Multi-Episode Schizophrenia is a common psychiatric disorder. It’s treatment is often difficult and costly, thus a more precise understanding of oral antipsychotic efficacy is needed. Antipsychotics are the main course of treatment for Schizophrenia, however, these drugs come with serious side effects that can lead to serious disability or death.2 A network meta-analysis of placebo-controlled and head-to-head randomized controlled trials was conducted to compare 32 popular antipsychotics.1 The results were defined by the primary outcome which was operationally defined as a “change in overall symptoms measured with standardized rating scales”.1 The authors identified 54.417 different citations which included data on 53,463 participants. It was found that all antipsychotics met the primary outcome when compared to placebo, however, 6 were not statistically significant. Further inspection of side effects was also studied. The major side effects which were examined were: extra-pyramidal side effects, weight gain, akathisia, prolactin levels, sedation or somnolence, QTc prolongation, and anticholinergic side effects. It was found that while efficacies varied only slightly side effects varied greatly. The most efficacious drugs were found to be: clozapine, amisulpride, zotepine, olanzapine and risperidone. As expected, antipsychotics scored worse than placebo for side-effect outcomes. Older antipsychotics were associated with more extrapyramidal side effects and prolactin elevation due to dopamine effect in the pituitary hypothalamus circuit, and dopamine’s effect in the nigrostriatal pathway. Some older antipsychotics which were exceptions to this finding were include: amisulpride, paliperidone, and risperidone. The newer antipsychotics were also not without side effects. New generation antipsychotics had side effects like weight gain and sedation. These types of side effects are considered a good proxy for metabolic side effects.1 Some antipsychotic drugs were found to increase the QTc interval. This side effects is sometimes tolerable in healthy patients, in patients with an already widened interval it can have deadly consequences, like a progression to a rhythm known as torsade de pointes. Among the studied antipsychotics it was found that lurasidone and the other partial dopamine agonists were the most benign in this category. Data presented in the study as listed in figure 1. 

Clinicians in any field are often weighing the risk / reward of treatments, surgeries, and medications. It is a fundamental aspect of being a physician which is why understand the expected risks and rewards of medications is so important. This study does a good job of helping clinicians understand which medications may have a better efficacy while limiting side effects, but ultimately it is up to the physician to understand the patient and decided which medication will benefit them the most. Even in the class room I find myself relearning things that I have learned in the past because indications have changed. Even the research I am currently working on has the hopes of changing current guidelines and indications, thus data like this which takes a step back and looks at all the different medications is vastly important in helping clinicians keep their patients best care in mind. As students we will need to get used to being up to date on studies such as these to ensure that we are making the best decisions based on the most recent evidence supported data. 

Figure 1. 

Overall Symptom Reduction  From –0·89 (95% CrI –1·08 to –0·71) for clozapine to –0·03 (–0·59 to 0·52) for levomepromazine (40815 participants)
Reduction of Positive Symptoms  From –0·69 (95% CrI –0·86 to –0·52) for amisulpride to –0·17 (–0·31 to –0·04) for brexpiprazole (31179 participants)
Reduction of Negative Symptoms  From –0·62 (–0·84 to –0·39; clozapine) to –0·10 (–0·45 to 0·25; flupentixol) (32015 participants)
Reduction of Depressive Symptoms From –0·90 (–1·36 to –0·44; sulpiride) to 0·04 (–0·39 to 0·47; flupentixol) (19683 participants)
All Cause Discontinuation  From 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide) (42672 participants)
Sedation  From 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol) (30770 participants),
Use of Anti-Parkinson Medication  From 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide) (24911 participants)
Weight Gain From –0·16 kg (–0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine) (28317 participants)
Prolactin Elevation  From –77·05 ng/mL (–120·23 to –33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) (21569 participants)
QTc Prolongation  From –2·21 ms (–4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). (15467 participants)

*Data taken from “Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis” 1



  1. Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., Arndt, T., Bäckers, L., Rothe, P., Cipriani, A., Davis, J., Salanti, G. and Leucht, S. (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. The Lancet, 394(10202), pp.939-951.
  2. Oehl M, Hummer M, Fleischhacker WW. Compliance with antipsychotic treatment. Acta Psychiatr Scand 2000: 102: 83–86.


About the author: Eliot Parascandolo Sackler Class of 2022 

I am a medical student from Long Island, New York. I decided on studying medicine after having a wonderful experience shadowing a family friend in his pediatrics office. I am drawn to the science, humanity, and passion which accompanies the field of medicine. I am primarily interested in cardiology and neurology and am currently conducting research in both areas. My favorite part of medical school is getting to learn things I am interested in knowing that one day I will be able to apply this knowledge to directly help people. Thank you for reading.

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