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A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

/ Depressive Disorders, Ketamine, Papers, Psychology / / , , , , , ,

Abstract

IMPORTANCE:
Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
OBSERVATIONS:
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
CONCLUSIONS AND RELEVANCE:
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., … & Nemeroff, C. B. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. Jama psychiatry, 74(4), 399-405. 10.1001/jamapsychiatry.2017.0080
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Use of Ketamine in Clinical PracticeA Time for Optimism and Caution

/ Depressive Disorders, Ketamine, Papers, Psychology / / ,

Abstract

Increasing evidence, primarily from small studies, supports the idea that the dissociative anesthetic ketamine has rapid antidepressant effects in patients with treatment-refractory major depression.1 The beneficial effects of ketamine are observed within hours of administration and can last approximately 1 week. Given that up to one-third of patients with major depression fail current treatments,2 there is a clear need for novel and more effective treatments. Results to date have led to increasing off-label use of ketamine in clinical practices, with little guidance about clinical administration. In this issue of the JAMA Psychiatry, Sanacora and colleagues3 provide a much-needed consensus statement to help guide clinical use of ketamine.
Zorumski, C. F., & Conway, C. R. (2017). Use of ketamine in clinical practice: a time for optimism and caution. Jama psychiatry, 74(4), 405-406. 10.1001/jamapsychiatry.2017.0078
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Limitations to ‘Psychedelics and the science of self experience’

/ Papers, Philosophy & Religious Studies, Psychology / / , ,

Abstract

We read Matthew Nour and Robin Carhart-Harris editorial with enthusiasm. The Section History Ethics & Philosophy of Psychiatry Queensland meets once a month in the Brisbane area. The writers of this eLetter met at the end of March 2017and discussed this editorial. We congratulate and we agree with Derek K Tracy in “highlights of this issue” that it is a mesmerising read. We found that the editorial is well composed, interesting in its logic and we notice the structure to the editorial. There are 6 separate headings: defining the self, self in neuroscience, self disturbance , psychedelics as a window into the self, therapeutic implications, and conclusions. We discussed that overall the paper only presents a reductionist, non-compatabilist, materialist theory of self, which becomes a fallacy of a circular argument. For the purpose of this editorial such a reduction of a complex philosophical area is indeed suitable, but ignores other models and we miss a paragraph on these limitations. We feel that it would have assisted if there had been frank comments on the reductionist approach and the diverse facets to self relevant to psychiatry.
The quantitative meta analysis locates self experience to default mode network in a cortical median and anterior cingulate brain anatomy. Other theories of the self in the light of memories and emotions for example, made us curious about FMRI findings in the amygdala and hippocampal areas. However acknowledging FMRI as “correlation”, the subtext is identity with the subject of the correlation.
We were reminded that after all the self is a very complex philosophical area that preoccupied many eminent thinkers in the past (Remes P& Sihvola) We believe that also a discussion of other pathologies of self, multiple selves associated with dissociation and multiple personality disorder would have been more inclusive. We were curious about the role of language especially in people who speak several languages as the narrative (McAdams) of the self is based on semantics.
We believe that a paragraph highlighting the limitations to the approach would have made this a more balanced editorial. Also referencing evidence on psychedelics and clinical experience of their use, references that highlight a number of the risks and side effects (Larsen JK and Johnson M et al) would have added . There are merits in to including that psychedelics are also a potential double edged sword.
Beckmann, K. M., Brennan, R., & Arnold, J. (2017). Limitations to’Psychedelics and the science of self experience’.
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Limitations to 'Psychedelics and the science of self experience'

/ Papers, Philosophy & Religious Studies, Psychology / / , ,

Abstract

We read Matthew Nour and Robin Carhart-Harris editorial with enthusiasm. The Section History Ethics & Philosophy of Psychiatry Queensland meets once a month in the Brisbane area. The writers of this eLetter met at the end of March 2017and discussed this editorial. We congratulate and we agree with Derek K Tracy in “highlights of this issue” that it is a mesmerising read. We found that the editorial is well composed, interesting in its logic and we notice the structure to the editorial. There are 6 separate headings: defining the self, self in neuroscience, self disturbance , psychedelics as a window into the self, therapeutic implications, and conclusions. We discussed that overall the paper only presents a reductionist, non-compatabilist, materialist theory of self, which becomes a fallacy of a circular argument. For the purpose of this editorial such a reduction of a complex philosophical area is indeed suitable, but ignores other models and we miss a paragraph on these limitations. We feel that it would have assisted if there had been frank comments on the reductionist approach and the diverse facets to self relevant to psychiatry.
The quantitative meta analysis locates self experience to default mode network in a cortical median and anterior cingulate brain anatomy. Other theories of the self in the light of memories and emotions for example, made us curious about FMRI findings in the amygdala and hippocampal areas. However acknowledging FMRI as “correlation”, the subtext is identity with the subject of the correlation.
We were reminded that after all the self is a very complex philosophical area that preoccupied many eminent thinkers in the past (Remes P& Sihvola) We believe that also a discussion of other pathologies of self, multiple selves associated with dissociation and multiple personality disorder would have been more inclusive. We were curious about the role of language especially in people who speak several languages as the narrative (McAdams) of the self is based on semantics.
We believe that a paragraph highlighting the limitations to the approach would have made this a more balanced editorial. Also referencing evidence on psychedelics and clinical experience of their use, references that highlight a number of the risks and side effects (Larsen JK and Johnson M et al) would have added . There are merits in to including that psychedelics are also a potential double edged sword.
Beckmann, K. M., Brennan, R., & Arnold, J. (2017). Limitations to’Psychedelics and the science of self experience’.
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Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

/ Mushrooms / Psilocybin, Papers, Psychology, Publications / / , , , , , ,

Abstract

INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.

METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.

RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.

CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.

Brown, R. T., Nicholas, C. R., Cozzi, N. V., Gassman, M. C., Cooper, K. M., Muller, D., … & Hutson, P. R. (2017). Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clinical Pharmacokinetics, 1-12. 10.1007/s40262-017-0540-6
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An online survey of tobacco smoking cessation associated with naturalistic psychedelic use

/ LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / / , , ,

Abstract

Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years’ abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3–6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation.

Johnson, M. W., Garcia-Romeu, A., Johnson, P. S., & Griffiths, R. R. (2017). An online survey of tobacco smoking cessation associated with naturalistic psychedelic use. Journal of Psychopharmacology, 0269881116684335. 10.1177/0269881116684335
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Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates

/ Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / / ,

Abstract

This chapter begins with a brief review of descriptions and definitions of mystical-type experiences and the historical connection between classic hallucinogens and mystical experiences. The chapter then explores the empirical literature on experiences with classic hallucinogens in which claims about mystical or religious experiences have been made. A psychometrically validated questionnaire is described for the reliable measurement of mystical-type experiences occasioned by classic hallucinogens. Controlled laboratory studies show that under double-blind conditions that provide significant controls for expectancy bias, psilocybin can occasion complete mystical experiences in the majority of people studied. These effects are dose-dependent, specific to psilocybin compared to placebo or a psychoactive control substance, and have enduring impact on the moods, attitudes, and behaviors of participants as assessed by self-report of participants and ratings by community observers. Other studies suggest that enduring personal meaning in healthy volunteers and therapeutic outcomes in patients, including reduction and cessation of substance abuse behaviors and reduction of anxiety and depression in patients with a life-threatening cancer diagnosis, are related to the occurrence of mystical experiences during drug sessions. The final sections of the chapter draw parallels in human neuroscience research between the neural bases of experiences with classic hallucinogens and the neural bases of meditative practices for which claims of mystical-type experience are sometimes made. From these parallels, a functional neural model of mystical experience is proposed, based on changes in the default mode network of the brain that have been observed after the administration of classic hallucinogens and during meditation practices for which mystical-type claims have been made.
Barrett, F. S., & Griffiths, R. R. (2017). Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates. 10.1007/7854_2017_474
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Chemistry and Structure-Activity Relationships of Psychedelics

/ LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Publications / /

Abstract

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT2Areceptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.
Nichols, D. E. (2017). Chemistry and Structure–Activity Relationships of Psychedelics. 10.1007/7854_2017_475
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Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome

/ Depressive Disorders, Ketamine, Papers, Psychiatry & Medicine, Psychology / / , , , , , ,

Abstract

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Kiraly, D. D., Horn, S. R., Van Dam, N. T., Costi, S., Schwartz, J., Kim-Schulze, S., … & Iosifescu, D. V. (2017). Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Translational psychiatry, 7(3), e1065. 10.1038/tp.2017.31
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Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: from neurotransmitter imbalance to impaired neurogenesis

/ Ayahuasca, Depressive Disorders, Neuroscience, Papers / / , ,

Abstract

Type A monoamine oxidase (MAOA) catabolizes monoamine transmitters, serotonin, norepinephrine and dopamine, and plays a major role in the onset, progression and therapy of neuropsychiatric disorders. In depressive disorders, increase in MAOA expression and decrease in brain levels of serotonin and norepinephrine are proposed as the major pathogenic factors. The functional polymorphism of MAOA gene and genes in serotonin signal pathway are associated with depression. This review presents recent advance in studies on the role of MAOA in major depressive disorder and related emotional disorders. MAOA and serotonin regulate the prenatal development and postnatal maintenance of brain architecture and neurocircuit, as shown by MAOA-deficient humans and MAO knockout animal models. Impaired neurogenesis in the mature hippocampus has been proposed as “adult neurogenesis” hypothesis of depression. MAOA modulates the sensitivity to stress in the stages of brain development and maturation, and the interaction of gene–environmental factors in the early stage regulates the onset of depressive behaviors in adulthood. Vice versa environmental factors affect MAOAexpression by epigenetic regulation. MAO inhibitors not only restore compromised neurotransmitters, but also protect neurons from cell death in depression through induction of anti-apoptotic Bcl-2 and prosurvival neurotrophic factors, especially brain-derived neurotrophic factor, the deficiency of which is detected in depression. This review discusses novel role of MAOA and serotonin in the pathogenesis and therapy of depressive disorders.

Naoi, M., Maruyama, W., & Shamoto-Nagai, M. (2017). Type A monoamine oxidase and serotonin are coordinately involved in depressive disorders: from neurotransmitter imbalance to impaired neurogenesis. Journal of Neural Transmission, 1-14. 10.1007/s0070
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