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 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.”
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.
“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.
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.”
Poster Number: EI 5 Ketamine in Late Life Treatment-ResistantDepression 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.
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
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:
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.
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.
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.
“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.
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.
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) , 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
 and that GluN2B is necessary for long-term potentiation (LTP) within the BNST . Furthermore, we have previously shown that
non-contingent chronic intermittent ethanol enhances LTP within
the BNST which is dependent on the GluN2B subunit .
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.
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:
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.
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.
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.
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.
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.”
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.”
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 . 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 . 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 . 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 . 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 . Furthermore, ketamine has also been shown to work on nicotinic and opioid receptors . 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  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 . Another study found increased levels of the cytokine interleukin-6 in cerebrospinal fluid from patients who had attempted suicide . 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 . 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 . In their landmark study, Berman et al.  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 .
Characterizing the course of suicidal ideation response to ketamine
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.
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