Journal of Psychopharmacology最新文献

Background: Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments-including preparatory, integration, sensory immersion, and psychotherapy sessions-could decrease PTSD symptoms meaningfully.

Methods: A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials.

Results: Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients' final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms.

Conclusion: Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine's potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule's cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.

Background: Ketamine has demonstrated both rapid and sustained efficacy in treating depression, especially in treatment-resistant cases. However, concerns regarding the addictive potential of ketamine during long-term depression treatment persist among clinicians.

Aim: This review aimed to summarise the evidence on addiction phenomena associated with ketamine treatment of depression.

Methods: A comprehensive search was conducted in MEDLINE, Embase, PsycInfo and Global Health databases, with additional relevant studies identified through reference lists. Sixteen studies were included, comprising six randomised controlled trials, three single-arm open-label studies, one retrospective study, three case series and three case reports, for a total of 2174 patients.

Results: The studies employed various routes of administration, including intravenous, intramuscular, intranasal, oral and sublingual. Ketamine was administered in the racemic form, except for the studies that utilised intranasal esketamine. Among the included population, four patients were reported to exhibit clear signs of tolerance to the antidepressant effect of ketamine or dependence on the drug, while the majority did not. Cases of addiction phenomena reported in studies that did not meet the inclusion criteria are also discussed.

Conclusions: Despite the heterogeneity in study designs and outcome assessment methods, the review underscores the relative safety of ketamine treatment for adult patients with depression, emphasising the importance of medically supervised administration, vigilant monitoring and judicious dosing. Future long-term studies employing quantitative scales to assess dependence phenomena could contribute to strengthening the evidence for the safe and effective use of ketamine in the treatment of depression.

Background: Ketamine's popularity has surged globally in the past decade, especially among young men. Emergency department visits due to its toxicity remain relatively rare, often linked to co-occurring use of other substances.

Aims: Using data from the Global Drug Survey (GDS) 2018, this study explored the correlates associated with lifetime and past-year ketamine use, and estimated the socio-demographic characteristics, usage patterns and experiences of respondents seeking emergency medical treatment (EMT) after ketamine use.

Methods: Secondary analysis of GDS 2018, an online cross-sectional survey on drug use patterns conducted between November 2017 and January 2018.

Results: The survey received 130,761 valid responses, with 5.93% reporting lifetime ketamine use, of which 57.70% used ketamine within the past year. Predominantly, respondents were from Germany, England and Denmark. Within the past year, 8.55% met the criteria for ketamine dependence. Respondents who used ketamine in their lifetime tended to be young (mean (x̄) = 27.37 years), men, heterosexual and of white ethnicity. Younger age (x̄ = 24.84 years), gay sexual orientation, student status, past-year use of other drugs and no lifetime mental health diagnosis were associated with past-year ketamine use. Among 4477 respondents reporting past-year ketamine use, 120 adverse events were reported, with less than 0.10% prompting EMT seeking.

Conclusion: The study reveals frequent ketamine use but low harm occurrence, underscoring the complex interplay between ketamine use, substance use and dependence, and related factors. This underscores the need to reassess EMT priorities, implement tailored harm reduction strategies and incorporate comprehensive screening for addressing ketamine and substance dependence challenges.

Background: Treatment-resistant depression (TRD) is defined as the failure of at least two antidepressants in adequate doses and timing during a major depressive episode. Esketamine intranasal (ESK-IN) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of TRD in combination with other antidepressants.

Aims: To assess the effectiveness and tolerability of a sample of TRD patients who received treatment with ESK-IN as part of the compassionate use program.

Methods: A retrospective, observational study was carried out on patients with a diagnosis of TRD enrolled in the early access program of ESK-IN in nine centers. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS) at four time points: baseline, 28, 90, and 180 days of treatment.

Results: The sample included 71 patients (70% women) with a mean baseline MADRS score of 38.27 ± 5.9 and total or partial work disability rates of 85%. ESK-IN treatment was associated with a statistically and clinically significant reduction in the severity of depressive symptoms at all time points assessed. The presence of side effects was common but the majority were mild in severity and resolved after the observation period. Those patients who received psychotherapy in combination with ESK-IN showed a significantly lower MADRS score at 90 and 180 days than those patients who did not undergo psychotherapy.

Conclusion: ESK-IN has proven to be effective and safe in a clinical sample of patients with severe TRD. To optimize clinical outcomes, the pharmacological treatment for TRD should always be integrated into a comprehensive therapeutic plan that encompasses strategies such as psychotherapy, social support, and family interventions.

Background: Obsessive-Compulsive Disorder (OCD) may respond to ketamine treatment.

Aim: To examine the responsiveness and tolerability of treatment-refractory OCD to intramuscular (IM) ketamine compared to IM fentanyl.

Methods: This was a randomised double-blind psychoactive-controlled study with single doses of racemic ketamine 0.5 mg/kg, 1.0 mg/kg or fentanyl 50 µg (psychoactive control). Pre-dosing with 4 mg oral ondansetron provided nausea prophylaxis. Eligible participants were aged between 18 and 50 years with severe treatment-resistant OCD. The primary efficacy measure was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Tolerability was measured with the Clinician-Administered Dissociative States Scale (CADSS). Repeated measures analysis of variance with orthogonal polynomial trends was used to assess the effect of drug treatment on Y-BOCS and CADSS scores.

Results: Twelve participants were randomised and 10 completed the study (7 females, 3 males, mean age 33 years). Two participants dropped out due to not tolerating dissociative effects associated with the study medication. The reductions in Y-BOCS scores were greater and statistically dose-related for both ketamine doses than fentanyl (dose [linear], F(1, 9) = 6.5, p = 0.031). Score changes for all treatments were maximal at 1-2 h with a steady separation of scores out to 168 h. Ketamine was associated with short-term dissociative and cardiovascular effects.

Conclusions: We provide further preliminary evidence for the efficacy and tolerability of IM ketamine in an outpatient cohort of OCD. Additional work is required to establish the optimal dosing regimen and longer-term role of ketamine for OCD. These findings are encouraging given the well-known limitations that exist for treatments in this area.

The recent rejection of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy by the U.S. Food and Drug Administration (FDA) is a dramatic moment in the re-emergence of psychedelic research. In this perspective, I argue that it represents a case study for paradigmatic tensions within psychopharmacology. The regulatory system is still influenced by a paradigm that sees the therapeutic effects of drugs as primarily biological, and context is noise to control for. An emergent paradigm considers the therapeutic effects of drugs as interactive with context. Psychedelics are the anomaly that questions the dominant paradigm, mainly due to the determination of psychedelic researchers that the medicines are drugs with psychotherapy. While some of the critique offered by the FDA towards MAPS/Lykos's studies is crucial, much of it is related to the experiential and psychotherapeutic elements - which the FDA claims not to regulate. This leads to some paradoxes within the regulatory procedure, which hint at a need for a shift in how psychedelic-assisted therapy is regulated and researched. Both regulators and researchers will need to find ways to accommodate each other in service of a successful integration of a new paradigm in which drugs and psychotherapy interact.

Current models of psychedelic action in the brain propose changes along the dorsal-ventral and anterior-posterior axes but neglect to address the lateral axis. This article proposes a novel model of psychedelic action called HEALS (Hemispheric Annealing and Lateralization Under Psychedelics) which involves the reversal of the typical hierarchical relationship between the two hemispheres of the brain. In typical modes of consciousness, the hemispheres act in parallel process with the left predominating. Under psychedelics, as well as in other altered states of consciousness (ASCs), this hierarchy is reversed, with the right hemisphere released from inhibition by the left. In support of this model, the available neuroimaging evidence for lateralization under psychedelics is reviewed. Then, various cognitive and emotional changes observed under psychedelics are contrasted with those same functions in each hemisphere. These include attention; social and emotional intelligence; creativity and insight; and language. The article concludes with a review of laterality in other ASCs, such as meditative and trance states, and suggests that many phenomena associated with psychedelics, and other ASCs, might be explained by an atypical annealing between the hemispheres toward right hemisphere predominance.

Importance: Individuals with autism spectrum disorder (ASD) and intellectual disability often experience persistent challenges related to aggressive behaviour and agitation, highlighting the critical need for evidence-based pharmacological interventions among other strategies. Despite previous network meta-analyses (NMAs), the rapidly evolving landscape of treatment options necessitates ongoing and updated assessments.

Objective: To evaluate the efficacy and tolerability of various pharmacotherapies in managing agitation in children and adults with ASD or intellectual disabilities (ID).

Methods: Employing a systematic review and network meta-analysis methodology, we conducted an exhaustive search across multiple databases for double-blind, randomized controlled trials focusing on pharmacotherapies targeting agitation in these neurodevelopmental disorders. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, our assessment of study quality utilized the Cochrane Risk of Bias Tool to ensure methodological rigour and accuracy in data synthesis. Primary outcomes encompassed measures of reduced agitation, as indicated by treatment response on standardized agitation scales, alongside dropout rates, providing a comprehensive overview of treatment efficacy and tolerability.

Results: Our analysis included data from 38 eligible trials, involving 2503 participants across both pediatric and adult populations. Key pharmacological interventions, such as arbaclofen, risperidone plus buspirone, omega-3 fatty acids, risperidone plus palmitoylethanolamide, aripiprazole and risperidone, demonstrated significant efficacy in reducing agitation compared to placebo. Importantly, these treatments were generally well-tolerated, with no significant increase in all-cause dropouts compared to placebo, highlighting their suitability for clinical use in managing agitation in individuals with ASD or ID.

Conclusions: This study underscores the efficacy and tolerability of several pharmacotherapies in managing agitation among children and adults with ASD or ID. Our findings provide robust evidence that specific treatments, such as arbaclofen, risperidone plus buspirone and omega-3 fatty acids, are both effective and well-tolerated, offering valuable therapeutic options for clinicians. The study emphasizes the need for ongoing research to ensure that treatment strategies remain aligned with the evolving clinical landscape, ultimately improving patient outcomes in this challenging population.

Background: Antidiabetic medications have shown efficacy in alleviating autism symptoms. However, there is a lack of clinical research on the impact of metformin on irritability associated with autism. This study aimed to assess the efficacy and safety of metformin as an adjuvant therapy with risperidone for managing irritability in children diagnosed with Autism Spectrum Disorder (ASD).

Methods: This is a randomized, 10-week, double-blind, placebo-controlled trial conducted at the children's autism clinic of Roozbeh Hospital (Tehran, Iran) from March 2024 to May 2024. Participants were divided into two groups of risperidone plus metformin (500 mg per day) and risperidone plus placebo and were assessed at baseline, weeks 5 and 10 with the aberrant behavior checklist-community scale (ABC-C).

Results: A total of 55 patients were included in the final analysis. Irritability (primary outcome measure) sharply decreased in the metformin compared to the placebo group (p = 0.008). Among the other four subscales of ABC-C, the hyperactivity/noncompliance score showed a significant drop during the baseline-to-week-5 period (p = 0.021). In addition, inappropriate speech subscales decreased significantly from baseline-to-week 5 in the metformin compared to the placebo group (p = 0.045). No other significant finding was observed among ABC-C scores for lethargy/social withdrawal or stereotypic behavior subscales.

Conclusion: Metformin demonstrated promising results in reducing irritability in ASD patients, which is in concordance with previous studies. However, further studies are required before any broad clinical recommendation.

Background: Schizophrenia is considered to have a lifetime prevalence of around 1%. Up to 30% of patients diagnosed with schizophrenia are subsequently categorised as treatment resistant. Current guidelines advise against the use of antipsychotic polypharmacy (APP) or high-dose antipsychotic therapy (HDAT) in the treatment of schizophrenia; however, these treatment approaches continue to be used in up to 25% of cases.

Aims: This review was to evaluate the evidence for the efficacy and tolerability of APP and HDAT as an alternative to antipsychotic monotherapy at standard doses in the treatment of schizophrenia.

Methods: This is a systematic review. We searched PubMed, EMBASE and PsycINFO, for eligible trials published prior to 24 March 2023. The protocol was registered on PROSPERO (CRD42023408785). Quality assessment was conducted using the Revised Cochrane risk-of-bias tool for randomised trials.

Results: A total of 14 studies were included in this review. Two studies demonstrated clinically significant improvement with APP compared to standard treatment. There was no clear evidence that APP or HDAT is definitively less tolerable than antipsychotic monotherapy at a standard dose.

Conclusions: This review found limited evidence for the efficacy of APP and HDAT in the treatment of schizophrenia over the use of antipsychotic monotherapy at a standard dose. The relative tolerability was unclear. Management of treatment-resistant schizophrenia remains a prominent clinical issue and further research, including high-quality large-scale Randomised Controlled Trials (RCTs) of APP and HDAT in patients who have been unresponsive to clozapine, would be of significant benefit to the field of psychiatry.