OPEN Foundation

Psychosis

Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion

January 23, 2017 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , ,

Abstract

New and encouraging findings regarding the use of ketamine for depression in the context of psychotic symptoms have been published by Pennybaker et al. (1). In their analysis, patients with bipolar disorder without a history of psychosis had a more robust response to ketamine, and patients with a history of psychosis had a significant response compared with placebo as well. Concerning dissociative symptoms, even though patients with a history of psychosis endorsed more symptoms, these were not maintained after a 40-minute period, and no full psychosis was induced in their sample.

da Frota Ribeiro, C. M., Sanacora, G., & Ostroff, R. (2017). Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry. 10.1016/j.biopsych.2017.01.012
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d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

November 23, 2016 / LSD, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , ,

Abstract

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2Areceptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.

De Gregorio, D., Comai, S., Posa, L., & Gobbi, G. (2016). d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology. International Journal of Molecular Sciences, 17(11), 1953. 10.3390/ijms17111953
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Ketamine: NMDA Receptors and Beyond

November 2, 2016 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Psychotherapy / By / , ,

Abstract

Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine’s actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses.
Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016). Ketamine: NMDA receptors and beyond. Journal of Neuroscience, 36(44), 11158-11164. 10.1523/JNEUROSCI.1547-16.2016
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A systematic review of the effects of novel psychoactive substances ‘legal highs’ on people with severe mental illness

April 1, 2016 / New substances, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications, Safety / By / , , ,

Abstract

WHAT IS KNOWN ON THE SUBJECT?: Novel psychoactive substances (NPS) include synthetic drugs mimicking the effects of illicit drugs, e.g. synthetic cannabinoids, and herbs such as Salvia divinorum. NPS are substances that can trigger hallucinations and other effects altering the mind, and are currently uncontrolled by the United Nations’ 1961 Narcotic Drugs/1971 Psychotropic Substances Conventions. NPS affect brain chemistry that induces the psychoactive effects, such as hallucinations and feeling ‘high’. It is unknown what effects such drugs have on people with severe mental illness (i.e. psychotic illnesses).

WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Our review demonstrates that little is known about the effects of various NPS on people with severe mental illness. Almost nothing is known about the long-term consequences of NPS use on the mental and physical health of SMI patients. Patients may lack understanding that NPS are psychoactive drugs that can impact on their mental and physical wellbeing.

WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Some patients might be reluctant or do not think it is relevant to disclose NPS use. Commonly used illicit drug screening is unlikely to detect the presence of NPS, therefore health and mental health professionals should directly enquire about NPS and actively encourage patients with severe mental illness to disclose any substance use.

PATIENT AND PUBLIC INVOLVEMENT IN THE RESEARCH: There was no significant patient and public involvement in the development and conduct of this study .

ABSTRACT: Introduction Novel psychoactive substances (NPS) are synthetic substances that have been developed to produce altered states of consciousness and perceptions. People with severe mental illness (SMI) are more likely to use NPS than people without mental illness, but the short- and long-term effects of NPS are largely unknown. Method We systematically reviewed the literature about the effects of NPS on people with SMI. Results We included 12 case reports, 1 cross-sectional survey and 1 qualitative study. Participants included mostly males aged between 20 and 35 years. A variety of NPS were used, including synthetic cathinones and herbs such as Salvia. The most commonly reported effects of NPS were psychotic symptoms (in some cases novel in form and content to the patients’ usual symptoms) and significant changes in behaviour, including agitation, aggression and violence. Patients’ vital signs, such as blood pressure, pulse rate and temperature, were also commonly affected.

CONCLUSION: NPS potentially have serious effects on people with SMI, but our findings have limited generalizability due to a reliance on case studies. There is a paucity of evidence about the long-term effects of these substances. Further research is required to provide a better understanding about how different NPS affect patients’ mental and physical health.

Gray, R., Bressington, D., Hughes, E., & Ivanecka, A. (2016). A systematic review of the effects of novel psychoactive substances ‘legal highs’ on people with severe mental illness. Journal of Psychiatric and Mental Health Nursing. http://dx.doi.org/10.1111/jpm.12297

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A systematic review of the effects of novel psychoactive substances 'legal highs' on people with severe mental illness

April 1, 2016 / New substances, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications, Safety / By / , , ,

Abstract

WHAT IS KNOWN ON THE SUBJECT?: Novel psychoactive substances (NPS) include synthetic drugs mimicking the effects of illicit drugs, e.g. synthetic cannabinoids, and herbs such as Salvia divinorum. NPS are substances that can trigger hallucinations and other effects altering the mind, and are currently uncontrolled by the United Nations’ 1961 Narcotic Drugs/1971 Psychotropic Substances Conventions. NPS affect brain chemistry that induces the psychoactive effects, such as hallucinations and feeling ‘high’. It is unknown what effects such drugs have on people with severe mental illness (i.e. psychotic illnesses).

WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Our review demonstrates that little is known about the effects of various NPS on people with severe mental illness. Almost nothing is known about the long-term consequences of NPS use on the mental and physical health of SMI patients. Patients may lack understanding that NPS are psychoactive drugs that can impact on their mental and physical wellbeing.

WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Some patients might be reluctant or do not think it is relevant to disclose NPS use. Commonly used illicit drug screening is unlikely to detect the presence of NPS, therefore health and mental health professionals should directly enquire about NPS and actively encourage patients with severe mental illness to disclose any substance use.

PATIENT AND PUBLIC INVOLVEMENT IN THE RESEARCH: There was no significant patient and public involvement in the development and conduct of this study .

ABSTRACT: Introduction Novel psychoactive substances (NPS) are synthetic substances that have been developed to produce altered states of consciousness and perceptions. People with severe mental illness (SMI) are more likely to use NPS than people without mental illness, but the short- and long-term effects of NPS are largely unknown. Method We systematically reviewed the literature about the effects of NPS on people with SMI. Results We included 12 case reports, 1 cross-sectional survey and 1 qualitative study. Participants included mostly males aged between 20 and 35 years. A variety of NPS were used, including synthetic cathinones and herbs such as Salvia. The most commonly reported effects of NPS were psychotic symptoms (in some cases novel in form and content to the patients’ usual symptoms) and significant changes in behaviour, including agitation, aggression and violence. Patients’ vital signs, such as blood pressure, pulse rate and temperature, were also commonly affected.

CONCLUSION: NPS potentially have serious effects on people with SMI, but our findings have limited generalizability due to a reliance on case studies. There is a paucity of evidence about the long-term effects of these substances. Further research is required to provide a better understanding about how different NPS affect patients’ mental and physical health.

Gray, R., Bressington, D., Hughes, E., & Ivanecka, A. (2016). A systematic review of the effects of novel psychoactive substances ‘legal highs’ on people with severe mental illness. Journal of Psychiatric and Mental Health Nursing. http://dx.doi.org/10.1111/jpm.12297

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5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis

August 19, 2015 / Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Psychiatry, Psychology, Psychosis, Publications / By / ,

Abstract

Serotonin [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][5-hydroxytryptamine (5-HT)] and glutamate have both been implicated in the pathophysiology of neuropsychiatric disorders but also in the mechanism of antipsychotic and hallucinogenic drug actions. Furthermore, close antagonistic interactions between 5-HT2A and metabotropic glutamate (mGlu)2/3 receptors have been established over the last decades on the basis of numerous electrophysiological, biochemical, and behavioral studies. Besides synaptic mechanisms, more recent findings suggested that heterodimeric 5-HT2A-mGlu2 receptor complexes in the prefrontal cortex may account for the functional crosstalk between these two receptor subtypes. In this review, we focus on in-vitro and in-vivo studies documenting the important relationship between 5-HT2A and mGlu2/3 receptors, with relevance to both normal behavioral function and psychosis.

Wischhof, L., & Koch, M. (2015). 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behavioural pharmacology. https://dx.doi.org/10.1097/FBP.0000000000000183
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Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.

July 18, 2015 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , , ,

Abstract

RATIONALE:

Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders.

OBJECTIVES:

We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe.

METHODS:

Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity.

RESULTS:

In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia.

CONCLUSIONS:

This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.

Grimm, O., Gass, N., Weber-Fahr, W., Sartorius, A., Schenker, E., Spedding, M., … & Meyer-Lindenberg, A. (2015). Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats. Psychopharmacology, 1-11.
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Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe

July 6, 2015 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , ,

Abstract

Ketamine produces effects in healthy humans that resemble the positive, negative and cognitive symptoms of schizophrenia. We investigated the effect of ketamine administration on brain activity as indexed by blood-oxygen-level-dependent (BOLD) signal change response, and its relationship to ketamine-induced subjective changes, including perceptual distortion. Thirteen healthy participants volunteered for the study. All underwent a 15-min functional MRI acquisition with a ketamine infusion commencing after 5 min (approx 0.26 mg/kg over 20s followed by an infusion of approx. 0.42 mg/kg/h). Following the scan, participants self-rated ketamine-induced effects using the Psychotomimetic States Inventory. Ketamine led to widespread cortical and subcortical increases in BOLD response (FWE-corrected p < 0.01). Self-rated perceptual distortions and delusional thoughts correlated with increased BOLD response in the paracentral lobule (FWE-corrected p < 0.01). The findings suggest that BOLD increases in parietal cortices reflect ketamine effects on circuits that contribute to its capacity to produce perceptual alterations and delusional interpretations.

Stone, J., Kotoula, V., Dietrich, C., De Simoni, S., Krystal, J. H., & Mehta, M. A. (2015). Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. Journal of Psychopharmacology, 0269881115592337. https://dx.doi.org/10.1177/0269881115592337
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The use of ketamine for the treatment of depression in the context of psychotic symptoms

June 4, 2015 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , ,

Abstract

Mounting evidence from a series of small clinical trials and case series suggests ketamine can have rapid and robust antidepressant(1), and possibly anti-suicidal effects(2) in patients who had not responded to standard treatment options. However, due to ketamine’s variable psychotomimetic effects in healthy volunteers and exacerbation of previously experienced positive symptoms in schizophrenic volunteers(3,4), patients previously experiencing psychotic features have been excluded from the reported studies and trials.

da Frota Ribeiro, C. M., Sanacora, G., Hoffman, R., & Ostroff, R. (2015). The use of ketamine for the treatment of depression in the context of psychotic symptoms. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2015.05.016
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Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

May 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Personality, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , ,

Abstract

Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one’s “self,” “ego,” or “I” is disintegrating or that the border between one’s self and the external world is dissolving, “ego-disintegration” or “dissolution” is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in “magic mushrooms”). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to “ego-dissolution”, was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a “disintegration” of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of “self”or “ego,” as a perceptual phenomenon, may rest on the normal functioning of these systems.

Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego‐dissolution under psilocybin. Human brain mapping. https://dx.doi.org/10.1002/hbm.22833
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30 April - Q&A with Rick Strassman

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