Antipsychotic drugs in first-episode psychosis: a target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health.

Efficacy of long-acting injectable versus oral antipsychotic drugs in early psychosis: A systematic review and meta-analysis.

AIM: Long-acting injectable antipsychotic drugs (LAIs) are often used as an alternative to oral antipsychotics (OAPs) in individuals with psychosis who demonstrate poor medication adherence. Previous meta-analyses have found mixed results on the efficacy of LAIs, compared to OAPs, in patients with psychotic disorders. The objective of this meta-analysis was to compare the effectiveness of using LAIs versus OAPs in the early stages of psychosis. METHODS: Major electronic databases were used to search for any studies examining the comparative effectiveness (i.e., relapse, adherence, hospitalization, and all-cause discontinuation) of any LAIs versus OAPs in early stages of psychosis. Studies published up to 6 June, 2019 were included and no language restriction was applied. Inclusion criteria were a diagnosis of schizophrenia or related disorder, where patients were in their first episode or had a duration of illness ≤5 years. Data were analysed using a random-effects model. RESULTS: Fifteen studies (n = 10 584) were included, of which were 7 RCTs, 7 observational studies, and 1 post-hoc analysis. We found that LAIs provided advantages over OAPs in terms of relapse rates. No significant differences were found between LAI and OAP groups in terms of all-cause discontinuation, hospitalization, and adherence rates. However, considering only RCTs revealed advantages of LAIs over OAPs in terms of hospitalization rates. CONCLUSIONS: LAIs may provide benefits over OAPs with respect to reducing relapse and hospitalization rates in early psychosis patients. There is a need for larger and better-designed studies comparing OAPs and LAIs specifically in early psychosis patients.

Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis.

Early intervention is essential for favorable long-term outcomes in schizophrenia. However, there is limited guidance in the scientific literature on how best to choose between dopamine D2 receptor (D2R) partial agonists and D2R antagonists in early stages of schizophrenia. The aim of this meta-analysis was to directly compare D2R partial agonists with D2R antagonists for efficacy and tolerability, using randomized controlled trials (RCTs) that involved participants diagnosed with first-episode psychosis, schizophrenia, or related psychotic disorders with a duration of illness ≤5 years. Fourteen RCTs, involving 2494 patients, were included in the meta-analysis. Aripiprazole was the only identified D2R partial agonist, and was not significantly different from pooled D2R antagonists for overall symptom reduction or all-cause discontinuation. However, aripiprazole was more favorable than pooled D2R antagonists for depressive symptoms, prolactin levels, and triglyceride levels. Specifically, aripiprazole was more favorable than paliperidone for triglyceride levels and more favorable than risperidone and olanzapine, but less favorable than ziprasidone, for weight gain. In addition, aripiprazole was less favorable for akathisia compared with second-generation D2R antagonists, in particular olanzapine and quetiapine, and less favorable for discontinuation due to inefficacy than risperidone. Lastly, aripiprazole was more favorable than haloperidol for various efficacy and tolerability outcomes. In conclusion, aripiprazole's efficacy did not differ substantially from D2R antagonists in the early course of schizophrenia, whereas differential tolerability profiles were noted. More double-blind RCTs are required comparing the efficacy and tolerability of aripiprazole as well as other D2R partial agonists with D2R antagonists in early stages of schizophrenia.

Association between Serum Lipids and Antipsychotic Response in Schizophrenia.

Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled trials, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.

Assessment of arterial stiffness among schizophrenia-spectrum disorders using aortic pulse wave velocity and arterial compliance: a pilot study.

Cardiovascular disease (CVD) is the leading cause of death in individuals with chronic schizophrenia. Arterial stiffness provides a non-invasive indication of cardiovascular disease risk. To date, arterial stiffness, which has been shown to have independent predictive value for CVD morbidity and mortality, has not been evaluated in this population. We aimed to examine aortic pulse wave velocity (aPWV) as well as large and small artery compliance (Comp1 and Comp2) in patients being treated for schizophrenia, compared to healthy volunteers. Ten patients and 10 age and gendermatched volunteers underwent a comprehensive evaluation of arterial stiffness including: aPWV, Comp1, Comp2, stroke volume, cardiac output, and systemic vascular resistance. Patient aPWV was significantly elevated compared to healthy volunteers (9.1 ± 4.11 vs. 5.7 ± 1.4, P=0.03). Increased age, blood pressure, heart rate, and cigarettes/day were associated with reduced arterial health in patients. This is the first time aPWV has been described in those treated for schizophrenia. Arterial stiffness is increased in this population. Measuring arterial stiffness is a non-invasive, sensitive and effective tool for evaluating CVD risk in this population.

Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension.

Second-generation antipsychotics (SGAs) are associated with significant comorbid metabolic abnormalities. Adjunct medications may be prescribed to treat these metabolic side effects, but the evidence supporting this practice (especially for the management of antipsychotic-associated dyslipidemia and hypertension) is limited. The purpose of this review was to evaluate the effects of adjunct medications on triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein, and blood pressure levels in participants taking SGAs for psychosis. Studies were systematically searched and evaluated. Studies were included for review if participants were taking SGAs and if lipid and/or blood pressure levels were included as outcome measures. Statins, conventional lipid-lowering agents, fluvoxamine, ramelteon, topiramate, valsartan, telmisartan, omega-3 fatty acids, metformin (including both immediate-release and extended-release formulations), and a combination of metformin-sibutramine seemed to have beneficial effects on lipid levels. Valsartan, telmisartan, and topiramate appeared to be effective for controlling increases in blood pressure. The literature on adjunct medications for the treatment of antipsychotic-associated dyslipidemia and hypertension is not exhaustive, and long-term randomized-controlled trials would offer valuable results.

Improving metabolic and cardiovascular health at an early psychosis intervention program in vancouver, Canada.

Psychotic disorders most commonly appear during the late teenage years and early adulthood. A focused and rapid clinical response by an integrated health team can help to improve the quality of life of the patient, leading to a better long-term prognosis. The Vancouver Coastal Health early psychosis intervention program covers a catchment area of approximately 800,000 people in the cities of Vancouver and Richmond, Canada. The program provides a multidisciplinary approach to supporting patients under the age of 30 who have recently experienced first-break psychosis. The program addresses the needs of the treatment environment, medication, and psychological therapies. A critical part of this support includes a program to specifically improve patients' physical health. Physical health needs are addressed through a two-pronged, parallel approach. Patients receive routine metabolic health assessments during their first year in the program, where standard metabolic parameters are recorded. Based on the results of clinical interviews and laboratory tests, specific actionable interventions are recommended. The second key strategy is a program that promotes healthy lifestyle goal development. Patients work closely with occupational therapists to develop goals to improve cardiometabolic health. These programs are supported by an active research environment, where patients are able to engage in studies with a focus on improving their physical health. These studies include a longitudinal evaluation of the effects of integrated health coaching on maintaining cardiometabolic health in patients recently admitted to the program, as well as a clinical study that evaluates the effects of low versus higher metabolic risk antipsychotic drugs on central adiposity. An additional pharmacogenomic study is helping to identify genetic variants that may predict cardiometabolic changes following treatment with antipsychotic drugs.