November 2024

Purpose/background: Antipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations. Methods/procedures: This 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days. Findings/results: In a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics. Implications/conclusions: APP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.

Introduction: Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG. Materials and methods: Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists. Results: Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was -2.48 kg (95% Confidence Interval (CI) -5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was -4.70 kg (95% CI -4.85 to -4.56; p < 0.001). The mean change in BMI was -0.82 (95% CI -1.56 to -0.09; p = 0.03) in the exenatide groups and -1.52 (95% CI -1.83 to -1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea. Conclusion: The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed.

Background: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder. Methods: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used. Results: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88). Conclusions: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose.

Background: Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow-up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c). Methods: We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first-episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital-based diagnosis and redeemed prescriptions for glucose-lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within-subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before. Results: In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03-9.76] per 1000 person-years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75-2.38). We found a dose-response association, particularly for second-generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication. Conclusion: This comprehensive real-world two-cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES.

Interpersonal psychotherapy (IPT) and antidepressant medications are both first-line interventions for adult depression, but their relative efficacy in the long term and on outcome measures other than depressive symptomatology is unknown. Individual participant data (IPD) meta-analyses can provide more precise effect estimates than conventional meta-analyses. This IPD meta-analysis compared the efficacy of IPT and antidepressants on various outcomes at post-treatment and follow-up (PROSPERO: CRD42020219891). A systematic literature search conducted May 1st, 2023 identified randomized trials comparing IPT and antidepressants in acute-phase treatment of adults with depression. Anonymized IPD were requested and analyzed using mixed-effects models. The prespecified primary outcome was post-treatment depression symptom severity. Secondary outcomes were all post-treatment and follow-up measures assessed in at least two studies. IPD were obtained from 9 of 15 studies identified (N = 1536/1948, 78.9%). No significant comparative treatment effects were found on post-treatment measures of depression (d = 0.088, p = 0.103, N = 1530) and social functioning (d = 0.026, p = 0.624, N = 1213). In smaller samples, antidepressants performed slightly better than IPT on post-treatment measures of general psychopathology (d = 0.276, p = 0.023, N = 307) and dysfunctional attitudes (d = 0.249, p = 0.029, N = 231), but not on any other secondary outcomes, nor at follow-up. This IPD meta-analysis is the first to examine the acute and longer-term efficacy of IPT v. antidepressants on a broad range of outcomes. Depression treatment trials should routinely include multiple outcome measures and follow-up assessments.

Since 2003, the Food and Drug Administration (FDA) has warned that antidepressants may be associated with suicidal thoughts and behaviors among youth. An FDA advisory in 2003 and a black-box warning in 2005 focused on children and adolescents younger than age eighteen. The FDA expanded the black-box warning in 2007 to include young adults. Both warnings were intended to increase physician monitoring of suicidal thoughts and behaviors. Our systematic review identified thirty-four studies of depression and suicide-related outcomes after these warnings; eleven of these studies met research design criteria established to reduce biases. The eleven studies examined monitoring for suicidal thoughts and behaviors, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use, and psychotropic drug poisonings (a proxy for suicide attempts) and suicide deaths. We assessed possible spillover to adults not targeted by the warnings. The one study that measured intended physician monitoring of suicidal thoughts and behaviors did not find evidence of an increase. Multiple studies found significant unintended reductions in mental health care after the warnings. After these reductions, there were marked increases in psychotropic drug poisonings and suicide deaths. These findings support reevaluation of risks and benefits of the FDA's black-box antidepressant warnings.

Importance: Interest in and use of hallucinogens has been increasing rapidly. While a frequently raised concern is that hallucinogens may be associated with an increased risk of psychosis, there are limited data on this association. Objectives: To examine whether individuals with an emergency department (ED) visit involving hallucinogen use have an increased risk of developing a schizophrenia spectrum disorder (SSD). Design, settings, and participants: This population-based, retrospective cohort study (January 2008 to December 2021) included all individuals aged 14 to 65 years in Ontario, Canada, with no history of psychosis (SSD or substance induced). Data were analyzed from May to August 2024. Exposure: An incident ED visit involving hallucinogen use. Main outcomes and measures: Diagnosis of SSD using a medical record-validated algorithm. Associations between ED visits involving hallucinogens and SSD were estimated using cause-specific adjusted hazard models. Individuals with an incident ED visit involving hallucinogens were compared with members of the general population (primary analysis) or individuals with ED visits involving alcohol or cannabis (secondary analysis). Results: The study included 9 244 292 individuals (mean [SD] age, 40.4 [14.7] years; 50.2% female) without a history of psychosis, with a median follow-up of 5.1 years (IQR, 2.3-8.6 years); 5217 (0.1%) had an incident ED visit involving hallucinogen use. Annual rates of incident ED visits involving hallucinogens were stable between 2008 and 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals). Individuals with ED visits involving hallucinogens had a greater risk of being diagnosed with an SSD within 3 years compared with the general population (age- and sex-adjusted hazard ratio [HR], 21.32 [95% CI, 18.58-24.47]; absolute proportion with SSD at 3 years, 208 of 5217 with hallucinogen use [3.99%] vs 13 639 of 9 239 075 in the general population [0.15%]). After adjustment for comorbid substance use and mental health conditions, individuals with hallucinogen ED visits had a greater risk of SSD compared with the general population (HR, 3.53; 95% CI, 3.05-4.09). Emergency department visits involving hallucinogens were associated with an increased risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model. Conclusions and relevance: In this cohort study, individuals with an ED visit involving hallucinogen use had a greater risk of developing an SSD compared with both the general population and with individuals with ED visits for other types of substances. These findings have important clinical and policy implications given the increasing use of hallucinogens and associated ED visits.

Background: Given both the large volume and manifold preferences of patients with depression, the availability of various effective treatments is important. Psychodynamic psychotherapy (PDT) has received less research in comparison to cognitive behavioural therapy (CBT) for major depressive disorder (MDD). This study aimed to establish whether short-term psychodynamic supportive psychotherapy (SPSP) is non-inferior to CBT in the treatment of MDD. Methods: A non-inferiority trial was conducted in a Dutch mental health setting, with 290 patients randomised to receive 16 sessions of either CBT or SPSP, over eight weeks. Primary outcome was depressive symptom severity assessed using the self-rated Inventory of Depressive Symptomatology (IDS-SR). The non-inferiority margin was prespecified as a - 5 post-treatment difference on the IDS-SR. Secondary outcome measures were functional impairment caused by symptoms assessed using the Sheehan disability scale (SDS), and wellbeing measured by the Mental Health Continuum-Short Form (MHC-SF). Results: Both intention-to-treat (baseline-adjusted mean difference 1.62, 95 % CI -1.82 to 5.05) and per-protocol analyses (mean difference 2.54; 95 % CI -0.63 to 5.72) showed SPSP to be non-inferior to CBT in reducing depressive symptoms. SPSP showed slightly but significantly higher remission rates and wellbeing scores. Limitations: Patients opting for other therapies or medication did not take part in the trial. Follow-up measures or clinician-rated questionnaires were not included. Conclusions: The findings support SPSP as a viable treatment option for MDD, expanding the available choices for patients and broadening treatment options.

Background: Fibromyalgia (FM) is a common illness with a wide range of symptoms, mainly manifested by unexplained chronic systemic musculoskeletal pain, sleep disorders and fatigue, sometimes accompanied by cognitive impairment, psychiatric symptoms and autonomic dysfunction. Previous studies have indicated a correlation between depression and the risk of FM; however, it remains uncertain whether this association reflects a causal relationship. Methods: We evaluated the etiological association between the genetically predicted depression and the risk of developing FM by conducting a two-sample Mendelian Randomization (MR) study. The data on single nucleotide polymorphisms (SNPs) related to depression were obtained from the UK Biobank (UKB) and the Psychiatric Genomics Consortium (PGC) of White British European ancestry, and the data for FM were from the 5th release of the FinnGen study. We adopted the Inverse Variance Weighted (IVW) approach as the principal standard. In order to detect the existence of horizontal pleiotropy and heterogeneity, we adopted the MR-Egger approach as the sensitivity analysis Results: In our MR analysis, 42 depression-related variants were identified as valid instrumental variables (IVs). The IVW approach's results manifest that there is no etiologic causality between genetically predicted depression and the risk of FM (odds ratio [OR]: 1.673, 95% confidence interval [CI]: 0.852-3.287, P = 0.135). The study did not find any significant heterogeneities or horizontal pleiotropies (P > 0.05). Conclusions: Our results suggest that there is no significant genetic evidence linking depression to an increased risk of FM. However, further research is necessary to investigate the potential relationship and underlying mechanisms between depression and the risk of FM.

Introduction: Traits of borderline personality disorder are important for the determination of the prognosis of mental illnesses and in evaluating risks of negativity as well as impulsivity. But, there is a lack of information about the distribution characteristics of borderline personality disorder traits and symptoms within clinical groups. The goal of the current study was to predict borderline personality disorder based on childhood trauma, using experiential avoidance as a mediator. Methods: All male patients hospitalized in local psychiatric health centers with a diagnosis of borderline personality disorder comprised the statistical population of the current study. The number of 60 patients were selected by the purposeful sampling method. The questionnaire included the Childhood Trauma Questionnaire (CTQ), the Experiential Avoidance Questionnaire (AAQ-II), and the Borderline Personality Disorder Symptoms (BSL-23). Results and discussion: The results demonstrated that there is a considerable and positive relationship between childhood trauma and experiential avoidance (r = 0.711, p< 0.01). In the mediating model, childhood trauma had significant direct predictive effects on borderline personality disorder (β = 0.546, p< 0.01). Also, between childhood trauma and BPD, experienced avoidance acts as a moderating factor. (β = 0.304, p< 0.01).

Psychedelics have long been used by individuals seeking peace and a sense of wellness. This article examines widespread adoption of ketamine as a proxy for psychedelics. For ketamine, there is a need to protect vulnerable persons from exploitation that should be balanced against risks of hypermedicalization. This article suggests strategies for striking such a balance, including by carefully differentiating between persons with psychiatric illnesses, such as treatment-resistant depression, who could benefit from psychedelics, and persons using psychedelics for peace and wellness under careful guidance.

Evidence indicates that ketamine is highly effective, has a lower side effect profile and is better tolerated compared to many augmentation strategies for refractory depression. This, combined with data on psychiatric treatment outcome mediators, suggests that earlier intervention with ketamine could improve outcomes for patients suffering from refractory depression.