saint Stephens Church King And Queen – 23149 Saluda Middlesex – 23150 Sandston Henrico – 23153 Sandy Hook Goochland – 23154 Schley Gloucester – 23155 Severn Gloucester – 23156 Shacklefords King And Queen – 23160 State Farm Goochland – 23161 Stevensville King And Queen – 23162 Studley Hanover – 23163 Susan Mathews – 23168 Toano James City – 23169 Topping Middlesex – 23170 Trevilians Louisa – 23173 University Of Richmond Richmond City – 23175 Urbanna Middlesex – 23176 Wake Middlesex View
Map 23177 Walkerton King And Queen – 23178 Ware Neck Gloucester – 23180 Water View Middlesex – 23181 West Point King William – 23183 White Marsh Gloucester – 23184 Wicomico Gloucester – 23185 Williamsburg James City – 23186 Williamsburg Williamsburg City – 23187 Williamsburg Williamsburg City – 23188 Williamsburg James City – 23190 Woods Cross Roads Gloucester – 23192 Montpelier Hanover – 23218 Richmond Richmond City – 23219 Richmond Richmond City – 23220 Richmond Richmond City – 23221 Richmond Richmond City – 23222 Richmond Richmond City – 23223 Richmond Richmond City – 23224 Richmond Richmond City View
Map 23225 Richmond Richmond City – 23226 Richmond Henrico – 23227 Richmond Henrico – 23228 Richmond Henrico – 23229 Richmond Henrico – 23230 Richmond Henrico – 23231 Richmond Henrico – 23232 Richmond Richmond City – 23233 Richmond Henrico – 23234 Richmond Chesterfield – 23235 Richmond Chesterfield – 23236 Richmond Chesterfield – 23237 Richmond Chesterfield – 23238 Richmond Henrico – 23240 Richmond Richmond City – 23241 Richmond Richmond City – 23242 Richmond Henrico – 23249 Richmond Richmond City – 23250 Richmond Henrico View
Map 23255 Richmond Henrico – 23260 Richmond Richmond City – 23261 Richmond Richmond City – 23269 Richmond Richmond City – 23273 Richmond Richmond City – 23274 Richmond Richmond City – 23276 Richmond Richmond City – 23278 Richmond Richmond City – 23279 Richmond Richmond City – 23282 Richmond Richmond City – 23284 Richmond Richmond City – 23285 Richmond Richmond City – 23286 Richmond Richmond City – 23288 Richmond Henrico – 23289 Richmond Richmond City – 23290 Richmond Richmond City – 23291 Richmond Richmond City – 23292 Richmond Richmond City – 23293 Richmond Richmond City View
Map 23294 Richmond Henrico – 23295 Richmond Richmond City – 23297 Richmond Chesterfield – 23298 Richmond Richmond City – 23301 Accomac Accomack – 23302 Assawoman Accomack – 23303 Atlantic Accomack – 23304 Battery Park Isle Of Wight – 23306 Belle Haven Accomack – 23307 Birdsnest Northampton – 23308 Bloxom Accomack – 23310 Cape Charles Northampton – 23313 Capeville Northampton – 23314 Carrollton Isle Of Wight – 23315 Carrsville Isle Of Wight – 23316 Cheriton Northampton – 23320 Chesapeake Chesapeake City – 23321 Chesapeake Chesapeake City – 23322 Chesapeake Chesapeake City View
Map 23323 Chesapeake Chesapeake City – 23324 Chesapeake Chesapeake City – 23325 Chesapeake Chesapeake City – 23326 Chesapeake Chesapeake City – 23327 Chesapeake Chesapeake City – 23328 Chesapeake Chesapeake City – 23336 Chincoteague Island Accomack – 23337 Wallops Island Accomack – 23341 Craddockville Accomack – 23345 Davis Wharf Accomack – 23347 Eastville Northampton – 23350 Exmore Northampton – 23354 Franktown Northampton – 23356 Greenbackville Accomack – 23357 Greenbush Accomack – 23358 Hacksneck Accomack – 23359 Hallwood Accomack – 23389 Harborton Accomack – 23395 Horntown Accomack View
Map 23396 Oak Hall Accomack – 23397 Isle Of Wight Isle Of Wight – 23398 Jamesville Northampton – 23399 Jenkins Bridge Accomack – 23401 Keller Accomack – 23404 Locustville Accomack – 23405 Machipongo Northampton – 23407 Mappsville Accomack – 23408 Marionville Northampton – 23409 Mears Accomack – 23410 Melfa Accomack – 23412 Modest Town Accomack – 23413 Nassawadox Northampton – 23414 Nelsonia Accomack – 23415 New Church Accomack – 23416 Oak Hall Accomack – 23417 Onancock Accomack – 23418 Onley Accomack – 23419 Oyster Northampton View
Map 23420 Painter Accomack – 23421 Parksley Accomack – 23422 Pungoteague Accomack – 23423 Quinby Accomack – 23424 Rescue Isle Of Wight – 23426 Sanford Accomack – 23427 Saxis Accomack – 23429 Seaview Northampton – 23430 Smithfield Isle Of Wight – 23431 Smithfield Isle Of Wight – 23432 Suffolk Suffolk City – 23433 Suffolk Suffolk City – 23434 Suffolk Suffolk City – 23435 Suffolk Suffolk City – 23436 Suffolk Suffolk City – 23437 Suffolk Suffolk City – 23438 Suffolk Suffolk City – 23439 Suffolk Suffolk City – 23440 Tangier Accomack View
Map 23441 Tasley Accomack – 23442 Temperanceville Accomack – 23443 Townsend Northampton – 23450 Virginia Beach Virginia Beach City – 23451 Virginia Beach Virginia Beach City – 23452 Virginia Beach Virginia Beach City – 23453 Virginia Beach Virginia Beach City – 23454 Virginia Beach Virginia Beach City – 23455 Virginia Beach Virginia Beach City – 23456 Virginia Beach Virginia Beach City – 23457 Virginia Beach Virginia Beach City – 23458 Virginia Beach Virginia Beach City – 23459 Virginia Beach Virginia Beach City – 23460 Virginia Beach Virginia Beach City – 23461 Virginia Beach Virginia Beach City – 23462 Virginia Beach Virginia Beach City – 23463 Virginia Beach Virginia Beach City – 23464 Virginia Beach Virginia Beach City – 23465 Virginia Beach Virginia Beach City View
Map 23466 Virginia Beach Virginia Beach City – 23467 Virginia Beach Virginia Beach City – 23471 Virginia Beach Virginia Beach City – 23479 Virginia Beach Virginia Beach City – 23480 Wachapreague Accomack – 23482 Wardtown Northampton – 23483 Wattsville Accomack – 23486 Willis Wharf Northampton – 23487 Windsor Isle Of Wight – 23488 Withams Accomack – 23501 Norfolk Norfolk City – 23502 Norfolk Norfolk City – 23503 Norfolk Norfolk City – 23504 Norfolk Norfolk City – 23505 Norfolk Norfolk City – 23506 Norfolk Norfolk City – 23507 Norfolk Norfolk City – 23508 Norfolk Norfolk City – 23509 Norfolk Norfolk City View
Map 23510 Norfolk Norfolk City – 23511 Norfolk Norfolk City – 23512 Norfolk Norfolk City – 23513 Norfolk Norfolk City – 23514 Norfolk Norfolk City – 23515 Norfolk Norfolk City – 23517 Norfolk Norfolk City – 23518 Norfolk Norfolk City – 23519 Norfolk Norfolk City – 23520 Norfolk Norfolk City – 23521 Norfolk Norfolk City – 23523 Norfolk Norfolk City – 23529 Norfolk Norfolk City – 23541 Norfolk Norfolk City – 23551 Norfolk Norfolk City – 23601 Newport News Newport News City – 23602 Newport News Newport News City – 23603 Newport News Newport News City – 23604 Fort Eustis Newport News City View
Map 23605 Newport News Newport News City – 23606 Newport News Newport News City – 23607 Newport News Newport News City – 23608 Newport News Newport News City – 23609 Newport News Newport News City – 23612 Newport News Newport News City – 23628 Newport News Newport News City – 23630 Hampton Hampton City – 23651 Fort Monroe Hampton City – 23661 Hampton Hampton City – 23662 Poquoson Poquoson City – 23663 Hampton Hampton City – 23664 Hampton Hampton City – 23665 Hampton York – 23666 Hampton Hampton City – 23667 Hampton Hampton City – 23668 Hampton Hampton City – 23669 Hampton Hampton City – 23670 Hampton Hampton City View
Map 23681 Hampton Hampton City – 23690 Yorktown York – 23691 Yorktown York – 23692 Yorktown York – 23693 Yorktown York – 23694 Lackey York – 23696 Seaford York – 23701 Portsmouth Portsmouth City – 23702 Portsmouth Portsmouth City – 23703 Portsmouth Portsmouth City – 23704 Portsmouth Portsmouth City – 23705 Portsmouth Portsmouth City – 23707 Portsmouth Portsmouth City – 23708 Portsmouth Portsmouth City – 23709 Portsmouth Portsmouth City – 23801 Fort Lee Prince George – 23803 Petersburg Petersburg City – 23804 Petersburg Petersburg City – 23805 Petersburg Petersburg City View
Map 23806 Petersburg Petersburg City – 23821 Alberta Brunswick – 23822 Ammon Dinwiddie – 23824 Blackstone Nottoway – 23825 Blackstone Nottoway – 23827 Boykins Southampton – 23828 Branchville Southampton – 23829 Capron Southampton – 23830 Carson Dinwiddie – 23831 Chester Chesterfield – 23832 Chesterfield Chesterfield – 23833 Church Road Dinwiddie – 23834 Colonial Heights Colonial Heights City – 23836 Chester Chesterfield – 23837 Courtland Southampton – 23838 Chesterfield Chesterfield – 23839 Dendron Surry – 23840 Dewitt Dinwiddie – 23841 Dinwiddie Dinwiddie View
Map 23842 Disputanta Prince George – 23843 Dolphin Brunswick – 23844 Drewryville Southampton – 23845 Ebony Brunswick – 23846 Elberon Surry – 23847 Emporia Greensville – 23850 Ford Dinwiddie – 23851 Franklin Franklin City – 23856 Freeman Brunswick – 23857 Gasburg Brunswick – 23860 Hopewell Hopewell City – 23866 Ivor Southampton – 23867 Jarratt Greensville – 23868 Lawrenceville Brunswick – 23870 Jarratt Greensville – 23872 Mc Kenney Dinwiddie – 23873 Meredithville Brunswick – 23874 Newsoms Southampton – 23875 Prince George Prince George View
Map 23876 Rawlings Brunswick – 23878 Sedley Southampton – 23879 Skippers Greensville – 23881 Spring Grove Surry – 23882 Stony Creek Sussex – 23883 Surry Surry – 23884 Sussex Sussex – 23885 Sutherland Dinwiddie – 23887 Valentines Brunswick – 23888 Wakefield Sussex – 23889 Warfield Brunswick – 23890 Waverly Sussex – 23891 Waverly Sussex – 23893 White Plains Brunswick – 23894 Wilsons Dinwiddie – 23897 Yale Sussex – 23898 Zuni Isle Of Wight – 23899 Claremont Surry – 23901 Farmville Prince Edward View
Map 23909 Farmville Prince Edward – 23915 Baskerville Mecklenburg – 23917 Boydton Mecklenburg – 23919 Bracey Mecklenburg – 23920 Brodnax Brunswick – 23921 Buckingham Buckingham – 23922 Burkeville Nottoway – 23923 Charlotte Court House Charlotte – 23924 Chase City Mecklenburg – 23927 Clarksville Mecklenburg – 23930 Crewe Nottoway – 23934 Cullen Charlotte – 23936 Dillwyn Buckingham – 23937 Drakes Branch Charlotte – 23938 Dundas Lunenburg – 23939 Evergreen Appomattox – 23941 Fort Mitchell Lunenburg – 23942 Green Bay Prince Edward – 23943 Hampden Sydney Prince Edward View
Map 23944 Kenbridge Lunenburg – 23947 Keysville Charlotte – 23950 La Crosse Mecklenburg – 23952 Lunenburg Lunenburg – 23954 Meherrin Prince Edward – 23955 Nottoway Nottoway – 23958 Pamplin Appomattox – 23959 Phenix Charlotte – 23960 Prospect Prince Edward – 23962 Randolph Charlotte – 23963 Red House Charlotte – 23964 Red Oak Charlotte – 23966 Rice Prince Edward – 23967 Saxe Charlotte – 23968 Skipwith Mecklenburg – 23970 South Hill Mecklenburg – 23974 Victoria Lunenburg – 23976 Wylliesburg Charlotte – 24001 Roanoke Roanoke City View
Map 24002 Roanoke Roanoke City – 24003 Roanoke Roanoke City – 24004 Roanoke Roanoke City – 24005 Roanoke Roanoke City – 24006 Roanoke Roanoke City – 24007 Roanoke Roanoke City – 24008 Roanoke Roanoke City – 24009 Roanoke Roanoke City – 24010 Roanoke Roanoke City – 24011 Roanoke Roanoke City – 24012 Roanoke Roanoke City – 24013 Roanoke Roanoke City – 24014 Roanoke Roanoke City – 24015 Roanoke Roanoke City – 24016 Roanoke Roanoke City – 24017 Roanoke Roanoke City – 24018 Roanoke Roanoke – 24019 Roanoke Roanoke – 24020 Roanoke Roanoke View
Map 24022 Roanoke Roanoke City – 24023 Roanoke Roanoke City – 24024 Roanoke Roanoke City – 24025 Roanoke Roanoke City – 24026 Roanoke Roanoke City – 24027 Roanoke Roanoke City – 24028 Roanoke Roanoke City – 24029 Roanoke Roanoke City – 24030 Roanoke Roanoke City – 24031 Roanoke Roanoke City – 24032 Roanoke Roanoke City – 24033 Roanoke Roanoke City – 24034 Roanoke Roanoke City – 24035 Roanoke Roanoke City – 24036 Roanoke Roanoke City – 24037 Roanoke Roanoke City – 24038 Roanoke Roanoke City – 24040 Roanoke Roanoke City – 24042 Roanoke Roanoke City View
Map 24043 Roanoke Roanoke City – 24044 Roanoke Roanoke City – 24045 Roanoke Roanoke City – 24048 Roanoke Roanoke City – 24050 Roanoke Botetourt – 24053 Ararat Patrick – 24054 Axton Henry – 24055 Bassett Henry – 24058 Belspring Pulaski – 24059 Bent Mountain Roanoke – 24060 Blacksburg Montgomery – 24061 Blacksburg Montgomery – 24062 Blacksburg Montgomery – 24063 Blacksburg Montgomery – 24064 Blue Ridge Botetourt – 24065 Boones Mill Franklin – 24066 Buchanan Botetourt – 24067 Callaway Franklin – 24068 Christiansburg Montgomery View
Map 24069 Cascade Pittsylvania – 24070 Catawba Roanoke – 24072 Check Floyd – 24073 Christiansburg Montgomery – 24076 Claudville Patrick – 24077 Cloverdale Botetourt – 24078 Collinsville Henry – 24079 Copper Hill Floyd – 24082 Critz Patrick – 24083 Daleville Botetourt – 24084 Dublin Pulaski – 24085 Eagle Rock Botetourt – 24086 Eggleston Giles – 24087 Elliston Montgomery – 24088 Ferrum Franklin – 24089 Fieldale Henry – 24090 Fincastle Botetourt – 24091 Floyd Floyd – 24092 Glade Hill Franklin View
Map 24093 Glen Lyn Giles – 24095 Goodview Bedford – 24101 Hardy Franklin – 24102 Henry Franklin – 24104 Huddleston Bedford – 24105 Indian Valley Floyd – 24111 Mc Coy Montgomery – 24112 Martinsville Martinsville City – 24113 Martinsville Martinsville City – 24114 Martinsville Martinsville City – 24115 Martinsville Martinsville City – 24120 Meadows Of Dan Patrick – 24121 Moneta Bedford – 24122 Montvale Bedford – 24124 Narrows Giles – 24126 Newbern Pulaski – 24127 New Castle Craig – 24128 Newport Giles – 24129 New River Pulaski View
Map 24130 Oriskany Botetourt – 24131 Paint Bank Craig – 24132 Parrott Pulaski – 24133 Patrick Springs Patrick – 24134 Pearisburg Giles – 24136 Pembroke Giles – 24137 Penhook Franklin – 24138 Pilot Montgomery – 24139 Pittsville Pittsylvania – 24141 Radford Radford – 24142 Radford Radford – 24143 Radford Radford – 24146 Redwood Franklin – 24147 Rich Creek Giles – 24148 Ridgeway Henry – 24149 Riner Montgomery – 24150 Ripplemead Giles – 24151 Rocky Mount Franklin – 24153 Salem Salem View
Map 24155 Roanoke Salem – 24157 Roanoke Salem – 24161 Sandy Level Pittsylvania – 24162 Shawsville Montgomery – 24165 Spencer Henry – 24167 Staffordsville Giles – 24168 Stanleytown Henry – 24171 Stuart Patrick – 24174 Thaxton Bedford – 24175 Troutville Botetourt – 24176 Union Hall Franklin – 24177 Vesta Patrick – 24178 Villamont Bedford – 24179 Vinton Roanoke – 24184 Wirtz Franklin – 24185 Woolwine Patrick – 24201 Bristol Bristol – 24202 Bristol Washington – 24203 Bristol Bristol View
Map 24209 Bristol Bristol – 24210 Abingdon Washington – 24211 Abingdon Washington – 24212 Abingdon Washington – 24215 Andover Wise – 24216 Appalachia Wise – 24217 Bee Dickenson – 24218 Ben Hur Lee – 24219 Big Stone Gap Wise – 24220 Birchleaf Dickenson – 24221 Blackwater Lee – 24224 Castlewood Russell – 24225 Cleveland Russell – 24226 Clinchco Dickenson – 24228 Clintwood Dickenson – 24230 Coeburn Wise – 24236 Damascus Washington – 24237 Dante Russell – 24239 Davenport Buchanan View
Map 24243 Dryden Lee – 24244 Duffield Scott – 24245 Dungannon Scott – 24246 East Stone Gap Wise – 24248 Ewing Lee – 24250 Fort Blackmore Scott – 24251 Gate City Scott – 24256 Haysi Dickenson – 24258 Hiltons Scott – 24260 Honaker Russell – 24263 Jonesville Lee – 24265 Keokee Lee – 24266 Lebanon Russell – 24269 Mc Clure Dickenson – 24270 Mendota Washington – 24271 Nickelsville Scott – 24272 Nora Dickenson – 24273 Norton Norton City – 24277 Pennington Gap Lee View
Map 24279 Pound Wise – 24280 Rosedale Russell – 24281 Rose Hill Lee – 24282 Saint Charles Lee – 24283 Saint Paul Wise – 24290 Weber City Scott – 24292 Whitetop Grayson – 24293 Wise Wise – 24301 Pulaski Pulaski – 24311 Atkins Smyth – 24312 Austinville Wythe – 24313 Barren Springs Wythe – 24314 Bastian Bland – 24315 Bland Bland – 24316 Broadford Tazewell – 24317 Cana Carroll – 24318 Ceres Bland – 24319 Chilhowie Smyth – 24322 Cripple Creek Wythe View
Map 24323 Crockett Wythe – 24324 Draper Pulaski – 24325 Dugspur Carroll – 24326 Elk Creek Grayson – 24327 Emory Washington – 24328 Fancy Gap Carroll – 24330 Fries Grayson – 24333 Galax Galax City – 24340 Glade Spring Washington – 24343 Hillsville Carroll – 24347 Hiwassee Pulaski – 24348 Independence Grayson – 24350 Ivanhoe Wythe – 24351 Lambsburg Carroll – 24352 Laurel Fork Carroll – 24354 Marion Smyth – 24360 Max Meadows Wythe – 24361 Meadowview Washington – 24363 Mouth Of Wilson Grayson View
Map 24366 Rocky Gap Bland – 24368 Rural Retreat Wythe – 24370 Saltville Smyth – 24374 Speedwell Wythe – 24375 Sugar Grove Smyth – 24377 Tannersville Tazewell – 24378 Troutdale Grayson – 24380 Willis Floyd – 24381 Woodlawn Carroll – 24382 Wytheville Wythe – 24401 Staunton Staunton City – 24402 Staunton Staunton City – 24411 Augusta Springs Augusta – 24412 Bacova Bath – 24413 Blue Grass Highland – 24415 Brownsburg Rockbridge – 24416 Buena Vista Buena Vista City – 24421 Churchville Augusta – 24422 Clifton Forge Alleghany View
Map 24426 Covington Covington City – 24430 Craigsville Augusta – 24431 Crimora Augusta – 24432 Deerfield Augusta – 24433 Doe Hill Highland – 24435 Fairfield Rockbridge – 24437 Fort Defiance Augusta – 24438 Glen Wilton Botetourt – 24439 Goshen Rockbridge – 24440 Greenville Augusta – 24441 Grottoes Rockingham – 24442 Head Waters Highland – 24445 Hot Springs Bath – 24448 Iron Gate Alleghany – 24450 Lexington Lexington City – 24457 Low Moor Alleghany – 24458 Mc Dowell Highland – 24459 Middlebrook Augusta – 24460 Millboro Bath View
Map 24463 Mint Spring Augusta – 24464 Montebello Nelson – 24465 Monterey Highland – 24467 Mount Sidney Augusta – 24468 Mustoe Highland – 24469 New Hope Augusta – 24471 Port Republic Rockingham – 24472 Raphine Rockbridge – 24473 Rockbridge Baths Rockbridge – 24474 Selma Alleghany – 24476 Steeles Tavern Augusta – 24477 Stuarts Draft Augusta – 24479 Swoope Augusta – 24482 Verona Augusta – 24483 Vesuvius Rockbridge – 24484 Warm Springs Bath – 24485 West Augusta Augusta – 24486 Weyers Cave Augusta – 24487 Williamsville Bath View
Map 24501 Lynchburg Lynchburg City – 24502 Lynchburg Lynchburg City – 24503 Lynchburg Lynchburg City – 24504 Lynchburg Lynchburg City – 24505 Lynchburg Lynchburg City – 24506 Lynchburg Lynchburg City – 24512 Lynchburg Lynchburg City – 24513 Lynchburg Lynchburg City – 24514 Lynchburg Lynchburg City – 24515 Lynchburg Lynchburg City – 24517 Altavista Campbell – 24520 Alton Halifax – 24521 Amherst Amherst – 24522 Appomattox Appomattox – 24523 Bedford Bedford – 24526 Big Island Bedford – 24527 Blairs Pittsylvania – 24528 Brookneal Campbell – 24529 Buffalo Junction Mecklenburg View
Map 24530 Callands Pittsylvania – 24531 Chatham Pittsylvania – 24533 Clifford Amherst – 24534 Clover Halifax – 24535 Cluster Springs Halifax – 24536 Coleman Falls Bedford – 24538 Concord Campbell – 24539 Crystal Hill Halifax – 24540 Danville Danville City – 24541 Danville Danville City – 24543 Danville Danville City – 24544 Danville Danville City – 24549 Dry Fork Pittsylvania – 24550 Evington Campbell – 24551 Forest Bedford – 24553 Gladstone Nelson – 24554 Gladys Campbell – 24555 Glasgow Rockbridge – 24556 Goode Bedford View
Map 24557 Gretna Pittsylvania – 24558 Halifax Halifax – 24562 Howardsville Buckingham – 24563 Hurt Pittsylvania – 24565 Java Pittsylvania – 24566 Keeling Pittsylvania – 24569 Long Island Pittsylvania – 24570 Lowry Bedford – 24571 Lynch Station Campbell – 24572 Madison Heights Amherst – 24574 Monroe Amherst – 24576 Naruna Campbell – 24577 Nathalie Halifax – 24578 Natural Bridge Rockbridge – 24579 Natural Bridge Station Rockbridge – 24580 Nelson Mecklenburg – 24581 Norwood Nelson – 24586 Ringgold Pittsylvania – 24588 Rustburg Campbell View
Map 24589 Scottsburg Halifax – 24590 Scottsville Albemarle – 24592 South Boston Halifax – 24593 Spout Spring Appomattox – 24594 Sutherlin Pittsylvania – 24595 Sweet Briar Amherst – 24597 Vernon Hill Halifax – 24598 Virgilina Halifax – 24599 Wingina Buckingham – 24601 Amonate Tazewell – 24602 Bandy Tazewell – 24603 Big Rock Buchanan – 24604 Bishop Tazewell – 24605 Bluefield Tazewell – 24606 Boissevain Tazewell – 24607 Breaks Dickenson – 24608 Burkes Garden Tazewell – 24609 Cedar Bluff Tazewell – 24612 Doran Tazewell View
Map 24613 Falls Mills Tazewell – 24614 Grundy Buchanan – 24619 Horsepen Tazewell – 24620 Hurley Buchanan – 24622 Jewell Ridge Tazewell – 24624 Keen Mountain Buchanan – 24627 Mavisdale Buchanan – 24628 Maxie Buchanan – 24630 North Tazewell Tazewell – 24631 Oakwood Buchanan – 24634 Pilgrims Knob Buchanan – 24635 Pocahontas Tazewell – 24637 Pounding Mill Tazewell – 24639 Raven Buchanan – 24640 Red Ash Tazewell – 24641 Richlands Tazewell – 24646 Rowe Buchanan – 24647 Shortt Gap Buchanan – 24649 Swords Creek Russell View
Map 24651 Tazewell Tazewell – 24656 Vansant Buchanan – 24657 Whitewood Buchanan – 24658 Wolford Buchanan – 24701 Bluefield Mercer – 24712 Athens Mercer – 24714 Beeson Mercer – 24715 Bramwell Mercer – 24716 Bud Wyoming – 24719 Covel Wyoming – 24724 Freeman Mercer – 24726 Herndon Wyoming – 24729 Hiawatha Mercer – 24731 Kegley Mercer – 24732 Kellysville Mercer – 24733 Lashmeet Mercer – 24736 Matoaka Mercer – 24737 Montcalm Mercer – 24738 Nemours Mercer View
Map 24739 Oakvale Mercer – 24740 Princeton Mercer – 24747 Rock Mercer – 24751 Wolfe Mercer – 24801 Welch Mcdowell – 24808 Anawalt Mcdowell – 24811 Avondale Mcdowell – 24813 Bartley Mcdowell – 24815 Berwind Mcdowell – 24816 Big Sandy Mcdowell – 24817 Bradshaw Mcdowell – 24818 Brenton Wyoming – 24822 Clear Fork Wyoming – 24823 Coal Mountain Wyoming – 24824 Coalwood Mcdowell – 24826 Cucumber Mcdowell – 24827 Cyclone Wyoming – 24828 Davy Mcdowell – 24829 Eckman Mcdowell View
Map 24830 Elbert Mcdowell – 24831 Elkhorn Mcdowell – 24834 Fanrock Wyoming – 24836 Gary Mcdowell – 24839 Hanover Wyoming – 24842 Hemphill Mcdowell – 24843 Hensley Mcdowell – 24844 Iaeger Mcdowell – 24845 Ikes Fork Wyoming – 24846 Isaban Mcdowell – 24847 Itmann Wyoming – 24848 Jenkinjones Mcdowell – 24849 Jesse Wyoming – 24850 Jolo Mcdowell – 24851 Justice Mingo – 24853 Kimball Mcdowell – 24854 Kopperston Wyoming – 24855 Kyle Mcdowell – 24857 Lynco Wyoming View
Map 24859 Marianna Wyoming – 24860 Matheny Wyoming – 24861 Maybeury Mcdowell – 24862 Mohawk Mcdowell – 24866 Newhall Mcdowell – 24867 New Richmond Wyoming – 24868 Northfork Mcdowell – 24869 North Spring Wyoming – 24870 Oceana Wyoming – 24871 Pageton Mcdowell – 24872 Panther Mcdowell – 24873 Paynesville Mcdowell – 24874 Pineville Wyoming – 24878 Premier Mcdowell – 24879 Raysal Mcdowell – 24880 Rock View Wyoming – 24881 Roderfield Mcdowell – 24882 Simon Wyoming – 24884 Squire Mcdowell View
Map 24887 Switchback Mcdowell – 24888 Thorpe Mcdowell – 24892 War Mcdowell – 24894 Warriormine Mcdowell – 24895 Wilcoe Mcdowell – 24898 Wyoming Wyoming – 24901 Lewisburg Greenbrier – 24902 Fairlea Greenbrier – 24910 Alderson Greenbrier – 24915 Arbovale Pocahontas – 24916 Asbury Greenbrier – 24918 Ballard Monroe – 24920 Bartow Pocahontas – 24924 Buckeye Pocahontas – 24925 Caldwell Greenbrier – 24927 Cass Pocahontas – 24931 Crawley Greenbrier – 24934 Dunmore Pocahontas – 24935 Forest Hill Summers View
Map 24938 Frankford Greenbrier – 24941 Gap Mills Monroe – 24943 Grassy Meadows Greenbrier – 24944 Green Bank Pocahontas – 24945 Greenville Monroe – 24946 Hillsboro Pocahontas – 24951 Lindside Monroe – 24954 Marlinton Pocahontas – 24957 Maxwelton Greenbrier – 24961 Neola Greenbrier – 24962 Pence Springs Summers – 24963 Peterstown Monroe – 24966 Renick Greenbrier – 24970 Ronceverte Greenbrier – 24974 Secondcreek Monroe – 24976 Sinks Grove Monroe – 24977 Smoot Greenbrier – 24981 Talcott Summers – 24983 Union Monroe View
Map 24984 Waiteville Monroe – 24985 Wayside Monroe – 24986 White Sulphur Springs Greenbrier – 24991 Williamsburg Greenbrier – 24993 Wolfcreek Monroe – 25002 Alloy Fayette – 25003 Alum Creek Kanawha – 25005 Amma Roane – 25007 Arnett Raleigh – 25008 Artie Raleigh – 25009 Ashford Boone – 25011 Bancroft Putnam – 25015 Belle Kanawha – 25019 Bickmore Clay – 25021 Bim Boone – 25022 Blair Logan – 25024 Bloomingrose Boone – 25025 Blount Kanawha – 25026 Blue Creek Kanawha View
Map 25028 Bob White Boone – 25030 Bomont Clay – 25031 Boomer Fayette – 25033 Buffalo Putnam – 25035 Cabin Creek Kanawha – 25036 Cannelton Fayette – 25039 Cedar Grove Kanawha – 25040 Charlton Heights Fayette – 25043 Clay Clay – 25044 Clear Creek Raleigh – 25045 Clendenin Kanawha – 25047 Clothier Logan – 25048 Colcord Raleigh – 25049 Comfort Boone – 25051 Costa Boone – 25053 Danville Boone – 25054 Dawes Kanawha – 25057 Deep Water Fayette – 25059 Dixie Nicholas View
Map 25060 Dorothy Raleigh – 25061 Drybranch Kanawha – 25062 Dry Creek Raleigh – 25063 Duck Clay – 25064 Dunbar Kanawha – 25067 East Bank Kanawha – 25070 Eleanor Putnam – 25071 Elkview Kanawha – 25075 Eskdale Kanawha – 25076 Ethel Logan – 25079 Falling Rock Kanawha – 25081 Foster Boone – 25082 Fraziers Bottom Putnam – 25083 Gallagher Kanawha – 25085 Gauley Bridge Fayette – 25086 Glasgow Kanawha – 25088 Glen Clay – 25090 Glen Ferris Fayette – 25093 Gordon Boone View
Map 25102 Handley Kanawha – 25103 Hansford Kanawha – 25106 Henderson Mason – 25107 Hernshaw Kanawha – 25108 Hewett Boone – 25109 Hometown Putnam – 25110 Hugheston Kanawha – 25111 Indore Clay – 25112 Institute Kanawha – 25113 Ivydale Clay – 25114 Jeffrey Boone – 25115 Kanawha Falls Fayette – 25118 Kimberly Fayette – 25119 Kincaid Fayette – 25121 Lake Logan – 25123 Leon Mason – 25124 Liberty Putnam – 25125 Lizemores Clay – 25126 London Kanawha View
Map 25130 Madison Boone – 25132 Mammoth Kanawha – 25133 Maysel Clay – 25134 Miami Kanawha – 25136 Montgomery Fayette – 25139 Mount Carbon Fayette – 25140 Naoma Raleigh – 25141 Nebo Clay – 25142 Nellis Boone – 25143 Nitro Kanawha – 25148 Orgas Boone – 25149 Ottawa Boone – 25152 Page Fayette – 25154 Peytona Boone – 25156 Pinch Kanawha – 25159 Poca Putnam – 25160 Pond Gap Kanawha – 25161 Powellton Fayette – 25162 Pratt Kanawha View
Map 25164 Procious Clay – 25165 Racine Boone – 25168 Red House Putnam – 25169 Ridgeview Boone – 25173 Robson Fayette – 25174 Rock Creek Raleigh – 25177 Saint Albans Kanawha – 25180 Saxon Boone – 25181 Seth Boone – 25183 Sharples Logan – 25185 Mount Olive Fayette – 25186 Smithers Fayette – 25187 Southside Mason – 25193 Sylvester Boone – 25201 Tad Kanawha – 25202 Tornado Kanawha – 25203 Turtle Creek Boone – 25204 Twilight Boone – 25205 Uneeda Boone View
Map 25206 Van Boone – 25208 Wharton Boone – 25209 Whitesville Boone – 25211 Widen Clay – 25213 Winfield Putnam – 25214 Winifrede Kanawha – 25231 Advent Jackson – 25234 Arnoldsburg Calhoun – 25235 Chloe Calhoun – 25239 Cottageville Jackson – 25241 Evans Jackson – 25243 Gandeeville Roane – 25244 Gay Jackson – 25245 Given Jackson – 25247 Hartford Mason – 25248 Kenna Jackson – 25251 Left Hand Roane – 25252 Le Roy Jackson – 25253 Letart Mason View
Map 25259 Looneyville Roane – 25260 Mason Mason – 25261 Millstone Calhoun – 25262 Millwood Jackson – 25264 Mount Alto Mason – 25265 New Haven Mason – 25266 Newton Roane – 25267 Normantown Gilmer – 25268 Orma Calhoun – 25270 Reedy Roane – 25271 Ripley Jackson – 25275 Sandyville Jackson – 25276 Spencer Roane – 25285 Wallback Clay – 25286 Walton Roane – 25287 West Columbia Mason – 25301 Charleston Kanawha – 25302 Charleston Kanawha – 25303 Charleston Kanawha View
Map 25304 Charleston Kanawha – 25305 Charleston Kanawha – 25306 Charleston Kanawha – 25309 Charleston Kanawha – 25311 Charleston Kanawha – 25312 Charleston Kanawha – 25313 Charleston Kanawha – 25314 Charleston Kanawha – 25315 Charleston Kanawha – 25317 Charleston Kanawha – 25320 Charleston Kanawha – 25321 Charleston Kanawha – 25322 Charleston Kanawha – 25323 Charleston Kanawha – 25324 Charleston Kanawha – 25325 Charleston Kanawha – 25326 Charleston Kanawha – 25327 Charleston Kanawha – 25328 Charleston Kanawha View
Map 25329 Charleston Kanawha – 25330 Charleston Kanawha – 25331 Charleston Kanawha – 25332 Charleston Kanawha – 25333 Charleston Kanawha – 25334 Charleston Kanawha – 25335 Charleston Kanawha – 25336 Charleston Kanawha – 25337 Charleston Kanawha – 25338 Charleston Kanawha – 25339 Charleston Kanawha – 25350 Charleston Kanawha – 25356 Charleston Kanawha – 25357 Charleston Kanawha – 25358 Charleston Kanawha – 25360 Charleston Kanawha – 25361 Charleston Kanawha – 25362 Charleston Kanawha – 25364 Charleston Kanawha View
Map 25365 Charleston Kanawha – 25375 Charleston Kanawha – 25387 Charleston Kanawha – 25389 Charleston Kanawha – 25392 Charleston Kanawha – 25396 Charleston Kanawha – 25401 Martinsburg Berkeley – 25402 Martinsburg Berkeley – 25403 Martinsburg Berkeley – 25404 Martinsburg Berkeley – 25405 Martinsburg Berkeley – 25410 Bakerton Jefferson – 25411 Berkeley Springs Morgan – 25413 Bunker Hill Berkeley – 25414 Charles Town Jefferson – 25419 Falling Waters Berkeley – 25420 Gerrardstown Berkeley – 25421 Glengary Berkeley – 25422 Great Cacapon Morgan View
Map 25423 Halltown Jefferson – 25425 Harpers Ferry Jefferson – 25427 Hedgesville Berkeley – 25428 Inwood Berkeley – 25429 Martinsburg Berkeley – 25430 Kearneysville Jefferson – 25431 Levels Hampshire – 25432 Millville Jefferson – 25434 Paw Paw Morgan – 25437 Points Hampshire – 25438 Ranson Jefferson – 25440 Ridgeway Berkeley – 25441 Rippon Jefferson – 25442 Shenandoah Junction Jefferson – 25443 Shepherdstown Jefferson – 25444 Slanesville Hampshire – 25446 Summit Point Jefferson – 25501 Alkol Lincoln – 25502 Apple Grove Mason View
Map 25503 Ashton Mason – 25504 Barboursville Cabell – 25505 Big Creek Logan – 25506 Branchland Lincoln – 25507 Ceredo Wayne – 25508 Chapmanville Logan – 25510 Culloden Cabell – 25511 Dunlow Wayne – 25512 East Lynn Wayne – 25514 Fort Gay Wayne – 25515 Gallipolis Ferry Mason – 25517 Genoa Wayne – 25520 Glenwood Mason – 25521 Griffithsville Lincoln – 25523 Hamlin Lincoln – 25524 Harts Lincoln – 25526 Hurricane Putnam – 25529 Julian Boone – 25530 Kenova Wayne View
Map 25534 Kiahsville Wayne – 25535 Lavalette Wayne – 25537 Lesage Cabell – 25540 Midkiff Lincoln – 25541 Milton Cabell – 25544 Myra Lincoln – 25545 Ona Cabell – 25547 Pecks Mill Logan – 25550 Point Pleasant Mason – 25555 Prichard Wayne – 25557 Ranger Lincoln – 25559 Salt Rock Cabell – 25560 Scott Depot Putnam – 25562 Shoals Wayne – 25564 Sod Lincoln – 25565 Spurlockville Lincoln – 25567 Sumerco Lincoln – 25569 Teays Putnam – 25570 Wayne Wayne View
Map 25571 West Hamlin Lincoln – 25572 Woodville Boone – 25573 Yawkey Lincoln – 25601 Logan Logan – 25606 Accoville Logan – 25607 Amherstdale Logan – 25608 Baisden Mingo – 25611 Bruno Logan – 25612 Chauncey Logan – 25614 Cora Logan – 25617 Davin Logan – 25621 Gilbert Mingo – 25624 Henlawson Logan – 25625 Holden Logan – 25628 Kistler Logan – 25630 Lorado Logan – 25632 Lyburn Logan – 25634 Mallory Logan – 25635 Man Logan View
Map 25637 Mount Gay Logan – 25638 Omar Logan – 25639 Peach Creek Logan – 25644 Sarah Ann Logan – 25646 Stollings Logan – 25647 Switzer Logan – 25649 Verdunville Logan – 25650 Verner Mingo – 25651 Wharncliffe Mingo – 25652 Whitman Logan – 25653 Wilkinson Logan – 25654 Yolyn Logan – 25661 Williamson Mingo – 25665 Borderland Mingo – 25666 Breeden Mingo – 25667 Chattaroy Mingo – 25669 Crum Wayne – 25670 Delbarton Mingo – 25671 Dingess Mingo View
Map 25672 Edgarton Mingo – 25674 Kermit Mingo – 25676 Lenore Mingo – 25678 Matewan Mingo – 25685 Naugatuck Mingo – 25686 Newtown Mingo – 25688 North Matewan Mingo – 25690 Ragland Mingo – 25691 Rawl Mingo – 25692 Red Jacket Mingo – 25696 Varney Mingo – 25697 Vulcan Mingo – 25699 Wilsondale Wayne – 25701 Huntington Cabell – 25702 Huntington Cabell – 25703 Huntington Cabell – 25704 Huntington Wayne – 25705 Huntington Cabell – 25706 Huntington Cabell View
Map 25707 Huntington Cabell – 25708 Huntington Cabell – 25709 Huntington Cabell – 25710 Huntington Cabell – 25711 Huntington Cabell – 25712 Huntington Cabell – 25713 Huntington Cabell – 25714 Huntington Cabell – 25715 Huntington Cabell – 25716 Huntington Cabell – 25717 Huntington Cabell – 25718 Huntington Cabell – 25719 Huntington Cabell – 25720 Huntington Cabell – 25721 Huntington Cabell – 25722 Huntington Cabell – 25723 Huntington Cabell – 25724 Huntington Cabell – 25725 Huntington Cabell View
Map 25726 Huntington Cabell – 25727 Huntington Cabell – 25728 Huntington Cabell – 25729 Huntington Cabell – 25755 Huntington Cabell – 25770 Huntington Cabell – 25771 Huntington Cabell – 25772 Huntington Cabell – 25773 Huntington Cabell – 25774 Huntington Cabell – 25775 Huntington Cabell – 25776 Huntington Cabell – 25777 Huntington Cabell – 25778 Huntington Cabell – 25779 Huntington Cabell – 25801 Beckley Raleigh – 25802 Beckley Raleigh – 25810 Allen Junction Wyoming – 25811 Amigo Wyoming View
Map 25812 Ansted Fayette – 25813 Beaver Raleigh – 25816 Blue Jay Raleigh – 25817 Bolt Raleigh – 25818 Bradley Raleigh – 25820 Camp Creek Mercer – 25823 Coal City Raleigh – 25825 Cool Ridge Raleigh – 25826 Corinne Wyoming – 25827 Crab Orchard Raleigh – 25831 Danese Fayette – 25832 Daniels Raleigh – 25833 Dothan Fayette – 25836 Eccles Raleigh – 25837 Edmond Fayette – 25839 Fairdale Raleigh – 25840 Fayetteville Fayette – 25841 Flat Top Mercer – 25843 Ghent Raleigh View
Map 25844 Glen Daniel Raleigh – 25845 Glen Fork Wyoming – 25846 Glen Jean Fayette – 25848 Glen Rogers Wyoming – 25849 Glen White Raleigh – 25851 Harper Raleigh – 25853 Helen Raleigh – 25854 Hico Fayette – 25855 Hilltop Fayette – 25857 Josephine Raleigh – 25860 Lanark Raleigh – 25862 Lansing Fayette – 25864 Layland Fayette – 25865 Lester Raleigh – 25866 Lochgelly Fayette – 25868 Lookout Fayette – 25870 Maben Wyoming – 25871 Mabscott Raleigh – 25873 Mac Arthur Raleigh View
Map 25875 Mc Graws Wyoming – 25876 Saulsville Wyoming – 25878 Midway Raleigh – 25879 Minden Fayette – 25880 Mount Hope Fayette – 25882 Mullens Wyoming – 25901 Oak Hill Fayette – 25902 Odd Raleigh – 25904 Pax Fayette – 25906 Piney View Raleigh – 25907 Prince Fayette – 25908 Princewick Raleigh – 25909 Prosperity Raleigh – 25911 Raleigh Raleigh – 25913 Ravencliff Wyoming – 25914 Redstar Fayette – 25915 Rhodell Raleigh – 25916 Sabine Wyoming – 25917 Scarbro Fayette View
Map 25918 Shady Spring Raleigh – 25919 Skelton Raleigh – 25920 Slab Fork Raleigh – 25921 Sophia Raleigh – 25922 Spanishburg Mercer – 25926 Sprague Raleigh – 25927 Stanaford Raleigh – 25928 Stephenson Wyoming – 25932 Surveyor Raleigh – 25936 Thurmond Fayette – 25938 Victor Fayette – 25942 Winona Fayette – 25943 Wyco Wyoming – 25951 Hinton Summers – 25958 Charmco Greenbrier – 25962 Rainelle Greenbrier – 25965 Elton Summers – 25966 Green Sulphur Springs Summers – 25969 Jumping Branch Summers View
Map 25971 Lerona Mercer – 25972 Leslie Greenbrier – 25976 Meadow Bridge Fayette – 25977 Meadow Creek Summers – 25978 Nimitz Summers – 25979 Pipestem Summers – 25981 Quinwood Greenbrier – 25984 Rupert Greenbrier – 25985 Sandstone Summers – 25986 Spring Dale Fayette – 25989 White Oak Raleigh – 26003 Wheeling Ohio – 26030 Beech Bottom Brooke – 26031 Benwood Marshall – 26032 Bethany Brooke – 26033 Cameron Marshall – 26034 Chester Hancock – 26035 Colliers Brooke – 26036 Dallas Marshall View
Map 26037 Follansbee Brooke – 26038 Glen Dale Marshall – 26039 Glen Easton Marshall – 26040 Mcmechen Marshall – 26041 Moundsville Marshall – 26047 New Cumberland Hancock – 26050 Newell Hancock – 26055 Proctor Marshall – 26056 New Manchester Hancock – 26058 Short Creek Brooke – 26059 Triadelphia Ohio – 26060 Valley Grove Ohio – 26062 Weirton Hancock – 26070 Wellsburg Brooke – 26074 West Liberty Ohio – 26075 Windsor Heights Brooke – 26101 Parkersburg Wood – 26102 Parkersburg Wood – 26103 Parkersburg Wood View
Map 26104 Parkersburg Wood – 26105 Vienna Wood – 26106 Parkersburg Wood – 26120 Mineral Wells Wood – 26121 Mineral Wells Wood – 26133 Belleville Wood – 26134 Belmont Pleasants – 26136 Big Bend Calhoun – 26137 Big Springs Calhoun – 26138 Brohard Wirt – 26141 Creston Wirt – 26142 Davisville Wood – 26143 Elizabeth Wirt – 26146 Friendly Tyler – 26147 Grantsville Calhoun – 26148 Macfarlan Ritchie – 26149 Middlebourne Tyler – 26150 Mineral Wells Wood – 26151 Mount Zion Calhoun View
Map 26152 Munday Calhoun – 26155 New Martinsville Wetzel – 26159 Paden City Wetzel – 26160 Palestine Wirt – 26161 Petroleum Ritchie – 26162 Porters Falls Wetzel – 26164 Ravenswood Jackson – 26167 Reader Wetzel – 26169 Rockport Wood – 26170 Saint Marys Pleasants – 26175 Sistersville Tyler – 26178 Smithville Ritchie – 26180 Walker Wood – 26181 Washington Wood – 26184 Waverly Wood – 26186 Wileyville Wetzel – 26187 Williamstown Wood – 26201 Buckhannon Upshur – 26202 Fenwick Nicholas View
Map 26203 Erbacon Webster – 26205 Craigsville Nicholas – 26206 Cowen Webster – 26208 Camden On Gauley Webster – 26209 Snowshoe Pocahontas – 26210 Adrian Upshur – 26215 Cleveland Upshur – 26217 Diana Webster – 26218 French Creek Upshur – 26219 Frenchton Upshur – 26222 Hacker Valley Webster – 26224 Helvetia Randolph – 26228 Kanawha Head Upshur – 26229 Lorentz Upshur – 26230 Pickens Randolph – 26234 Rock Cave Upshur – 26236 Selbyville Upshur – 26237 Tallmansville Upshur – 26238 Volga Barbour View
Map 26241 Elkins Randolph – 26250 Belington Barbour – 26253 Beverly Randolph – 26254 Bowden Tucker – 26257 Coalton Randolph – 26259 Dailey Randolph – 26260 Davis Tucker – 26261 Richwood Nicholas – 26263 Dryfork Randolph – 26264 Durbin Pocahontas – 26266 Upperglade Webster – 26267 Ellamore Randolph – 26268 Glady Randolph – 26269 Hambleton Tucker – 26270 Harman Randolph – 26271 Hendricks Tucker – 26273 Huttonsville Randolph – 26275 Junior Barbour – 26276 Kerens Randolph View
Map 26278 Mabie Randolph – 26280 Mill Creek Randolph – 26282 Monterville Randolph – 26283 Montrose Randolph – 26285 Norton Randolph – 26287 Parsons Tucker – 26288 Webster Springs Webster – 26289 Red Creek Tucker – 26291 Slatyfork Pocahontas – 26292 Thomas Tucker – 26293 Valley Bend Randolph – 26294 Valley Head Randolph – 26296 Whitmer Randolph – 26298 Bergoo Webster – 26301 Clarksburg Harrison – 26302 Clarksburg Harrison – 26306 Clarksburg Harrison – 26320 Alma Tyler – 26321 Alum Bridge Lewis View
Map 26323 Anmoore Harrison – 26325 Auburn Ritchie – 26327 Berea Ritchie – 26330 Bridgeport Harrison – 26335 Burnsville Braxton – 26337 Cairo Ritchie – 26338 Camden Lewis – 26339 Center Point Doddridge – 26342 Coxs Mills Gilmer – 26343 Crawford Lewis – 26346 Ellenboro Ritchie – 26347 Flemington Taylor – 26348 Folsom Wetzel – 26349 Galloway Barbour – 26351 Glenville Gilmer – 26354 Grafton Taylor – 26361 Gypsy Harrison – 26362 Harrisville Ritchie – 26366 Haywood Harrison View
Map 26369 Hepzibah Harrison – 26372 Horner Lewis – 26374 Independence Preston – 26376 Ireland Lewis – 26377 Jacksonburg Wetzel – 26378 Jane Lew Lewis – 26384 Linn Gilmer – 26385 Lost Creek Harrison – 26386 Lumberport Harrison – 26404 Meadowbrook Harrison – 26405 Moatsville Barbour – 26408 Mount Clare Harrison – 26410 Newburg Preston – 26411 New Milton Doddridge – 26412 Orlando Lewis – 26415 Pennsboro Ritchie – 26416 Philippi Barbour – 26419 Pine Grove Wetzel – 26421 Pullman Ritchie View
Map 26422 Reynoldsville Harrison – 26424 Rosemont Taylor – 26425 Rowlesburg Preston – 26426 Salem Harrison – 26430 Sand Fork Gilmer – 26431 Shinnston Harrison – 26434 Shirley Tyler – 26435 Simpson Taylor – 26436 Smithburg Doddridge – 26437 Smithfield Wetzel – 26438 Spelter Harrison – 26440 Thornton Taylor – 26443 Troy Gilmer – 26444 Tunnelton Preston – 26447 Walkersville Lewis – 26448 Wallace Harrison – 26451 West Milford Harrison – 26452 Weston Lewis – 26456 West Union Doddridge View
Map 26461 Wilsonburg Harrison – 26463 Wyatt Harrison – 26501 Morgantown Monongalia – 26502 Morgantown Monongalia – 26504 Morgantown Monongalia – 26505 Morgantown Monongalia – 26506 Morgantown Monongalia – 26507 Morgantown Monongalia – 26508 Morgantown Monongalia – 26519 Albright Preston – 26520 Arthurdale Preston – 26521 Blacksville Monongalia – 26524 Bretz Preston – 26525 Bruceton Mills Preston – 26527 Cassville Monongalia – 26531 Dellslow Monongalia – 26534 Granville Monongalia – 26537 Kingwood Preston – 26541 Maidsville Monongalia View
Map 26542 Masontown Preston – 26543 Osage Monongalia – 26544 Pentress Monongalia – 26546 Pursglove Monongalia – 26547 Reedsville Preston – 26554 Fairmont Marion – 26555 Fairmont Marion – 26559 Barrackville Marion – 26560 Baxter Marion – 26561 Big Run Wetzel – 26562 Burton Wetzel – 26563 Carolina Marion – 26566 Colfax Marion – 26568 Enterprise Harrison – 26570 Fairview Marion – 26571 Farmington Marion – 26572 Four States Marion – 26574 Grant Town Marion – 26575 Hundred Wetzel View
Map 26576 Idamay Marion – 26578 Kingmont Marion – 26581 Littleton Wetzel – 26582 Mannington Marion – 26585 Metz Marion – 26586 Montana Mines Marion – 26587 Rachel Marion – 26588 Rivesville Marion – 26590 Wana Monongalia – 26591 Worthington Marion – 26601 Sutton Braxton – 26610 Birch River Nicholas – 26611 Cedarville Gilmer – 26615 Copen Braxton – 26617 Dille Clay – 26619 Exchange Braxton – 26621 Flatwoods Braxton – 26623 Frametown Braxton – 26624 Gassaway Braxton View
Map 26627 Heaters Braxton – 26629 Little Birch Braxton – 26631 Napier Braxton – 26636 Rosedale Gilmer – 26638 Shock Gilmer – 26651 Summersville Nicholas – 26656 Belva Nicholas – 26660 Calvin Nicholas – 26662 Canvas Nicholas – 26667 Drennen Nicholas – 26671 Gilboa Nicholas – 26675 Keslers Cross Lanes Nicholas – 26676 Leivasy Nicholas – 26678 Mount Lookout Nicholas – 26679 Mount Nebo Nicholas – 26680 Nallen Fayette – 26681 Nettie Nicholas – 26684 Pool Nicholas – 26690 Swiss Nicholas View
Map 26691 Tioga Nicholas – 26704 Augusta Hampshire – 26705 Aurora Preston – 26707 Bayard Grant – 26710 Burlington Mineral – 26711 Capon Bridge Hampshire – 26714 Delray Hampshire – 26716 Eglon Preston – 26717 Elk Garden Mineral – 26719 Fort Ashby Mineral – 26720 Gormania Grant – 26722 Green Spring Hampshire – 26726 Keyser Mineral – 26731 Lahmansville Grant – 26739 Mount Storm Grant – 26743 New Creek Mineral – 26750 Piedmont Mineral – 26753 Ridgeley Mineral – 26755 Rio Hampshire View
Map 26757 Romney Hampshire – 26761 Shanks Hampshire – 26763 Springfield Hampshire – 26764 Terra Alta Preston – 26767 Wiley Ford Mineral – 26801 Baker Hardy – 26802 Brandywine Pendleton – 26804 Circleville Pendleton – 26807 Franklin Pendleton – 26808 High View Hampshire – 26810 Lost City Hardy – 26812 Mathias Hardy – 26814 Riverton Pendleton – 26815 Sugar Grove Pendleton – 26817 Bloomery Hampshire – 26818 Fisher Hardy – 26823 Capon Springs Hampshire – 26833 Maysville Grant – 26836 Moorefield Hardy View
Map 26838 Milam Hardy – 26845 Old Fields Hardy – 26847 Petersburg Grant – 26851 Wardensville Hardy – 26852 Purgitsville Hampshire – 26855 Cabins Grant – 26865 Yellow Spring Hampshire – 26866 Upper Tract Pendleton – 26884 Seneca Rocks Pendleton – 26886 Onego Pendleton

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