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Depression

Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial

October 1, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

OBJECTIVE:
Synthesize and assess the available scientific evidence from the period 2008-2012 on interventions of demonstrated efficacy in the treatment and rehabilitation of adolescents and adults engaged in the problematic use of alcohol and other substances.

METHODS:
A systematic review was undertaken with search and analysis of national and international literature on the subject in Spanish and English in the main international databases: PubMed/MEDLINE, LILACS, Embase, PsycINFO, SciELO, the databases of the York University Centre for Reviews and Dissemination (DARE, ETS Database), the Cochrane Library, and other sources of gray literature. The search criteria included randomized clinical trials and systematic reviews but excluded observational studies, qualitative studies, and articles of poor methodological quality.

RESULTS:
The final sample consisted of 69 studies. The psychosocial interventions shown to be effective were cognitive behavioral therapy, family interventions, self-help interventions using the Internet, couples behavioral therapy, community strengthening and family training, telephone monitoring and support, and integrated therapy for substance abuse disorder with anxiety and depression comorbidity. Pharmacological interventions of demonstrated effectiveness were acamprosate, lysergic acid diethylamide (LSD), and benzodiazepines in problematic alcohol use, as well as maintenance therapy with high-dose opioids.

CONCLUSIONS:
The demonstrated effectiveness of psychosocial and pharmacological interventions is slight but significant. However, strongly multidisciplinary interventions that use a cognitive behavioral approach and the involvement of people close to the consumer, as well as some of the specific pharmacological interventions, have been shown to yield the best results in terms of indicators of abstinence and prevention of relapses.

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., … Mathew, S. J. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 170(10), 1134-1142. http://dx.doi.org/10.1176/appi.ajp.2013.13030392
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Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use?

October 1, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Editorial

Treatment-resistant depression is a significant clinical problem with great morbidity and mortality (1). The report by Murrough et al. (2), published concurrently with this editorial, of their two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression is an exciting and important step in evaluating a new and promising approach for these patients. Should our desire as clinicians to help these often desperate patients propel us to adopt ketamine now, or do we need to know more before proceeding? More studies, or change practice now? Let’s take a look.

The effect of ketamine on treatment-resistant depression appears to be both quick and quite substantial. Overall, two-thirds (64%) of the patients in the trial of Murrough et al. (2) responded, and about one-third (number needed to treat, or NNT, 2.8) responded specifically to ketamine, which is a large effect size. By way of comparison, the NNT in placebo-controlled phase 3 Food and Drug Administration registration trials is 6–7 in depressed outpatients who are not treatment resistant. About half of those in the Murrough et al. study who responded to ketamine relapsed over the next week—apparently without a sharp increase in suicidal ideation. Distressing adverse events were encountered on both the day of and the day following the infusion—including anxiety, which might raise the risk of suicidal thinking. Overall, eight of the 47 patients who received ketamine (17%) had significant dissociative symptoms, which could be quite disturbing to persons with borderline personality disorder. Blood pressure in the ketamine group rose from 122/72 mm Hg (pretreatment) to 141/81 (40 minutes after infusion), and two subjects required their infusions to be stopped for hemodynamic reasons. Other adverse effects were reported.

We do not know who responds to ketamine and who does not. An intriguing suggestion from Laje et al. (3), noted by Murrough et al. in their discussion, is that some of those patients who do not respond to ketamine are carriers of a Val66Met (rs6265) single-nucleotide polymorphism (SNP) that is associated with an attenuation of brain-derived neurotrophic factor (BDNF) functioning).

How certain and generalizable are the findings from this report? The internal validity of the study might be challenged since the subjective effects of midazolam are likely to be quite different than those of ketamine. If blinding was incomplete, the NNT might be larger. On the other hand, the overall study results were comparable at the two individual sites. Furthermore, as Murrough et al. note, additional studies of ketamine in treatment-resistant depression that provide similar response rates or effect sizes have been reported.

While certainty of the results is seemingly high, generalizability is much more limited since the inclusion and exclusion criteria were quite selective and properly so. Only 73 of the 116 screened participants entered the study. Those with acute suicidal risk, history of psychosis, unstable general medical conditions, substance abuse in the last 2 years, abnormal ECGs, or various other features were excluded.

In patients with nonresistant depression, we know that over three out of four who do receive antidepressant medication in practice are excluded from well-designed, internally valid randomized placebo-controlled phase 3 trials (4). The inclusion and exclusion criteria in the trial of Murrough et al. (2) were at least as, if not more, restrictive than those in the usual phase 3 trials. Perhaps only one in four patients with treatment-resistant depression in practice would have been eligible to enter this particular trial. Consequently, we do not know whether ketamine is safe or effective in a wider, more representative group of patients with treatment-resistant depression for whom ketamine is likely to be used. Potential risks in this wider group include exacerbation of prior or even concurrent psychiatric or general medical conditions—borderline personality disorder, posttraumatic stress disorder; bipolar spectrum disorders, substance abuse, cardiovascular problems, etc.

Additional practical issues loom. For example, all of the subjects in the trial of Murrough et al. were medication free for at least 7 days (28 days for fluoxetine) prior to the ketamine infusion. In practice, the acquisition of a 7-day medication-free state in patients with treatment-resistant depression is very challenging given the exigencies of practice and restrictive coverage policies. The effects of ketamine when used in patients who are taking other psychotropic agents represents an unexplored risk in ketamine treatment of patients with treatment-resistant depression.

In addition, how to manage those patients who both do and do not respond to ketamine is unknown but very important. Do the previously ineffective antidepressant medications now work in ketamine responders, so that the follow-on treatment is a return to these medications? Are repeated ketamine infusions called for in the nonresponders or responders? Do they work?

While we lack several key pieces of information that are needed before we revise practice, this study does take several important steps: 1) it provides strong clinical evidence that the pathways targeted by ketamine deserve greater investigation and should be targets for drug development; 2) it suggests that some SNPs may usefully exclude at least some patients with treatment-resistant depression from ketamine infusion, which is an important step in targeting treatment (5); and 3) it suggests that with informed consent, a wider range of patients with treatment-resistant depression should be studied under controlled circumstances to better identify those who should and should not get ketamine—whether because of lack of efficacy or because of side effects. Multisite registries using an open design or point-of-care randomized trial designs (6) could be a rapid way to move the field forward at lower costs to elaborate on the risks as well as the pretreatment predictors of ketamine treatment.

While insufficient to recommend a wholesale change in practice presently, these results certainly provide substantial hope for patients with treatment-resistant depression, insight into the biology of this condition, and a major obligation by clinician scientists and funding agencies to answer this next set of important clinical questions for our patients with refractory depression.

Rush, A. J. (2013) Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use? American Journal of Psychiatry, 170(10), 1079-1081. http://dx.doi.org/10.1176/appi.focus.12.2.244
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Self-Medication of LSD and MDMA to Treat Mental Disorders: A Case Series

September 18, 2013 / Anxiety disorders / PTSD, Depression, LSD, MDMA, Other subjects, Papers, Psychiatry, Psychology, Publications / By /

Abstract

50 years ago LSD was prescribed to treat a variety of mental illnesses. More recently LSD and MDMA (ecstasy) have become widely used outside medicine as both recreational drugs and by some patients as ‘self-medication’. These brief reports gather together five patients’ experiences using psychedelic drugs to treat their mental disorders. They are discussed in relation to the medical profession’s current growing interest in re-visiting psychedelic drugs as therapeutic treatments in psychiatry. The first case describes the successful self-treatment for depression using LSD, followed by a case in which doctors administered LSD in the 1960s and 1970s to successfully treat a case of obsessive-compulsive disorder (OCD) and chronic fatigue syndrome. The third and fourth cases describe the successful self-treatment of OCD using respectively MDMA and then LSD and the final case describes a self-treatment with LSD to manage Anorexia Nervosa. All the participants describing their use of these drugs give a positive report of self-treatment with minimal adverse effects. They also all support a resumption of more research into the therapeutic use of hallucinogens/psychedelic drugs as potential clinical therapies.

Sessa, B. (2010). Self-medication of LSD and MDMA to treat mental disorders: A case series. The Journal of Alternative Medicine Research, 2(2), 245-249.
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Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression

June 25, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

OBJECTIVES:
Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.
METHODS:
In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.
RESULTS:
Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.
CONCLUSION:
The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.
Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., & Palenicek, T. (2013). Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinology Letters, 34(4), 287-293.
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NMDA Receptor Antagonists for Treatment of Depression

April 3, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

Ates-Alagoz, Z., & Adejare, A. (2013). NMDA Receptor Antagonists for Treatment of Depression. Pharmaceuticals, 6(4), 480-499. http://dx.doi.org/10.3390/ph6040480
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Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors

December 19, 2012 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

Background
Serotonin (5-HT) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders. These receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects. However, the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown.

Methods
In a randomized, double-blind study, 17 healthy human subjects received on 4 separate days placebo, psilocybin (215 g/kg), the preferential 5-HT2A antagonist ketanserin (50 mg), or psilocybin plus ketanserin. Mood states were assessed by self-report ratings, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues.

Results
Psilocybin enhanced positive mood and attenuated recognition of negative facial expression. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression.

Conclusions
This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. These findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin’s putative antidepressant effects.

Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., Seifritz, E., & Vollenweider, F. X. (2012). Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors. Biological Psychiatry, 72(11), 898-906. http://dx.doi.org/10.1016/j.biopsych.2012.04.005
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The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions

July 27, 2012 / Anxiety disorders / PTSD, Depression, Ketamine, Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychology, Publications / By / , , , ,

Abstract

Rationale
Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases.

Objectives
This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases.

Methods
S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP.

Results
Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces.

Conclusion
This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.

Schmidt, A., Kometer, M., Bachmann, R., Seifritz, E., & Vollenweider, F.X. (2012). The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. Psychopharmacology, 225(1), 227-239. http://dx.doi.org/doi:10.1007/s00213-012-2811-0
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Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

January 31, 2012 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Background

Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample.

Methods

In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion.

Results

Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point.

Conclusion

This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Zarate Jr., A., Brutsche, N. E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N., Cravchik, A., … Luckenbaugh, D. A. (2011). Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial. Biological Psychiatry, 71(11), 939-946. http://dx.doi.org/10.1016/j.biopsych.2011.12.010
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A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department

September 1, 2011 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

We examined the preliminary feasibility, tolerability and efficacy of single-dose, intravenous (i.v.) ketamine in depressed emergency department (ED) patients with suicide ideation (SI). Fourteen depressed ED patients with SI received a single i.v. bolus of ketamine (0.2 mg/kg) over 1–2 min. Patients were monitored for 4 h, then re-contacted daily for 10 d. Treatment response and time to remission were evaluated using the Montgomery–Asberg Depression Rating Scale (MADRS) and Kaplan–Meier survival analysis, respectively. Mean MADRS scores fell significantly from 40.4 (S.E.M.=1.8) at baseline to 11.5 (S.E.M.=2.2) at 240 min. Median time to MADRS score f10 was 80 min (interquartile range 0.67–24 h). SI scores (MADRS item 10) decreased significantly from 3.9 (S.E.M.=0.4) at baseline to 0.6 (S.E.M.=0.2) after 40 min post-administration ; SI improvements were sustained over 10 d. These data provide preliminary, open-label support for the feasibility and efficacy of ketamine as a rapid-onset antidepressant in the ED.

Larkin, G. L., & Beautrais, A. L. (2011). A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. International Journal of Neuropsychopharmacology, 1127-1131. http://dx.doi.org/10.1017/S1461145711000629

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Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

August 1, 2011 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10 mg/kg and ketamine at the dose of 5 mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20 mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.

Réus, G. Z., Stringari, R. B., Ribeiro, K. F.,  Ferraro, A. K.,  Vitto, M. F., Cesconetto, P., … Quevedo, J. (2011). Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behavioural Brain Research, 221(1), 166-171. http://dx.doi.org/10.1016/j.bbr.2011.02.024
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30 April - Q&A with Rick Strassman

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