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Psychology

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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Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

January 29, 2012 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., … Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America, 109(6), 2138-2143. http://dx.doi.org/10.1073/pnas.1119598109
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Could MDMA be useful in the treatment of post-traumatic stress disorder?

December 15, 2011 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By /

Abstract

In recent studies, 3,4-methylenedioxymethylamphetamine (MDMA) has shown promise in the treatment of post-traumatic stress disorder (PTSD) as an adjunct to post-trauma psychological therapy. However, because of historical associations with its use as the recreational drug ecstasy, MDMA research remains a controversial subject. Dr Sessa discusses these controversies and describes a UK-based MDMA/PTSD currently in development.

Sessa, B. (2011). Could MDMA be useful in the treatment of post-traumatic stress disorder? Progress in Neurology and Psychiatry, 15(6), 4–7. http://dx.doi.org/10.1002/pnp.216
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Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

September 28, 2011 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

The serotonin-2A receptor (5-HT2AR) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT2AR or 5-HT1AR agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT2A/2CR antagonist ketanserin. A total of 16 healthy participants received placebo,ketanserin (40 mg p.o.), psilocybin (260 µg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT2AR stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT2AR system.

Quednow, B. B., Kometer, M., Geyerand, M. A., & Vollenweider, F. X. (2012). Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers. Neuropsychopharmacology, 37, 630-640. http://dx.doi.org/10.1038/npp.2011.228
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Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness

September 28, 2011 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , ,

Abstract

A large body of evidence, including longitudinal analyses of personality change, suggests that core personality traits are predominantly stable after age 30. To our knowledge, no study has demonstrated changes in personality in healthy adults after an experimentally manipulated discrete event. Intriguingly, double-blind controlled studies have shown that the classic hallucinogen psilocybin occasions personally and spiritually significant mystical experiences that predict long-term changes in behaviors, attitudes and values. In the present report we assessed the effect of psilocybin on changes in the five broad domains of personality – Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness. Consistent with participant claims of hallucinogen-occasioned increases in aesthetic appreciation, imagination, and creativity, we found significant increases in Openness following a high-dose psilocybin session. In participants who had mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than 1 year after the session. The findings suggest a specific role for psilocybin and mystical-type experiences in adult personality change.

MacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011). Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness. Journal of Psychopharmacology, 25(11), 1453-1461. http://dx.doi.org/10.1177/0269881111420188
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Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion

September 16, 2011 / Ayahuasca, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

The hallucinogenic brew Ayahuasca, a rich source of serotonergic agonists and reuptake inhibitors, has been used for ages by Amazonian populations during religious ceremonies. Among all perceptual changes induced by Ayahuasca, the most remarkable are vivid “seeings.” During such seeings, users report potent imagery. Using functional magnetic resonance imaging during a closed-eyes imagery task, we found that Ayahuasca produces a robust increase in the activation of several occipital, temporal, and frontal areas. In the primary visual area, the effect was comparable in magnitude to the activation levels of natural image with the eyes open. Importantly, this effect was specifically correlated with the occurrence of individual perceptual changes measured by psychiatric scales. The activity of cortical areas BA30 and BA37, known to be involved with episodic memory and the processing of contextual associations, was also potentiated by Ayahuasca intake during imagery. Finally, we detected a positive modulation by Ayahuasca of BA 10, a frontal area involved with intentional prospective imagination, working memory and the processing of information from internal sources. Therefore, our results indicate that Ayahuasca seeings stem from the activation of an extensive network generally involved with vision, memory, and intention. By boosting the intensity of recalled images to the same level of natural image, Ayahuasca lends a status of reality to inner experiences. It is therefore understandable why Ayahuasca was culturally selected over many centuries by rain forest shamans to facilitate mystical revelations of visual nature.

de Aurojo, D. B., Ribeiro, S., Cecchi, G. A., Carvalho, F. M., Sanchez, T. A., Pinto, J. P., … Santos, A. C. (2011). Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion. Human Brain Mapping, 33(11), 2550-2560. http://dx.doi.org/10.1002/hbm.21381
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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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MDMA-Assisted Psychotherapy Using Low Doses in a Small Sample of Women with Chronic Posttraumatic Stress Disorder

September 8, 2011 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , , , ,

Abstract

The purpose of this study was to investigate the safety of different doses of MDMA-assisted psychotherapy administered in a psychotherapeutic setting to women with chronic PTSD secondary to a sexual assault, and also to obtain preliminary data regarding efficacy. Although this study was originally planned to include 29 subjects, political pressures led to the closing of the study before it could be finished, at which time only six subjects had been treated. Preliminary results from those six subjects are presented here. We found that low doses of MDMA (between 50 and 75 mg) were both psychologically and physiologically safe for all the subjects. Future studies in larger samples and using larger doses are needed in order to further clarify the safety and efficacy of MDMA in the clinical setting in subjects with PTSD.

Bouso, J. C., Doblin, R., Farré, M., Alcázar, M. Á., & Gómez-Jarabo, G. (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of psychoactive drugs, 40(3), 225-236., 10.1080/02791072.2008.10400637
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Combating substance abuse with ibogaine: pre- and posttreatment recommendations and an example of successive model fitting analyses

September 7, 2011 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Ibogaine is an indole alkaloid derived from the root bark of the African shrub Tabernan the iboga and it has been used for many years as a medicinal and ceremonial agent in West Central Africa. Furthermore, both anecdotal observations and recent studies suggest that ibogaine alleviates withdrawal symptoms and reduces drug cravings. Although ibogaine articles typically include information bearing on the duration of drug abstinence following treatment, little if any attention is given to the psychological and environmental factors that might facilitate a positive treatment outcome. Hence, a major purpose of the present review is to suggest a number of theory-driven, pretreatment and posttreatment recommendations that have good potential for enhancing ibogaine’s effectiveness. The second major purpose of this review is to demonstrate, through a reanalysis of previously published results, the utility of conducting successive model fitting analyses on ibogaine treatment data. Such analyses are useful for determining both the strength and form of the association between pre-ibogaine treatment variables and post-ibogaine treatment outcomes. Finally, in order to facilitate future quantitative reviews, the authors recommend that a minimum set of patient- and treatment-related variables be included in all ibogaine publications involving human participants.

Hittner, J. B., & Quello, S. B. (2004). Mechanisms of antiaddictive actions of ibogaine. Journal of Psychoactive Drugs, 36(2), 191-199. http://dx.doi.org/10.1080/02791072.2004.10399729
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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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