Skip to main content
NCBI home page
Schizophrenia Bulletin logoLink to Schizophrenia Bulletin
. 2020 May 16;46(6):1439–1458. doi: 10.1093/schbul/sbaa063

Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis

Hiroyoshi Takeuchi 1,2,✉, Nicole E MacKenzie 2,3, Dominic Samaroo 2,4, Ofer Agid 2,5,6, Gary Remington 2,5,6,7, Stefan Leucht 8
PMCID: PMC7707077  PMID: 32415847

Abstract

Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose–response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.

Keywords: antipsychotics, dose, schizophrenia

Introduction

Although antipsychotic efficacy for acute symptoms of schizophrenia is well established,1 little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia.2,3 A recent meta-analysis examining the dose–response relationship of each antipsychotic demonstrated that, in general, antipsychotic efficacy proportionally increased up to the risperidone equivalent of 3–5 mg/d, and thereafter plateaued4; however, this meta-analysis focused on efficacy and did not examine any safety outcomes. Antipsychotics can induce various undesirable side effects,1 with at least some of these dose dependent,5–7 so striking a balance between efficacy and safety is clinically relevant when choosing antipsychotic dose.

The minimum effective dose (MED), defined as the lowest dose that significantly differs from placebo in terms of efficacy,8 is useful in clinical decision making because it serves as a milestone for an initial dose and a benchmark for increased dosing. In fact, an international consensus study recommended that antipsychotic dose for acute schizophrenia should be targeted in the range of 2-fold to 3-fold MED.9 The aim of the present study was to employ the concept of MED in examining the balance between higher antipsychotic doses, efficacy, and safety in acute schizophrenia.

Methods

Minimum Effective Doses of Antipsychotics

The MED was identified for each antipsychotic through a previous systematic review8 as well as a recent dose–response meta-analysis.4 The systematic review involved the following 2 steps to determine MED for each antipsychotic: (1) identifying double-blind placebo-controlled randomized trials involving fixed-dose antipsychotic monotherapy in adult patients during the acute phase of schizophrenia or schizoaffective disorder and (2) defining MED as a dose that was significantly superior to placebo for the primary outcome in at least 1 identified studies (MED according to the primary criteria = MED1) or in at least 2 identified studies (but used the next higher dose that was superior in another trial if a dose was superior in only 1 identified study) (MED according to the more conservative secondary criteria = MED2). The MED1 and MED2 of the following antipsychotics in oral form were determined as follows: aripiprazole (10 mg/d for both), asenapine (10 mg/d for both), clozapine (300 mg/d and none), haloperidol (4 and 4.5 mg/d), iloperidone (8 and 12 mg/d), lurasidone (40 mg/d and none), olanzapine (7.5 and 10 mg/d), paliperidone (3 and 6 mg/d), quetiapine (150 and 250 mg/d), risperidone (2 and 4 mg/d), sertindole (12 and 16 mg/d), and ziprasidone (40 and 80 mg/d).8 The most recent meta-analysis identified MED1 of the 2 newest antipsychotics, brexpiprazole (2 mg/d), and cariprazine (1.5 mg/d).4

MED1 was used as the primary comparison. When MED1 was not available, MED2 was used as a substitute and was then compared against 2-fold or 3-fold MED2.

Study Selection

Studies were selected from a recent meta-analysis examining the dose–response relationship of second-generation antipsychotics and haloperidol.4 We identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in adult patients in the acute phase of schizophrenia or schizoaffective disorder, and compared the identified MED with higher doses of the same oral antipsychotic. We excluded fixed-dose range studies.

Risk of bias for each included study was available elsewhere because all studies were extracted from a recently published meta-analysis.4

Data Extraction

Three authors (H.T., N.M., and D.S.) independently extracted the following clinical outcome data in the MED and higher dose groups from the selected studies: (1) number of patients who discontinued the study due to all causes, lack of efficacy, and adverse events; (2) mean ± SD changes from baseline to endpoint in the Positive and Negative Syndrome Scale (PANSS)10 or the Brief Psychiatric Rating Scale (BPRS)11 total scores, the PANSS positive subscale or factor or BPRS core item scores, and the PANSS negative subscale or factor or the Schedule for the Assessment of Negative Symptoms (SANS) total or summary scores,12 and the Clinical Global Impression-Severity scale (CGI-S)13 scores as psychopathology measures; (4) mean ± SD changes in the Simpson-Angus Scale (SAS)14 total scores, the Barnes Akathisia Rating Scale (BARS)15 total or global scores, and the Abnormal Involuntary Movement Scale (AIMS)13 total or Item 8 scores; and (5) number of patients who experienced individual treatment-emergent adverse events (TEAEs) that were reported in ≥2 comparisons. Any disagreements about data extraction were resolved by consensus.

Data Analysis

Meta-analyses were performed using Review Manager (RevMan) version 5.3. Outcome data were combined and compared between the MED and 2-fold or 3-fold MED groups. For dichotomous and continuous outcomes, pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) were calculated with 2-sided 95% confidence intervals (CIs) using a random-effects model, respectively. Study heterogeneities were quantified using I2 statistic with an I2 ≥ 50%, indicating significant heterogeneity. All effect sizes with a P ≤ 0.05 were considered significant.

As sensitivity analyses, we excluded studies comparing MED2 with 2-fold or 3-fold MED2.

Publication bias was assessed using visual inspection of funnel plots for each outcome. The absence of obvious asymmetry was taken to reflect a low possibility of significant publication bias.

Results

Included Studies

A total of 26 studies involving 5618 patients met eligibility criteria.16–38 As 1 study compared MEDs of 2 antipsychotics with their higher doses, a total of 27 comparisons were included in the meta-analysis. The characteristics of the included studies are summarized in table 1. All were short-term studies in the range of 4–16 weeks. The following antipsychotics were examined: aripiprazole (N = 2), asenapine (N = 2), brexpiprazole (N = 3), cariprazine (N = 1), clozapine (N = 1), haloperidol (N = 1), lurasidone (N = 4), paliperidone (N = 4), quetiapine (N = 1), risperidone (N = 4), sertindole (N = 1), and ziprasidone (N = 3). For paliperidone, risperidone, and ziprasidone, only studies including MED2 contributed to the comparisons of MED with 2-fold MED.

Table 1.

Randomized Controlled Trials Examining Minimum Effective Dose vs Higher Dose of Antipsychotics in Patients With Acute Schizophrenia

Study Blinding Duration Diagnosis (frequency) Antipsychotics MED1 N MED2 N 2-fold MED1 N 2-fold MED2 N 3-fold MED1 N 3-fold MED2 N
McEvoy (2007) Double blind 6 wk SCZ (100%) Aripiprazole 10 mg/d 106 NA NA 20 mg/d 100 NA NA NA NA NA NA
Study 94202 Double blind 4 wk SCZ (100%) Aripiprazole 10 mg/d 60 NA NA NA NA NA NA 30 mg/d 61 NA NA
Kane (2010) Double blind 6 wk SCZ (100%) Asenapine 10 mg/d 114 NA NA 20 mg/d 106 NA NA NA NA NA NA
Study 041021 Double blind 6 wk SCZ (100%) Asenapine 10 mg/d 106 NA NA 20 mg/d 102 NA NA NA NA NA NA
Correll (2015) Double blind 6 wk SCZ (100%) Brexpiprazole 2 mg/d 182 NA NA 4 mg/d 180 NA NA NA NA NA NA
Ishigooka (2018) Double blind 6 wk SCZ (100%) Brexpiprazole 2 mg/d 115 NA NA 4 mg/d 113 NA NA NA NA NA NA
Kane (2015) Double blind 6 wk SCZ (100%) Brexpiprazole 2 mg/d 186 NA NA 4 mg/d 184 NA NA NA NA NA NA
Durgam (2014) Double blind 6 wk SCZ (100%) Cariprazine 1.5 mg/d 145 NA NA 3 mg/d 146 NA NA 4.5 mg/d 147 NA NA
Simpson (1999) Double blind 16 wk SCZ (78%a), SCA (22%a) Clozapine 300 mg/d 17 NA NA 600 mg/d 17 NA NA NA NA NA NA
Zimbroff (1997) (HAL arm) Double blind 8 wk SCZ (100%) Haloperidol 4 mg/d 71 NA NA 8 mg/d 67 NA NA NA NA NA NA
Meltzer (2011) Double blind 6 wk SCZ (100%) Lurasidone 40 mg/d 120 NA NA NA NA NA NA 120 mg/d 119 NA NA
Nasrallah (2013) Double blind 6 wk SCZ (100%) Lurasidone 40 mg/d 125 NA NA 80 mg/d 123 NA NA 120 mg/d 124 NA NA
Ogasa (2013) Double blind 6 wk SCZ (100%) Lurasidone 40 mg/d 50 NA NA NA NA NA NA 120 mg/d 49 NA NA
Potkin (2015) Double blind 6 wk SCZ (100%) Lurasidone 40 mg/d 67 NA NA 80 mg/d 71 NA NA NA NA NA NA
Canuso (2010) Double blind 6 wk SCA (100%) Paliperidone NA NA 6 mg/d 109 NA NA 12 mg/d 100 NA NA NA NA
Davidson (2007) Double blind 6 wk SCZ (100%) Paliperidone 3 mg/d 127 NA NA NA NA NA NA 9 mg/d 125 NA NA
Kane (2007) Double blind 6 wk SCZ (100%) Paliperidone NA NA 6 mg/d 123 NA NA 12 mg/d 130 NA NA NA NA
Marder (2007) Double blind 6 wk SCZ (100%) Paliperidone NA NA 6 mg/d 112 NA NA 12 mg/d 112 NA NA NA NA
Arvanitis (1997) Double blind 6 wk SCZ (100%) Quetiapine 150 mg/d 48 NA NA 300 mg/d 52 NA NA NA NA NA NA
Chouinard (1993) Double blind 8 wk SCZ (100%) Risperidone 2 mg/d 24 NA NA NA NA NA NA 6 mg/d 22 NA NA
Marder (1994) Double blind 8 wk SCZ (100%) Risperidone 2 mg/d 63 NA NA NA NA NA NA 6 mg/d 64 NA NA
Peuskens (1995) Double blind 8 wk SCZ (100%) Risperidone NA NA 4 mg/d 227 NA NA 8 mg/d 230 NA NA 12 mg/db 226b
Study RIS-USA-72 Double blind 4 wk SCZ (100%) Risperidone NA NA 4 mg/d 85 NA NA 8 mg/d 78 NA NA NA NA
Zimbroff (1997) (SER arm) Double blind 8 wk SCZ (100%) Sertindole 12 mg/d 76 NA NA 24 mg/d 72 NA NA NA NA NA NA
Daniel (1999) Double blind 6 wk SCZ (77%a), SCA (23%a) Ziprasidone NA NA 80 mg/d 106 NA NA 160 mg/d 104 NA NA NA NA
Keck (1998) Double blind 4 wk SCZ (63%a), SCA (37%a) Ziprasidone 40 mg/d 44 NA NA NA NA NA NA 120 mg/d 47 NA NA
Study 115 Double blind 6 wk SCZ (NA), SCA (NA) Ziprasidone 40 mg/d 87 NA NA NA NA NA NA 120 mg/d 78 NA NA
Open in a new tab

Note: MED1, minimum effective dose according to the primary criteria; MED2, minimum effective dose according to the more conservative secondary criteria; NA, not applicable; SCA, schizoaffective disorder; SCZ, schizophrenia.

aAmong all patients (ie, including patients assigned to placebo arm).

bThis arm did not contribute to the meta-analysis because of our criteria (see Methods section).

Study Discontinuation

Although there were no significant differences in study discontinuation due to all causes or adverse events between MED1&2 and higher doses, significant differences were found in study discontinuation due to lack of efficacy between MED1&2 and higher doses in favor of 2-fold MED1&2 (N = 15, n = 3673, RR = 1.24, 95% CI = 1.00–1.54, P = 0.05, I2 = 30%) and 3-fold MED1&2 (N = 10, n = 1681, RR = 1.44, 95% CI = 1.10–1.89, P < 0.001, I2 = 33%) (figure 1). No obvious publication biases were observed.

Fig. 1.

Fig. 1.

Fig. 1.

Fig. 1.

Fig. 1.

Fig. 1.

Fig. 1.

Open in a new tab

Study discontinuation. (A) Study discontinuation due to all causes: (A-1) MED vs 2-fold MED, (A-2) MED vs 3-fold MED. (B) Study discontinuation due to lack of efficacy: (B-1) MED vs 2-fold MED, (B-2) MED vs 3-fold MED. (C) Study discontinuation due to adverse events: (C-1) MED vs 2-fold MED, (C-2) MED vs 3-fold MED. Abbreviation: MED, minimum effective dose.

Psychopathology

There were significant differences in the PANSS/BPRS total and positive symptom scores, and the CGI-S scores between both MED1&2 and 2-fold MED1&2, as well as MED1&2 and 3-fold MED1&2 (figure 2). On the other hand, no significant difference was found in the PANSS/SANS negative symptom scores between either MED and 2-fold MED1&2, or MED1&2 and 3-fold MED1&2 (figure 2). No obvious publication biases were observed.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Fig. 2.

Open in a new tab

Psychopathology. (A) PANSS/BPRS total score: (A-1) MED vs 2-fold MED, (A-2) MED vs 3-fold MED. (B) PANSS/BPRS positive symptom score: (B-1) MED vs 2-fold MED, (B-2) MED vs 3-fold MED. (C) PANSS/SANS negative symptom score: (C-1) MED vs 2-fold MED, (C-2) MED vs 3-fold MED; (D) CGI-S score: (D-1) MED vs 2-fold MED, (D-2) MED vs 3-fold MED. Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression—Severity scale; MED, minimum effective dose; PANSS, Positive and Negative Syndrome Scale; SANS, Schedule for the Assessment of Negative Symptoms.

Extrapyramidal Symptoms

The only significant difference between MED1&2 and higher doses was found in the SAS scores, in favor of MED1&2 vs 2-fold MED1&2 (N = 6, n = 1316, SMD = −0.15, 95% CI = −0.26 to −0.04, P = 0.05, I2 = 30%) (supplementary figure 2). No obvious publication biases were observed.

Treatment-Emergent Adverse Events

Among 22 TEAEs that were reported in ≥2 comparisons, 2-fold MED1&2 proved significantly inferior to MED1&2 for diarrhea (N = 3, n = 792, RR = 0.36, 95% CI = 0.16–0.82, P = 0.01, I2 = 0%) (supplementary table 1). On the other hand, among 17 TEAEs that were reported in ≥2 studies, 3-fold MED1&2 was inferior for akathisia (N = 4, n = 675, RR = 0.53, 95% CI = 0.36–0.77, P = 0.01, I2 = 0%), somnolence (N = 6, n = 1053, RR = 0.65, 95% CI = 0.45–0.95, P = 0.03, I2 = 0%), and vomiting (N = 7, n = 1345, RR = 0.51, 95% CI = 0.31–0.84, P < 0.01, I2 = 0%) (supplementary table 1). No obvious publication biases were observed.

Sensitivity Analysis

After excluding 6 studies comparing MED2 and 2-fold or 3-fold MED2 (paliperidone, N = 3; risperidone; N = 2, ziprasidone, N = 1), there were significant differences between MED1 and 2-fold MED1 in the SAS scores, diarrhea, and vomiting in favor of MED1 (data not shown). There were significant differences between MED1 and 3-fold MED1 in study discontinuation due to lack of efficacy, the PANSS/BPRS total and positive symptom scores, and the CGI-S score in favor of 3-fold MED1; akathisia and somnolence favored MED1, however (data not shown).

Discussion

The findings of the current meta-analysis are 3-fold: (1) both 2-fold and 3-fold MEDs were superior to MED for effectiveness (ie, study discontinuation due to lack of efficacy) and efficacy (ie, total and positive symptom reduction); (2) MED was superior to 2-fold and 3-fold MEDs for side effects; and (3) 3-fold MED was associated with a greater effectiveness, efficacy, and number of side effects than 2-fold MED, even though the sample size in the 3-fold MED group was smaller than that in the 2-fold MED group. In summary, effectiveness, efficacy, and some antipsychotic side effects increased in a dose-dependent fashion. Differences between the current and recent dose–response meta-analyses include (1) the former compared a certain dose and higher doses utilizing the MED concept as a unit of dose, whereas the latter showed dose–response curves treating dose as a continuous variable and (2) the former examined both efficacy and side effects, whereas the latter elucidated only efficacy.

The effect sizes of antipsychotic effectiveness (ie, study discontinuation due to lack of efficacy) and efficacy (ie, total symptom reduction) compared with MED were larger in 3-fold MED (1.44 and 0.17, respectively) than 2-fold MED (1.24 and 0.08, respectively), although some antipsychotics were not included in the 3-fold MED group but in the 2-fold MED group (and vice versa), indicating that antipsychotic efficacy increases in a dose-dependent fashion. This aligns with a recent dose–response meta-analysis demonstrating that antipsychotic efficacy proportionally increased up to risperidone equivalent 3–5 mg/d.4 This consistency in results suggests that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia. All higher doses included in the current meta-analysis are approved by authorities as a licensed dose based on the findings of fixed-dose trials; indeed, 2-fold and 3-fold MEDs are within the range of antipsychotic doses recommended by an international consensus.9 The current meta-analysis cannot address antipsychotic efficacy and safety beyond 3-fold MED; however, the dose–response meta-analysis4 and another meta-analysis of RCTs comparing standard dose with high doses of antipsychotics demonstrated no further gain in efficacy beyond standard doses in general.39

It should be noted that the current findings cannot be taken as evidence that clinicians should increase the antipsychotic dose if a patient does not respond to MED. Indeed, a recent meta-analysis of RCTs demonstrated no significant difference in efficacy between increasing and maintaining antipsychotic dose in patients who did not respond to the initial dose.40 This may reflect significant differences in study design between fixed-dose studies and studies involving dose increases (eg, administrating a fixed-dose antipsychotic in patients who are not necessarily refractory vs increasing an antipsychotic dose in those who are not responsive to an initial dose), as well as differences in sample sizes between the meta-analyses being compared (eg, n = 3673/1681 vs n = 336 for study discontinuation due to lack of efficacy, respectively; n = 3918/1363 vs n = 258 for total symptom reduction, respectively) rather than true effect differences. Related to this issue, there remain clinically important questions such as when clinicians should undertake an antipsychotic increase or switch after a patient fails to respond to the initial dose, which are not addressed in the current meta-analysis but partially examined in other meta-analyses.41,42

To our knowledge, the present study is the first meta-analysis to examine the relationship between antipsychotic dose and various specific side effects. The present findings revealed that 2-fold MED was inferior to MED for parkinsonism and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. These results suggest that not only extrapyramidal symptoms occur in a dose-dependent fashion, but somnolence and digestive symptoms do as well. As noted, clinicians are required to balance occurrence or exacerbation of side effects against improvement of symptoms when considering increases in antipsychotic dose.

The results of the current meta-analysis should be interpreted with caution for several reasons. First, given differences in pharmacological profiles between antipsychotics, it remains questionable whether combining results across antipsychotics represents the optimal strategy, although it is worth pointing out that no significant study heterogeneities were found across the effectiveness/efficacy outcomes. The recent meta-analysis revealed substantial differences in the relationship between dose and efficacy across various antipsychotics,4 which can also be applied to side effects; indeed, antipsychotics tend to manifest greater differences in side effects compared with efficacy.1 In addition, some antipsychotics such as amisulpride, zotepine, and first-generation antipsychotics other than haloperidol were not included in the current meta-analysis because the MEDs of these drugs were not available. Furthermore, iloperidone and olanzapine were not included because no studies met the eligibility criteria, even though the MEDs of these drugs were available. Furthermore, only 1 study was available for cariprazine, clozapine, haloperidol, quetiapine, and sertindole. Additional fixed-dose RCTs with commonly used antipsychotics, such as amisulpride, cariprazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, and zotepine, are needed to identify the MEDs and expand the findings of the current meta-analysis.

There are other limitations that should be noted. First, the method to identify MEDs has its own limitations, which have been detailed elsewhere.8 Second, the number of studies was small for some side effects, which may have led to type II errors. Third, we did not collect information on metabolic parameters beyond weight gain reported as TEAEs, as older studies did not examine or provide these outcomes. Fourth, the original paper defined MED with “study-defined primary outcome,” which is total symptoms in the vast majority of studies; thus, the validity of findings in terms of both positive and negative symptoms is questionable. Lastly, the present findings cannot be applied to long-acting injectable antipsychotics and conditions other than chronic schizophrenia, eg, first-episode or treatment-resistant schizophrenia.

In conclusion, the current meta-analysis showed that antipsychotic effectiveness, efficacy, and some side effects increased in a dose-dependent fashion. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.

Supplementary Material

sbaa063_suppl_Supplemental_figure_1
Click here for additional data file. (141.5KB, docx)
sbaa063_suppl_Supplemental_table_1
Click here for additional data file. (37.4KB, pdf)

Funding

None declared.

Conflict of Interest

Dr. Takeuchi has received research grants from Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), SENSHIN Medical Research Foundation, and Novartis Pharma; fellowship grants from Astellas Foundation for Research on Metabolic Disorders, the Canadian Institutes of Health Research (CIHR), Centre for Addiction and Mental Health (CAMH) Foundation, and the Japanese Society of Clinical Neuropsychopharmacology (JSCNP); speaker’s fees from Kyowa, Janssen, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin; and manuscript fees from Sumitomo Dainippon Pharma. Ms. MacKenzie and Mr. Samaroo report no financial relationships with commercial interests. Dr. Agid has been a consultant and/or advisor to or honoraria from HLS Therapeutics, Janssen-Ortho (Johnson & Johnson), Lundbeck, Medscape, Minerva Neurosciences, Mylan, Otsuka, and Sumitomo Dainippon Pharma; and grant support from Acadia, Boehringer Ingelheim, DiaMentis, Janssen-Ortho (Johnson & Johnson), Neurocrine Biosciences, Otsuka, and Syneurx. Dr. Remington has received research support from the Canadian Institutes of Health Research (CIHR), HLS Therapeutics, and Research Hospital Fund–Canada Foundation for Innovation (RHF-CFI); conference support from Neurocrine Biosciences for data presentation; and advisory board support from HLS Therapeutics and Mitsubishi Tanabe Pharma. Dr. Leucht has received honoraria for service as a consultant or adviser and/or for lectures from Angelini, Boehringer Ingelheim, Gedeon Richter, Janssen, Johnson & Johnson, LB Pharma, LTS Lohmann, Lundbeck, MSD, Otsuka, Recordati, Sandoz, Sanofi-Aventis, Sunovion, and TEVA.

References

  • 1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, 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. 2019;394(10202):939–951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Buchanan RW, Carpenter WT. Clinically meaningful gaps between clinical trials and patient treatment. Schizophr Bull. 2018;44(4):701–702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Hui CLM, Lam BST, Lee EHM, et al.  A systematic review of clinical guidelines on choice, dose, and duration of antipsychotics treatment in first- and multi-episode schizophrenia. Int Rev Psychiatry. 2019;31(5–6):441–459. [DOI] [PubMed] [Google Scholar]
  • 4. Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry. 2020;177(4):342–353. [DOI] [PubMed] [Google Scholar]
  • 5. Simpson GM, Lindenmayer JP. Extrapyramidal symptoms in patients treated with risperidone. J Clin Psychopharmacol. 1997;17(3):194–201. [DOI] [PubMed] [Google Scholar]
  • 6. Knowles EE, David AS, Reichenberg A. Processing speed deficits in schizophrenia: reexamining the evidence. Am J Psychiatry. 2010;167(7):828–835. [DOI] [PubMed] [Google Scholar]
  • 7. 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(3):225–235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull. 2014;40(2):314–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167(6):686–693. [DOI] [PubMed] [Google Scholar]
  • 10. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. [DOI] [PubMed] [Google Scholar]
  • 11. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10(3):799–812. [Google Scholar]
  • 12. Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry. 1982;39(7):789–794. [DOI] [PubMed] [Google Scholar]
  • 13. Guy W.  ECDEU Assessment Manual for Psychopharmacology.  Rockville, MD: National Institute of Mental Health; 1976. [Google Scholar]
  • 14. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–19. [DOI] [PubMed] [Google Scholar]
  • 15. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–676. [DOI] [PubMed] [Google Scholar]
  • 16. McEvoy JP, Daniel DG, Carson WH Jr, McQuade RD, Marcus RN. A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20 mg/day for the treatment of patients with acute exacerbations of schizophrenia. J Psychiatr Res. 2007;41(11):895–905. [DOI] [PubMed] [Google Scholar]
  • 17. Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106–115. [DOI] [PubMed] [Google Scholar]
  • 18. Meltzer HY, Cucchiaro J, Silva R, et al.  Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957–967. [DOI] [PubMed] [Google Scholar]
  • 19. Potkin SG, Kimura T, Guarino J. A 6-week, double-blind, placebo- and haloperidol-controlled, phase II study of lurasidone in patients with acute schizophrenia. Ther Adv Psychopharmacol. 2015;5(6):322–331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Davidson M, Emsley R, Kramer M, et al.  Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007;93(1–3):117–130. [DOI] [PubMed] [Google Scholar]
  • 21. Kane J, Canas F, Kramer M, et al.  Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res. 2007;90(1-3):147–161. [DOI] [PubMed] [Google Scholar]
  • 22. Marder SR, Kramer M, Ford L, et al.  Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007;62(12):1363–1370. [DOI] [PubMed] [Google Scholar]
  • 23. Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, et al.  A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder. J Clin Psychiatry. 2010;71(5):587–598. [DOI] [PubMed] [Google Scholar]
  • 24. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42(4):233–246. [DOI] [PubMed] [Google Scholar]
  • 25. Peuskens J. Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group. Br J Psychiatry. 1995;166(6):712–26; discussion 727. [DOI] [PubMed] [Google Scholar]
  • 26. Chouinard G, Jones B, Remington G, et al.  A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol. 1993;13(1):25–40. [PubMed] [Google Scholar]
  • 27. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825–835. [DOI] [PubMed] [Google Scholar]
  • 28. Correll CU, Skuban A, Ouyang J, et al.  Efficacy and safety of brexpiprazole for the treatment of acute Schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870–880. [DOI] [PubMed] [Google Scholar]
  • 29. Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999;20(5):491–505. [DOI] [PubMed] [Google Scholar]
  • 30. Goff DC, Posever T, Herz L, et al.  An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 1998;18(4):296–304. [DOI] [PubMed] [Google Scholar]
  • 31. Keck P Jr, Buffenstein A, Ferguson J, et al.  Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl). 1998;140(2):173–184. [DOI] [PubMed] [Google Scholar]
  • 32. Ishigooka J, Iwashita S, Tadori Y. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: a 6-week, randomized, double-blind, placebo-controlled study. Psychiatry Clin Neurosci. 2018;72(9):692–700. [DOI] [PubMed] [Google Scholar]
  • 33. Kane JM, Skuban A, Ouyang J, et al.  A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164(1–3):127–135. [DOI] [PubMed] [Google Scholar]
  • 34. Durgam S, Starace A, Li D, et al.  An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014;152(2–3):450–457. [DOI] [PubMed] [Google Scholar]
  • 35. Simpson GM, Josiassen RC, Stanilla JK, et al.  Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry. 1999;156(11):1744–1750. [DOI] [PubMed] [Google Scholar]
  • 36. Zimbroff DL, Kane JM, Tamminga CA, et al.  Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. Am J Psychiatry. 1997;154(6):782–791. [DOI] [PubMed] [Google Scholar]
  • 37. Ogasa M, Kimura T, Nakamura M, Guarino J. Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study. Psychopharmacology (Berl). 2013;225(3):519–530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Nasrallah HA, Silva R, Phillips D, et al.  Lurasidone for the treatment of acutely psychotic patients with schizophrenia: a 6-week, randomized, placebo-controlled study. J Psychiatr Res. 2013;47(5):670–677. [DOI] [PubMed] [Google Scholar]
  • 39. Dold M, Fugger G, Aigner M, Lanzenberger R, Kasper S. Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Res. 2015;166(1–3):187–193. [DOI] [PubMed] [Google Scholar]
  • 40. Samara MT, Klupp E, Helfer B, Rothe PH, Schneider-Thoma J, Leucht S. Increasing antipsychotic dose for non response in schizophrenia. Cochrane Database Syst Rev. 2018;5:CD011883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Samara MT, Klupp E, Helfer B, Rothe PH, Schneider-Thoma J, Leucht S. Increasing antipsychotic dose versus switching antipsychotic for non response in schizophrenia. Cochrane Database Syst Rev. 2018;5:CD011883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Samara MT, Leucht C, Leeflang MM, et al.  Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry. 2015;172(7):617–629. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

sbaa063_suppl_Supplemental_figure_1
Click here for additional data file. (141.5KB, docx)
sbaa063_suppl_Supplemental_table_1
Click here for additional data file. (37.4KB, pdf)

Articles from Schizophrenia Bulletin are provided here courtesy of Oxford University Press

RESOURCES