Journal of Psychopharmacology最新文献

Background: Whether responses to treatment of major depressive episodes differ between women and men or with bipolar (BD) and major depressive disorders (MDD) remains unresolved.

Aims: To test for diagnostic and sex differences in responses to treatment of depression.

Methods: We compared changes in the 21-item Hamilton Depression Rating Scale (HDRS₂₁) ratings of depression (n = 3243) between women (64.7%) and men, and between DSM-5-TR BD ([n = 253] and subtypes I [BD1] vs II [BD2]) and MDD (n = 2990), using bivariate comparisons and multivariate modeling.

Results: Treatments included clinically individualized use of antidepressants (by 92.4%, in doses averaging 90.0 mg/day imipramine-equivalent), sometimes with mood-stabilizing agents (32.1%), second-generation antipsychotics (18.8%), or psychotherapy (38.6%). Depression ratings decreased by 60.6% to a final mean HDRS score of 7.44; response rate (⩾50% reduction in HDRS) averaged 63.7%. Outcomes were very similar in women and men as well as with BD versus MDD, and between BD subtypes. Moreover, age, duration of illness, initial HDRS score, dose of antidepressant, and weeks of treatment, as well as sex and diagnosis were not associated with improvement of HDRS with treatment. Only 6/42 comparisons involving 21 individual HDRS items differed significantly in improvement between sexes or diagnoses. Results were very similar to the Montgomery-Åsberg Depression Rating Scale depression ratings. Only 2.0% of the subjects experienced mood-switching into clinical (hypo)mania and the final Young Mania Rating Scale ratings averaged 0.63.

Conclusions: Responses to clinical treatment (as % reduction of HDRS score, response rate, or final HDRS score) of depressed women versus men, and BD (including BD1 vs BD2) versus MDD were substantial and very similar.

Background: Methotrexate (MTX) is a cytotoxic drug that can trigger neurotoxicity via enhancing oxidative stress, apoptosis, and inflammation. On the other hand, erythropoietin (EPO) functions as an antioxidant, anti-apoptotic, and anti-inflammatory agent, in addition to its hematopoietic effects.

Aim: The present study was developed to examine the neuroprotective impact of EPO against MTX-provoked neurotoxicity in rats.

Methods: Chemo fog was elicited in Wistar rats via injection of one dosage of MTX (20 mg/kg, i.p) on the sixth day of the study. EPO was injected at 500 IU/kg/day, i.p for 10 successive days.

Results: MTX triggered memory and learning impairment as evidenced by Morris water maze, passive avoidance, and Y-maze cognitive tests. In addition, MTX induced oxidative stress as evident from the decline in hippocampal Nrf2 and HO-1 levels. MTX brought about apoptosis, as demonstrated by the elevation in p53, caspase-3, and Bax levels, as well as the decrease in Bcl2 levels. MTX also decreased Beclin-1, an autophagy-related marker, and increased P62 expression. In addition, MTX downregulated Sirt-1/AKT/FoxO3a pathway and increased miRNA-34a gene expression. Moreover, MTX increased acetylcholinesterase activity and reduced neurogenesis. EPO administration remarkably counteracted MTX-induced molecular and behavioral disorders in rat hippocampi.

Conclusion: Our findings impart preclinical indication for repurposing of EPO as a promising neuroprotective agent through modulating miRNA-34a, autophagy, and the Sirt-1/FoxO3a signaling pathway.

Objective: Therapeutic drug monitoring (TDM) indicators have been suggested to predict overall outcome responses to olanzapine (OLZ) treatments in terms of efficacy and metabolic syndrome. This study aimed to investigate whether paraoxonase-1 (PON-1) activity can be used to predict schizophrenia patient outcomes.

Methods: Schizophrenic patients (N = 50) aged between 20 and 65 years who received OLZ treatment were recruited, and their Positive and Negative Syndrome Scale scores, PON-1 activity, and olanzapine drug levels normalized by dose (OLZ/D) and its metabolite N-desmethyl-olanzapine (DMO), together with biochemical parameters, were determined.

Results: PON-1 activity and OLZ/D were significantly correlated in 50 patients (correlation coefficient, r = 0.355; p = 0.0115). There was also a statistically significant correlation between the ratio of PON-1 activity normalized by homocysteine (Hcy) and OLZ/D (correlation coefficient r = 0.361; p = 0.01) and a significant negative correlation between the ratio of PON-1 activity normalized by Hcy and triglyceride/high-density lipoprotein (TG/HDL; correlation coefficient r = -0.328; p = 0.02).

Conclusions: PON-1 activity can be used as an alternative tool for monitoring TDM through the measurement of OLZ together with its metabolite, DMO, to identify patients who have higher activity. Those who show an optimal response or who have lower activity might have greater cardiometabolic risk under long-term olanzapine treatment. Longitudinal monitoring is warranted to confirm such observations.

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.

Background: Among the available pharmacological treatments for acute major depressive disorder (MDD), vortioxetine, a serotonin transporter inhibitor (SERT), has been widely used for its multimodal action on serotonin neurotransmission, which produces essential changes also on glutamate, gamma amino butyric acid (GABA), norepinephrine, acetylcholine, and dopamine.

Aim: This systematic review and meta-analysis aimed to evaluate the acute efficacy of vortioxetine across multiple dosing and to evaluate whether there is a dose-response effect and as well there is a dose-response issue with respect to side effects in acute depression.

Methods: According to PRISMA guidelines, we systematically searched three major electronic databases (PubMed/MEDLINE, PsycINFO, and Cochrane Central Register of Controlled Trials) for Randomized Controlled Trial (RCT) studies published between January 2013 and April 2024. Twenty-four studies were included in the review and two meta-analyses were conducted to determine whether the mean Montgomery-Asberg Depression Rating Scale (MADRS) scale values in the placebo groups differ significantly from the mean MADRS scale values in the group receiving vortioxetine 10 mg or vortioxetine 20 mg.

Results: Vortioxetine significantly improved acute depression severity, anxiety symptoms, and cognitive function, with high response and remission rates in acute MDD. It was also well tolerated with a relatively low occurrence of severe or serious treatment-emergent adverse events (TEAEs). Observing the results of the meta-analysis, the effect was significant for both vortioxetine 10 and 20 mg, with a greater effect size for vortioxetine 20 mg.

Conclusion: Vortioxetine should be considered efficacious as a first- and second-line therapy.

Background: Options for 'treatment-resistant bipolar depression' (TRBD) are limited. Two small, short-term, trials of pramipexole suggest it might be an option.

Aims: To evaluate the clinical effectiveness and safety of pramipexole in the management of TRBD.

Methods: A multi-centre randomised, double-blind controlled trial including participants ⩾18 years old with TRBD (failure to respond, tolerate or clinical contraindication/patient refusal of ⩾2 of quetiapine, olanzapine, lamotrigine or lurasidone) randomised 1:1 to pramipexole (max 2.5 mg/day salt weight) or placebo added to ongoing mood stabiliser (n = 39). Primary outcome: Quick Inventory of Depressive Symptoms, Self-rated (QIDS-SR) at 12 weeks. Up to 48 weeks follow-up.

Results: Pramipexole (n = 18) was associated with a greater reduction in QIDS-SR score at 12 weeks versus placebo (n = 21, 4.4 (4.8) vs 2.1 (5.1)): a medium sized (d = -0.72) but not statistically significant difference (95% CI: -0.4 to 6.3, p = 0.087). Similarly, there was a non-significant approximate 2-point (d = -0.76) improvement in pleasure at 6 weeks (95% CI: -0.11 to 4.20). Significant advantages of pramipexole on QIDS-SR score (6.28 points: 95% CI: 1.85-10.71) and psychosocial function (5.36 points: 95% CI: 0.38-10.35) were seen at 36 weeks post-randomisation, and on the response (46% vs 6%; p = 0.026) and remission (31% vs 0%; p = 0.030) rates at trial exit (48 weeks or last available data after 16 weeks for those affected by the early study closure). Hypomania ratings were significantly higher at 12 weeks. Otherwise, pramipexole was well tolerated.

Conclusions: Clinically large, but statistically non-significant, effects of pramipexole on depression at 12 weeks, with significant longer-term benefits on mood and function were observed. Pramipexole use was complicated by dose titration and increased hypomanic symptoms. The small sample size limits interpretation. Furthermore, larger randomised placebo-controlled trials are warranted.

Background: Recent clinical trials suggest promising antidepressant effects of psilocybin, despite methodological challenges. While various studies have investigated distinct mechanisms and proposed theoretical opinions, a comprehensive understanding of psilocybin's neurobiological and psychological antidepressant mechanisms is lacking.

Aims: Systematically review potential antidepressant neurobiological and psychological mechanisms of psilocybin.

Methods: Search terms were generated based on existing evidence of psilocybin's effects related to antidepressant mechanisms. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, 15 studies were systematically reviewed, exploring various therapeutic change principles such as brain dynamics, emotion regulation, cognition, self-referential processing, connectedness, and interpersonal functioning.

Results: Within a supportive setting, psilocybin promoted openness, cognitive and neural flexibility, and greater ability and acceptance of emotional experiences. A renewed sense of connectedness to the self, others, and the world emerged as a key experience. Imaging studies consistently found altered brain dynamics, characterized by reduced global and within default mode network connectivity, alongside increased between-network connectivity.

Conclusions: Together, these changes may create a fertile yet vulnerable window for change, emphasizing the importance of a supportive set, setting, and therapeutic guidance. The results suggest that psilocybin, within a supportive context, may induce antidepressant effects by leveraging the interplay between neurobiological mechanisms and common psychotherapeutic factors. This complements the view of purely pharmacological effects, supporting a multileveled approach that reflects various relevant dimensions of therapeutic change, including neurobiological, psychological, and environmental factors.

Ketamine has recently been shown to be non-inferior to electroconvulsive therapy (ECT), one of psychiatry's most effective treatments for depression. Given the novelty of ketamine as well as its interventional nature, ketamine is currently viewed as an alternative to ECT and as such, considered a third-line agent for treatment-refractory depression. However, available data suggest that ketamine carries a low side-effect burden and is better tolerated than many second-line augmentation strategies for depression. With this combination of higher efficacy and lower side-effect burden in conjunction with what is known about treatment outcomes in relation to the duration of untreated illness, it is in the best interest of patients for the field of psychiatry to evaluate ketamine as a second-line augmentation strategy for refractory depression.

Background: Ketamine has received attention owing to its rapid and long-lasting antidepressant effects; however, its clinical application is restricted by its addictiveness and adverse effects. S-ketamine, which is the S-enantiomer of ketamine, is considered safer and better tolerated by patients than ketamine.

Aims: This study aimed to identify the key gene targets and potential signalling pathways associated with the mechanism of S-ketamine in major depressive disorder (MDD) treatment.

Methods: The GSE98793 dataset was extracted from the Gene Expression Omnibus database, and differentially expressed genes were identified in blood samples from patients with MDD and healthy individuals. The hub genes among the differentially expressed genes were identified and enrichment analysis was performed. The therapeutic targets and related signalling pathways of S-ketamine in MDD treatment were analysed. The 3D structures of the target proteins were predicted using AlphaFold2, and molecular docking was performed to verify whether S-ketamine could be successfully docked to the predicted targets. A quantitative polymerase chain reaction was performed to determine the effect of ketamine on the screened targets. Among 228 target genes annotated using pharmacophore target gene analysis, 3 genes were identified and 2 therapeutic signalling pathways were discovered.

Results: S-ketamine exerts downregulatory effects on TGM2 and HSP90AB1 expression but exerts an up-regulatory effect on ADORA3 expression. The protein structures of the therapeutic targets were successfully predicted using AlphaFold2.

Conclusions: S-ketamine may alleviate depression by targeting specific genes, including TGM2, HSP90AB1 and ADORA3, as well as signalling pathways, including the gonadotropin-releasing hormone and relaxin signalling pathways.