Journal of Psychopharmacology最新文献

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: Research on caffeine and cognitive performance remains controversial. Variations in genes associated with caffeine metabolism and response such as CYP1A2, AHR and ADORA2A may account for variable findings.

Aim: To investigate caffeine × gene interactions on cognitive performance in all key domains of cognition in healthy individuals.

Methods: Participants completed a lifestyle and food frequency questionnaire and a cognitive test battery including validated tasks to assess the domains of social cognition, memory, attention and executive function. Genotyping was performed for AHR rs6968554, CYP1A2 rs2472297, ADORA2A rs5751876, ADA rs73598374 and APOE rs429358 and rs7412.

Results: Significant gene × caffeine interactions were observed for the domains of social cognition, (F_{2, 123} = 5.848, p = 0.004) and executive function (F_{2, 109} = 3.690, p = 0.028). 'Slow' metabolisers had a higher performance in social cognition compared with 'fast' metabolisers among high-caffeine consumers (p = 0.004), while 'fast' metabolisers had a higher performance in executive function compared with 'slow' metabolisers among moderate caffeine consumers (p = 0.002).

Conclusions: The present findings suggest an association between genetic caffeine metabolism, habitual caffeine intake and cognitive function in the domains of social cognition and executive function. More research in naturalistic environments using larger cohorts is needed to confirm these findings to add to our understanding of how habitual caffeine may influence cognitive function based on individual genotype.

Background: Daridorexant is a dual orexin receptor antagonist approved for the treatment of chronic insomnia disorder.

Aims: Investigate the auditory awakening threshold (AAT), postural stability, and cognitive function during the night following evening administration of daridorexant 25 and 50 mg.

Methods: Double-blind, placebo-controlled, randomized, 3-way (placebo, 25, 50 mg) crossover study in 36 healthy male and female nonelderly adult and elderly subjects (1:1 sex/age ratio). Four hours after bedtime administration, the AAT was determined, followed by investigation of the main pharmacodynamic endpoint nocturnal postural stability (body sway) as well as functional mobility using the Timed Up and Go (TUG) test, and cognitive function/memory using the Visual Verbal Learning Test (VVLT).

Results: All 36 subjects completed the study. The average AAT was approximately 60 dB across treatments, i.e., there were no differences between daridorexant and placebo. Daridorexant marginally increased body sway by approximately 22%, while it had no clinically meaningful effect on the time to complete the TUG test (⩽1 s increase), and the VVLT (immediate and delayed number of correctly recalled words) showed minimal and clinically not meaningful differences of up to one word, all compared to placebo. Delayed word recognition was not different from placebo. The increase in body sway in the overall population was driven by nonelderly adults, as effects in elderly subjects were similar to placebo.

Conclusions: Following bedtime administration, daridorexant maintained the ability to awaken to an external noise stimulus in the middle of the night, allowing subjects to function safely.

Clinicaltrials.gov identifier: NCT05702177.

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.

Objective: Utilizing two-sample Mendelian randomization (TSMR) analysis, this study aims to explore the potential bidirectional causal relationship between common nonsteroidal anti-inflammatory drugs (paracetamol, ibuprofen, aspirin) and major depression (MD) from a genetic standpoint.

Methods: We employed summarized data from a Genome-Wide Association Study (GWAS) of European populations. The inverse variance weighted (IVW) method was used for TSMR analysis; outcomes were evaluated based on p-value, OR (Odds Ratio), and 95% confidence interval (95% CI).

Results: From a genetic perspective, the study found that the use of paracetamol and ibuprofen increased the risk of MD (IVW (MRE): OR = 2.314, 95% CI: 1.609-3.327; p = 6.07E-06) and (IVW (MRE): OR = 2.308, 95% CI: 1.780-3.653; p = 0.002), respectively. No significant causal relationship was found between aspirin and MD (p > 0.05). Reverse TSMR analysis found that MD increased the genetic predisposition to use paracetamol, ibuprofen, and aspirin (IVW (MRE): OR = 1.042, 95% CI: 1.030-1.054, p = 3.07E-12), (IVW (FE): OR = 1.015, 95% CI: 1.007-1.023, p = 1.13E-04), (IVW (MRE): OR = 1.019, 95% CI: 1.009-1.030, p = 4.22E-04), respectively. Other analytical methods and sensitivity analyses further supported the robustness and reliability of these findings.

Conclusion: This study provides preliminary genetic evidence through bidirectional TSMR analysis that MD increases the genetic predisposition to use paracetamol, ibuprofen, and aspirin, aiding clinicians in devising preventive strategies against the misuse of non-steroidal anti-inflammatory drugs. Moreover, we found that the use of paracetamol and ibuprofen increases the risk of MD, whereas aspirin did not. This suggests a crucial clinical implication: clinicians treating MD patients could opt for the relatively safer aspirin over paracetamol and ibuprofen.

Background: Benzodiazepines bind to γ-aminobutyric acid type A (GABA_A) receptor subtypes identified by different α subunits (i.e., α1GABA_A, α2GABA_A, α3GABA_A, and α5GABA_A). Sedative-motor effects of benzodiazepines are thought to involve α1GABA_A and α3GABA_A subtypes.

Aims: We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABA_A receptors), with varying degrees of selective efficacy at different GABA_A receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABA_A and α3GABA_A efficacy.

Methods: Adult female rhesus monkeys (N = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABA_A subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABA_A subtypes), and MP-III-22 (preferential potency and efficacy for α5GABA_A subtypes).

Results: As with alprazolam, all GABAkines induced significant levels of mild sedation ("rest/sleep posture"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABA_A subtypes.

Conclusions: GABAkines with preferential efficacy at α2/α3GABA_A and/or α5GABA_A subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABA_A activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABA_A subtype in this milder form of sedation.

Background: Pharmacogenetics is considered a promising avenue for improving treatment outcomes, yet evidence arguing for the use of pharmacogenetics in the treatment of psychotic disorders is mixed and clinical usefulness is under debate. Many patients with psychosis use multiple medications, which can alter the metabolic capacity of CYP enzymes, a process called phenoconversion. In clinical studies, treatment outcomes of drugs for psychosis management may have been influenced by phenoconversion.

Aim: Here we evaluate the impact and predictive value of CYP2D6 phenoconversion in patients with psychotic disorders under pharmacological treatment.

Method: Phenoconversion-corrected phenotype was determined by accounting for inhibitor strength. Phenoconversion-corrected and genotype-predicted phenotypes were compared in association with side effects, subjective well-being and symptom severity.

Results: Phenoconversion led to a large increase in poor metabolizers (PMs; 17-82, 16% of sample), due to concomitant use of the serotonin reuptake inhibitors fluoxetine and paroxetine. Neither CYP2D6-predicted nor phenoconversion-corrected phenotype was robustly associated with outcome measures. Risperidone, however, was most affected by the CYP2D6 genotype.

Conclusion: Polypharmacy and phenoconversion were prevalent and accounted for a significant increase in PMs. CYP2D6 may play a limited role in side effects, symptoms and well-being measures. However, due to the high frequency of occurrence, phenoconversion should be considered in future clinical trials.

Background: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of several conditions including anxiety disorders, but the basic neurobiology of serotonin function remains unclear. The amygdala and prefrontal cortex are strongly innervated by serotonergic projections and have been suggested to play an important role in anxiety expression. However, serotonergic function in behaviour and SSRI-mediated neurobiological changes remain incompletely understood.

Aims: To investigate the neural correlates of subchronic antidepressant administration.

Methods: We investigated whether the 2- to 3-week administration of a highly selective SSRI (escitalopram) would alter brain activation on a task robustly shown to recruit the bilateral amygdala and frontal cortices in a large healthy volunteer sample. Participants performed the task during a functional magnetic resonance imaging acquisition before (n = 96) and after subchronic escitalopram (n = 46, days of administration mean (SD) = 15.7 (2.70)) or placebo (n = 40 days of administration mean (SD) = 16.2 (2.90)) self-administration.

Results: Compared to placebo, we found an elevation in right amygdala activation to the task after escitalopram administration without significant changes in mood. This effect was not seen in the left amygdala, the dorsomedial region of interest, the subgenual anterior cingulate cortex or the right fusiform area. There were no significant changes in connectivity between the dorsomedial cortex and amygdala or the subgenual anterior cingulate cortex after escitalopram administration.

Conclusions: To date, this most highly powered study of subchronic SSRI administration indicates that, contrary to effects often seen in patients with anxiety disorders, subchronic SSRI treatment may increase amygdala activation in healthy controls. This finding highlights important gaps in our understanding of the functional role of serotonin.

Background: Treatment optimization is mandatory in psychiatric diseases and the use of population pharmacokinetics (popPK) models through model informed precision dosing (MIPD) has the potential to improve patient medical care. In this perspective, meta-modelling methods could provide popPK models with improved predictive performances and most of covariates of interest. The aims of this study were to develop meta-models of clozapine and lithium, assess their predictability and propose optimized dosing regimens for both drugs.

Methods: Two popPK models for each drug were retained to develop the meta-models. For clozapine, the model with the best predictive performances and gender as a covariate and one with smoking status were retained. For lithium, the model with the best predictive performances and fat-free mass as covariate and one with glomerular filtration rate were retained.

Results: Both meta-models showed improved predictability compared to the original models. Clozapine meta-model simulations allowed us to propose dosing regimen according to gender and smoking status. Steady-state doses ranged from 375 to 725 mg/day for clozapine once daily, and from 350 to 650 mg/day for clozapine twice daily. Lithium meta-model simulations allowed us to propose dosing regimen according to weight, body mass index, gender and GFR. Our steady-state dose propositions ranged from 625 to 1125 mg/day for males, and from 375 to 750 mg/day for females.

Conclusion: Both meta-models met the acceptability criteria for use in clinical practice on all subpopulations of interest. Those models could be used in the perspective of MIPD for clozapine and lithium.