Antipsychotic Medications: 73 Recent Meta-Analyses

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Antipsychotic Medications: 73 Meta-Analytic Studies Published in 2013-2017

Kenneth S. Pope, Ph.D., ABPP

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This site includes 3 other sets of recent meta-analytic resources:

For each brand name and generic antipsychotic medication, I searched out meta-analytic studies on its effectiveness, risks, side effects, differential effects on different populations, etc.--to help clinicians, expert witnesses, researchers, and others to stay abreast of the evolving research in this area. 

I focused on studies published in 2013-17, and included both the citation and a brief excerpt for each study:

  1. Almandil et al. (2013). "Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: a systematic review and meta-analysis." Paediatr Drugs 15(2): 139-150.

    EXCERPT: "Olanzapine, risperidone, and aripiprazole were all associated with statistically significant weight gain. Olanzapine was associated with the most weight gain and aripiprazole the least."

  2. Alvarez et al. (2013). "Antipsychotic drugs in cocaine dependence: a systematic review and meta-analysis." J Subst Abuse Treat 45(1): 1-10.

    EXCERPT: "In comparison to placebo, antipsychotics did not significantly reduce cocaine use...or improve retention in treatment .... Risperidone reduced slightly dropouts in comparison to placebo.... To date there is insufficient evidence to justify the use of antipsychotic drugs for cocaine dependence."

  3. Andrade, C., et al. (2015). "Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials." J Psychiatr Res 60: 14-21.

    EXCERPT: Cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results.... We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia."

  4. Correll, C. U., et al. (2016). "Efficacy for Psychopathology and Body Weight and Safety of Topiramate-Antipsychotic Cotreatment in Patients With Schizophrenia Spectrum Disorders: Results From a Meta-Analysis of Randomized Controlled Trials." J Clin Psychiatry 77(6): e746-756.

    EXCERPT: "Topiramate-antipsychotic cotreatment significantly reduced total, positive, negative, and general psychopathology and weight/BMI in patients with schizophrenia spectrum disorder while being well tolerated."

  5. Coughlin, C. G., et al. (2015). "Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy." Obstet Gynecol 125(5): 1224-1235.

    EXCERPT: "Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation.".

  6. De Deyn, et al. (2013). "Aripiprazole in the treatment of Alzheimer's disease." Expert Opin Pharmacother 14(4): 459-474.

    EXCERPT: "In randomized placebo-controlled clinical trials, aripiprazole shows modest efficacy in the treatment of AD-related psychosis. Neuropsychiatric symptoms alleviated were predominantly psychotic features and agitation. In individual trials, aripiprazole was generally well tolerated, serious side effects were seldom reported and included accidental injury and somnolence. Meta-analyses however demonstrated increased mortality as a class effect for atypical, but also for typical antipsychotics. No increased cardiovascular outcomes, cerebrovascular accidents, increased appetite or weight gain were demonstrated in meta-analyses for aripiprazole-treated patients with psychosis of dementia. Aripiprazole was found to induce sedation. Aripiprazole should only be used in selected patient populations resistant to non-pharmacological treatment with persisting or severe psychotic symptoms and/or agitation, and in which symptoms lead to significant morbidity, patient suffering and potential self-harm. The indication for continuing treatment should be revised regularly.

  7. Dold et al. (2013). "Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials." Int J Neuropsychopharmacol 16(3): 557-574.

    EXCERPT: " Significant efficacy was identifiable only for risperidone, but not for quetiapine and olanzapine. The results regarding aripiprazole and haloperidol were inconsistent. Overall, about one-third of SRI-resistant OCD patients benefited from an augmentation strategy with antipsychotics. Based on the favourable risk:benefit ratio, risperidone can be considered as the agent of first choice and should be preferred to quetiapine and olanzapine."

  8. Dold, M., et al. (2015). "Antipsychotic Augmentation of Serotonin Reuptake Inhibitors in Treatment-Resistant Obsessive-Compulsive Disorder: An Update Meta-Analysis of Double-Blind, Randomized, Placebo-Controlled Trials." Int J Neuropsychopharmacol 18(9).

    EXCERPT: "Antipsychotic augmentation of serotonin reuptake inhibitors can be regarded as an evidence-based measure in treatment-resistant obsessive-compulsive disorder."

  9. Dold et al. (2013). "Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: A meta-analysis and cochrane review of randomized controlled trials." Eur Neuropsychopharmacol 23(9): 1023-1033.

    EXCERPT: "There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders."

  10. Dold, M., et al. (2015). "Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials." Schizophr Res 166(1-3): 187-193.

    EXCERPT: "This meta-analysis suggests no evidence for a dose-escalation of the investigated antipsychotic drugs fluphenazine, haloperidol, quetiapine, and ziprasidone in case of initial non-response to standard-dose pharmacotherapy."

  11. Dold, M., et al. (2015). "Second-Generation Antipsychotic Drugs in Anorexia Nervosa: A Meta-Analysis of Randomized Controlled Trials." Psychother Psychosom 84(2): 110-116.

    EXCERPT: "Based on the current evidence, pharmacological treatment of anorexia nervosa with SGAs cannot be generally recommended although some individuals or subgroups of patients might benefit from an antipsychotic medication."

  12. Faure Walker, N., et al. (2015). "Linking the evidence between urinary retention and antipsychotic or antidepressant drugs: A systematic review." Neurourol Urodyn.

    EXCERPT: "The majority of case reports reported an improvement in UR on discontinuation or dose reduction.... Antipsychotics and antidepressants interact with the urinary system in many ways. Clinicians treating acute UR need to keep in mind the role of antipsychotic and antidepressants as a precipitating cause.'

  13. Fusar-Poli et al. (2013). "Efficacy and safety of second-generation long-acting injections in schizophrenia: A meta-analysis of randomized-controlled trials." International Clinical Psychopharmacology 28(2): 57-66.

    EXCERPT: " The present meta-analysis shows superior efficacy for the SGLAI over placebo on psychotic symptoms, although with a relatively small effect size; no evidence of superiority in efficacy over oral antipsychotics; and modest evidence of greater symptoms of extrapyramidal side effects. These data suggest that SGLAI lack an advantage in reducing psychotic symptoms over oral medications."

  14. Fusar-Poli et al. (2013). "Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies." Neurosci Biobehav Rev 37(8): 1680-1691.

    EXCERPTS: "The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity.... Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment."

  15. Galling, B., et al. (2015). "Safety and tolerability of antipsychotic-mood stabilizer co-treatment in the management of acute bipolar disorder: results from a systematic review and exploratory meta-analysis." Expert Opin Drug Saf 14(8): 1181-1199.

    EXCERPT: "Pooled together, MS+AP versus MS monotherapy (studies = 18, n = 4419) was associated with significantly higher burden regarding 21/53 (39.6%) individual AEs, particularly weight gain-related (5/5 = 100%), extrapyramidal (5/12 = 41.7%) and glucose/lipid-related AEs (3/8 = 37.5%). AP+MS versus AP monotherapy (studies = 3, n = 397) was associated with significantly higher burden regarding 4/21 (19.0%) individual AEs (>/= 1 AE, tremor, sedation/somnolence, vomiting).... Efficacy advantages of AP+MS co-treatment versus monotherapy should be balanced with its greater AE burden. AE risk is higher for adding AP to MS (17 additional AEs) than adding MS to an AP, including the particularly concerning cardiometabolic AEs."

  16. Galling, B., et al. (2016). "Safety and tolerability of antipsychotic co-treatment in patients with schizophrenia: results from a systematic review and meta-analysis of randomized controlled trials." Expert Opin Drug Saf 15(5): 591-612.

    EXCERT: "No double-blind evidence for altered AE burden associated with antipsychotic co-treatment was found. However, AEs [Adverse Events] were insufficiently and incompletely reported and follow-up duration was modest. Adjunctive partial D2-agonists might be beneficial for counteracting several AEs."

  17. Gilmore & Wolfe (2013). "Antipsychotic prophylaxis in surgical patients modestly decreases delirium incidence--but not duration--in high-incidence samples: a meta-analysis." Gen Hosp Psychiatry 35(4): 370-375.

    EXCERPTS: "Prophylactic antipsychotic treatment in surgical patients modestly decreases the incidence of delirium, but not the length of hospital stay, duration of delirium or its severity. Given the modest protective effect of antipsychotics and their potential adverse reactions, there is insufficient evidence to support its universal use as a preventive agent, though potential benefit may be seen in populations at high risk of developing delirium."

  18. Goikolea, et al. (2013). "Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in acute mania." Eur Neuropsychopharmacol 23(4): 305-316.

    EXCERPT: "Haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms."

  19. Goikolea et al. (2013). "Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol." J Affect Disord 144(3): 191-198.

    EXCERPT: "Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile."

  20. Han et al. (2014). The potential role of atypical antipsychotics for the treatment of posttraumatic stress disorder. Journal of Psychiatric Research, 56, 72-81.

    Excerpt: "AAs may have potential benefits for the treatment of PTSD as indicated by changes from baseline of the total score on the Clinician Administered PTSD Scale (CAPS; standardized mean difference [SMD] = −0.289, 95% confidence intervals [CIs] = −0.471, −0.106), P = 0.002). Additionally, AAs were found to be significantly more effective (P < 0.0001) than a placebo in terms of change from baseline for the intrusion sub-score on the CAPS (SMD = −0.373, 95% CIs = −0.568, −0.178) but there were no significant reductions for the avoidance and hyperarousal sub-symptoms. The responder rate and rate of improvement of depressive symptoms were also significantly higher in the AA group than the placebo group (P = 0.004 and P < 0.0001, respectively)."

  21. Hirota & Kishi. (2013). Prophylactic antipsychotic use for postoperative delirium: A systematic review and meta-analysis. Journal of Clinical Psychiatry, 74(12), e1136-e1144.

    EXCERPT: "Our results suggest that second-generation antipsychotics are more beneficial than placebo for preventing the incidence of delirium. Among patients who do develop delirium, the severity of delirium is not reduced in those who received prophylactic antipsychotics."

  22. Khanna et al. (2013). "Aripiprazole versus other atypical antipsychotics for schizophrenia." Cochrane Database Syst Rev 2: CD006569.

    EXCERPT: "Information on all comparisons are of limited quality, are incomplete and problematic to apply clinically. Aripiprazole is an antipsychotic drug with a variant but not absent adverse effect profile. Long-term data are sparse...."

  23. Kirson et al. (2013). "Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: Synthesizing results across different research designs." Journal of Clinical Psychiatry 74(6): 568-575.

    EXCERPT: "The comparative effectiveness of antipsychotic formulations is sensitive to research design. Depot formulations displayed significant advantages in nonrandomized observational studies, whereas in RCTs no difference was observed."

  24. Kisely, S., et al. (2015). "A systematic review and meta-analysis of the effect of depot antipsychotic frequency on compliance and outcome." Schizophr Res 166(1-3): 178-186.

    EXCERPT: "There were no differences in psychotic symptoms or quality of life between two- and four-weekly doses. Health service use was not reported. For ADRs, the only significant difference detected was that two-weekly injections were less likely to lead to site pain..."

  25. Kishi, T., et al. (2016). "Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials." J Neurol Neurosurg Psychiatry 87(7): 767-774.

    EXCERPT: "Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol."

  26. Kishi, T., et al. (2016). "Long-acting injectable antipsychotics for the prevention of relapse in patients with recent-onset psychotic disorders: A systematic review and meta-analysis of randomized controlled trials." Psychiatry Research 246: 750-755.

    EXCERPT: "Pooling the studies, there were no significant differences between LAI-APs and OAPs in the improvement of Positive and Negative Syndrome Scale scores or in discontinuation due to all-cause, adverse events (AEs), and death, but LAI-APs outperformed OAPs in terms of discontinuation due to inefficacy (RR = 0.34, NNT = ?50) and nonadherence (RR = 0.30, NNT = ?33). However, the LAI-APs were associated with a higher incidence of at least one AE (RR = 1.13) and tremor (RR = 2.38) compared with OAPs."

  27. Kishi et al. (2013). Add-on fluvoxamine treatment for schizophrenia: An updated meta-analysis of randomized controlled trials. European Archives of Psychiatry and Clinical Neuroscience, 263(8), 633-641.

    EXCERPT: "Our results suggest that fluvoxamine add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia who are primarily treated with FGAs. Given that a small number of studies were included in this meta-analysis, the results should be treated with caution."

  28. Kishi, et al. (2013). Antipsychotics for cocaine or psychostimulant dependence: Systematic review and meta-analysis of randomized, placebo-controlled trials. Journal of Clinical Psychiatry, 74(12), e1169-e1180.

    EXCERPT: "Antipsychotics had no advantages over placebo in regard to cocaine use and cocaine or psychostimulant abstinence or craving, while causing more intolerability-related discontinuations."

  29. Kishi et al. (2013). "Blonanserin for schizophrenia: Systematic review and meta-analysis of double-blind, randomized, controlled trials." Journal of Psychiatric Research 47(2): 149-154.

    EXCERPT: "Our results suggest that although blonanserin has a more beneficial effect on negative symptoms than haloperidol, there was a significant difference in the adverse events profile between blonanserin and other antipsychotics."

  30. Kishi. et al.  (2013). "Augmentation of antipsychotic drug action by azapirone 5-HT1A receptor partial agonists: a meta-analysis." Int J Neuropsychopharmacol 16(6): 1259-1266.

    EXCERPT: " NRI augmentation therapy was marginally superior to placebo for efficacy of depressive symptoms....  NRI augmentation therapy showed a significantly lower increase or larger reduction in body weight than placebo....  Reboxetine augmentation was associated with less weight gain that placebo in antipsychotic treated schizophrenia patients....: NRIs may exert an effect on depressive symptoms, and seem to be well-tolerated treatments."  

  31. Kishimoto et al. (2013). "Relapse prevention in schizophrenia: A systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics." Molecular Psychiatry 18(1): 53-66.

    EXCERPT: "Superiority of SGAs regarding relapse was modest (NNT = 17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several key outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors. "

  32. Kunitomi et al. (2013). "Indirect comparison analysis of efficacy and safety between olanzapine and aripiprazole for schizophrenia." Br J Clin Pharmacol.

    EXCERPT: "This study demonstrated that ICs between olanzapine and aripiprazole can deliver results consistent with those of DC. It is also suggested that the selection of a common comparator is important when control group bias is suspected in the data set."

  33. Lao, K. S. J., et al. (2016). "Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: A systematic review with meta-analysis of randomized controlled trials." CNS Drugs 30(11): 1043-1054.

    There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied.

  34. Lebow et al. (2013). "The effect of atypical antipsychotic medications in individuals with anorexia nervosa: A systematic review and meta-analysis." International Journal of Eating Disorders 46(4): 332-339.

    EXCERPT: "Compared with placebo, atypical antipsychotics were associated with a nonsignificant increase in BMI...and a nonsignificant effect on the drive for thinness and body dissatisfaction. Compared with placebo or active control, these medications led to an increase in anxiety and overall eating disorder symptoms. However, there was a significant reduction over placebo or active control on level of depression."

  35. Leucht et al. (2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis." Lancet 382(9896): 951-962.

    EXCERPT: "All drugs were significantly more effective than placebo.... Standardised mean differences compared with placebo for weight gain varied from -0.09 for the best drug (haloperidol) to -0.74 for the worst drug (olanzapine), for prolactin increase 0.22 (aripiprazole) to -1.30 (paliperidone), and for QTc prolongation 0.10 (lurasidone) to -0.90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses....  Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines."

  36. Li et al. (2013). "Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials." PLoS One 8(8): e70179.

    EXCERPT: "Adjunctive aripiprazole is both safe and effective as a reasonable choice treatment for patients with antipsychotic-induced hyperprolactinemia. The appropriate dose of adjunctive aripiprazole may be 5 mg/day."

  37. Liu et al. (2014). Efficacy and acceptability of atypical antipsychotics for the treatment of post-traumatic stress disorder: A meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Psychiatry Research.

    EXCERPT: "AAs may be superior to placebo in the treatment of PTSD, as indicated by the changes in Clinician Administered PTSD Scale (CAPS) total scores (weighted mean differences (WMD)=−5.89, 95% confidence interval (CI) [−9.21, −2.56], P=0.0005) and also in CAPS subscale intrusion (WMD=−2.58, 95% CI[−3.83, −1.33], P<0.0001 ) and subscale hyperarousal (WMD=−2.94, 95% CI[−5.45, −0.43], P=0.02)."

  38. Mahmood et al. (2013). "Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents." J Clin Psychopharmacol 33(1): 90-94.

    EXCERPT: "Upon meta-analysis, we found that patients receiving topiramate lost weight or had attenuated weight gain compared to control patients (weighted mean difference, -2.83 kg; 95% confidence interval, -4.62 to -1.03).... Our meta-analysis shows that using topiramate can prevent or reduce weight gain associated with AAPs."

  39. Matar et al. (2013). "Fluphenazine (Oral) Versus Placebo for Schizophrenia." Schizophr Bull.

    EXCERPT: "Results, based on this small selection of studies, suggested that there was no significant difference between oral fluphenazine and placebo for most outcomes, including global state and leaving the study early. Results did suggest a statistically significant effect favoring oral fluphenazine in the short term for levels of relapse...with levels of extrapyramidal adverse effects more frequent with oral fluphenazine. The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. In this review, for perhaps the first time, we objectively quantified the effects of oral administration of fluphenazine in comparison with placebo. It is indeed a potent antipsychotic but with considerable adverse effects. Other drugs may well be preferable."

  40. Meng, M., et al. (2015). "Using aripiprazole to reduce antipsychotic-induced hyperprolactinemia: meta-analysis of currently available randomized controlled trials." Shanghai Arch Psychiatry 27(1): 4-17.

    EXCERPT: "This study systematically reviewed and evaluated all relevant RCTs and found that adjunctive aripiprazole is effective and safe to use in the treatment of antipsychotic-induced HPL. However, the low quality of some of the studies, the incomplete methodological information provided for most of the studies, and the relatively short follow-up time of the studies raises question about the validity of the results."

  41. Misawa, F., et al. (2016). "Safety and tolerability of long-acting injectable versus oral antipsychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics." Schizophrenia Research 176(2-3): 220-230.

    EXCERPT: "LAIs and OAPs did not differ on all serious and > 90% of individual adverse events."

  42. Muralidharan et al. (2013). "Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: A meta-analysis of placebo-controlled trials." J Affect Disord.

    EXCERPT: "SGA are effective in treating acute mixed episodes of BD, with predominant manic symptoms. Their efficacy in treating depressed mixed episodes remains unclear. "

  43. Nagai & Watanabe (2013). "[Olanzapine]." Nihon Rinsho 71(4): 666-672.

    EXCERPT: "According to the head-to-head meta-analysis and large-scale studies like CATIE and EUFEST, olanzapine seems to have not only higher efficacy but also less discontinuation comparing to other anti-psychotics."

  44. Neufeld, K. J., et al. (2016). "Antipsychotic Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A Systematic Review and Meta-Analysis." J Am Geriatr Soc 64(4): 705-714.

    EXCERPT: "Using data reported from all 19 studies, antipsychotic use was not associated with change in delirium duration, severity, or hospital or ICU LOS, with high heterogeneity among studies. No association with mortality was detected…. Current evidence does not support the use of antipsychotics for prevention or treatment of delirium."

  45. Nielsen, R. E., et al. (2015). "Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials." Acta Psychiatr Scand 131(3): 185-196.

    EXCERPT: "On cognitive composite score, sertindole was superior to clozapine, effect size (ES) 0.87; 95% CI: 0.12-1.63, quetiapine, ES 0.75; 95% CI: 0.00-1.49, and first-generation antipsychotics (FGAs), ES 0.89; 95% CI: 0.14-1.64. Analyses on each cognitive domain showed clozapine, ES 0.37; 95% CI: 0.00-0.74, olanzapine, ES 0.31; 95%CI: 0.02-0.59, quetiapine, ES 0.34; 95% CI: 0.03-0.64, and FGAs, ES 0.51; 95% CI: 0.18-0.83 performing poorer on verbal working memory than ziprasidone, as well as FGAs performing poorer than risperidone, ES 0.31; 95% CI: 0.04-0.58. On executive function, sertindole performed better than clozapine, ES 0.82; 95% CI: 0.06-1.58, olanzapine, ES 0.81; 95% CI: 0.07-1.55, quetiapine, ES 0.76; 95% CI: 0.02-1.51, ziprasidone, ES 0.90; 95% CI: 0.14-1.67, and FGAs, ES 0.83; 95% CI: 0.08-1.58. On processing speed, FGAs performed poorer than sertindole, ES 0.97; 95% CI: 0.02-1.91, and quetiapine, ES 0.36; 95% CI: 0.01-0.72. On long-term verbal working memory, clozapine performed poorer than olanzapine, ES 0.41; 95% CI: 0.06-0.76. On verbal fluency, FGAs performed poorer than olanzapine, ES 0.26; 95% CI: 0.01-0.50, and clozapine, ES 0.44; 95% CI: 0.06-0.81. Lastly, FGAs, ES 0.41; 95% CI: 0.04-0.78, and clozapine, ES 0.44; 95% CI: 0.05-0.83, performed poorer on visuospatial skill compared to olanzapine.... The meta-analysis was able to detect some trends in the data analyzed, but did not show any drug having a uniform positive cognitive profile."

  46. Nose, M., et al. (2015). "Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-analysis of observational studies." Pharmacoepidemiol Drug Saf 24(8): 812-820.

    EXCERPT: "Systematic review of current observational evidence suggests that exposure to first-generation and second-generation AP drugs is associated with an increased risk of pneumonia. The present systematic review expands previous knowledge by showing that the increased risk not only applies to elderly individuals but also to younger patients."

  47. Okuyama, Y., et al. (2016). "Efficacy and tolerability of topiramate-augmentation therapy for schizophrenia: A systematic review and meta-analysis of randomized controlled trials." Neuropsychiatric Disease and Treatment 12.

    EXCERPT: " Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance."

  48. Pagsberg, A. K., et al. (2017). "Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: A systematic review and network meta-analysis." Journal of the American Academy of Child & Adolescent Psychiatry 56(3): 191-202.

    EXCERPT: "This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults."

  49. Park, S. Y., et al. (2016). "Antipsychotic Use Trends in Youth With Autism Spectrum Disorder and/or Intellectual Disability: A Meta-Analysis." J Am Acad Child Adolesc Psychiatry 55(6): 456-468 e454.

    EXCERPT: "Almost 1 in 10 antipsychotic-treated youth were diagnosed with ASD and/or ID, and 1 in 6 youth with ASD received antipsychotics. Both proportions increased in later years…."

  50. Potvin, S., et al. (2015). "Antipsychotic-induced changes in blood levels of leptin in schizophrenia: a meta-analysis." Can J Psychiatry 60(3 Suppl 2): S26-34.

    EXCERPT: "A moderate and positive effect size was observed across studies. Olanzapine, clozapine, and quetiapine produced moderate leptin elevations, whereas haloperidol and risperidone were associated with small (nonsignificant) leptin changes. Across studies, BMI changes were significantly associated with increases in leptin levels. There was no effect of sex on AP-induced changes in leptin. .... A physiological role of leptin in AP-induced weight gain is supported because the most significant leptin increases were observed with APs inducing the most weight gain and because of the observed association between leptin increases and BMI changes. The overall increase in leptin levels suggests that leptin acts as a negative feedback signal in the event of fat increase."

  51. Puyat et al. (2013). "Racial and ethnic disparities in the use of antipsychotic medication: a systematic review and meta-analysis." Soc Psychiatry Psychiatr Epidemiol.

    EXCERPT:  No significant differences were found in the odds of using any antipsychotics among African Americans...compared with non-African Americans and among Latinos...compared with non-Latinos. Small to moderate but statistically non-significant disparities were also noted in other ethnic groups: Asians..., Maoris... and Pacific Islanders.... Among those who received antipsychotic medication, African Americans... and Latinos...appeared to have lower odds of receiving newer antipsychotics compared with non-African Americans and non-Latinos.... No significant ethnic disparities in the use versus non-use of any antipsychotics were observed, but, among those who received antipsychotic treatment, ethnic minorities were consistently less likely than non-ethnic minorities to be treated with newer antipsychotics."

  52. Rao, A., et al. (2016). "Meta?analysis of population?based studies comparing risk of cerebrovascular accident associated with first? and second?generation antipsychotic prescribing in dementia." International Journal of Methods in Psychiatric Research 25(4): 289-298.

    EXCERPT: "Second-generation antipsychotics (SGAs) are often prescribed in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD), however, their use has been discouraged in light of clinical trials suggesting that they cause an increased risk of cerebrovascular accidents (CVAs)…. Meta-analysis of population-based data suggested that the use of SGAs as opposed to FGAs to control BPSD is not associated with significantly increased risk of CVA."

  53. Samara et al. (2014). Chlorpromazine versus every other antipsychotic for schizophrenia: A systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs. European Neuropsychopharmacology.

    EXCERPT: "Chlorpromazine was compared with 43 other antipsychotics and was more efficacious than four (butaperazine, mepazine, oxypertine and reserpine) and less efficacious than other four antipsychotics (clomacran, clozapine, olanzapine and zotepine) in the primary outcome. There were no statistically significant efficacy differences between chlorpromazine and the remaining 28 antipsychotics. The most important finding was that, due to low numbers of participants (median 50, range 8–692), most comparisons were underpowered. Thus we infer that the old antipsychotic drug literature was inconclusive and the claim for equal efficacy of antipsychotics was never evidence-based."

  54. Sikirica et al. (2014). Risk of death associated with the use of conventional vs. atypical antipsychotic medications: Evaluating the use of the emilia-romagna region database for pharmacoepidemiological studies. Journal of Clinical Pharmacy and Therapeutics, 39(1), 38-44.

    EXCERT: "Among 14,462 and 9,219 patients prescribed conventional and atypical antipsychotics, respectively, we observed 2,402 (16·6%) and 821 (8·9%) deaths during follow-up. Conventional antipsychotic initiators were older and generally had higher prevalence of outcome risk factors and higher baseline health service use intensity. The crude hazard ratio (HR) was 1·95, which decreased to 1·47...after full adjustment. We identified seven published studies that examined this association using similar methods. The pooled HR from these studies was 1·34.... Our results support the use of the RER database for pharmacoepidemiological studies and provide an up-to-date and pooled estimate of the magnitude of the association between mortality and conventional vs. atypical antipsychotics."

  55. Silva et al. (2013). "Olanzapine plus fluoxetine for bipolar disorder: a systematic review and meta-analysis." J Affect Disord 146(3): 310-318.

    EXCERPT: "OFC therapy improved the response, remission, and relapse rates among other outcomes. However, a worse profile of adverse reactions was observed in some comparisons. These data clarify the therapeutic use of OFC as an option to olanzapine in bipolar depression."

  56. Soares-Weiser et al. (2013). "Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis." European Neuropsychopharmacology 23(2): 118-125.

    EXCERPT: "Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective—in both RCTs and observational studies—than most SGAs and FGAs, except for clozapine. "

  57. Souza et al. (2013). "Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses." CNS Spectr 18(2): 82-89.

    EXCERPT: "The results of this study suggest that clozapine is significantly more efficacious than olanzapine in improving positive and negative symptoms in TRS patients."

  58. Spielmans et al. (2013). "Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes." PLoS Med 10(3): e1001403.

    EXCERPT: "All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48-2.73), OFC (OR, 1.42; 95% CI, 1.01-2.0), quetiapine (OR, 1.79; 95% CI, 1.33-2.42), and risperidone (OR, 2.37; 95% CI, 1.31-4.30).... All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58-2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87-1.93), quetiapine (OR, 1.53, 95% CI, 1.17-2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16-2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery-Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC).... Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm."

  59. Takeuchi, H., et al. (2017). "Gradual vs. Wait-and-gradual discontinuation in antipsychotic switching: A meta-analysis." Schizophrenia Research. Published online in advance of print publication.

    EXCERPT: "The meta-analysis of 5 studies (n=410) demonstrated no significant differences in any clinical outcomes, including study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events, between the two groups. These findings indicate either strategy can be used in clinical practice."

  60. Tan, L., et al. (2015). "Efficacy and safety of atypical antipsychotic drug treatment for dementia: a systematic review and meta-analysis." Alzheimers Res Ther 7(1): 20.

    EXCERPT: "Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognition function at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse events may offset the efficacy of atypical antipsychotics in dementia."

  61. Tek, C., et al. (2016). "Antipsychotic-induced weight gain in first-episode psychosis patients: a meta-analysis of differential effects of antipsychotic medications." Early Interv Psychiatry 10(3): 193-202.

    EXCERPT: "Except for ziprasidone, most AP medications were associated with body weight gain and BMI increase in FEP patients. Early and continuing effects of various AP medications on weight gain and BMI increase should be taken into consideration by clinicians."

  62. Teslyar et al. (2013). "Prophylaxis with antipsychotic medication reduces the risk of post-operative delirium in elderly patients: a meta-analysis." Psychosomatics 54(2): 124-131.

    EXCERPT: "The pooled relative risk of the five studies resulted in a 50% reduction in the relative risk of delirium among those receiving antipsychotic medication compared with placebo (RR(95% CI): 0.51 (0.33-0.79; heterogeneity, p < 0.01, random effects model). Examination of the funnel plot did not indicate publication bias.... Although few studies have examined prophylactic use of antipsychotics, this analysis suggests that perioperative use of prophylactic antipsychotics may effectively reduce the overall risk of postoperative delirium in elderly patients."

  63. Torres, et al. (2013). Structural brain changes associated with antipsychotic treatment in schizophrenia as revealed by voxel-based morphometric MRI: An activation likelihood estimation meta-analysis. BMC Psychiatry, 13, Article ID 342.

    EXCERPT: "The meta-analysis revealed seven clusters of areas with consistent structural brain changes in patients on antipsychotics compared to controls. The seven clusters included four areas of relative volumetric decrease in the left lateral temporal cortex [Brodmann area (BA) 20], left inferior frontal gyrus (BA 44), superior frontal gyrus extending to the left middle frontal gyrus (BA 6), and right rectal gyrus (BA 11), and three areas of relative volumetric increase in the left dorsal anterior cingulate cortex (BA 24), left ventral anterior cingulate cortex (BA 24) and right putamen."

  64. Vita, A., et al. (2015). "The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies." Biol Psychiatry 78(6): 403-412.

    EXCERPT: "Over time, patients with schizophrenia showed a significantly higher loss of total cortical GM volume. This was related to cumulative antipsychotic intake during the interval between scans in the whole study sample. Subgroup meta-analyses of studies on patients treated with second-generation antipsychotics and first-generation antipsychotics revealed a different and contrasting moderating role of medication intake on cortical GM changes: more progressive GM loss correlated with higher mean daily antipsychotic intake in patients treated with at least one first-generation antipsychotic and less progressive GM loss with higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics."

  65. Wang, H. R., et al. (2015). "Can Atypical Antipsychotic Augmentation Reduce Subsequent Treatment Failure More Effectively Among Depressed Patients with a Higher Degree of Treatment Resistance? A Meta-Analysis of Randomized Controlled Trials." Int J Neuropsychopharmacol 18(8).

    EXCERPT: "This finding strengthens the rationale for considering atypical antipsychotic augmentation among depressed patients with multiple previous treatment failures in clinical practice. The efficacy of atypical antipsychotic augmentation for non-TRD seems to be different from that for TRD and, thus, further studies of non-TRD populations are needed."

  66. Weisman et al. (2013). "Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents." Neurosci Biobehav Rev 37(6): 1162-1171.

    EXCERPT: "Our findings demonstrated significant benefit of both antipsychotics and alpha-2 agonists in treating tics but suggest alpha-2 agonists may have minimal benefit in tic patients without ADHD."

  67. Welten, C. C., et al. (2015). "Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis." Eur Neuropsychopharmacol 25(7): 1018-1026.

    EXCERPT: "Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity."

  68. Wolf, A., et al. (2017). "Do antipsychotics lead to cognitive impairment in dementia? A meta?analysis of randomised placebo?controlled trials." European Archives of Psychiatry and Clinical Neuroscience 267(3): 187-198.

    EXCERPT: " The random effects model of the pooled analysis showed a not significant effect (SMD = ?0.065, 95 % CI ?0.186 to 0.057, I2 = 41 %). Meta-regression revealed a significant correlation between cognitive impairment and treatment duration (R2 = 0.78, p < 0.02) as well as baseline MMSE (R2 = 0.92, p < 0.005). These correlations depend on only two out of ten studies and should interpret cautiously."

  69. Zhai, Y., et al. (2016). "Association between Antipsychotic Drugs and Mortality in Older Persons with Alzheimer's Disease: A Systematic Review and Meta-Analysis." J Alzheimers Dis 52(2): 631-639.

    EXCERPT: "The result of one double-blind randomized clinical trial indicated that antipsychotic drugs nearly doubled the risk of death in AD patients. In conclusion, there is no evidence of absence of association between antipsychotic drugs' use with death risk of AD patients. Careful assessments of potential benefits and risks should be made before prescribing antipsychotics for treatment of psychosis symptoms and behavioral problems of AD patients."

  70. Zheng et al. (2013). "Efficacy and safety of individual second-generation vs. first generation antipsychotics in first-episode psychosis: A systematic review and meta-analysis." International Journal of Neuropsychopharmacology 16(6): 1205-1218.

    EXCERPT: "Olanzapine, amisulpride and, less so, risperidone and quetiapine showed superior efficacy, greater treatment persistence and less EPS than FGAs. However, weight increase with olanzapine, risperidone and clozapine and metabolic changes with olanzapine were greater."

  71. Zheng, W., et al. (2016). "Efficacy and safety of adjunctive topiramate for schizophrenia: A meta-analysis of randomized controlled trials." Acta Psychiatrica Scandinavica 134(5): 385-398.

    EXCERPT: "These results indicate that adjunctive topiramate to antipsychotics is an effective and safe treatment choice for symptomatic improvement and weight reduction in patients with schizophrenia-spectrum disorders."

  72. Zheng, W., et al. (2016). "Efficacy and safety of adjunctive aripiprazole in schizophrenia: Meta-analysis of randomized controlled trials." Journal of Clinical Psychopharmacology 36(6): 628-636.

    EXCERPT: "Aripiprazole outperformed the comparison interventions for body weight in 9 RCTs (N = 505) with a WMD of ?5.08 kg (95% CI, ?7.14 to ?3.02; P< 0.00001; I2 = 35%) and for body mass index (BMI) in 14 RCTs (N = 809) with a WMD of ?1.78 (CI: ?2.25 to ?1.31; P< 0.00001; I2 = 54%). The BMI meta-regression analysis indicated aripiprazole's association with lower BMI was stronger in females. Adjunctive aripiprazole appears safe but better RCTs are needed to demonstrate efficacy. "

  73. Zhou, X. P., et al. (2015). "Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis." Int J Neuropsychopharmacol 18(11).

    EXCERPT: "All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects."

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