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Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use?

October 1, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, 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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Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression

June 25, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, 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 / Depressive Disorders, Ketamine, Papers, Psychology, 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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The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

March 19, 2013 / Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)–2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

Roth, B. L., Gibbons, S., Arunotayanun, W., Huang, X. P., Setola, V., Treble, R., & Iversen, L. (2013). The ketamine analogue methoxetamine and 3-and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One, 8(3), e59334. http://dx.doi.org/10.1371%2Fjournal.pone.0059334
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Hallucinogen persisting perception disorder: what do we know after 50 years?

March 1, 2013 / DMT, Ketamine, LSD, MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / ,

Abstract

‘Flashbacks’ following use of hallucinogenic drugs have been reported for decades; they are recognized in DSM-IV as ‘Hallucinogen Persisting Perception Disorder (Flashbacks)’, or HPPD. We located and analyzed 20 quantitative studies between 1955 and 2001 examining this phenomenon. However, many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, current knowledge of HPPD remains very limited. In particular (1) the term ‘flashbacks’ is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. At present, HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD.

Halpern, J. H., & Harrison, G. P. Jr. (2003). Hallucinogen persisting perception disorder: what do we know after 50 years? Drug and Alcohol Dependence, 69(2), 109-119. http://dx.doi.org/10.1016/S0376-8716(02)00306-X
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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, Depressive Disorders, Ketamine, Mushrooms / Psilocybin, Neuroscience, 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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Quantitative Analysis of Narrative Reports of Psychedelic Drugs

June 1, 2012 / Ayahuasca, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Background

Psychedelic drugs facilitate profound changes in consciousness and have potential to provide insights into the nature of human mental processes and their relation to brain physiology. Yet published scientific literature reflects a very limited understanding of the effects of these drugs, especially for newer synthetic compounds. The number of clinical trials and range of drugs formally studied is dwarfed by the number of written descriptions of the many drugs taken by people. Analysis of these descriptions using machine-learning techniques can provide a framework for learning about these drug use experiences.

Methods

We collected 1000 reports of 10 drugs from the drug information website Erowid.org and formed a term-document frequency matrix. Using variable selection and a random-forest classifier, we identified a subset of words that differentiated between drugs.

Results

A random forest using a subset of 110 predictor variables classified with accuracy comparable to a random forest using the full set of 3934 predictors. Our estimated accuracy was 51.1%, which compares favorably to the 10% expected from chance. Reports of MDMA had the highest accuracy at 86.9%; those describing DPT had the lowest at 20.1%. Hierarchical clustering suggested similarities between certain drugs, such as DMT and Salvia divinorum.

Conclusion

Machine-learning techniques can reveal consistencies in descriptions of drug use experiences that vary by drug class. This may be useful for developing hypotheses about the pharmacology and toxicity of new and poorly characterized drugs.

Coyle, J. R., Presti, D. E., Baggott, M. J. (2012). Quantitative Analysis of Narrative Reports of Psychedelic Drugs.
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Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial

January 31, 2012 / Depressive Disorders, Ketamine, Papers, Psychology, 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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Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence

September 8, 2011 / Ketamine, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

A prior study found that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence (Krupitsky et al. 2002). In this study of the efficacy of single versus repeated sessions of ketamine-assisted psychotherapy in promoting abstinence in people with heroin dependence, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups. Participants in the first group received two addiction counseling sessions followed by two KPT sessions, with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.

Krupitsky, E. M., Burakov, A. M., Dunaevsky, I. V., Romanova, T. N., Slavina, T. Y., & Grinenko, A. Y. (2007). Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence. Journal of psychoactive drugs, 39(1), 13-19. https://dx.doi.org/10.1080/02791072.2007.10399860
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A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department

September 1, 2011 / Depressive Disorders, Ketamine, Papers, Psychology, 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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