
==== Front
Schizophrenia (Heidelb)
Schizophrenia (Heidelb)
Schizophrenia
2754-6993
Nature Publishing Group UK London

39223138
492
10.1038/s41537-024-00492-y
Perspective
Updated rationale for the initial antipsychotic selection for patients with schizophrenia
Markota Matej Markota.Matej@mayo.edu

1
http://orcid.org/0000-0003-0103-2090
Morgan Robert J. III 1
http://orcid.org/0000-0003-3836-9375
Leung Jonathan G. 12
1 https://ror.org/02qp3tb03 grid.66875.3a 0000 0004 0459 167X Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN USA
2 https://ror.org/02qp3tb03 grid.66875.3a 0000 0004 0459 167X Department of Pharmacy, Mayo Clinic, 200 First Street SW, Rochester, MN USA
2 9 2024
2 9 2024
2024
10 1 7423 4 2024
31 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Subject terms

Schizophrenia
Psychiatric disorders
issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Expert groups differ in their recommendations for early-stage schizophrenia treatment. Some expert groups, including American Psychiatric Association (APA), are non-directive and do not specify preferred agents for patients with first-episode psychosis1–3. This approach, while patient-centric, may challenge early practitioners and learners. Others offer algorithmic guidelines, but existing algorithms only partially agree on “first-line” treatments (see the section “Summary of first-line treatment options for patients without concurrent violence” for definition), reflecting the complexity of risk-benefit analysis4–9. In addition, updates to guidelines are essential to incorporate the latest research.

Based on up-to-date evidence (as of January 2024), we present a rationale for the selection of “first-line treatments” for patients with early-stage schizophrenia and challenges surrounding the selection of these agents. We present a general rationale, such that when idiographic factors of individuals dictate a different approach, the considerations discussed here should defer to individualized plans, and patients and practitioners should engage in shared decision-making at every step.

Initial patient stratification

After diagnosis of schizophrenia spectrum disorder is made and need for treatment established, patients in this algorithm are stratified into two groups (see the section “Treatment of patients with violence” for rationale) based on comorbid violence (in research studies typically defined as high score on the Positive and Negative Syndrome Scale (PANSS) hostility item or Modified Overt Aggression Scale10,11; henceforward “violence” will be used for simplicity). Figure 1 summarizes selection of antipsychotics proposed in this manuscript.Fig. 1 Selection of antipsychotics in the treatment of patients with schizophrenia spectrum disorders.

The figure summarizes the guiding factors and sequential options involved in the decision-making process for selecting antipsychotic medications. *In alphabetical order.

Treatment of patients without violence

Initial treatment of patients without concurrent violence

Clinicians face challenges in balancing efficacy and side effects when prescribing antipsychotics to treatment-naive patients. Existing algorithms approach this issue by assigning high significance to a few side effects, such as weight gain and/or tardive dyskinesia, commonly leading to exclusion of agents such as olanzapine and first-generation antipsychotics (FGAs), respectively, as first-line treatments4,5,9. The approach here deviates from such a rationale. In our opinion, selection of first-line treatments should be guided by three key overlapping factors:Overall efficacy: Randomized controlled trials (RCTs) comparing antipsychotics with long-term follow-up should be preferentially considered. Most RCTs are only several weeks long12. Since schizophrenia is a disorder requiring treatment far longer in duration, shorter duration RCTs are less relevant (though still important) and have less external validity compared to studies with longer outcomes3.

All-cause discontinuation: Discontinuation is typically influenced by perceived (in)efficacy and tolerability13. Instead of weighing risks of particular side effects against effectiveness, we use all-cause discontinuation rates as a surrogate measure of side effect burden versus effectiveness. All-cause discontinuation is ideally based on RCTs with long-term follow-up.

Mortality: Schizophrenia has one of the highest mortality risks of all psychiatric disorders14. While complex and difficult to study, mortality is a crucial outcome deserving attention for antipsychotic selection3,15. There is an emerging consensus that untreated psychosis has more adverse health effects compared to risks posed by antipsychotics16,17, but there is little guidance on how to weigh risk of discontinuation (and associated risks of untreated psychosis) versus long-term side effects. One could imagine a scenario of a weight-gaining antipsychotic with higher efficacy and lower overall discontinuation rate initially, but higher long-term mortality because of cardiovascular problems associated with weight gain over a longer period. Increased mortality may exclude this medication from first-line therapies. Conversely, if a weight-gaining antipsychotic has higher efficacy, lower discontinuation rates, and similar or lower long-term mortality relative to alternative treatments, there is no convincing reason to exclude it from first-line treatments. Thus, mortality data combines the above factors to allow determination of the “safest” first-line treatment choices.

Regarding criteria 1 & 2 above we discuss selection of key published literature here. With regard to criterion 3, RCTs generally do not offer long-term mortality data, and we discuss relevant mortality literature for each medication below.

There is only one large-scale network meta-analysis focused directly on comparing RCTs of antipsychotics with at least 6-month follow-up of acutely ill patients12. Amongst all non-clozapine antipsychotics available in the U.S., five antipsychotics—lurasidone, olanzapine, perphenazine, risperidone, and aripiprazole—rank highest for overall efficacy and lowest overall discontinuation12.

Aripiprazole and risperidone are among first-line treatment options in most existing algorithms, and we find their place here to be non-controversial4,5,7,9. Sections below will contrast the remaining three antipsychotics to aripiprazole and risperidone to demonstrate how our rationale diverges from existing protocols.

Olanzapine

In RCTs, olanzapine consistently demonstrates superior efficacy compared to risperidone or aripiprazole; evidence is of moderate confidence and small effect size12. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, the number need to treat for olanzapine versus risperidone was ~10; for olanzapine versus perphenazine it was 9; and for olanzapine versus quetiapine it was 5.518. While equivalent dose of olanzapine was higher relative to other agents in CATIE19, other trials with comparable doses confirmed favorable efficacy of olanzapine over risperidone20,21. In addition, olanzapine has a significantly lower discontinuation rate, indicating favorable efficacy-to-tolerability ratio12. In a Finnish cohort study of patients discharged from first schizophrenia-related hospitalization, those discharged on oral olanzapine had lower risk of rehospitalization versus oral risperidone22.

On the other hand, olanzapine is associated with significantly more weight gain; higher total cholesterol and triglycerides (compared to aripiprazole, lurasidone, and risperidone)12,23; and is more strongly associated with incident diabetes relative to risperidone24. Since cardiovascular disease affects patients with schizophrenia at high rates, such side effects deserve serious attention25. Studies in adults with mean duration of 42 weeks show that olanzapine leads to 3 kg more of weight gain compared to aripiprazole and about 2 kg more compared to risperidone12; younger antipsychotic-naive patients may show more pronounced differences26. In the CATIE trial, olanzapine relative to risperidone was associated with an increase of 1% in the 10-year coronary heart disease risk, which was statistically significant27. However, consistent with its favorable efficacy profile and the hypothesis that improved psychiatric status leads to healthier lifestyles, Solmi and colleagues found that olanzapine ranked best among non-clozapine antipsychotics with regard to patients’ adherence to cardiometabolic drugs28. While olanzapine is clearly more metabolically unfavorable than other potential first-line agents, the key question is whether olanzapine’s advantages outweigh its disadvantages. We will attempt to answer this question quantitatively based on most recent data on antipsychotic-associated mortality.

In a 1-year, open label, randomized trial, ziprasidone and olanzapine had the same rate of non-suicidal mortality in patients with schizophrenia29. A prospective Finnish register study with 5-year follow-up of patients with first-episode schizophrenia found decreased overall mortality with olanzapine relative to non-users of antipsychotics; this effect was not observed for risperidone30. An 11-year follow-up study in patients with schizophrenia from Finland compared several antipsychotics with perphenazine serving as a reference. Overall mortality in users of olanzapine was not significantly different compared to perphenazine, but mortality was significantly higher in patients on risperidone31. Risk of death from ischemic heart disease was similar between risperidone and olanzapine, though trended higher in risperidone31. Cumulative exposure to olanzapine was similarly associated with a trend toward lower mortality relative to risperidone31. A study with up to 20 years of follow-up (FIN-20) found that monotherapy with olanzapine, risperidone, or aripiprazole was associated with the same risk of somatic hospitalization and same risk of cardiovascular hospitalization32. Overall mortality in patients on monotherapy with olanzapine was not different from aripiprazole and lower for olanzapine compared to risperidone; cardiovascular mortality was similar in patients on olanzapine and aripiprazole and trended towards lower mortality in olanzapine versus risperidone32. A number of large-scale studies not limited to schizophrenia describe similar findings33,34.

To summarize, the higher metabolic burden of olanzapine is a serious problem for some patients. However, decisions about olanzapine’s use as a first-line agent cannot simply be reduced to reflexive exclusion based on metabolic risk. Based on the three key criteria and findings described above, we do not see a legitimate reason to include risperidone among first-line treatment options while excluding olanzapine. Rather, we believe there are sufficient and legitimate reasons to consider olanzapine as a valid first-line treatment option (see the section “Summary of first-line treatment options for patients without concurrent violence”) while appropriately monitoring for metabolic effects. This conclusion is contrary to several existing algorithms and recommendations5,6,9,35 but in agreement with the Texas Medication Algorithm Project7. As discussed in the introduction, individual patient preferences are crucial, side effects influence adherence36, and thus for patients who list weight gain as a particularly undesirable outcome olanzapine should be reserved for later trials.

Perphenazine

Perphenazine is excluded from first-line treatment options due to recognized risk of tardive dyskinesia (TD) and other extrapyramidal side effects (EPS) associated with FGAs4–7,9. However, there is considerable variability in TD risk within FGA and second-generation antipsychotic (SGA) classes, a nuance frequently ignored by other algorithms. Perphenazine has one of the lowest known risks of TD among FGAs37. It also may have a lower risk of TD relative to some SGAs (e.g., lurasidone)37. Perphenazine users have higher antiparkinsonian medication use than aripiprazole users, but similar to risperidone users; akathisia risk is also comparable between perphenazine and risperidone12. Perphenazine trends toward less weight gain compared to aripiprazole and risperidone, and demonstrates significance versus olanzapine [12]. It is linked to lower prolactin elevation than risperidone12. Finally, in CATIE, perphenazine outperformed olanzapine and risperidone in exploratory analysis of neurocognitive performance at 18 months but not in the primary outcome of neurocognitive scores at 2 months38.

In the context of overall mortality, perphenazine outperformed risperidone in the 11-year follow-up study (as discussed in the section “Olanzapine”)31. In FIN-20, oral perphenazine trended toward lower risk of somatic hospitalization relative to risperidone32.

There is paucity of studies on perphenazine in first-episode psychosis (see the “Summary” section). Aside from this limitation, we see no other compelling rationale to include risperidone in first-line treatment options while excluding perphenazine. This contrasts with other available algorithms4–7,9.

Lurasidone

Lurasidone performed well in the recent network meta-analysis with regard to efficacy; however, evidence was low level12. Thus, true comparative efficacy remains uncertain, and mortality data is lacking, so lurasidone’s place amongst first-line treatment options remains unknown. Including mortality as a key selection factor risks excluding more novel antipsychotics which by definition will not have 10- to 20-year mortality data available. Hence, lurasidone’s known advantages and disadvantages need to be carefully weighed against aripiprazole, risperidone, olanzapine, and perphenazine.

Lurasidone has a favorable metabolic profile, similar to aripiprazole, but the latter has advantages of lower risk of EPS, easier administration (due to no caloric restrictions), and availability of long-acting formulation12,39,40. A second possible advantage of lurasidone is an antidepressant effect, but evidence from long-term trials is limited12. Short-term trials on depressive symptoms in patients with schizophrenia show that lurasidone did not outperform aripiprazole, olanzapine, or risperidone41. In summary, the currently available literature fails to reveal compelling advantages of lurasidone over aripiprazole or perphenazine (see the section “Perphenazine“). Consequently, based on the three core criteria and a fruitless analysis of other potential advantages, lurasidone does not currently merit inclusion among first-line treatment options, a conclusion that deviates from other algorithms4,5.

Summary of first-line treatment options for patients without concurrent violence

It is important to clarify the notion of “first-line treatment option” as used in this text. Given high number of Food and Drug Administration (FDA) approved antipsychotics in the U.S., it is impossible to comprehensively discuss advantages and side effects of all available medications within the confines of a clinical encounter. In our interpretation, “first-line options” pertain to a limited range of medications that can feasibly be discussed with a patient during a clinical encounter. Based on discussion above, we posit that it is reasonable to discuss risks and benefits of aripiprazole, risperidone, olanzapine, and perphenazine in this context.

Treatment after first unsuccessful trial

This algorithm does not meaningfully deviate from other algorithms and recommendations; hence we only provide a brief summary1,4,5,7. If initial trial does not lead to clinically satisfactory response despite sufficient duration42,43 and dose44, we recommend switching45 to monotherapy with an alternative antipsychotic with a different mechanism of action or metabolism. If initial failed trial was due to side effects, alternative antipsychotic with low propensity for that specific side effect should be selected12. Clozapine should be offered after two failed trials with appropriate monitoring1,8,46–48.

Treatment of patients with violence

Initial treatment of patients with concurrent violence

Approximately 9% of first-episode patients present with at least moderate hostility49. Rates of homicide in patients with psychosis were found to be elevated before treatment and decrease post-treatment50. It is crucial not to view violence solely as a psychopharmacological issue, and it is essential to understand the context within which it occurs and establish a therapeutic alliance. However, violence can disrupt development of therapeutic alliance, limit access to health care, and impair functioning in the community. Hostility is also associated with higher all-cause antipsychotic discontinuation51. Therefore, pharmacological means of decreasing violence is an important consideration, and differential effects of antipsychotics on violence merit attention.

A Swedish registry study found that use of clozapine, risperidone, or olanzapine was associated with fewer violent crime arrests in patients with psychotic disorders, compared to aripiprazole, haloperidol, or quetiapine52. Two randomized, double-blinded trials demonstrated that clozapine is superior to olanzapine which, in turn, was superior to haloperidol in reducing the number and severity of physical assaults and aggressive events in patients with schizophrenia11. In an open, randomized, European First Episode Schizophrenia Trial (EUFEST), olanzapine was superior to haloperidol, quetiapine, and amisulpride in decreasing hostility scores in the first 3 months10. In CATIE, olanzapine decreased hostility scores significantly more than perphenazine, quetiapine, risperidone, or ziprasidone53, and superiority was maintained beyond 9 months.

Given these outcomes, we recommend olanzapine as the preferred first-line treatment for patients with schizophrenia and significant violence concerns. In our opinion, the potential benefit of mitigating violence outweighs the concern for metabolic side effects. Olanzapine’s lower overall discontinuation rate also supports its preference in this population12,52. Finally, olanzapine offers the advantage of both oral, short-acting intramuscular, and long-acting (though latter is rarely used due to monitoring barriers and risk of post-injection delirium-sedation syndrome) formulations. If adherence with oral medications is a concern, preference for long-acting injectable (LAI) medications can be considered54. In summary, unless other individual characteristics of a patient dictate otherwise, we believe that patients with schizophrenia and comorbid violence should preferentially be offered olanzapine as a first-line treatment.

Treatment after first unsuccessful trial

If violence does not meaningfully improve with olanzapine, offering a non-clozapine antipsychotic as the next step could be considered suboptimal11,52,55,56. While clozapine is typically recommended after two unsuccessful trials in patients without violence, we propose modifying this strategy in patients with significant violence. After trialing olanzapine, if laboratory monitoring and medication compliance are feasible, clozapine should be offered as second-line treatment without the requirement of two failed trials. This aligns with APA’s recommendation to offer clozapine in patients with aggression (though APA does not recommend use of clozapine after one failed trial), as well as with Texas Medication Algorithm Project recommending early trial of clozapine in patients with violence1,7.

Summary

We propose a stepwise treatment rationale for patients with early-stage schizophrenia that diverges in small but important ways from established algorithms. The first point of departure is early patient stratification based on the presence or absence of comorbid violence. For patients with comorbid violence, we advocate for initiation of olanzapine as a preferred first-line treatment option, then (when feasible) clozapine if olanzapine fails. We also diverge in our selection of “first-line” (see the section “Summary of first-line treatment options for patients without concurrent violence”) treatment options for the general patient population, endorsing aripiprazole and risperidone4–7,9 but also recommending olanzapine and perphenazine as first-line options. Conversely, we demur regarding lurasidone, opining that its inclusion as a first-line agent may not (yet) be warranted.

Our proposed rationale has several limitations. First, this manuscript focuses on five antipsychotics which were selected based on long-term follow-up of acutely ill patients, but not first-episode patients12. Another reasonable strategy to select relevant literature for first-line treatments in drug naive patients would be to focus solely on trials with first-episode patients. However, there are fewer long-term studies available on this topic, and the available network meta-analyses and systematic reviews found no convincing difference in treatment response between first-episode patients compared to the general patient population—with the exception of quetiapine and olanzapine outperforming haloperidol, and olanzapine outperforming risperidone for negative symptoms57–60. These findings align with our recommendations. On a similar theme, it is often mentioned that antipsychotic-naive patients and those with shorter illness duration respond better to antipsychotics61, and hence focusing on overall efficacy may be less relevant in early stages of illness. However, medications that have traditionally been considered to be less efficacious, such as aripiprazole62, have nonetheless made it into our treatment recommendations based on the three key criteria, which we find reassuring.

Second, selection of antipsychotics for this Perspective was based on meta-analytic evidence of studies with longer follow-up durations12. This decision has at least two downstream consequences: it can exclude reasonable medication options that have not yet been tested in long-term trials, and the number of studies supporting our recommendations is lower relative to shorter-term trials. For example, perphenazine inclusion in our recommendations is based mostly on the CATIE trial; however, we note that studies with other designs, nonetheless support efficacy of perphenazine41,63.

Third, one of our core criteria for antipsychotic selection is association between specific antipsychotics and mortality. Mortality is inherently difficult to study, especially because randomized trials tend to be brief and epidemiological studies are prone to confounding. Despite these challenges, we believe that sufficient data has accumulated to give relevant guidance. Mortality is also a problematic criterion for novel antipsychotics due to absence of available long-term mortality data. As with lurasidone, serious consideration of novel antipsychotics as first-line agents will require more expansive analyses and consideration of novel advantages. At the time of this publication, trace amine-associated receptor 1 agents failed phase 3 trials, and xanomeline-trospium combination and emraclidine are not FDA-approved64. Current short-term trials have not demonstrated advantages of cariprazine or brexpiprazole, with perhaps the exception of cariprazine for negative symptoms41,65,66. Should any of the newer (e.g., brexpiprazole, cariprazine, lumateperone) or novel antipsychotics demonstrate superiority in efficacy and tolerability, our rationale does not prohibit their adoption as first-line treatments. Similarly, we did not deliberate on paliperidone, a newer but pharmacologically similar agent to risperidone, that has shown similar efficacy and discontinuation rates relative to risperidone in available meta-analyses12,41. This omission is based on non-pharmacological complexities associated with paliperidone use; in particular Medicaid in some states does not cover oral paliperidone, and its long-acting formulation is presently non-generic and may be expensive based on patient pharmacy benefits, leading to potential insurance/financial reasons for discontinuation in clinical practice in the United States. All authors of this Perspective clinically practice within the United States and have focused on agents available in the region. Based on the available literature, amisulpride is promising with regard to all three criteria12,67,68. However, since this agent is not available in the United States for treatment of schizophrenia, we have no firsthand experience with this medication, and we welcome other authors’ opinions on this matter.

Some of the recommended “first-line” antipsychotics are available as LAI formulations. The data on the clinical benefits (e.g., reduced hospitalization, decreased mortality) of LAIs is mixed14,69, and success likely depends on more than just pharmacology, such as the supports in place within LAI clinics (e.g., effort invested in reaching out and arranging follow-ups for patients who miss LAI appointments). We are of the opinion that LAIs are a reasonable option for patients in early stages of illness, that they should be offered to patients early and should not be reserved only for patients with documented adherence difficulties. In addition to potential clinical benefits, other relevant discussion points may include reduction of pill burden, convenience, extended-interval dosing, variable formulations, and decreased peak and trough effects. Stigma, costs, access to administration, and fear of needles may be barriers to LAIs.

Lastly, for all four “first-line” options listed here (olanzapine, perphenazine, aripiprazole, risperidone) and clozapine, women have been found to reach higher plasma concentrations in relation to dose, increasing risk of overmedication70–73. However, many other factors (e.g., smoking, race, co-prescribed medications, age, body weight, etc.) also influence concentration-to-dose ratio; hence sex is only one factor to consider in appropriate dosing of antipsychotics70–73. In addition to the limitations listed above, our rationale will require continued refinement as new data on older antipsychotics emerges, recognizing the dynamic nature of psychopharmacology.

Author contributions

Conceptualization, literature review, manuscript review, and editing: M.M., R.J.M., and J.L. Writing original draft: M.M.

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Keepers GA The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia Am. J. Psychiatry 2020 177 868 872 10.1176/appi.ajp.2020.177901 32867516
Keepers, G. A. et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am. J. Psychiatry 177, 868–872 (2020).32867516 10.1176/appi.ajp.2020.177901
2. Remington G Guidelines for the pharmacotherapy of schizophrenia in adults Can. J. Psychiatry 2017 62 604 616 10.1177/0706743717720448 28703015
Remington, G. et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can. J. Psychiatry 62, 604–616 (2017).28703015 10.1177/0706743717720448
3. Barnes TR Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology J. Psychopharmacol. 2020 34 3 78 10.1177/0269881119889296 31829775
Barnes, T. R. et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 34, 3–78 (2020).31829775 10.1177/0269881119889296
4. Taylor, D. M., Barnes, T, R. E. & Young, A. H. The Maudsley Prescribing Guidelines in Psychiatry. 14th edn (Wiley-Blackwell, 2021).
5. Osser, D. Schizophrenia. https://psychopharm.mobi/algo_live/# (2020).
6. Galletly C Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders Aust. N.Z. J. Psychiatry 2016 50 410 472 10.1177/0004867416641195 27106681
Galletly, C. et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust. N.Z. J. Psychiatry 50, 410–472 (2016).27106681 10.1177/0004867416641195
7. Argo, T. et al. Texas Medication Algorithm Project Procedural Manual: Schizophrenia Algorithm (Texas Department of State Health Services, 2008).
8. Hasan A World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance World J. Biol. Psychiatry 2012 13 318 378 10.3109/15622975.2012.696143 22834451
Hasan, A. et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J. Biol. Psychiatry 13, 318–378 (2012).22834451 10.3109/15622975.2012.696143
9. Takeuchi H Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms Hum. Psychopharmacol. 2021 36 e2804 10.1002/hup.2804 34241916
Takeuchi, H. et al. Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms. Hum. Psychopharmacol. 36, e2804 (2021).34241916 10.1002/hup.2804
10. Volavka J Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST) J. Clin. Psychiatry 2011 72 955 961 10.4088/JCP.10m06529 21824456
Volavka, J. et al. Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST). J. Clin. Psychiatry 72, 955–961 (2011).21824456 10.4088/JCP.10m06529
11. Krakowski MI Czobor P Citrome L Bark N Cooper TB Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder Arch. Gen. Psychiatry 2006 63 622 629 10.1001/archpsyc.63.6.622 16754835
Krakowski, M. I., Czobor, P., Citrome, L., Bark, N. & Cooper, T. B. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch. Gen. Psychiatry 63, 622–629 (2006).16754835 10.1001/archpsyc.63.6.622
12. Leucht S Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis World Psychiatry 2023 22 315 324 10.1002/wps.21089 37159349
Leucht, S. et al. Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis. World Psychiatry 22, 315–324 (2023).37159349 10.1002/wps.21089
13. Lieberman JA Effectiveness of antipsychotic drugs in patients with chronic schizophrenia N. Engl. J. Med. 2005 353 1209 1223 10.1056/NEJMoa051688 16172203
Lieberman, J. A. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209–1223 (2005).16172203 10.1056/NEJMoa051688
14. Correll CU Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors World Psychiatry 2022 21 248 271 10.1002/wps.20994 35524619
Correll, C. U. et al. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry 21, 248–271 (2022).35524619 10.1002/wps.20994
15. Torniainen M Antipsychotic treatment and mortality in schizophrenia Schizophr. Bull. 2015 41 656 663 10.1093/schbul/sbu164 25422511
Torniainen, M. et al. Antipsychotic treatment and mortality in schizophrenia. Schizophr. Bull. 41, 656–663 (2015).25422511 10.1093/schbul/sbu164
16. Correll CU Kane JM Ranking antipsychotics for efficacy and safety in schizophrenia JAMA Psychiatry 2020 77 225 226 10.1001/jamapsychiatry.2019.3377 31693073
Correll, C. U. & Kane, J. M. Ranking antipsychotics for efficacy and safety in schizophrenia. JAMA Psychiatry 77, 225–226 (2020).31693073 10.1001/jamapsychiatry.2019.3377
17. Vermeulen J Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis Psychol. Med. 2017 47 2217 2228 10.1017/S0033291717000873 28397632
Vermeulen, J. et al. Antipsychotic medication and long-term mortality risk in patients with schizophrenia; a systematic review and meta-analysis. Psychol. Med. 47, 2217–2228 (2017).28397632 10.1017/S0033291717000873
18. Citrome L Stroup TS Schizophrenia, clinical antipsychotic trials of intervention effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians? Int. J. Clin. Pract. 2006 60 933 940 10.1111/j.1742-1241.2006.01044.x 16893436
Citrome, L. & Stroup, T. S. Schizophrenia, clinical antipsychotic trials of intervention effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians? Int. J. Clin. Pract. 60, 933–940 (2006).16893436 10.1111/j.1742-1241.2006.01044.x
19. Meltzer HY Bobo WV Interpreting the efficacy findings in the CATIE study: what clinicians should know CNS Spectr. 2006 11 14 24 10.1017/S109285290002664X 16816796
Meltzer, H. Y. & Bobo, W. V. Interpreting the efficacy findings in the CATIE study: what clinicians should know. CNS Spectr. 11, 14–24 (2006).16816796 10.1017/S109285290002664X
20. Tran PV Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders J. Clin. Psychopharmacol. 1997 17 407 418 10.1097/00004714-199710000-00010 9315992
Tran, P. V. et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J. Clin. Psychopharmacol. 17, 407–418 (1997).9315992 10.1097/00004714-199710000-00010
21. Gureje O Olanzapine vs risperidone in the management of schizophrenia: a randomized double-blind trial in Australia and New Zealand Schizophr. Res. 2003 61 303 314 10.1016/S0920-9964(02)00226-8 12729882
Gureje, O. et al. Olanzapine vs risperidone in the management of schizophrenia: a randomized double-blind trial in Australia and New Zealand. Schizophr. Res. 61, 303–314 (2003).12729882 10.1016/S0920-9964(02)00226-8
22. Tiihonen J A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia Am. J. Psychiatry 2011 168 603 609 10.1176/appi.ajp.2011.10081224 21362741
Tiihonen, J. et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am. J. Psychiatry 168, 603–609 (2011).21362741 10.1176/appi.ajp.2011.10081224
23. Burschinski A Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials World Psychiatry 2023 22 116 128 10.1002/wps.21036 36640396
Burschinski, A. et al. Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials. World Psychiatry 22, 116–128 (2023).36640396 10.1002/wps.21036
24. Gianfrancesco FD Grogg AL Mahmoud RA Nasrallah HA Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database J. Clin. Psychiatry 2002 63 4485 10.4088/JCP.v63n1010
Gianfrancesco, F. D., Grogg, A. L., Mahmoud, R. A. & Nasrallah, H. A. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J. Clin. Psychiatry 63, 4485 (2002).10.4088/JCP.v63n1010
25. Correll CU Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls World Psychiatry 2017 16 163 180 10.1002/wps.20420 28498599
Correll, C. U. et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 16, 163–180 (2017).28498599 10.1002/wps.20420
26. Correll CU Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents Jama 2009 302 1765 1773 10.1001/jama.2009.1549 19861668
Correll, C. U. et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. Jama 302, 1765–1773 (2009).19861668 10.1001/jama.2009.1549
27. Daumit GL Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study Schizophr. Res. 2008 105 175 187 10.1016/j.schres.2008.07.006 18775645
Daumit, G. L. et al. Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study. Schizophr. Res. 105, 175–187 (2008).18775645 10.1016/j.schres.2008.07.006
28. Solmi M Antipsychotics use is associated with greater adherence to cardiometabolic medications in patients with schizophrenia: results from a nationwide, within-subject design study Schizophr. Bull. 2022 48 166 175 10.1093/schbul/sbab087 34286338
Solmi, M. et al. Antipsychotics use is associated with greater adherence to cardiometabolic medications in patients with schizophrenia: results from a nationwide, within-subject design study. Schizophr. Bull. 48, 166–175 (2022).34286338 10.1093/schbul/sbab087
29. Strom BL Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) Am. J. Psychiatry 2011 168 193 201 10.1176/appi.ajp.2010.08040484 21041245
Strom, B. L. et al. Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). Am. J. Psychiatry 168, 193–201 (2011).21041245 10.1176/appi.ajp.2010.08040484
30. Kiviniemi M Antipsychotics and mortality in first-onset schizophrenia: prospective Finnish register study with 5-year follow-up Schizophr. Res. 2013 150 274 280 10.1016/j.schres.2013.07.043 23953217
Kiviniemi, M. et al. Antipsychotics and mortality in first-onset schizophrenia: prospective Finnish register study with 5-year follow-up. Schizophr. Res. 150, 274–280 (2013).23953217 10.1016/j.schres.2013.07.043
31. Tiihonen J 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study) Lancet 2009 374 620 627 10.1016/S0140-6736(09)60742-X 19595447
Tiihonen, J. et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 374, 620–627 (2009).19595447 10.1016/S0140-6736(09)60742-X
32. Taipale H 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20) World Psychiatry 2020 19 61 68 10.1002/wps.20699 31922669
Taipale, H. et al. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 19, 61–68 (2020).31922669 10.1002/wps.20699
33. Pasternak B Svanström H Ranthe MF Melbye M Hviid A Atypical antipsychotics olanzapine, quetiapine, and risperidone and risk of acute major cardiovascular events in young and middle-aged adults: a nationwide register-based cohort study in Denmark CNS drugs 2014 28 963 973 10.1007/s40263-014-0176-0 24895158
Pasternak, B., Svanström, H., Ranthe, M. F., Melbye, M. & Hviid, A. Atypical antipsychotics olanzapine, quetiapine, and risperidone and risk of acute major cardiovascular events in young and middle-aged adults: a nationwide register-based cohort study in Denmark. CNS drugs 28, 963–973 (2014).24895158 10.1007/s40263-014-0176-0
34. Ray WA Chung CP Murray KT Hall K Stein CM Atypical antipsychotic drugs and the risk of sudden cardiac death N. Engl. J. Med. 2009 360 225 235 10.1056/NEJMoa0806994 19144938
Ray, W. A., Chung, C. P., Murray, K. T., Hall, K. & Stein, C. M. Atypical antipsychotic drugs and the risk of sudden cardiac death. N. Engl. J. Med. 360, 225–235 (2009).19144938 10.1056/NEJMoa0806994
35. Kreyenbuhl J Buchanan RW Dickerson FB Dixon LB The schizophrenia patient outcomes research team (PORT): updated treatment recommendations 2009 Schizophr. Bull. 2010 36 94 103 10.1093/schbul/sbp130 19955388
Kreyenbuhl, J., Buchanan, R. W., Dickerson, F. B. & Dixon, L. B. The schizophrenia patient outcomes research team (PORT): updated treatment recommendations 2009. Schizophr. Bull. 36, 94–103 (2010).19955388 10.1093/schbul/sbp130
36. DiBonaventura M Gabriel S Dupclay L Gupta S Kim E A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia BMC psychiatry 2012 12 1 7 10.1186/1471-244X-12-20 22230388
DiBonaventura, M., Gabriel, S., Dupclay, L., Gupta, S. & Kim, E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC psychiatry 12, 1–7 (2012).22230388 10.1186/1471-244X-12-20
37. Carbon M Kane JM Leucht S Correll CU Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis World Psychiatry 2018 17 330 340 10.1002/wps.20579 30192088
Carbon, M., Kane, J. M., Leucht, S. & Correll, C. U. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry 17, 330–340 (2018).30192088 10.1002/wps.20579
38. Keefe RS Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial Arch. Gen. Psychiatry 2007 64 633 647 10.1001/archpsyc.64.6.633 17548746
Keefe, R. S. et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry 64, 633–647 (2007).17548746 10.1001/archpsyc.64.6.633
39. Wu H Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials Schizophr. Bull. 2022 48 643 654 10.1093/schbul/sbac001 35137229
Wu, H. et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr. Bull. 48, 643–654 (2022).35137229 10.1093/schbul/sbac001
40. Carbon M Kane JM Leucht S Correll CU Tardive dyskinesia risk with first‐and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis World Psychiatry 2018 17 330 340 10.1002/wps.20579 30192088
Carbon, M., Kane, J. M., Leucht, S. & Correll, C. U. Tardive dyskinesia risk with first‐and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis. World Psychiatry 17, 330–340 (2018).30192088 10.1002/wps.20579
41. Huhn M 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 Lancet 2019 394 939 951 10.1016/S0140-6736(19)31135-3 31303314
Huhn, M. et al. 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. Lancet 394, 939–951 (2019).31303314 10.1016/S0140-6736(19)31135-3
42. Samara MT Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review Am. J. Psychiatry 2015 172 617 629 10.1176/appi.ajp.2015.14101329 26046338
Samara, M. T. et al. Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am. J. Psychiatry 172, 617–629 (2015).26046338 10.1176/appi.ajp.2015.14101329
43. Agid O Kapur S Arenovich T Zipursky RB Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected Arch. Gen. Psychiatry 2003 60 1228 1235 10.1001/archpsyc.60.12.1228 14662555
Agid, O., Kapur, S., Arenovich, T. & Zipursky, R. B. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch. Gen. Psychiatry 60, 1228–1235 (2003).14662555 10.1001/archpsyc.60.12.1228
44. Leucht S Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia Am. J. Psychiatry 2020 177 342 353 10.1176/appi.ajp.2019.19010034 31838873
Leucht, S. et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am. J. Psychiatry 177, 342–353 (2020).31838873 10.1176/appi.ajp.2019.19010034
45. Heres S Changing the antipsychotic in early nonimprovers to amisulpride or olanzapine: randomized, double-blind trial in patients with schizophrenia Schizophr. Bull. 2022 48 1273 1283 10.1093/schbul/sbac068 35857811
Heres, S. et al. Changing the antipsychotic in early nonimprovers to amisulpride or olanzapine: randomized, double-blind trial in patients with schizophrenia. Schizophr. Bull. 48, 1273–1283 (2022).35857811 10.1093/schbul/sbac068
46. Leung JG A systematic review of clozapine‐associated inflammation and related monitoring Pharmacotherapy: J. Hum. Pharmacol. Drug Ther. 2023 43 1364 10.1002/phar.2887
Leung, J. G. et al. A systematic review of clozapine‐associated inflammation and related monitoring. Pharmacotherapy: J. Hum. Pharmacol. Drug Ther. 43, 1364 (2023).10.1002/phar.2887
47. Leung JG Allen ND Markota M A case series of clozapine titrations affected by inflammatory processes Schizophr. Res. 2023 268 94 97 37633777
Leung, J. G., Allen, N. D. & Markota, M. A case series of clozapine titrations affected by inflammatory processes. Schizophr. Res. 268, 94–97 (2023).37633777
48. De Leon J An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels Pharmacopsychiatry 2022 55 73 86 10.1055/a-1625-6388 34911124
De Leon, J. et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 55, 73–86 (2022).34911124 10.1055/a-1625-6388
49. Faay MDM Hostility and aggressive behaviour in first episode psychosis: Results from the OPTiMiSE trial Schizophr. Res. 2020 223 271 278 10.1016/j.schres.2020.08.021 32928616
Faay, M. D. M. et al. Hostility and aggressive behaviour in first episode psychosis: Results from the OPTiMiSE trial. Schizophr. Res. 223, 271–278 (2020).32928616 10.1016/j.schres.2020.08.021
50. Nielssen O Large M Rates of homicide during the first episode of psychosis and after treatment: a systematic review and meta-analysis Schizophr. Bull. 2010 36 702 712 10.1093/schbul/sbn144 18990713
Nielssen, O. & Large, M. Rates of homicide during the first episode of psychosis and after treatment: a systematic review and meta-analysis. Schizophr. Bull. 36, 702–712 (2010).18990713 10.1093/schbul/sbn144
51. Volavka J Hostility in schizophrenia: an integrated analysis of the combined Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the European First Episode Schizophrenia Trial (EUFEST) studies Eur. Psychiatry 2016 31 13 19 10.1016/j.eurpsy.2015.10.003 26657597
Volavka, J. et al. Hostility in schizophrenia: an integrated analysis of the combined Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the European First Episode Schizophrenia Trial (EUFEST) studies. Eur. Psychiatry 31, 13–19 (2016).26657597 10.1016/j.eurpsy.2015.10.003
52. Sariaslan A Leucht S Zetterqvist J Lichtenstein P Fazel S Associations between individual antipsychotics and the risk of arrests and convictions of violent and other crime: a nationwide within-individual study of 74 925 persons Psychol. Med. 2022 52 3792 3800 10.1017/S0033291721000556
Sariaslan, A., Leucht, S., Zetterqvist, J., Lichtenstein, P. & Fazel, S. Associations between individual antipsychotics and the risk of arrests and convictions of violent and other crime: a nationwide within-individual study of 74 925 persons. Psychol. Med. 52, 3792–3800 (2022).10.1017/S0033291721000556
53. Volavka J Czobor P Citrome L Van Dorn RA Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study - ADDENDUM CNS Spectr. 2014 19 466 10.1017/S1092852914000364 25017569
Volavka, J., Czobor, P., Citrome, L. & Van Dorn, R. A. Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study - ADDENDUM. CNS Spectr. 19, 466 (2014).25017569 10.1017/S1092852914000364
54. Strassnig MT Nascimento V Deckler E Harvey PD Pharmacological treatment of violence in schizophrenia CNS Spectr. 2020 25 207 215 10.1017/S1092852919001226 31342892
Strassnig, M. T., Nascimento, V., Deckler, E. & Harvey, P. D. Pharmacological treatment of violence in schizophrenia. CNS Spectr. 25, 207–215 (2020).31342892 10.1017/S1092852919001226
55. Bhavsar V Clozapine treatment and offending: a within-subject study of patients with psychotic disorders in Sweden Schizophr. Bull. 2020 46 303 310 31150553
Bhavsar, V. et al. Clozapine treatment and offending: a within-subject study of patients with psychotic disorders in Sweden. Schizophr. Bull. 46, 303–310 (2020).31150553
56. Krakowski M Tural U Czobor P The importance of conduct disorder in the treatment of violence in schizophrenia: efficacy of clozapine compared with olanzapine and haloperidol Am. J. Psychiatry 2021 178 266 274 10.1176/appi.ajp.2020.20010052 33472389
Krakowski, M., Tural, U. & Czobor, P. The importance of conduct disorder in the treatment of violence in schizophrenia: efficacy of clozapine compared with olanzapine and haloperidol. Am. J. Psychiatry 178, 266–274 (2021).33472389 10.1176/appi.ajp.2020.20010052
57. Zhu Y Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses Lancet Psychiatry 2017 4 694 705 10.1016/S2215-0366(17)30270-5 28736102
Zhu, Y. et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry 4, 694–705 (2017).28736102 10.1016/S2215-0366(17)30270-5
58. Leucht S The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis Lancet Psychiatry 2022 9 884 893 10.1016/S2215-0366(22)00304-2 36228647
Leucht, S. et al. The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis. Lancet Psychiatry 9, 884–893 (2022).36228647 10.1016/S2215-0366(22)00304-2
59. McDonagh, M. S. et al. Treatments for Schizophrenia in Adults: A Systematic Review (2018).
60. Green A Olanzapine and haloperidol in first episode psychosis: two-year data Schizophr. Res. 2006 86 234 243 10.1016/j.schres.2006.06.021 16887334
Green, A. et al. Olanzapine and haloperidol in first episode psychosis: two-year data. Schizophr. Res. 86, 234–243 (2006).16887334 10.1016/j.schres.2006.06.021
61. Zhu Y How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis Eur. Neuropsychopharmacol. 2017 27 835 844 10.1016/j.euroneuro.2017.06.011 28669774
Zhu, Y. et al. How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. Eur. Neuropsychopharmacol. 27, 835–844 (2017).28669774 10.1016/j.euroneuro.2017.06.011
62. McCue RE Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia Br. J. Psychiatry 2006 189 433 440 10.1192/bjp.bp.105.019307 17077434
McCue, R. E. et al. Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. Br. J. Psychiatry 189, 433–440 (2006).17077434 10.1192/bjp.bp.105.019307
63. Kane JM Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine J. Clin. Psychiatry 2007 68 213 223 10.4088/JCP.v68n0206 17335319
Kane, J. M. et al. Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J. Clin. Psychiatry 68, 213–223 (2007).17335319 10.4088/JCP.v68n0206
64. Sumitomo-Pharma. Sumitomo Pharma and Otsuka Announce Topline Results from Phase 3 DIAMOND 1 and DIAMOND 2 Clinical Studies Evaluating Ulotaront in Schizophrenia. https://www.sumitomo-pharma.com/news/20230731-1.html (2023).
65. Phalguni A Systematic literature review and network meta-analysis of lurasidone, brexpiprazole and cariprazine for schizophrenia Int. Clin. Psychopharmacol. 2023 38 45 56 10.1097/YIC.0000000000000427 35916575
Phalguni, A. et al. Systematic literature review and network meta-analysis of lurasidone, brexpiprazole and cariprazine for schizophrenia. Int. Clin. Psychopharmacol. 38, 45–56 (2023).35916575 10.1097/YIC.0000000000000427
66. Fleischhacker W The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors Eur. Psychiatry 2019 58 1 9 10.1016/j.eurpsy.2019.01.015 30738380
Fleischhacker, W. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur. Psychiatry 58, 1–9 (2019).30738380 10.1016/j.eurpsy.2019.01.015
67. Pridan S Baruch Y Swartz M Barak Y Amisulpride for older patients with long-standing schizophrenia J. Clin. Psychopharmacol. 2014 34 736 737 10.1097/JCP.0000000000000226 25275673
Pridan, S., Baruch, Y., Swartz, M. & Barak, Y. Amisulpride for older patients with long-standing schizophrenia. J. Clin. Psychopharmacol. 34, 736–737 (2014).25275673 10.1097/JCP.0000000000000226
68. Lao KS Mortality risk associated with haloperidol use compared with other antipsychotics: an 11-year population-based propensity-score-matched cohort study CNS Drugs 2020 34 197 206 10.1007/s40263-019-00693-5 31916101
Lao, K. S. et al. Mortality risk associated with haloperidol use compared with other antipsychotics: an 11-year population-based propensity-score-matched cohort study. CNS Drugs 34, 197–206 (2020).31916101 10.1007/s40263-019-00693-5
69. Olfson M Marcus SC Ascher-Svanum H Treatment of schizophrenia with long-acting fluphenazine, haloperidol, or risperidone Schizophr. Bull. 2007 33 1379 1387 10.1093/schbul/sbm033 17470444
Olfson, M., Marcus, S. C. & Ascher-Svanum, H. Treatment of schizophrenia with long-acting fluphenazine, haloperidol, or risperidone. Schizophr. Bull. 33, 1379–1387 (2007).17470444 10.1093/schbul/sbm033
70. Jönsson AK Spigset O Reis M A compilation of serum concentrations of 12 antipsychotic drugs in a therapeutic drug monitoring setting Ther. Drug Monit. 2019 41 348 356 10.1097/FTD.0000000000000585 31025986
Jönsson, A. K., Spigset, O. & Reis, M. A compilation of serum concentrations of 12 antipsychotic drugs in a therapeutic drug monitoring setting. Ther. Drug Monit. 41, 348–356 (2019).31025986 10.1097/FTD.0000000000000585
71. Weiss U Marksteiner J Kemmler G Saria A Aichhorn W Effects of age and sex on olanzapine plasma concentrations J. Clin. Psychopharmacol. 2005 25 570 574 10.1097/01.jcp.0000185427.08268.db 16282840
Weiss, U., Marksteiner, J., Kemmler, G., Saria, A. & Aichhorn, W. Effects of age and sex on olanzapine plasma concentrations. J. Clin. Psychopharmacol. 25, 570–574 (2005).16282840 10.1097/01.jcp.0000185427.08268.db
72. Castberg I Westin AA Skogvoll E Spigset O Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine Acta Psychiatr. Scand. 2017 136 455 464 10.1111/acps.12794 28865402
Castberg, I., Westin, A. A., Skogvoll, E. & Spigset, O. Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr. Scand. 136, 455–464 (2017).28865402 10.1111/acps.12794
73. Patel MX Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009 J. Clin. Psychopharmacol. 2011 31 411 417 10.1097/JCP.0b013e318221b408 21694620
Patel, M. X. et al. Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009. J. Clin. Psychopharmacol. 31, 411–417 (2011).21694620 10.1097/JCP.0b013e318221b408
