Therapeutic Advances in Psychopharmacology最新文献

Background: Discontinuation of treatment in people with first episode psychosis (FEP) is common, but the extent to which this is related to specific adverse effects of antipsychotic medications is unclear.

Objectives: To investigate whether antipsychotic discontinuation is associated with the prescription of particular antipsychotics and particular adverse effects.

Design: Retrospective cohort study.

Methods: We assembled de-identified electronic health record (EHR) data from 2309 adults with FEP who received care from the South London and Maudsley NHS Foundation Trust between 1st April 2008 and 31st March 2019. Associations between antipsychotic medications, clinician-recorded side effects and treatment discontinuation were investigated across a mean follow-up period of 34.2 months using Cox regression.

Results: The mean age of patients was 26.7 years and 1492 (64.6%) were male. Among first prescribed antipsychotic medications, discontinuation occurred earlier with haloperidol [hazard ratio (HR) = 2.78, 95% CI = 1.69-4.60] and quetiapine (HR = 1.43, 95% CI = 1.16-1.80) than with olanzapine. Discontinuation occurred sooner when there was evidence of extrapyramidal symptoms (HR = 1.33, 95% CI = 1.08-1.64) or sexual dysfunction (HR = 1.59, 95% CI = 1.03-2.46). Among antipsychotics prescribed at any point during treatment, lurasidone (HR = 1.40, 95% CI = 1.10-1.78) and aripiprazole (HR = 1.09, 95% CI = 1.01-1.19) were associated with earlier discontinuation than olanzapine. Conversely, clozapine (HR = 0.55, 95% CI = 0.41-0.73) and paliperidone 1-monthly (PP1M) long-acting injectable (HR = 0.80, 95% CI = 0.68-0.94) were associated with later discontinuation. Unexpectedly, for antipsychotics prescribed at any stage of treatment, sedation (HR = 0.89, 95% CI = 0.81-0.97), weight gain (HR = 0.73, 95% CI = 0.64-0.83), and multiple side effects (HR = 0.83, 95% CI = 0.76-0.90) were associated with later discontinuation.

Conclusion: Earlier treatment discontinuation associated with sexual or extrapyramidal side effects could be related to their rapid onset and poor tolerability. Later treatment discontinuation associated with clozapine and PP1M could be related to the relative efficacy of these treatments. These findings merit consideration when selecting antipsychotic therapy for people with FEP.

Background: Potentially inappropriate prescribing (PIP) is frequent in geriatrics and results in an increased risk for adverse effects, morbidity, mortality and reduced quality of life. Research on PIP in psychiatry has mainly focused on elderly patients and inpatients.

Objectives: To determine the prevalence and the predictors of PIP of psychotropic medication in outpatients with severe mental illness.

Design: This study is part of the Muva study, a pragmatic open Stepped Wedge Cluster Randomized Trial of a physical activity intervention for patients (age ⩾ 16 years) with severe mental illness.

Methods: A structured medication interview, questionnaires on social functioning, quality of life and psychiatric symptoms, and BMI and waist circumference measurements were performed followed by a structured medication review. Patients were divided into groups: PIP versus no PIP. Between-group differences were calculated and a multivariate binary logistic regression was performed to examine predictors for PIP. A receiver operating characteristics analysis was performed to determine the area under the curve (AUC).

Results: In 75 patients, an average of 5.2 medications of which 2.5 psychotropic medication was used. 35 (46.7%) patients were identified with PIP. Unindicated long-term benzodiazepine use was the most frequently occurring PIP (34.1%). Predictors of PIP were female gender [odds ratio (OR) = 4.88, confidence interval (CI) = 1.16-20.58, p = 0.03], number of medications (OR = 1.41, CI = 1.07-1.86, p = 0.02) and lower social functioning (OR = 1.42, CI = 1.01-2.00, p = 0.05). The AUC was 0.88 for the combined prediction model.

Conclusion: The prevalence of PIP of psychotropic medication in outpatients with severe mental illness is high. It is therefore important to identify, and where possible, resolve PIP by frequently performing a medication review with specific attention to females, patients with a higher number of medications and patients with lower social functioning.

Trial registration: This trial was registered in The Netherlands Trial Register (NTR) as NTR NL9163 on 20 December 2020 (https://trialsearch.who.int/Trial2.aspx?TrialID=NL9163).

Background: Almost one-third of patients with major depressive disorder (MDD) do not respond to conventional antidepressants, and new treatments for MDD are urgently needed.

Objectives: This phase IIb clinical trial was designed to evaluate the efficacy and safety of Anyu Peibo capsules in the treatment of adults with MDD.

Design: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study.

Methods: A total of 172 patients with MDD from nine study centers were randomized (1:1) to receive placebo (n = 86) or oral Anyu Peibo capsules (0.8 g) twice per day (n = 86) for 6 weeks. The primary endpoint was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6, analyzed using an analysis of covariance (ANCOVA) approach with the baseline MADRS score, center effect and center by group interaction as the covariates. Other efficacy endpoints and variables included clinical response and remission rates according to the MADRS and the 17-item Hamilton Depression Rating Scale (HAMD-17) scores, the change in the HAMD-17, Clinical Global Impression - Severity scale and Clinical Global Impression - Improvement scale scores and the reduction in the Hamilton Anxiety Scale from baseline to week 6.

Results: The mean baseline MADRS total scores were 29.20 and 29.72 in the Anyu Peibo (n = 82) and placebo groups (n = 81), respectively. The least squares mean change in the MADRS score from baseline to week 6 was 16.59 points in the Anyu Peibo group and 14.51 points in the placebo group. Although there were greater reductions in the MADRS score from baseline to week 6 in the Anyu Peibo capsule group compared to the placebo group, the difference did not reach statistical significance (least-squares mean difference, 2.07 points; 95% confidence interval, -0.27 to 4.41; p = 0.0819). The results of sensitivity analyses by ANCOVA with the last observation carried forward method for missing data indicated that the administration of Anyu Peibo capsules may lead to a significant reduction in depressive symptoms compared to the placebo (least-squares mean difference: 3.29 points; 95% confidence interval: 0.64-5.93; p = 0.0152). Furthermore, Anyu Peibo capsules showed significant benefits over placebo when the change in the HAMD-17 score from baseline to week 6 was evaluated as the secondary analysis (t = 2.01; 95% confidence interval, 0.03-4.23; p = 0.0464).

Conclusion: Anyu Peibo capsules may have an effective and safe antidepressant effect, which warrants further research.

Medication nonadherence in depressed and anxious older adults is prevalent and associated with non-response to antidepressant pharmacotherapy. Evidence-based options to improve medication adherence are limited in this population. To review the state of the literature on the types and efficacy of psychosocial interventions for improving antidepressant pharmacotherapy adherence in depressed and anxious older adults. We conducted a scoping review according to PRISMA-ScR guidelines. PubMed/Medline and article references starting in 1980 up to 28 February 2023 were reviewed. Of the 710 records screened, 4 psychosocial interventions were included in the review. All studies included depressed older adults, and none included anxious older adults. Samples included racial and ethnic minorities and were primarily women. The psychosocial interventions consisted mainly of psychoeducation with usual care as the control comparison. Measures of antidepressant adherence included self-reported adherence or pill counting. Three of the four randomized controlled trials improved medication adherence rates and reduced depression symptom burden. Effective interventions exist for improving antidepressant medication adherence in depressed older adults. Improved adherence can reduce depression symptom burden. The lack of interventions for anxious older adults highlights the need to develop and deliver interventions for anxious older adults prescribed antidepressant pharmacotherapy.

This review presents a comprehensive guide for optimizing medication management in older adults with depression within an outpatient setting. Medication optimization involves tailoring the antidepressant strategy to the individual, ensuring the administration of appropriate medications at optimal dosages. In the case of older adults, this process necessitates not only adjusting or changing antidepressants but also addressing the concurrent use of inappropriate medications, many of which have cognitive side effects. This review outlines various strategies for medication optimization in late-life depression: (1) Utilizing the full dose range of a medication to maximize therapeutic benefits and strive for remission. (2) Transitioning to alternative classes (such as a serotonin and norepinephrine reuptake inhibitor [SNRI], bupropion, or mirtazapine) when first-line treatment with selective serotonin reuptake inhibitors [SSRIs] proves inadequate. (3) Exploring augmentation strategies like aripiprazole for treatment-resistant depression. (4) Implementing measurement-based care to help adjust treatment. (5) Sustaining an effective antidepressant strategy for at least 1 year following depression remission, with longer durations for recurrent episodes or severe presentations. (6) Safely discontinuing anticholinergic medications and benzodiazepines by employing a tapering method when necessary, coupled with counseling about the benefits of stopping them. Additionally, this article explores favorable medications for depression, as well as alternatives for managing anxiety, insomnia, allergy, overactive bladder, psychosis, and muscle spasm in order to avoid potent anticholinergics and benzodiazepines.

Background: Severe mental illness (SMI) is associated with increased cardiovascular risk. Dyslipidaemia is a potentially modifiable risk factor, which may be inadequately managed in patients with SMI.

Objectives: To assess management of dyslipidaemia in patients with SMI versus healthy controls (HCs) in 2005 and 2015.

Design and methods: Using Danish registers, we identified adult patients with SMI in the Greater Copenhagen Area (schizophrenia spectrum disorders or bipolar disorder) with ⩾1 general practitioner contact in the year before 2005 and 2015, respectively, and HCs without SMI matched on age and gender (1:5). Outcomes were lipid-profile measurements, presence of dyslipidaemia and redemption of lipid-lowering pharmacotherapy. Differences in outcomes between patients with SMI and controls were measured with multivariable logistic regression.

Results: We identified 7217 patients with SMI in 2005 and 9939 in 2015. After 10 years, patients went from having lower odds of lipid measurements to having higher odds of lipid measurements compared with HCs [odds ratio (OR)₂₀₀₅ 0.70 (99% confidence interval (CI) 0.63-0.78) versus OR₂₀₁₅ 1.34 (99% CI 1.24-1.44); p_{2005versus2015} < 0.01]. Patients had higher odds of dyslipidaemia during both years [OR₂₀₀₅ 1.43 (99% CI 1.10-1.85) and OR₂₀₁₅ 1.23 (99% CI 1.08-1.41)]. Patients went from having lower odds of receiving lipid-lowering pharmacotherapy to having higher odds of receiving lipid-lowering pharmacotherapy [OR₂₀₀₅ 0.77 (99% CI 0.66-0.89) versus OR₂₀₁₅ 1.37 (99% CI 1.24-1.51); p_{2005versus2015} < 0.01]. However, among persons at high cardiovascular risk, patients had lower odds of receiving lipid-lowering pharmacotherapy during both years, including subsets with previous acute coronary syndrome [OR₂₀₀₅ 0.30 (99% CI 0.15-0.59) and OR₂₀₁₅ 0.44 (99% CI 0.24-0.83)] and ischaemic stroke or transient ischaemic attack (TIA) [OR₂₀₀₅ 0.43 (99% CI 0.26-0.69) and OR ₂₀₁₅ 0.61 (99% CI 0.41-0.89)].

Conclusion: These results imply an increased general awareness of managing dyslipidaemia among patients with SMI in the primary prophylaxis of cardiovascular disease. However, secondary prevention with lipid-lowering drugs in patients with SMI at high cardiovascular risk may be lacking.

Background: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia surgery, especially in older people, that can persist weeks or months after surgery as a short-term impairment of cognitive abilities, or even for a prolonged duration over years, potentially progressing into permanent cognitive dysfunction. However, the pathogenesis of POCD is not fully understood, and therefore an optimal solution for preventing POCD has yet to be established. Some studies have shown that intraoperative ketamine/esketamine reduces the incidence of POCD, but this remains controversial.

Objectives: We evaluated the effect of intraoperative subanesthetic doses of ketamine/esketamine versus no intervention in adults undergoing general anesthesia surgery on the incidence of POCD.

Data sources: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched the PubMed, Embase, Ovid, Cochrane, Scopus, and Web of Science databases for the MeSH terms 'ketamine', 'esketamine', and 'Postoperative Cognitive Complications' from database inception to 25 June 2023.

Results: We found no statistically significant difference in the incidence of POCD within 7 days for intraoperative subanesthetic dose of ketamine/esketamine compared with the control group [relative risk (RR) = 0.57, 95% confidence interval (CI): 0.32, 1.01], and the results from the subgroup analysis based on age (>60 years) also revealed that the difference was not statistically significant (RR = 0.49, 95% CI: 0.23, 1.04).

Conclusion: Compared with controls, intraoperative subanesthetic dose of ketamine/esketamine has no advantage in preventing POCD in patients, or in elderly patients. This study provides reference data for POCD research and clinical drug intervention strategies.

Registration: Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42023401159).

Background: The paliperidone palmitate 6-month (PP6M) long-acting injectable formulation is currently the longest dosing interval available for schizophrenia treatment.

Objective: To compare treatment outcomes between a real-world external comparator arm (ECA; NeuroBlu database) and the PP6M open-label extension (OLE) clinical trial arm.

Methods: The ECA comprised patients receiving PP 1-month (PP1M) or PP 3-month (PP3M) for ⩾12 months without a relapse. The PP6M OLE arm included patients with PP1M treatment prior to randomization who completed the 12-month double-blind PP6M study on either PP3M or PP6M relapse-free. Inverse probability treatment weighting (IPTW) was used to study time-to-relapse (primary outcome) and change in Clinical Global Impressions-Severity (CGI-S) score (secondary outcome).

Results: At 24 months, 3.9% (7/178) of patients in the PP6M cohort experienced a relapse versus 15.6% (26/167) in the ECA. Time-to-relapse was longer in the PP6M cohort versus the ECA at 12-, 18-, and 24-months across the different weighting methods; median time-to-relapse was not reached in both cohorts. Hazard ratio (HR) for relapse was significantly lower for the PP6M cohort versus the ECA throughout the duration of the study [HR at 24 months: 0.18 (95% CI: 0.08-0.42), p < 0.001]. At 24 months, change in CGI-S score for the PP6M cohort was 0.76 points lower than the ECA (p < 0.001). Results were similar in a sensitivity analysis using propensity score matching (PSM); IPTW resulted in larger sample sizes in balanced dataset than PSM.

Conclusion: Consistent findings across weighting and matching methods suggest PP6M efficacy in reducing and delaying relapses and long-term symptom control compared to PP1M/PP3M in usual-care settings. Additional confounds, such as greater illness severity and more frequent comorbidities and comedications in the ECA, were not fully controlled by the applied statistical methods. Future real-world studies directly comparing PP6M with PP3M/PP1M and adjusting for these confounders are warranted.

Background: Previous studies reported higher incidences of venous thromboembolism and cardiovascular disease in schizophrenia patients and higher indicators of thrombosis, thrombocyte activation, and platelet dysfunction.

Objectives: To check if first-episode schizophrenia (FES) patients have a hypercoagulable state and determine whether acute and chronic antipsychotics have the same effect on blood coagulation or fibrinolysis-related biomarkers.

Design: Case-control study.

Methods: A total of 81 participants were grouped in FES, chronic schizophrenia (CS), and healthy controls (HCs). In addition to demographic data and clinical characteristics, immunological analyses were performed to measure plasma levels of D-dimer, plasminogen activator inhibitor-1 (PAI-1), soluble P selectin (sP-sel), tissue plasminogen activator (tPA), thrombotic precursor protein (TpP), and von Willebrand's disease factor (vWF).

Results: Compared to HC group, FES patients showed higher PAI-1 (28.61 ng/ml versus 15.69 ng/ml), sP-sel (2.78 ng/ml versus 1.18 ng/ml), and TpP (15.61 µg/ml versus 5.59 µg/ml) along with a higher PAI-1/tPA (3.12 versus 2.00). Acute antipsychotic medication reduced higher PAI-1 (28.61 → 21.99), sP-sel (2.78 → 1.87), tPA (9.59 → 5.83), TpP (15.61 → 10.54), and vWF (383.18 → 291.08) in FES patients. However, plasma sP-sel and vWF in CS patients returned to the pre-treatment levels in FES patients, and PAI-1/tPA significantly decreased compared to FES patients.

Conclusion: These results suggest a hypercoagulable state in FES patients and demonstrate contrast effects of acute and chronic antipsychotics on coagulation or fibrinolysis in schizophrenia patients.

Background: The therapeutic potential of subanesthetic doses of ketamine appears promising in unipolar depression; however, its effectiveness in treating bipolar depression (BD) remains uncertain.

Objective: This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability.

Design: Systematic review.

Methods: We conducted a systematic review of studies that investigated the use of ketamine for adults with BD. We searched PubMed and Embase for relevant randomized-controlled trials, open-label trials, and retrospective chart analyses published from inception to 13 March 2023.

Results: Eight studies were identified [pooled n = 235; mean (SD) age: 45.55 (5.54)]. All participants who received intravenous (IV) ketamine were administered a dose of 0.5-0.75 mg/kg as an adjunctive treatment to a mood-stabilizing agent, whereas participants who received esketamine were administered a dosage ranging from 28 to 84 mg. Flexible dosing was used in real-world analyses. A total of 48% of participants receiving ketamine achieved a response (defined as ⩾50% reduction in baseline depression severity), whereas only 5% achieved a response with a placebo. Real-world studies demonstrated lower rates of response (30%) compared to the average across clinical trials (63%). Reductions in suicidal ideation were noted in some studies, although not all findings were statistically significant. Ketamine and esketamine were well tolerated in most participants; however, six participants (2% of the overall sample pool, 5 receiving ketamine) developed hypomanic/manic symptoms after infusions. Significant dissociative symptoms were observed at the 40-min mark in some trials.

Conclusion: Preliminary evidence suggests IV ketamine as being safe and effective for the treatment of BD. Future studies should focus on investigating the effects of repeated acute and maintenance infusions using a randomized study design.