-
Molecular Psychiatry Aug 2023Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic... (Meta-Analysis)
Meta-Analysis
Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D receptor (DR) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The DR occupancy curves showed that the risk increased substantially when DR occupancy exceeded 75-85%, except for DR partial agonists that had smaller ORs albeit high DR occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current DR therapeutic window for EPS.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Haloperidol; Clozapine; Receptors, Dopamine D2; Drug-Related Side Effects and Adverse Reactions
PubMed: 37537284
DOI: 10.1038/s41380-023-02203-y -
Schizophrenia Bulletin Jan 2024Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. (Meta-Analysis)
Meta-Analysis
Long-Acting Injectable Second-Generation Antipsychotics vs Placebo and Their Oral Formulations in Acute Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled-Trials.
BACKGROUND AND HYPOTHESIS
Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia.
STUDY DESIGN
We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1.
STUDY RESULTS
Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations.
CONCLUSIONS
SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.
Topics: Humans; Antipsychotic Agents; Paliperidone Palmitate; Aripiprazole; Olanzapine; Risperidone; Delayed-Action Preparations; Schizophrenia
PubMed: 37350486
DOI: 10.1093/schbul/sbad089 -
Current Psychiatry Reports Nov 2023Despite clear evidence that sex differences largely impact the efficacy and tolerability of antipsychotic medication, current treatment guidelines for schizophrenia... (Review)
Review
PURPOSE OF REVIEW
Despite clear evidence that sex differences largely impact the efficacy and tolerability of antipsychotic medication, current treatment guidelines for schizophrenia spectrum disorders (SSD) do not differentiate between men and women. This review summarizes the available evidence on strategies that may improve pharmacotherapy for women and provides evidence-based recommendations to optimize treatment for women with schizophrenia.
RECENT FINDINGS
We systematically searched PubMed and Embase for peer-reviewed studies on three topics: (1) sex differences in dose-adjusted antipsychotic serum concentrations, (2) hormonal augmentation therapy with estrogen and estrogen-like compounds to improve symptom severity, and (3) strategies to reduce antipsychotic-induced hyperprolactinemia. Based on three database studies and one RCT, we found higher dose-adjusted concentrations in women compared to men for most antipsychotics. For quetiapine, higher concentrations were specifically found in older women. Based on two recent meta-analyses, both estrogen and raloxifene improved overall symptomatology. Most consistent findings were found for raloxifene augmentation in postmenopausal women. No studies evaluated the effects of estrogenic contraceptives on symptoms. Based on two meta-analyses and one RCT, adjunctive aripiprazole was the best-studied and safest strategy for lowering antipsychotic-induced hyperprolactinemia. Evidence-based recommendations for female-specific pharmacotherapy for SSD consist of (1) female-specific dosing for antipsychotics (guided by therapeutic drug monitoring), (2) hormonal replacement with raloxifene in postmenopausal women, and (3) aripiprazole addition as best evidenced option in case of antipsychotic-induced hyperprolactinemia. Combining these strategies could reduce side effects and improve outcome of women with SSD, which should be confirmed in future longitudinal RCTs.
Topics: Female; Humans; Male; Aged; Antipsychotic Agents; Schizophrenia; Aripiprazole; Hyperprolactinemia; Raloxifene Hydrochloride; Estrogens
PubMed: 37864676
DOI: 10.1007/s11920-023-01460-6 -
Medicine Sep 2023Atypical antipsychotic (AAP) augmentation is an alternative strategy for patients with major depressive disorder (MDD) who had an inadequate response to antidepressant... (Meta-Analysis)
Meta-Analysis
Comparative efficacy and safety of 4 atypical antipsychotics augmentation treatment for major depressive disorder in adults: A systematic review and network meta-analysis.
BACKGROUND
Atypical antipsychotic (AAP) augmentation is an alternative strategy for patients with major depressive disorder (MDD) who had an inadequate response to antidepressant therapy (ADT). We aimed to compare and rank the efficacy and safety of 4 AAPs in the adjuvant treatment of MDD.
METHODS
We searched randomized controlled trials (RCTs) published and unpublished from the date of databases and clinical trial websites inception to April 30, 2023. The evidence risk of bias (RoB) and certainty are assessed using the Cochrane bias risk tool and grading of recommendations assessment, development, and evaluation (GRADE) framework, respectively. Using network meta-analysis, we estimated summary risk ratios (RRs) or standardized mean difference (SMD) based on the random effects model.
RESULTS
56 eligible studies comprising 11448 participants were included. In terms of primary efficacy outcome, compared with placebo (PBO), all AAPs had significant efficacy (SMD = -0.40; 95% CI, -0.68 to -0.12 for quetiapine (QTP); -0.35, -0.59 to -0.11 for olanzapine (OLA); -0.28, -0.47 to -0.09 for aripiprazole (ARI) and -0.25, -0.42 to -0.07 for brexpiprazole (BRE), respectively). In terms of acceptability, no significant difference was found, either agents versus agents or agents versus PBO. In terms of tolerability, compared with the PBO, QTP (RR = 0.24; 95% CI,0.11-0.53), OLA (0.30,0.10-0.55), ARI (0.39,0.22-0.69), and BRE (0.37,0.18-0.75) were significantly less well tolerated. 8 (14.2%) of 56 trials were assessed as low RoB, 38 (67.9%) trials had moderate RoB, and 10 (17.9%) had high RoB; By the GRADE, the certainty of most evidence was low or very low.
CONCLUSION
Adjuvant AAPs had significant efficacy compared with PBO, but treatment decisions must be made to balance the risks and benefits.
Topics: Adult; Humans; Depressive Disorder, Major; Antipsychotic Agents; Network Meta-Analysis; Quetiapine Fumarate; Aripiprazole; Olanzapine; Adjuvants, Immunologic; Adjuvants, Pharmaceutic
PubMed: 37746943
DOI: 10.1097/MD.0000000000034670 -
Psychopharmacology Feb 2024Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia.
METHODS
We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies.
RESULTS
We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome 'slight improvement' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for 'moderate improvement' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for-'slight improvement' (RR 1.05 (95% CI 0.6, 1.81)) and 'moderate improvement' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis.
CONCLUSIONS
VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD.
Topics: Adult; Humans; Antipsychotic Agents; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Vesicular Monoamine Transport Proteins
PubMed: 38238580
DOI: 10.1007/s00213-023-06488-3 -
Journal of Affective Disorders Oct 2023Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical antipsychotics in treating unipolar and bipolar depression in adolescents and young adults.
METHOD
We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies (RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary outcome of interest was change in depressive symptoms from baseline to trial endpoint.
RESULTS
No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combination, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean difference (WMD) was -4.58 (95 % CI, -6.59 to -2.57) between antipsychotic and placebo-treated groups. Response and remission rates were also significantly in favor of antipsychotic treatment.
LIMITATIONS
There were few studies, several did not address risk-of-bias domains and there was a lack of non-industry sponsored studies.
CONCLUSION
There is an absence of evidence for the use of antipsychotic medications in treatment of youth unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of antipsychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with bipolar depression. However, this evidence is limited and more studies investigating the use of these medications in young people are needed.
Topics: Child; Adolescent; Young Adult; Humans; Antipsychotic Agents; Bipolar Disorder; Fluoxetine; Olanzapine; Lurasidone Hydrochloride
PubMed: 37467794
DOI: 10.1016/j.jad.2023.07.082 -
CNS Drugs Aug 2023Considering the improvement in adherence and convenience, once-monthly paliperidone palmitate (PP1M) has been increasingly used in the treatment of schizophrenia.... (Meta-Analysis)
Meta-Analysis
Effectiveness and Safety of Switching from Oral Antipsychotics to Once-Monthly Paliperidone Palmitate (PP1M) in the Management of Schizophrenia: A Systematic Review and Meta-Analysis.
BACKGROUND
Considering the improvement in adherence and convenience, once-monthly paliperidone palmitate (PP1M) has been increasingly used in the treatment of schizophrenia. However, the outcomes for patients who switch from oral antipsychotics (OAPs) to PP1M have not been reliably assessed. The objective of this systematic review and meta-analysis was to investigate the efficacy and safety of PP1M in the management of patients with schizophrenia with a prior history of OAP use.
METHODS
We conducted a systematic search in PubMed, EMBASE, and the Cochrane Library on 19 July 2022 to identify eligible studies. All studies that examined the effectiveness and safety of switching from OAPs to PP1M in patients with schizophrenia were included. The primary outcomes were relapse rate, hospitalisation rate, and the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. The secondary outcomes included the changed number of inpatient visits, changed length of stay hospitalisation, change from baseline in the Clinical Global Impressions-Severity (CGI-S) score and the personal and social performance (PSP) total score, response rate, proportion of treatment discontinuation, and adverse events. We included randomised-controlled trials (RCTs), single-arm studies, and observational studies. Case reports, case series, and reviews were excluded. The quality assessment of included studies was performed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB2), the 9-point Newcastle-Ottawa Scale (NOS) instrument for non-randomised studies and cohort studies, and the 12-item National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) study without control group. Follow-up times were reported as short- (≤ 13 weeks), medium- (14-26 weeks), and long term (≥ 27 weeks). Data were pooled using meta-analysis.
RESULTS
Fifteen studies with a total of 4740 patients were included. The long-term relapse rates and hospitalisation rates were 12% (95% CI 0.07-0.18) and 18% (95% CI 0.15-0.20), respectively. The short-, medium-, and long-term change in PANSS total score was - 21.69 (95% CI - 30.02 to -13.36), - 14.98 (95% CI - 21.45 to - 8.51) and - 17.88 (95% CI - 31.94 to -3.82), respectively. Approximately 50% of patients reported at least a 30% reduction in the PANSS score at the short-term follow-up. Improvements in CGI-S and PSP score were observed during various periods. There was a reduction in the length of stay hospitalisation and the number of inpatient visits at the medium- and long-term follow-ups. Low discontinuation and adverse event rates were reported.
CONCLUSION
Based on our findings, this study may support the efficacy and safety of switching from OAPs to PP1M for the treatment of patients with schizophrenia. Future large-scale studies are warranted to confirm our findings.
Topics: Humans; Antipsychotic Agents; Paliperidone Palmitate; Schizophrenia; Administration, Oral; Recurrence; Chronic Disease
PubMed: 37490267
DOI: 10.1007/s40263-023-01028-1 -
Psychological Medicine Jul 2023Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy.
METHODS
A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events.
RESULTS
Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior.
CONCLUSION
Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Risperidone; Depressive Disorder, Major; Amisulpride; Olanzapine; Benzodiazepines; Dibenzothiazepines
PubMed: 35510505
DOI: 10.1017/S0033291722000745 -
Critical Care (London, England) Aug 2023Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium.
METHODS
This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.
RESULTS
We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo.
CONCLUSIONS
Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients.
TRIAL REGISTRATION
CRD42017081133, date of registration 28 November 2017.
Topics: Humans; Haloperidol; Coma; Critical Illness; Quality of Life; Delirium; Randomized Controlled Trials as Topic
PubMed: 37633991
DOI: 10.1186/s13054-023-04621-4 -
Journal of Psychiatric Research Jun 2024Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and... (Review)
Review
Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3-8) for risperidone literature and 5 for aripiprazole (range: 4-6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested.
Topics: Humans; Aripiprazole; Cytochrome P-450 CYP2D6; Risperidone; Cytochrome P-450 CYP2C19; Antipsychotic Agents
PubMed: 38631139
DOI: 10.1016/j.jpsychires.2024.04.001