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.

Background: The interest in psychedelics as a therapeutic intervention for existential distress of people with terminal illness grounds on their mechanism of action and effect on the spiritual/existential aspects accompanying end-of-life experiences.

Aims: This systematic review and network meta-analysis aimed at examining the efficacy and safety of psychedelic compounds for existential distress in terminally ill people.

Methods: PubMed, CINAHL, PsycINFO, EMBASE, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) administering psychedelics for existential distress in people with terminal illnesses. Meta-analysis estimated the standardized mean difference (SMD) and odds ratio (OR), with corresponding 95% confidence intervals (95% CI), between treated and control groups in pairwise and network comparisons, using random-effects models. Post-treatment measures of depression and anxiety, as proxies of existential distress, and tolerability were the primary outcomes.

Results: Nine studies, involving 606 participants (362 treated with psychedelics: psilocybin, ketamine, 3,4-methylenedioxymethamphetamine, and lysergic acid diethylamide (LSD)) were included. The meta-analysis supported the efficacy of psychedelics on depression (SMD: -0.80 (95% CI: -0.98, -0.63)) and anxiety (SMD: -0.84 (95% CI: -1.20, -0.48)). Network meta-analysis identified psilocybin as the most effective compound for depression, and LSD for anxiety. However, head-to-head comparison between psychedelics did not reach statistical significance. The rates of treatment discontinuation and adverse events between psychedelics and controls were comparable.

Conclusions: Psychedelics, especially psilocybins and LSD, showed promising effects on depression and anxiety in people with terminal illnesses. Limitations include the small number of RCTs, methodological issues related to blinding, and the lack of direct comparisons between psychedelic compounds. Larger studies and comparative research are needed to consolidate these findings.

Background: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States.

Aims: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol.

Methods: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated.

Results: All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's |d| = 0.126-0.76); effects were larger with alprazolam (Cohen's |d| = 0.523-0.93) and ethanol (Cohen's |d| = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's |d| = 0.6-1.227) or ethanol (Cohen's |d| = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity.

Conclusion: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol.

Background: Sensory reactivity differences are experienced by between 5% and 15% of the population, often taking the form of sensory over-responsivity (SOR), in which sensory stimuli are experienced as unusually intense and everyday function is affected. A potential mechanism underlying over-responsivity is an imbalance between neural excitation and inhibition in which inhibitory influences are relatively weakened. Therefore, interventions that boost neural inhibition or reduce neural excitation may reduce SOR; Vitamin-B6 is the coenzyme for the conversion of excitatory glutamate to inhibitory gamma-aminobutyric acid (GABA), and in animal models, it both increases the concentration of GABA and reduces glutamate.

Aims: To discover whether taking a high dose of Vitamin-B6 reduces SOR and other aspects of sensory reactivity.

Methods: We recruited 300 adults (249 females) from the general population who completed the Sensory Processing 3-Dimensions Scale (SP-3D) first at baseline, and again following randomisation to either 1 month's supplementation with 100 mg Vitamin-B6, or one of two control conditions (1000 µg Vitamin-B12 or placebo). To focus on individuals who experience SOR, we analysed the effects of supplementation only on individuals with high baseline SOR scores (above the 87th percentile).

Results: In individuals with SOR at baseline, Vitamin-B6 selectively reduced SOR compared to both placebo and Vitamin-B12. We also found that Vitamin-B6 selectively reduced postural disorder in individuals with high scores on this subscale at baseline, but there were no effects on the four remaining SP-3D subscales.

Conclusions: Clinical trials and mechanistic studies should now be conducted in autism, attention deficit hyperactivity disorder and other groups with SOR.