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Reasons to treat depression rapidly – Depression causes rapid aging> Consider using a rapid – acting antidepressant!

Depression ‘makes us biologically older’  BBC Article

Major depressive disorder and accelerated cellular aging

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease,
diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be
indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether
depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are
from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510
control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene
copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp).
MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews.
Compared with control subjects (mean bp = 5541), sociodemographic-adjusted TL was shorter among remitted MDD patients
(mean bp = 5459; P = 0.014) and current MDD patients (mean bp = 5461; P = 0.012). Adjustment for health and lifestyle variables did
not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity
(P<0.01) and longer symptom duration in the past 4 years (P = 0.01) were associated with shorter TL. Our results demonstrate that
depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and
chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD
had shorter TL than controls

In this large cohort study we demonstrated that currently
depressed persons had shorter TL than never-depressed controls.
Based on an estimated mean telomere shortening rate of 14–20
bp per year as found in this and other studies,20,23,26 the
differences observed indicate 4–6 years of accelerated aging for
the current MDD sample as compared to controls. We also showed
evidence for the imprint of past exposure to depression since
those with remitted MDD also had shorter TL than control
subjects. These observed associations remained significant after
controlling for lifestyle and somatic health variables, suggesting that the shortened telomeres were not simply due to unhealthylifestyle or poorer somatic health among depressed persons.
Finally, the association between MDD and TL showed a ‘dose–
response’ gradient, since the most severely and chronically
depressed patients had the shortest telomeres.

MDD is thus associated with shortened TL, which resembles
accelerated biological aging. The disorder has previously also been
associated with dysregulations of the hypothalamus–pituitary–
adrenal (HPA) axis,43,45 the immune system,46,47 the autonomic
nervous system (ANS)48,49 and increased oxidative stress.50
Shortened telomeres, in turn, are suggested to be a consequence
or a concomitant of these dysregulated biological stress systems.
In line with this, several in vitro and in vivo studies found increased
cortisol,51 oxidative stress52 and pro-inflammatory cytokines53
to be associated with shorter TL. Dysregulations of these stress systems could contribute to telomere shortening in MDD patients.9,12
However, the exact biological mechanisms that mediate the relation
between depression and telomere shortening, as well as the
direction of the link, remain to be further explored.

Oxidative stress shortens telomeres

Elevated DNA Oxidation and DNA Repair Enzyme Expression in Brain White Matter in Major Depressive Disorder.

The Role of Oxidative Stress in Depressive Disorders

Abstract:

Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest
burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research.
Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to
alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in
neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression.

Membrane damage in blood of patients with depression has
been shown by elevated of omega 3- fatty-acids [45] and by increased
lipid peroxidation products in patients with DD [42, 45,
[46, 47]. Furthermore, DNA-strand brakes have been reported in
the blood of these patients [48]. DD has been linked to increased
serum levels of malondialdehyde (MDA), a breakdown product of
oxidized apolipoprotein B-containing lipoproteins, and thus a
marker of the rate of peroxide breakdown [49, 50].

In patients with DD (Depressive Disorders), elevated levels of MDA adversely affect
the efficiency of visual-spatial and auditory-verbal working memory,
short-term declarative memory and delayed recall declarative
memory [51]. Higher concentration of plasma MDA in patients
with recurrent depression is associated with the severity of depressive
symptoms, both at the beginning of antidepressant pharmacotherapy,
and after 8 weeks of treatment. Statistically significant
differences were found in the intensity of depressive symptoms,
measured on therapy onset versus the examination results after
8 weeks of treatment [51]. Although this is used as a marker of lipid peroxidation, it is considered to be less stable than 8-iso-PGF2a, and more susceptible to confounding factors such as antioxidants from diet [52]. Therefore, the best way to investigate oxidative disruptions to lipids in humans is via assessing levels of F2-
isoprostanes [52-54]. These are stable compounds produced in the
process of lipid peroxidation [52, 54]. 8-iso-PGF2a are specific F2-
isoprostane molecules produced during the peroxidation of arachnidonic acid. However, the mean serum level of 8-iso-PGF2a was shown to be significantly higher in a group of patients with DD,
controlling for lifestyle variables such as body mass index, alcohol
consumption, and physical activity [55, 56]. Cerebral membrane
abnormalities and altered membrane phospholipids have been suggested by an increased choline-containing compound seen in the
putamen of patients with DD [57] which has been interpreted as a
result of increased oxidative stress in patients with DD.

A Meta-Analysis of Oxidative Stress Markers in Depression

Results
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin,
high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy
(p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After
antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were
no difference

Conclusion
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher
than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The
pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.

Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) [4], mononuclear cells [5], urine [6], cerebrospinal
fluid [7] and postmortem brains [8] were abnormal. Antioxidant system disturbance in peripheral blood has also been reported [9]. Autoimmune responses against neoepitopes
induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11].
Lower glutathione (GSH) levels [12] and a negative relationship between anhedonia severity
and occipital GSH levels [13] were found through magnetic resonance spectroscopy (MRS).

Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive
oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide
(NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high
content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems [16].
The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have
been reported [17]. 8-F2-isoprostane (8-iso-PGF2α) is another product of LP [18] that is considered
to be a marker of LP because of its chemical stability [19]. The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are
the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes
in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The nonenzymatic
antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on.
The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.

Discussion
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we
found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels
were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress
markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and
serum MDA levels were decreased.

The serum antioxidant levels are significantly lower in depression in our study and previous
reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10 [146] and GSH [4, 38].
Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t
scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules
such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant
therapy can reverse these abnormal oxidative stress parameters. It has proved
these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo
and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of
depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of
PON1Q192R was associated with depression [147]. In addition, poor appetite, psychological
stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle
may also contribute to it [148]. Furthermore, oxidative stress activates the immuneinflammatory
pathways [148]. But some studies supported decrease in albumin, zinc and
HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as
interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of newepitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage [149]. In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].

Malondialdehyde plasma concentration correlates with declarative and working memory in patients with recurrent depressive disorder

Abstract

Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.

Antioxidant /Antidepressant-like Effect of Ascorbic acid (Vitamine
C) and Fluoxetine
Another study investigated the influence of ascorbic acid
(which is an antioxidant with antidepressant-like effects in animals)
on both depressive-like behaviour induced by a chronic unpredictable
stress (CUS) paradigm and on serum markers of oxidative
stress and in cerebral cortex and hippocampus of mice [120]. The
CUS-model is an animal model for induced depression-like behaviour
in animals. Depressive-like behaviour induced by CUS was
accompanied by significantly increased lipid peroxidation (cerebral
cortex and hippocampus), decreased catalase (CAT) (cerebral cortex
and hippocampus) and glutathione reductase (GR) (hippocampus)
activities and reduced levels of glutathione (cerebral cortex).
Repeated ascorbic acid as well as fluoxetine administration significantly
reversed CUS-induced depressive-like behaviour as well as
oxidative damage. No alterations were observed in locomotor activity
and glutathione peroxidase (GPx) activity in the same sample.
These findings pointed to a rapid and robust effect of ascorbic acid
in reversing behavioural and biochemical alterations induced in an
animal model [120].  Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.

 

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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 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.

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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

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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.

A little smile may make you less depressed – Botox and depression treatment

treatment-of-depression-with-onabotulinumtoxina-a-randomized-trial-2013

Summary:

Converging lines of evidence suggest a role for facial expressions in the pathophysiology and treatment of mood disorders. To determine the antidepressant effect of onabotulinumtoxinA (OBA) treatment of corrugator and procerus muscles in people with major depressive disorder, we conducted a double blind, randomized, placebo-controlled trial. In an outpatient clinical research center, eighty-five subjects with DSM-IV major depression were randomized to receive either OBA (29 units for females and 40 units for males) or saline injections into corrugator and procerus frown muscles (74 subjects were entered into the analysis). Subjects were rated at screening, and 3 and 6 weeks after OBA treatment. The primary outcome measure was the response rate, as defined by ! 50% decrease in score on the MontgomeryeAsberg Depression Rating Scale (MADRS). Response rates at 6 weeks from the date of injection were 52% and 15% in the OBA and placebo groups, respectively (Chi-Square (1) ¼ 11.2, p < 0.001, Fisher p < 0.001). The secondary outcome measure of remission rate (MADRS score of 10 or less) was 27% with OBA and 7% with placebo (Chi-square (1) ¼ 5.1, p < 0.02, Fisher p < 0.03). Six weeks after a single treatment, MADRS scores of subjects were reduced on average by 47% in those given OBA, and by 21% in those given placebo (ManneWhitney U, p < 0.0005). In conclusion, a single treatment with OBA to the corrugator and procerus muscles appears to induce a significant and sustained antidepressant effect in patients with major depression.

emotional-proprioception-treatment-of-depression-with-afferent-facial-feedback

We develop the concept of emotional proprioception, whereby the muscles of facial expression play a central role in encoding and transmitting information to the brain’s emotional circuitry, and describe its underlying neuroanatomy. We explore the role of facial expression in both reflecting and influencing depressed mood. The circuitry involved in this latter effect is a logical target for treatment with botulinum toxin, and we review the evidence in support of this strategy. Clinical trial data suggest that botulinum toxin is effective in treating depression. We discuss the clinical and theoretical implications of these data. This novel treatment approach is just one example of the potential importance of the cranial nerves in the treatment of depression.

prospective-analysis-of-the-use-of-onabotulinumtoxina-botox-in-the-treatment-of-chronic-migraine

Background:

Chronic migraine affects 2% of the population. It results in substantial disability and reduced quality of life. Medications used for prophylaxis in episodic migraine may also work in chronic migraine. The efficacy and safety of OnabotulinumtoxinA (BOTOX) in adults with chronic migraine was confirmed in the PREEMPT programme. However, there are few real-life data of its use.

Method: 254 adults with chronic migraine were injected with OnabotulinumtoxinA BOTOX as per PREEMPT Protocol between July 2010 and May 2013, their headache data were collected using the Hull headache diary and analysed to look for headache, migraine days decrements, crystal clear days increment in the month post treatment, we looked at the 50% responder rate as well.

Results: Our prospective analysis shows that OnabotulinumtoxinA, significantly, reduced the number of headache and migraine days, and increased the number of headache free days. OnabotulinumtoxinA Botox also improved patients’ quality of life. We believe that these results represent the largest post-marketing cohort of patients treated with OnabotulinumtoxinA in the real-life clinical setting.

 Conclusion: OnabotulinumtoxinA is a valuable addition to current treatment options in patients with chronic migraine. Our results support findings of PREEMPT study in a large cohort of patients, we believe, is representative of the patients seen in an average tertiary headache centre. While it can be used as a first line prophylaxis its cost may restrict its use to more refractory patients who failed three oral preventive treatments

http://www.botoxfordepression.com/ < Website promoting botox use for depression

 

Insane Medicine – Inflammation as a cause of psychiatric conditions!

 

 

 

 

Clustering of Depression and Inflammation in Adolescents Previously Exposed to Childhood Adversity

http://www.sobp.org/files/public/BPS%20Press%20Release_Miller%20and%20Cole_FINAL.pdf   <<< Childhood Adversity Increases Risk for Depression and Chronic Inflammation

Insane Medicine – Cardiac Rehabilitation will save your life

Cardiac rehab and healthy eating save lives
Cardiac rehab and healthy eating save lives!

eat healthy

  • Have you had a heart attack? Then why aren’t you in cardiac rehab if your doctor says it’s okay?
  • Those who are involved in cardiac rehab have a 47 % decrease in heart attack risk over the next two years! Also, those who participate have fewer hospital admissions and live longer.
  • Cardiac rehab is an option post-heart attack, as well as for those with arrhythmias and heart failure. It is associated with decreased mortality and prolonged survival.
  • Cardiac Rehab is coached by trained professionals who teach you how to appropriately exercise based on your capabilities and prescription. This improves your functional status.
  • It also involves nutritional counseling, teaching the patient to eat a low fat and sodium diet to help manage cholesterol levels and blood pressure. This allows you to maintain a healthy weight.
  • cardiac rehab also helps you maintain a regimen. More important, one must take their prescribed medications for optimal outcomes. Compliance leads to success. Education about medications that are important is a key  factor.
  • Cardiac rehab also educates one to avoid unhealthy habits, such as smoking and maintaining diet. likewise, the mental aspect of a post-cardiac condition is crucial in maximizing outcomes. Depression and other mental disorders must be fully addressed and treated.
  • Exercise creates stronger muscles and improved cardiovascular fitness that improves ones emotional state as well. Cardiac rehab must be continued in the home environment for maximal impact.
  • The journal BMJ showed that even a little bit of exercise provides noticeable benefits of health. the goal is 150 minutes of exercise per week, but even small amounts of physical activity may decrease the mortality risk.
  • Exercise helps with depression and boosts your natural endorphins that make you feel better, resulting in increased energy levels. Exercise allows you to take control of your life and is a mood enhancer that gives you an overall sense of well-being.
  • Depression and anxiety can be blunted by such exercise programs, especially when they are maintained at home as well. Meditation and behavior modification are key components to creating a healthy lifestyle. People who are depressed and feel hopeless have a higher rate of dying from their cardiac disease. exercise at least 30 minutes a day, working your way up to that amount even if you don’t have the internal motivation to do so.

Insane Medicine – Lowering Dementia Risk

Dementia
Dementia

Research is demonstrating that treating multiple risk factors for dementia results in better outcomes than treating each factor individually. Risk factors include:

  1. Poor nutrition
  2. obesity’smoking
  3. physical inactivity
  4. cardiovascular risks
  5. depression
  6. social isolation
  7. lack of mental stimulation

Strategies to help deal with these risks have been shown to help improve cognitive performance. Just treating single variables such as high blood pressure or lack of exercise has less effect than hitting multiple factors at once. A study in Lancet Neurology (August 2014) revealed that one-third of Alzheimer’s Disease (AD) cases are attributable to modifiable factors and thus AD may be reduced in prevalence by improved education , treatment of depression, and management of vascular risk factors such as physical inactivity, smoking, hypertension, obesity, and diabetes.

  • Get regular exercise: this reduces stress, improves blood flow to the brain, strengthens connection of neurons in the brain, improves medical health and balance, thus reducing falls. The goal is 30 minutes of aerobic activity five times a week (walking, dancing, biking as examples) and strength training twice a week.
  • Challenge your brain: Demanding brain activities utilizing different aspects of your intellect help protect against cognitive decline, making your mind more efficient and able to focus. So expose yourself to new ideas and challenges mentally, so that you can maintain your memory skills and concentration abilities. Things like cross-word puzzles, checkers or cards help build up your brain as do math problems. Research shows that staying intellectually engaged may prevent AD. These types of brain challenges add to your cognitive reserve. Social interaction also plays a role in preventing cognitive decline. It has been found that those who play more games or puzzles were more likely to perform better on test of memory, learning, and information processing. They also have greater brain volume in areas associated with memory. Mental workouts enhance brain blood flow and promote cell growth, stronger neuron connections, and keep the brain efficient. It makes the brain less sensitive to trauma such as drugs, stroke, or disease. The internet has resources to help:  http://brainworkshop.sourceforge.net/  or http://sporcle.com/  or http://syvum.com/teasers/  or http://www.braingle.com/  or http://www.billsgames.com/brain-teasers/   So consider crossword puzzles, jigsaw puzzles, word searches, math problems, an brainteasers to exercise your mind!
  • Treat mental illness, especially depression: Sadness, hopelessness, and lack of energy may signal depression. Depression is associated with a high risk of cognitive decline. See your doctor to help get treatment.
  • Eat a healthy diet: Eat complex carbohydrates such as whole grains, legumes, fruits, and vegetables. Avoid sodas, sweets, and excess sugars. Protein is essential for growth and cell maintenance, so consider lean meats, fish, poultry, eggs, low fat dairy,  nuts, and beans. Chose healthy fats such as omega-3 fatty acids found in flaxseed oil, fish, and nuts. Monounsaturated fats are also healthful and is present in olive and canola oils. Polyunsaturated fats from corn, safflower, and sunflower seeds are fine as well. Avoid trans-fats. Remember to include your micronutrients and phytochemicals (found in plant sources).
  • Treat cardiovascular risks: Stop smoking, lose weight, be physically active, treat high blood pressure and diabetes, take your prescribed medications.

Avoid Trans-fats in your diet. It is found in many junk foods, especially fast foods, processed foods, baked goods, margarine, and other sources. These products and trans-fats perform about 10% worse on cognitive tests than those who consumed minimal amounts. Trans-fats promote oxidative stress and damage the memory center of the brain, the hippocampus.

Magnesium is essential for brain functioning. It is found in green leafy vegetables, whole grains, nuts, legumes, and hard water. Magnesium helps in energy production, needed especially in the brain. It helps in the formation and release of neurotransmitters as well as functioning of connections in the brain (synapses) to process new information. Studies in Molecular Brain (September 2014) demonstrated that magnesium L-threonate (MgT) supplementation prevented memory decline and prevented synapse loss in mice prone to AD. It also reduced the deposition of beta-amyloid protein in the brain (a cause of AD) Risk factors for magnesium depletion include chronic alcoholism, diabetes, excessive coffee intake, inflammatory bowel disease such as Chrone’s disease, diuretic intake, liver and kidney disease,  and excessive soda and salt intake.The RDA is 400 mg a day – http://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/  This link points to sources of magnesium for your diet. Foods included are Almonds, spinach, cashews, peanuts, shredded wheat cereal, soy milk, black beans, whole wheat bread, avocado, baked potato, brown rice, plain yogurt, and others.

This sounds dumb but avoid head injury – it has been shown that older adults who have a head injury are at higher risk of dementia, especially over the age of 65. The main reason for these injuries are falls, many of which are preventable and may be due to deconditioning and weakness from lack of exercise. Remember that exercise increases strength and balance.

Remember to not be anxious over your health – don’t become a hypochondriac. Maintain your health through proper eating, exercise, risk management of cardiovascular problems (high blood pressure, high cholesterol, smoking cessation), taking your prescribed medications, and regular physician check-ups will maximize your health. Don’t get preoccupied with health matters and fears of disease such that they interfere with your daily activities and enjoyments in life. Keep yourself busy and distracted by learning new tasks and volunteering. Consider meditation, relaxing your body and mind, concentrating on the present moment. Exercise your body to reduce stress and reduce your anxiety. This will build your physical strength and increase your feelings of well-being. Keep your head up with positive feeling and be grateful for the good things in your life and those things you can control. Don’t stress out!!

 

 

 

Insane medicine: Pregnant mothers may need to watch their fat intake during pregnancy – it may affect their children!

Insane medicine - Fat mice get fat by eating fat diets. The effect damages their progeny.
Insane medicine – Fat mice get fat by eating fat diets. The effect damages their progeny.
  • The average American diet has 37% fat content. The recommended amount is 25-35% according to the 2010 dietary guidelines. Four studies have shown the bad impact that high fat consumption during pregnancy has on the fetus.
  • Mice fed 45 % fat diets during pregnancy demonstrated deficits in memory with higher anxiety and depression scores as well! What’s worse is there was epigenetic effect as well – the following generation of mice displayed memory loss and behavioral change as well. Here is the link: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3527&sKey=f830412f-200d-4363-8e53-e8af37236afe&cKey=f00a8887-5be2-467f-a500-480d7b3bcac8&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7
  • A study in rats also showed that the mother’s diet, if high in saturated fat and branched chain amino acids(BCAA), would prime the microglia of their offspring. Microglia are the mmune cells of the brain and will secrete pro-inflammatory cytokines in the hippocampus (a learning center). Also high levels of BCAA compete with tryptophan transport across the blood brain barrier. When there is less tryptophan in the brain, the brain makes less serotonin which then results in anxiety! The pups were found to have depression and anxiety scores that were much higher than pups born to mothers who ate a more fat-restricted diet. Here is the link: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=8d86b6b5-65d9-4dc4-9b97-53b5a5db4027&cKey=529d5e00-6f15-426c-8ee3-c9c61424e666&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7
  • Other studies demonstrated that a high fat diet in the pregnant mother causes the down-regulation of oxytocin systems in the brain of offspring and causes anxiety to be prevalant in the progeny. This effect does not occur in the pups of normal fed pregnant female rats. In this study it was found that the fewer numbers of oxytocin-positive neurons within the PVN (paraventricular nucleus), the more anxious the rats were as adults. Oxytocin projections to the brainstem acts as an appetite suppressant,  hence leading to overeating in the progeny of overfed pregnant females. Oxytocin also plays a role in maternal behaviors as well. Mother rats literally groom their daughters to be attentive or neglectful mothers themselves and this is associated with the presence of normal numbers of oxytocin projections. If a rat has fewer oxytocin projections, they will be neglectful parents more likely. Hence multiple pathways of brain function  may be affected in the young of a high-fat diet mother. Here is a link: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=93a801db-9e49-4d58-b917-97948ec69a18&cKey=74611e5c-0fa7-4ff0-9276-b94be31da2df&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7
  • These effects also occur in primate studies as well – monkeys whose mothers are fed high fat diets have fewer dopamine projections to the nucleus accumbens ‘reward center’ of the brain. As a result, they have a reward deficiency when they eat food and don’t get satiated at a normal level of food. Rather, they  must take in more food to get the same amount of reward as another monkey that came from a normal-fed mother and had normal dopamine projections in the brain. Thus they get fatter.
  • Dietary guidelines recommend a diet of 25-27% fat. See this link for the recommendations of a standard diet:  http://www.health.gov/dietaryguidelines/dga2010/DietaryGuidelines2010.pdf  However, the average person takes in 37% fat or more!! See this link showing how much we really take in:  http://jn.nutrition.org/content/140/10/1832.long
  • We eat more than we think. We need to recognize that our food choices and stress patterns can affect our children through epigenetic mechanisms especially. We can set up our children for failure. These studies are done in standard models for humans and show the impact high fat diets in pregnancy  have on their children: Memory deficits, anxiety, depression, and future weight problems may echo the studies in rat and monkey populations.  The apple doesn’t fall far from the tree, for it seems that overweight parents have overweight children. Food for thought!!
  • http://fatmouse.org/