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Psychology

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

October 1, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, 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 / 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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Self-Medication of LSD and MDMA to Treat Mental Disorders: A Case Series

September 18, 2013 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, MDMA, Papers, 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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Psychedelics linked to lower mental health risks

December 6, 2021 / Psychology, Publications / By

The use of LSD, magic mushrooms, or peyote does not increase a person’s risk of developing mental health problems, according to an analysis of information from more than 130,000 randomly chosen people, including 22,000 people who had used psychedelics at least once.

Researcher Teri Krebs and clinical psychologist Pål-Ørjan Johansen, from the Norwegian University of Science and Technology’s (NTNU), cleverly used data from a US national health survey to study the association between psychedelic drug use and mental health problems.

The researchers relied on data from the 2001-2004 National Survey on Drug Use and Health, in which participants were asked about mental health treatment and symptoms of a variety of mental health conditions over the past year. The specific symptoms examined were general psychological distress, anxiety disorders, mood disorders, and psychosis.

The study showed that lifetime use of psilocybin or mescaline and past year use of LSD were associated with lower rates of serious psychological distress. Lifetime use of LSD was also significantly associated with a lower rate of outpatient mental health treatment and psychiatric medicine prescription, although the nature of these relations were not demonstrated in the Norwegians’ study.

Interestingly, the results of this study confirm the outcomes of recent clinical trials that likewise do not demonstrate lasting harmful effects from the use of psychedelics in a clinical setting. It further shows that even when used non-clinically, psychedelic substances might be able to play a role in alleviating mental health issues.

The results are published in the journal PLOS One and are freely available online.

A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment

September 1, 2013 / Ayahuasca, DMT, Iboga / Ibogaine, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.

Burdick, B. V., & Adinoff, B. (2013). A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment. The American Journal of Drug and Alcohol Abuse, 39(5), 291-297. http://dx.doi.org/10.3109/00952990.2013.811513
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Psychedelics and Mental Health: A Population Study

August 19, 2013 / MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Abstract

Background
The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.

Objective
To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.

Method
Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.

Results
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion
We did not find use of psychedelics to be an independent risk factor for mental health problems.

Krebs, T. S., & Johansen, P. Ø. (2013) Psychedelics and Mental Health: A Population Study. PLoS ONE, 8(8), 1-9. http://dx.doi.org/10.1371/journal.pone.0063972
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Spatiotemporal Brain Dynamics of Emotional Face Processing Modulations Induced by the Serotonin 1A/2A Receptor Agonist Psilocybin

July 16, 2013 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168–189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211–242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168–189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211–242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.

Bernasconi, F., Schmidt, A., Pokorny, T., Kometer, M., Seifritz, E., & Vollenweider, F. X. (2013). Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin. Cerebral Cortex, bht178. 10.1093/cercor/bht178
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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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Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users.

June 21, 2013 / Ayahuasca, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

BACKGROUND:
Ayahuasca, a South American psychotropic plant tea containing the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine, has been shown to increase regional cerebral blood flow in prefrontal brain regions after acute administration to humans. Despite interactions at this level, neuropsychological studies have not found cognitive deficits in abstinent long-term users.

OBJECTIVES:
Here, we wished to investigate the effects of acute ayahuasca intake on neuropsychological performance, specifically on working memory and executive function.

METHODS:
Twenty-four ayahuasca users (11 long-term experienced users and 13 occasional users) were assessed in their habitual setting using the Stroop, Sternberg, and Tower of London tasks prior to and following ayahuasca intake.

RESULTS:
Errors in the Sternberg task increased, whereas reaction times in the Stroop task decreased and accuracy was maintained for the whole sample following ayahuasca intake. Interestingly, results in the Tower of London showed significantly increased execution and resolution times and number of movements for the occasional but not the experienced users. Additionally, a correlation analysis including all subjects showed that impaired performance in the Tower of London was inversely correlated with lifetime ayahuasca use.

CONCLUSIONS:
Acute ayahuasca administration impaired working memory but decreased stimulus-response interference. Interestingly, detrimental effects on higher cognition were only observed in the less experienced group. Rather than leading to increased impairment, greater prior exposure to ayahuasca was associated with reduced incapacitation. Compensatory or neuromodulatory effects associated with long-term ayahuasca intake could underlie preserved executive function in experienced users.

Bouso, J. C., Fábregas, J. M., Antonijoan, R. M., Rodríguez-Fornells, A., & Riba, J. (2013). Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users. Psychopharmacology, 230(3), 415-424. http://dx.doi.org/10.1007/s00213-013-3167-9
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Peak Experiences of Psilocybin Users and Non-Users

June 4, 2013 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Abstract

Maslow (1970) defined peak experiences as the most wonderful experiences of a person’s life, which may include a sense of awe, well-being, or transcendence. Furthermore, recent research has suggested that psilocybin can produce experiences subjectively rated as uniquely meaningful and significant (Griffiths et al. 2006). It is therefore possible that psilocybin may facilitate or change the nature of peak experiences in users compared to non-users. This study was designed to compare the peak experiences of psilocybin users and non-users, to evaluate the frequency of peak experiences while under the influence of psilocybin, and to assess the perceived degree of alteration of consciousness during these experiences. Participants were recruited through convenience and snowball sampling from undergraduate classes and at a musical event. Participants were divided into three groups, those who reported a peak experience while under the influence of psilocybin (psilocybin peak experience: PPE), participants who had used psilocybin but reported their peak experiences did not occur while they were under the influence of psilocybin (non-psilocybin peak experience: NPPE), and participants who had never used psilocybin (non-user: NU). A total of 101 participants were asked to think about their peak experiences and complete a measure evaluating the degree of alteration of consciousness during that experience. Results indicated that 47% of psilocybin users reported their peak experience occurred while using psilocybin. In addition, there were significant differences among the three groups on all dimensions of alteration of consciousness. Future research is necessary to identify factors that influence the peak experiences of psilocybin users in naturalistic settings and contribute to the different characteristics of peak experiences of psilocybin users and non-users.

Cummins, C., & Lyke, J. (2013). Peak Experiences of Psilocybin Users and Non-Users. Journal of psychoactive drugs, 45(2), 189-194. 10.1080/02791072.2013.785855
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