General Psychiatry

Efficacy and Tolerability of Seven Antipsychotic Drugs in Acutely Ill Patients With Schizophrenia: A Randomized, Multicenter, Assessor-Blinded Trial
Guorui Zhao, Yaoyao Sun, Yuyanan Zhang, Tianlan Lu, Zhe Lu, Zhewei Kang, Johannes Schneider-Thoma, Wuxiang Xie, Yang Yang, Jing Guo, Yunqing Zhu, Rui Yuan, Junyuan Sun, Xiaoyang Feng, Yundan Liao, Dongxue Chen, Lingjiang Li , Tao Li, Fude Yang, Chuanyue Wang, Dai Zhang, Hao Yan, Stefan Leucht, Weihua Yue

Abstract:

Objective: Antipsychotic drugs are the mainstay of schizophrenia treatment; yet, controversy persists regarding their relative efficacy and side effects, and guideline recommendations on efficacy differences are particularly vague. The aim of this trial was to compare seven antipsychotics in acutely ill patients with schizophrenia.

Methods: The authors performed a multicenter (32 hospitals), industry-independent, parallel, assessor-blinded, flexible-dosage randomized trial (Schizophrenia in Non-Occidental Participants). Eligible inpatients 18-45 years of age with schizophrenia experiencing acute exacerbation were recruited and randomized to 6 weeks of monotherapy with one of seven antipsychotic drugs: olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, perphenazine, and haloperidol.

Results: A total of 3,067 patients were randomized, of whom 82% completed follow-up. The mixed model indicated significant differences in the primary outcome percentage change in Positive and Negative Syndrome Scale (PANSS) score between the antipsychotics. At week 6, olanzapine and risperidone showed a significantly higher percentage change in PANSS score than aripiprazole, ziprasidone, and quetiapine (mean differences: 5.52-7.93) but not haloperidol or perphenazine. Olanzapine was associated with the highest risk of weight gain (relative risk: 1.44-3.22). Aripiprazole was associated with lower risk of hyperprolactinemia than all the other drugs (relative risks: 0.11-0.21). Ziprasidone and aripiprazole were associated with lower risks of weight gain and metabolic side effects. Haloperidol was associated with a higher risk of extrapyramidal symptoms than all other drugs (relative risks: 0.13-0.61). Aripiprazole was least sedating (relative risks: 0.30-0.39). Olanzapine and risperidone showed lower all-cause discontinuation rates than ziprasidone and haloperidol (hazard ratios: 0.61-0.73).

Conclusions: This trial fills important knowledge gaps in acute antipsychotic treatment of schizophrenia. It confirms hierarchies in efficacy and side effects of antipsychotics from related evidence.

Annotation

The finding: This was a massive randomized trial of generically available antipsychotics in Chinese patients hospitalized for exacerbations of schizophrenia. ~3,000 patients were randomized to olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, perphenazine, or haloperidol, and followed for 6 weeks – with the entire duration occurring inpatient. Olanzapine and risperidone appeared most effective, and were statistically superior to aripiprazole, ziprasidone, and quetiapine – with haloperidol and perphenazine somewhere in the middle. Adverse effects were fairly consistent with prior head-to-head trials and meta-analyses: the most weight gain with olanzapine, prolactin elevation with risperidone, EPS with haloperidol, and QTc prolongation with ziprasidone.

Strength and weaknesses: The major weakness of the trial is its limited blinding: both patients and psychiatrists knew the medications they were receiving, with only trial assessors being blinded to allocation. Its obvious strengths are its size (twice that of CATIE!) and the number of medications compared (two more than CATIE!).

Relevance: On the one hand, this study does little to upend preexisting hierarchies of efficacy and side effects of antipsychotics – its findings are remarkably consistent with the results of the large network meta-analyses that represented the best available evidence beforehand. On the other hand, having these direct comparisons from a well-powered RCT is quite useful for directly trading off risks and benefits – you can now say with some confidence, for example, that using olanzapine rather than aripiprazole affords a ~10% greater chance of treatment response at a cost of a ~20% higher chance of significant weight gain. And for patients with significant medical reasons to absolutely avoid specific adverse effects, this paper gives you the data to choose the safest antipsychotic possible.

The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis

Toby Pillinger, Atheeshaan Arumuham, Robert A McCutcheon, Enrico D'Ambrosio, Georgios Basdanis, Marco Branco, Richard Carr, Valeria Finelli, Toshi A Furukawa, Siobhan Gee, Adrian Heald, Sameer Jauhar, Zihan Ma, Valentina Mancini, Calum Moulton, Georgia Salanti, David M Taylor, Anneka Tomlinson, Allan H Young, Orestis Efthimiou, Oliver D Howes, Andrea Cipriani

Abstract:

Background: Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs).

Methods: We searched MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and the US Food and Drug Administration (FDA) website from database inception to April 21, 2025. We included single-blinded and double-blinded RCTs comparing antidepressants and placebo in acute monotherapy of any psychiatric disorder. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in weight; total cholesterol; glucose; heart rate; systolic and diastolic blood pressure; corrected QT interval (QTc); sodium; potassium; aspartate transferase (AST); alanine transaminase (ALT); alkaline phosphatase (ALP); bilirubin; urea; and creatinine. We did meta-regressions to examine study-level associations between physiological change and age, sex, and baseline weight. We estimated the correlation between depressive symptom severity change and metabolic parameter change.

Findings: Of 26 252 citations, 151 studies and 17 FDA reports met inclusion criteria. The overall sample included 58 534 participants, comparing 30 antidepressants with placebo. Median treatment duration was 8 weeks (IQR 6·0-8·5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects, including an approximate 4 kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate change between fluvoxamine and nortriptyline, and over 11 mmHg difference in systolic blood pressure between nortriptyline and doxepin. Paroxetine, duloxetine, desvenlafaxine, and venlafaxine were associated with increases in total cholesterol and, for duloxetine, glucose concentrations, despite all drugs reducing bodyweight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP concentrations, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc, or concentrations of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline bodyweight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST, and higher baseline age was associated with larger antidepressant-induced increases in glucose. We did not observe an association between changes in depressive symptoms and metabolic disturbance.

Interpretation: We found strong evidence that antidepressants differ markedly in their physiological effects, particularly for cardiometabolic parameters. Treatment guidelines should be updated to reflect differences in physiological risk, but choice of antidepressant should be made on an individual basis, considering clinical presentation and preferences of patients, carers, and clinicians.

Annotation

The finding: This was a large network meta-analysis of antidepressant adverse effects, comprising ~170 RCTs with a total of ~60,000 patients. The authors examined comparative rates of numerous somatic adverse effects and – as with any network meta-analysis – described the findings with pages and pages of fascinating charts. Perhaps surprisingly, the drugs differed quite a bit from one another – both between mechanistic classes and within them. Notable findings included: significant weight gain with amitriptyline and mirtazapine vs. weight loss with fluoxetine and bupropion; heart rate increases of 10-15 BPM with most TCAs; and no significant effect on QTc from any antidepressant including citalopram.

Strength and weaknesses: This is the most comprehensive analysis to date of somatic adverse effects of antidepressants, and it has produced a correspondingly vast array of tables and figures. Especially from a consult-liaison perspective, its most significant limitation is the underlying patient population – RCTs tend to exclude patients with significant medical comorbidities, so these adverse event rates may not be perfectly applicable to medically hospitalized patients.

Relevance: This study abounds with insights for providers prescribing antidepressants to medically fragile patients – and depending on your patient’s specific array of medical issues, can help you feel confident in selecting the specific antidepressant that is least likely to cause dangerous adverse effects. Of particular note for consult-liaison psychiatrists is the absence of identifiable QTc prolongation with any antidepressant evaluated – while you still shouldn’t be cavalier with antidepressants in patients with baseline prolonged QTc or significant cardiac comorbidities, this should provide some reassurance that in the vast majority of patients no antidepressant will confer a substantial risk of torsades.