Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Ketamine for depression.

Over the last two decades, the dissociative anaesthetic agent ketamine, an uncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist, has emerged as a novel therapy for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects within hours of administration. Ketamine is a racemic mixture composed of equal amounts of (S)-ketamine and (R)-ketamine. Although ketamine currently remains an off-label treatment for TRD, an (S)-ketamine nasal spray has been approved for use in TRD (in conjunction with an oral antidepressant) in the United States and Europe. Despite the promise of ketamine, key challenges including how to maintain response, concerns regarding short and long-term side-effects and the potential for abuse remain. This review provides an overview of the history of ketamine, its use in psychiatry and its basic pharmacology. The clinical evidence for the use of ketamine in depression and potential adverse effects associated with treatment are summarized. A synopsis of some of the putative neurobiological mechanisms underlying ketamine's rapid-acting antidepressant effects is provided before finally outlining future research directions, including the need to identify biomarkers for predicting response and treatment targets that may be used in the development of next-generation rapid-acting antidepressants that may lack ketamine's side-effects or abuse potential.

Historic psychedelic drug trials and the treatment of anxiety disorders.

INTRODUCTION: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD-10 anxiety disorders. METHODS: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD-10 anxiety and related disorders. Twenty-four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD-10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD-10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis. RESULTS: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of "psychoneurotic anxiety reaction" as defined by Diagnostic and Statistical Manual of Mental Disorders-I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation. CONCLUSION: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient.

Guidelines for ketamine use in clinical psychiatry practice.

In this editorial, we emphasise the efficacy and challenges of using ketamine in treatment-resistant depression. We highlight the need for comprehensive evidence-based guidelines to manage the use of both licensed and off-licence ketamine formulations and discuss recent efforts by Beaglehole et al to develop ketamine guidelines in New Zealand. We finally advocate for national registries to monitor ketamine therapy, ensuring its responsible and effective use in the management of depression.

Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects.

BACKGROUND: Ketamine may be effective in treating symptoms of anxiety, but the time profile of ketamine's anxiolytic effect is ill-defined. This systematic review and meta-analysis investigated the anxiolytic effect of ketamine at different time points across a range of clinical settings. METHODS: Electronic databases were searched to capture randomised control trials measuring the anxiolytic effects of ketamine in contexts including mood disorders, anxiety disorders and chronic pain. Meta-analyses were conducted using a random-effects model. The correlations between (1) improvements in mean anxiety and depression scores, and (2) peak dissociation and improvements in mean anxiety scores were also assessed. RESULTS: In all, 14 studies met inclusion criteria. Risk of bias was high in 11 studies. Ketamine significantly reduced anxiety scores compared to placebo at acute (<12 h; standard mean difference (SMD): -1.17, 95% confidence interval (CI) [-1.89, -0.44], p < 0.01), subacute (24 h; SMD: -0.44, 95% CI [-0.65, -0.22], p < 0.01) and sustained (7-14 days; SMD: -0.40, 95% CI [-0.63, -0.17], p < 0.01) time points. Exploratory analyses revealed improvements in anxiety and depression symptoms correlated at both subacute (R2 = 0.621, p = 0.035) and sustained time points (R2 = 0.773, p = 0.021). The relationship between peak dissociation and improvement in anxiety was not significant. CONCLUSIONS: Ketamine appears to offer rapid and sustained anxiety symptom relief across a range of clinical settings, with anxiolytic effects occurring within the first 12 h of administration and remaining effective for 1-2 weeks. Future studies could explore the effects of ketamine maintenance therapy on anxiety symptoms.

The opioid system in depression.

Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.

Variants in the zinc transporter-3 encoding gene (SLC30A3) in schizophrenia and bipolar disorder: Effects on brain glutamate-A pilot study.

Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex (p < 0.05). There was no effect of SLC30A3 genotype on BOLD activation during n-back or on cortical brain volume. This study supports the further investigation of SLC30A3 and its role in glutamatergic neurotransmission and in the neuropathology of mental illness.

The anterior cingulate cortex as a key locus of ketamine's antidepressant action.

The subdivisions of the anterior cingulate cortex (ACC) - including subgenual, perigenual and dorsal zones - are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.

Ketamine: A tale of two enantiomers.

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

New Pharmacological Interventions in Bipolar Disorder.

The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.

A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis.

RATIONALE: Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials. OBJECTIVE: To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD. METHODS: Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck's Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within 7 days of intervention. RESULTS: Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75 mg (MD -46.90; 95% (confidence intervals) CI -58.78, -35.02), 125 mg (MD -20.98; 95% CI -34.35, -7.61) but not 100 mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75 mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after 7 days. CONCLUSION: These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck's Depression Inventory. Better powered RCTs are required to investigate further. INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS: CRD42019109132 available online at www.crd.york.ac.uk/prospero.

Imaging Brain Glx Dynamics in Response to Pressure Pain Stimulation: A 1H-fMRS Study.

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies.

Functional magnetic resonance spectroscopy in patients with schizophrenia and bipolar affective disorder: Glutamate dynamics in the anterior cingulate cortex during a working memory task.

The glutamate system is implicated in the pathophysiology of schizophrenia and mood disorders. Using functional magnetic resonance spectroscopy (1H-fMRS), it is possible to monitor glutamate dynamically in activated brain areas and may give a closer estimate of glutamatergic neurotransmission than standard magnetic resonance spectroscopy. 14 patients with schizophrenia, 15 patients with bipolar disorder II (BPII) and 14 healthy volunteers underwent a 15 min N-back task in a 48s block design during 1H-fMRS acquisition. Data from the first, second and third 16s group of 8 spectra for each block were analysed to measure levels of glutamate and Glx (glutamate + glutamine), scaled to total creatine (TCr), across averaged 0-back and 2-back conditions. A 6 × 3 repeated-measures analysis of variance (rmANOVA) demonstrated a significant main effect of time for Glx/TCr (P = 0.022). There was a significant increase in Glu/TCr (P = 0.004) and Glx/TCr (P < 0.001) between the final spectra of the 0-back and first spectra of the 2-back condition in the healthy control group only. 2 × 2 rmANOVA revealed a significant time by group interaction for Glx/TCr (P = 0.019) across the 0-back condition, with levels reducing in healthy controls and increasing in the schizophrenia group. While healthy volunteers showed significant increases in glutamatergic measures between task conditions, the lack of such a response in patients with schizophrenia and BPII may reflect deficits in glutamatergic neurotransmission. Abnormal increases during periods of relatively low executive load, without the same dynamic modulation as healthy volunteers with increasing task difficulty, further suggests underlying abnormalities of glutamatergic neurotransmission in schizophrenia.

Inflammation, Glutamate, and Cognition in Bipolar Disorder Type II: A Proof of Concept Study.

Background: Two current theories regarding the neuroscientific bases of mood disorders involve alterations in glutamatergic neurotransmission and excessive activation of inflammatory pathways. We hypothesized that glutamate (Glu) levels and peripheral inflammatory markers would be associated with cognitive function, in patients with Bipolar Disorder Type II (BP-II), and that such factors would be associated with psychological treatment outcomes. Aims: The primary aim of this study was to explore the relationship between the neurotransmitter Glu, cytokines (CRP, IL_6, and TNFa) and neuropsychological and related functioning. The secondary aim was to assess cognitive functioning as a predictor of poor response to psychological therapy. Methods: Proton magnetic resonance spectroscopy data were acquired from the anterior cingulate cortex (ACC) of 15 participants with BP-II, and 13 healthy controls in a 3T magnetic resonance imaging scanner. The Digit Symbol Task (DST) for processing speed, TMT-B for executive function and Rey Auditory Verbal Learning Test (RAVLT) were administered to assess cognitive domains. Results: There was no significant difference in anterior cingulate Glu, or inflammatory markers between groups. Furthermore, we found no significant difference between groups in any cognitive tests. Scores on the DST were found to be significantly associated with poor response to psychological therapy. Conclusions: This study may highlight an association between neuropsychological dysfunction and treatment outcome in euthymic patients with BP-II. We did not find any association between peripheral inflammatory markers and brain Glu levels. This may have been in part due to the small sample size.

Beyond static measures: A review of functional magnetic resonance spectroscopy and its potential to investigate dynamic glutamatergic abnormalities in schizophrenia.

Abnormalities of the glutamate system are increasingly implicated in schizophrenia but their exact nature remains unknown. Proton magnetic resonance spectroscopy (1H-MRS), while fundamental in revealing glutamatergic alterations in schizophrenia, has, until recently, been significantly limited and thought to only provide static measures. Functional magnetic resonance spectroscopy (fMRS), which uses sequential scans for dynamic measurement of a range of brain metabolites in activated brain areas, has lately been applied to a variety of task or stimulus conditions, producing interesting insights into neurometabolite responses to neural activation. Here, we summarise the existing 1H-MRS studies of brain glutamate in schizophrenia. We then present a comprehensive review of research studies that have utilised fMRS, and lastly consider how fMRS methods might further the understanding of glutamatergic abnormalities in schizophrenia.

Psychedelics in the treatment of unipolar mood disorders: a systematic review.

Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.