Site maintenance Wednesday, November 13th, 2024. Please note that access to some content and account information will be unavailable on this date.
Skip to main content

Abstract

Objective:

This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses.

Methods:

The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation (“acceptability”). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation).

Results:

Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone).

Conclusions:

LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.
Long-acting injectable (LAI) antipsychotics allow for a complete tracking of adherence and decrease the risk of misuse (14). Although they can be perceived as a last-resort option (5, 6), a broader and earlier use of LAIs has been emphasized in recent evidence-based guidelines (710), mainly based on the growing evidence of their effectiveness in preventing relapse and rehospitalization (2, 3, 11, 12), the well-established data on the negative consequences of poor adherence during the early phases of psychosis (13, 14), and their possible role in relieving the daily burden of oral antipsychotic administration (15, 16). However, although existing guidelines consider LAIs to be an important option for the maintenance treatment of schizophrenia, they do not provide any clear suggestion on which should be considered as first-choice options. Pragmatically, the U.K. National Institute for Health and Care Excellence recommends the use of the same criteria that are applied for the choice of oral antipsychotics (7), but this guidance does not consider practical differences in the administration modalities of individual LAIs that may account for different efficacy and acceptability profiles (e.g., long compared with short intervals of administration, the need for oral supplementation in the first few weeks of LAI administration, the need for monitoring after administration, or local pain) (1). Further, pharmacokinetic and pharmacodynamic differences between oral and LAI formulations may account for different efficacy and tolerability profiles (4, 17). Existing systematic reviews and meta-analyses have focused mainly on the comparison between oral and LAI antipsychotics, generally sorted into broad and heterogeneous groups (2, 3, 18, 19), without considering the different clinical profiles of the various LAIs. Randomized controlled trials comparing two or more LAIs in people with schizophrenia and other nonaffective psychosis have provided conflicting results (20, 21). Based on these considerations, we conducted a network meta-analysis to assess the differential efficacy and acceptability of individual LAIs among people with nonaffective psychoses.

Methods

This study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines specific for network meta-analysis (22) (see Supplement A in the online supplement). The study protocol was registered in advance in PROSPERO (International Prospective Register of Systematic Reviews; registration number: CRD42019120240).

Study Selection and Data Extraction

We searched for randomized controlled trials that included adults (≥18 years old) who were diagnosed with a nonaffective psychotic disorder according to any validated diagnostic criteria and who required antipsychotic maintenance treatment. No time or language restrictions were applied. All available LAIs, according to the Anatomical Therapeutic Chemical (ATC) classification system of the World Health Organization (WHO) (https://www.whocc.no/atc_ddd_index), were eligible. Although the ultimate goal of this review was to compare LAIs with one another, we also included studies comparing LAIs with placebo and with oral antipsychotics to develop a more informative network of comparisons. First-generation oral antipsychotics were grouped according to chemical classes as defined by the ATC. We excluded studies comparing oral antipsychotics head to head or against placebo, considering clinical differences relative to LAI randomized controlled trials and also considering the risk of violating the transitivity assumption required for network meta-analyses (23). Studies comparing LAIs with a mixture of oral antipsychotics were also excluded. Finally, as relapse was a primary outcome, we excluded randomized controlled trials lasting <12 weeks, as has been suggested (24).
We searched the electronic databases MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL; online trial registers (e.g., ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform); and databases of regulatory agencies and pharmaceutical companies. We searched records from database inception to June 8, 2020 (for the full search strategy, see Supplement B in the online supplement). Two of us (G.O., F.B.) independently assessed titles, abstracts, and full texts of potentially relevant articles and extracted data following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (25). Two of us (F.B., C.G.) assessed the methodological quality of included studies using the Cochrane risk of bias tool. Disagreements were resolved by discussion and consensus with a third author (C.B.).

Outcomes

Two primary outcomes were considered: the number of patients who experienced at least one study-defined relapse by the end of the trial, as a proportion of the total number of patients who underwent randomized assignment (indicated as “relapse”); and the number of patients who dropped out by the end of the trial for any cause, as a proportion of the total number of patients who underwent randomized assignment (indicated as “acceptability”).
Secondary outcomes included the mean change in scores on validated rating scales measuring psychopathology at study endpoint (“efficacy”), the number of patients who dropped out by study endpoint because of any adverse event (“tolerability”), and the mean change in scores on validated rating scales measuring quality of life at the end of the trial. Additional secondary outcomes, not included in the original protocol, were analyzed to provide further results on efficacy and side effects and were regarded as merely exploratory. These included functioning, hospitalization, sedation, QTc prolongation, weight gain, hyperprolactinemia, and extrapyramidal symptoms.

Statistical Analysis

We performed a standard pairwise random-effects meta-analysis for every comparison and, for each outcome, a network meta-analysis with a random-effects model in a frequentist framework, using the Stata mvmeta package. For dichotomous outcomes, we calculated and pooled relative risks with 95% confidence intervals. For continuous outcomes, we pooled the mean differences between treatment arms at the end of the study if all trials used the same rating scale; otherwise, we pooled standardized mean differences. We calculated dichotomous data on a strict intention-to-treat basis, considering as the denominator the total number of patients who underwent random assignment. For continuous variables, we applied a modified intention-to-treat analysis, whereby participants with at least one postbaseline measurement were represented by their last observations carried forward. The two primary outcomes were tested independently, without applying correction for multiple testing, as recommended by the Cochrane Handbook (26).
When a study included different arms of the same antipsychotic (LAI or oral) at different doses, we pooled these arms into a single one (25), provided that they were administered within a therapeutic dose range (27, 28). Very low doses of antipsychotics were considered as pseudo placebo, as endorsed by regulatory agencies (29), and were pooled together with placebo in the analysis. Furthermore, considering their pharmacological similarity (30), fluphenazine enanthate and decanoate, as well as clopenthixol and zuclopenthixol decanoate, were pooled together.
We asked trial authors to supply missing data or, alternatively, we imputed data with validated statistical methods (25). We calculated missing standard deviations based on the standard error, t statistics, or p values (31). If this was not possible, we substituted missing standard deviations with a mean of those reported in the other included trials (32). As a last option, we used the standard deviation of the mean baseline score. Missing data for relapse were imputed according to commonly used cutoff scores of validated rating scales (namely, an increase ≥25% on scores on the Positive and Negative Syndrome Scale [PANSS], an increase ≥30% on scores on the Brief Psychiatric Rating Scale [BPRS], and an increase ≥2 points on scores on the Clinical Global Impressions severity scale [CGI-S]) (3335), using a validated methodology (36).
For pairwise meta-analyses, we assessed heterogeneity by visual inspection of forest plots and by I2 statistics. For the network meta-analysis, common heterogeneity across all comparisons was assumed and estimated in each network (37).
We evaluated the assumption of transitivity by extracting potential effect modifiers (e.g., blinding, sample size, follow-up length, antipsychotic doses) and comparing their distribution across comparisons in the network.
We evaluated the presence of incoherence by comparing direct and indirect evidence within each closed loop (38) and comparing the goodness of fit for a network meta-analysis model that assumes consistency with a model that allows for incoherence in a design-by-treatment framework (3941), using the Stata commands mvmeta and ifplot (42, 43) and the Stata network suite (44). Incoherence was further investigated through node-splitting (45) and side-splitting (44) approaches between comparisons.
For the primary outcomes, we produced a treatment hierarchy by means of surface under the cumulative ranking curve (SUCRA) and mean ranks (46).
If ≥10 studies were included in a primary outcome, we assessed publication bias by visually inspecting the funnel plot, testing for asymmetry with the Egger’s regression test (47), and investigating possible reasons for funnel plot asymmetry.
For each primary outcome, we assessed the certainty of evidence from network meta-analyses through the CINeMA application (https://cinema.ispm.ch), an adaptation of the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) (23, 48).
Finally, for each primary outcome, we conducted four sensitivity analyses excluding trials that did not employ a double-blind design; trials that compared LAIs with placebo; trials that involved ≤50 participants and were published before 1990; and trials that had a high risk of bias (i.e., ≥3 risk of bias items at “high risk”).

Results

Characteristics of Included Studies

Our database and manual searches identified 4,368 records. After removing duplicates and examining titles and abstracts, we selected 285 records for full-text assessment. Of these, 86 studies (49134) (corresponding to 141 full-text articles) were eligible for inclusion. Of these studies, 78 (90.7%), which included 11,505 participants and 12 different LAIs, provided data for one or more outcomes of interest (see the PRISMA flowchart in Supplement C, as well as the list of included and excluded studies in Supplement D, in the online supplement).
Included studies were published across 50 years (1968 to 2018), and 43 (50%) were published before 1990 (for characteristics of included studies, see Supplement E in the online supplement). Forty-three studies (50%) compared LAIs head to head. Nineteen studies (22.1%) included placebo, and two studies (2.3%) included very low doses of LAIs, which were regarded as pseudo placebo (73, 91). In all cases, placebo was administered in an injectable form. Twenty-six studies (30.2%) included an oral antipsychotic comparator. Four studies (4.7%) had a three-arm design, and three (3.5%) had multiple arms that included different doses of LAIs (73, 91, 92). The mean follow-up length was 40.5 weeks (range=12–104). Sixty-six studies (76.7%) were double-blind, and the remaining were open-label, except for four studies where this information was missing. Overall, 12,065 individuals were included (range=12–1,065), with 36 studies (41.9%) including ≤50 participants. The mean age of included participants was 39.8 years (range=21.5–57.1). Four studies included only men. In the remaining studies, the mean proportion of included women was 40.1% (range=11.1%−83.3%). Most studies included only people with schizophrenia (86%), although three studies had additional inclusion criteria: patients whose symptoms were “highly resistant to treatment” (119), patients with comorbid alcohol abuse (79), and patients with comorbid obesity (60). One study included only patients with schizoaffective disorder (74), and the remaining nine studies (10.5%) included participants with various nonaffective psychosis diagnoses. In one of them, 11% of participants had bipolar disorder with psychotic features (62). Notably, diagnostic criteria varied between studies, reflecting the large time frame in which the studies were conducted. The most frequently employed diagnostic manuals were DSM-IV (16.3%) and DSM-III (12.8%). A high risk of attrition bias, reporting bias, and sponsorship bias emerged for several of the included studies (see Supplement F in the online supplement).

Primary Outcomes

The characteristics of studies included in the two primary outcome analyses are summarized in Table 1, and the corresponding network plots are shown in Figure 1. Every LAI was included in at least one closed loop. The results of the network meta-analysis for individual LAIs for the primary outcomes are shown in Figure 2 in the form of a net league table. For primary and secondary outcomes, all standard pairwise meta-analyses, network meta-analyses, and assessments of heterogeneity and incoherence are reported in the online supplement.
TABLE 1. Characteristics of randomized controlled trials included in each network of primary outcomes in a meta-analysis of long-acting injectable (LAI) antipsychotics for nonaffective psychoses
CharacteristicRelapse NetworkAcceptability Network
Number of studies6974
Number of patients included11,17611,385
MeanSDMeanSD
Age (years)4012.73912.7
N%N%
Women3,66332.83,70032.5
Study follow-up duration
 12–26 weeks2231.92635.1
 27–52 weeks3550.73547.3
 ≥53 weeks1217.41317.6
Study blinding
 Double-blind5275.41520.3
 Open-label1521.75574.3
 Unclear or not reported22.945.4
Year of publication
 Through 19893246.43547.3
 1990–20091826.12027
 2010–20191927.61925.7
Type of comparison
 LAI compared with placebo1826.12027
 LAI compared with oral antipsychotics2536.22432.4
 LAI compared with LAI2536.22939.2
 LAI compared with oral antipsychotics and placebo11.511.4
Setting
 Inpatient1521.71520.3
 Outpatient3550.73851.3
 Mixed1420.31418.9
 Unclear or not reported57.379.5
FIGURE 1. Network plots of evidence for relapse and acceptability in a meta-analysis of long-acting injectable (LAI) antipsychotics for nonaffective psychosesa
a The thickness of lines is proportional to the precision of each direct estimate, and the size of circles is proportional to the number of studies that included the treatment. The N indicates the number of participants who were randomly assigned to each treatment, and the phenothiazines are fluphenazine, trifluoperazine, and chlorpromazine. DBP=diphenylbutylpiperidine derivatives (pimozine, penfluridol).
FIGURE 2. Net league table of head-to-head comparisons for relapse and acceptability in a meta-analysis of long-acting injectable (LAI) antipsychotics for nonaffective psychosesa
a Relative risks and 95% confidence intervals are reported. For both relapse and acceptability, relative risks lower than 1 favor the column-defining treatment. Treatments are ordered alphabetically. Statistically significant results are in boldface.

Relapse.

The following LAIs (ordered from the largest to the smallest point estimate) were significantly more effective than placebo: paliperidone (3-month formulation) (relative risk=0.27, 95% CI=0.17–0.42), aripiprazole (relative risk=0.29, 95% CI=0.21–0.39), flupenthixol (relative risk=0.32, 95% CI=0.16–0.65), fluphenazine (relative risk=0.34, 95% CI=0.24–0.48), risperidone (relative risk=0.34, 95% CI=0.23–0.52), pipothiazine (relative risk=0.35, 95% CI=0.20–0.62), olanzapine (relative risk=0.37, 95% CI=0.26–0.53), paliperidone (1-month formulation) (relative risk=0.39, 95% CI=0.30–0.50), and haloperidol (relative risk=0.57, 95% CI=0.33–0.97) (Figure 3). Head-to-head comparisons showed paliperidone (3-month formulation), aripiprazole, and fluphenazine to be more effective than haloperidol (Figure 2). No relevant heterogeneity emerged from pairwise comparisons (i.e., I2>50%), and the network did not show significant overall heterogeneity (estimated between-studies standard deviation, 0.07) or overall incoherence (design-by-treatment test, p=0.45). Intraloop incoherence emerged for four loops, all of them involving placebo and haloperidol. Results of the network meta-analyses were consistent with results from pairwise meta-analyses, except for the comparisons between haloperidol and placebo (favoring the latter in the direct estimate) and between fluphenazine and haloperidol (not significant in the direct estimate). Generally, there was statistical agreement between direct and indirect estimates, except for four comparisons: fluphenazine, haloperidol, and paliperidone (3-month formulation) relative to placebo, and paliperidone (1-month formulation) relative to paliperidone (3-month formulation).
FIGURE 3. Forest plots comparing each long-acting injectable (LAI) antipsychotic with placebo for relapse and acceptability with the corresponding ranking probability and certainty of evidence, as assessed with the CINeMA appraisal, for each intervention in a meta-analysis of LAIs for nonaffective psychosesa
a Statistically significant results appear in green. Values below 1 favor LAI antipsychotics. The ranking probability was assessed by SUCRA (surface under the cumulative ranking curve), and the certainty of evidence was assessed by GRADE (Grading of Recommendations Assessment, Development, and Evaluation).
Paliperidone (3-month formulation), aripiprazole, and flupenthixol ranked best according to the mean SUCRA. Compared with placebo, the certainty of evidence was “high” for paliperidone (3-month formulation) and paliperidone (1-month formulation) and was “moderate” for aripiprazole, risperidone, pipothiazine, and olanzapine. The certainty of evidence was also “moderate” for the comparison between paliperidone (3-month formulation) and paliperidone (1-month formulation), while it was “very low” or “low” for most comparisons because of within-study bias, which includes high risk of reporting bias, attrition bias, and sponsorship bias (see Figure 3 and Supplement G in the online supplement). The results of sensitivity analyses generally confirmed those of the primary analysis, but they suggested that placebo-controlled studies might have been responsible for most of the observed intraloop incoherence. Further, statistical disagreement between direct and indirect estimates disappeared after placebo-controlled studies were removed from the analysis (see Supplements H–K in the online supplement).

Acceptability.

The following LAIs (ordered from the largest to the smallest point estimate) were significantly more acceptable than placebo: (zu)clopenthixol (relative risk=0.33, 95% CI=0.13–0.84), aripiprazole (relative risk=0.49, 95% CI=0.41–0.58), paliperidone (3-month formulation) (relative risk=0.60, 95% CI=0.43–0.84), olanzapine (relative risk=0.62, 95% CI=0.48–0.79), flupenthixol (relative risk=0.62, 95% CI=0.44–0.89), haloperidol (relative risk=0.64, 95% CI=0.50–0.81), fluphenazine (relative risk=0.67, 95% CI=0.55–0.81), risperidone (relative risk=0.70, 95% CI=0.57–0.85), paliperidone (1-month formulation) (relative risk=0.70, 95% CI=0.58–0.85), and pipothiazine (relative risk=0.73, 95% CI=0.56–0.96) (Figure 3). Head-to-head comparisons showed aripiprazole to be significantly superior to bromperidol, fluphenazine, paliperidone (1-month formulation), pipothiazine, and risperidone (Figure 2). Moderate heterogeneity was detected for three pairwise comparisons (olanzapine LAI relative to olanzapine oral formulation, placebo relative to haloperidol LAI, and fluphenazine LAI relative to oral formulations of phenothiazines), although the network did not show significant overall heterogeneity (estimated between-studies standard deviation, 0.08) or overall incoherence (design-by-treatment test, p=0.22). The test for intraloop incoherence was statistically significant for the loop including placebo, haloperidol LAI, and paliperidone LAI (1-month formulation). Results of the network meta-analyses were consistent with those from pairwise meta-analyses, except for haloperidol and pipothiazine relative to placebo and aripiprazole relative to paliperdone (1-month formulation) (not significant in the direct estimate). There was statistical agreement between direct and indirect estimates, except for haloperidol and paliperidone (1-month formulation) relative to placebo. Among those LAIs significantly superior to placebo, (zu)clopenthixol, aripiprazole, and paliperidone (3-month formulation) ranked best according to the SUCRA. Compared with placebo, the certainty of evidence was “high” for paliperidone (3-month formulation) and “moderate” for (zu)clopenthixol, aripiprazole, olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). For most of the head-to-head comparisons, the certainty of evidence was “very low” or “low” because of within-study bias and imprecision of results (see Figure 3 and Supplement L in the online supplement). Results of sensitivity analyses generally confirmed those of the primary analysis, but they suggested that placebo-controlled studies and older and smaller studies may have been responsible for most of the observed intraloop incoherence and that studies with high overall risk of bias also contributed to the overall incoherence of the network. Statistical disagreement between direct and indirect estimates disappeared after placebo-controlled studies were removed from the analysis (see Supplements M–P in the online supplement).

Secondary Outcomes

Regarding dropouts due to adverse events (tolerability), paliperidone (1-month formulation) was less tolerable than placebo, while for other LAIs, no differences relative to placebo emerged (Figure 4). Aripiprazole was more tolerable than paliperidone (1-month formulation), and no other significant differences emerged in head-to-head comparisons. No relevant overall heterogeneity and incoherence and no intraloop incoherence emerged for this network (see Supplement Q in the online supplement).
FIGURE 4. Net league table of head-to-head comparisons for tolerability and efficacy in a meta-analysis of long-acting injectable (LAI) antipsychotics for nonaffective psychosesa
a For tolerability, relative risks and 95% confidence intervals are reported. Relative risks lower than 1 favor the column-defining treatment. For efficacy, standardized mean differences and 95% confidence intervals are reported. Standardized mean differences lower than 0 favor the column-defining treatment. Treatments are ordered alphabetically. Statistically significant results are in boldface.
Regarding efficacy measured as the change in mean scores, the following LAIs, ordered from the largest to the smallest point estimate, were significantly superior to placebo: perphenazine, pipothiazine, risperidone, aripiprazole, haloperidol, fluphenazine, and paliperidone (1-month formulation). No significant differences emerged from head-to-head comparisons (Figure 4). Significant overall heterogeneity and incoherence emerged, related to relevant heterogeneity in some pairwise comparisons and intraloop incoherence, mostly involving placebo, haloperidol, aripiprazole, and fluphenazine. There was statistical agreement between direct and indirect estimates (see Supplement R in the online supplement).
Regarding quality of life, data were available for three LAIs only (aripiprazole, risperidone, and the 1-month formulation of paliperidone), and placebo was not included. The network had no triangular or quadratic loops. In head-to-head comparisons, aripiprazole was superior to paliperidone (1-month formulation). Significant overall heterogeneity and incoherence emerged for this network, related to the very high heterogeneity for the comparison between aripiprazole and paliperidone (1-month formulation). There was statistical agreement between direct and indirect estimates (see Supplement S in the online supplement).
For some of the additional secondary outcomes (namely, functioning, QTc prolongation, and sedation), the network meta-analysis could not be performed because one loop was formed of a three-arm trial and there were too few studies per comparison. For these outcomes, only pairwise meta-analyses were performed, but no significant differences between treatments emerged, with the exception that paliperidone (3-month formulation) showed better functioning than placebo and lower risk of QTc prolongation than paliperidone (1-month formulation), both based on results from one study only (see Supplements T–V in the online supplement). The other secondary analyses showed, with LAIs ordered from the largest to the smallest point estimate, significantly lower hospitalization rates for aripiprazole, paliperidone (3-month formulation), haloperidol, fluphenazine, and paliperidone (1-month formulation) compared with placebo (see Supplement W in the online supplement); significantly higher weight gain for paliperidone (1-month formulation), paliperidone (3-month formulation), and aripiprazole compared with placebo (see Supplement X in the online supplement); and significantly higher risk of hyperprolactinemia for paliperidone (1-month formulation), paliperidone (3-month formulation), and olanzapine compared with placebo (see Supplement Y in the online supplement). No LAIs showed a significantly higher risk of extrapyramidal symptoms relative to placebo (see Supplement Z in the online supplement).

Discussion

In this network meta-analysis, most LAIs were superior to placebo in preventing relapse and were significantly more acceptable than placebo. For both of these primary outcomes, most LAIs had fairly similar effect sizes, and no relevant differences emerged when they were compared head to head, except for aripiprazole, which performed particularly well against other LAIs regarding acceptability. Importantly, the certainty of evidence was moderate or high for a number of LAIs, particularly second-generation LAIs. However, only the 3-month formulation of paliperidone, the 1-month formulation of paliperidone, aripiprazole, and olanzapine were supported by a moderate to high certainty of evidence in both primary outcomes and therefore can be regarded as reasonable first-line maintenance treatments in people with schizophrenia and related nonaffective psychosis. In general, these findings were confirmed by secondary analyses, such as efficacy measured via rating scales, hospitalization rates, and tolerability outcomes, although data on quality of life and functioning were lacking. The 3-month formulation of paliperidone and aripiprazole LAI were among the best performing treatments against placebo in many analyses and had very high SUCRA rankings in both primary outcomes.
The analysis of individual adverse events, although limited by relatively few and heterogeneous data, confirmed that weight gain and hyperprolactinemia may be relevant also for those LAIs with good overall acceptability and tolerability (i.e., paliperidone [1- and 3-month formulations], aripiprazole, and olanzapine).
The findings of this network meta-analysis are consistent with those from the largest randomized trials comparing LAIs head to head (106, 112, 118) and with large observational studies that analyzed the efficacy of individual LAIs in preventing rehospitalization (11, 135).
To our knowledge, this is the first comparison of individual LAIs using a network meta-analysis methodology. This approach allowed comparisons of LAIs for which no direct evidence was available while avoiding questionable pooled subgroups (i.e., first- or second-generation LAIs) and obtaining more precise estimates. The primary analyses included more than 11,000 participants, making this the largest meta-analysis conducted on LAIs to date. Furthermore, estimates for dichotomous outcomes are conservative, as they were calculated considering the total number of patients who underwent randomized assignment in the denominator.
Despite these strengths, several limitations should be considered when interpreting the results. First, although we aimed to evaluate the ability of LAIs in preventing relapse in patients already stabilized, for some randomized controlled trials, stabilization was not clearly described. Therefore, several factors were considered as proxy measures of stabilization (e.g., the PANSS score at recruitment), which may lack precision. Second, included randomized controlled trials were published across a long time span and therefore are heterogeneous in terms of methodology, diagnostic criteria, follow-up periods, and outcomes. Despite that, overall coherence appeared to be well preserved for most analyses. Third, for a relevant number of studies, important information was lacking, and imputation methods had to be employed. Although this is an acceptable approximation in most cases (32), some degree of imprecision cannot be excluded. Fourth, placebo-controlled studies may suffer from intrinsic limitations (20, 136), in particular, the selection of relatively well-stabilized patients. The sensitivity analyses that removed these studies confirmed that placebo-controlled studies may have introduced some overall heterogeneity and incoherence, although overall results did not change substantially. Placebo-controlled studies of paliperidone (3-month formulation) may be of particular concern, considering that patients in these studies underwent a stabilization phase with paliperidone (1-month formulation) before randomization to the 3-month formulation or placebo. This study design may have inflated the effect size of the 3-month formulation of paliperidone by using a particularly enriched sample for benefit and tolerability in patients ultimately randomized to the placebo discontinuation phase of the study. Fifth, risk of bias was relatively high for many studies, particularly regarding attrition, reporting, and sponsorship biases. However, a sensitivity analysis showed that primary outcomes did not relevantly change after removing these studies. Sixth, some secondary outcomes, such as quality of life, functioning, and common adverse events, which might play a relevant role in helping clinicians to tailor LAIs to individual patients, were poorly reported by the original studies, leading to poorly populated and connected networks, high imprecision, and heterogeneity. These outcomes were not originally included in the protocol and were regarded as merely exploratory. Nevertheless, a meta-analysis found that LAIs and their corresponding oral antipsychotics did not differ significantly in 97% of the 119 analyzed adverse effects (137). Seventh, as no comparison included ≥10 studies, the risk of publication bias could not be ruled out. Considering that we included only one unpublished trial (87) and that many data from old studies were included, publication bias cannot be completely excluded, although it is expected to be less relevant compared with studies of other classes of psychotropic drugs (138). Lastly, the network meta-analytic approach is not free from technical and theoretical shortcomings, including the risk related to multiple statistical assumptions and the challenges in addressing the problem of intransitivity and incoherence (139).
The findings of this network meta-analysis have relevant implications for policy and research. Current guidelines emphasize the importance of considering LAIs for maintenance treatment of patients who might prefer this formulation for practical reasons, that is, those in the earliest illness phases and those with adherence problems (710). However, no clear indication is provided on which LAIs should be considered the first-choice options. Guidelines from the U.K. National Institute for Health and Care Excellence suggest following the same criteria used for oral antipsychotics, but it is unclear whether the efficacy and tolerability of the two formulations are identical (4, 11, 135, 137, 140), and results from this network meta-analysis suggest that LAI characteristics, such as the time between administrations, might play a relevant role. Results from this study can help clinicians in tailoring the choice of LAI even from the first episode of psychosis, considering the impact of a successful maintenance treatment on long-term outcomes (141). From a global health standpoint, it is relevant to consider that the WHO Model List of Essential Medicines (142) includes only fluphenazine as an LAI formulation, although this medication is no longer regularly supplied globally, causing a disservice for the most vulnerable populations (i.e., those in low- and middle-income countries and humanitarian settings). Therefore, we argue that results from this network meta-analysis should rapidly inform the update of guidelines from the WHO and other organizations, with the aim of informing and improving psychiatric care worldwide.
Large, pragmatic, and high-quality head-to-head studies comparing LAIs are needed to overcome the methodological limitations mentioned above, including the lack of information on functioning, quality of life, common adverse events, and cost-effectiveness. Further, studies recruiting patients after the first episode of psychosis are needed to confirm the clinical utility of LAIs when utilized from the earliest phases of the disease, reversing the paradigm of LAIs as treatments reserved for patients with the most severe and chronic forms of illness.

Acknowledgments

The authors thank Dr. Ying Wang (Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing) for helping translate Chinese articles and Dr. Farhad Shokraneh (Cochrane Schizophrenia Group, Divisions of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham) and Dr. Gian Paolo Morgano (Department of Health Research Methods, Evidence, and Impact, McMaster University Health Sciences Centre) for helping with the retrieval of full-text articles.

Footnote

Dr. Correll has been a consultant and/or adviser to or has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/Johnson & Johnson, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva; he has provided expert testimony for Janssen and Otsuka; he has served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; he has received grant support from the Berlin Institute of Health, Janssen, NIMH, the Patient-Centered Outcomes Research Institute, Takeda, and the Thrasher Foundation; he has received royalties from UpToDate; and he holds stock options in LB Pharma. The other authors report no financial relationships with commercial interests.

Supplementary Material

File (appi.ajp.2020.20071120.ds001.pdf)

References

1.
Correll CU, Citrome L, Haddad PM, et al : The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry 2016 ; 77 ( suppl 3 ): 1 – 24
2.
Kishimoto T, Hagi K, Nitta M, et al : Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull 2018 ; 44 : 603 – 619
3.
Kishimoto T, Nitta M, Borenstein M, et al : Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry 2013 ; 74 : 957 – 965
4.
Ostuzzi G, Bighelli I, So R, et al : Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies. Schizophr Res 2017 ; 183 : 10 – 21
5.
Narasimhan M, Un Pae C, Masand N, et al : Partial compliance with antipsychotics and its impact on patient outcomes. Int J Psychiatry Clin Pract 2007 ; 11 : 102 – 111
6.
Brissos S, Veguilla MR, Taylor D, et al : The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol 2014 ; 4 : 198 – 219
7.
National Institute for Health and Care Excellence (NICE): Psychosis and schizophrenia in adults: prevention and management. National clinical guideline number 178. London, NICE, 2014. https://www.nice.org.uk/guidance/cg178
8.
American Psychiatric Association: The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Washington, DC, American Psychiatric Association Publishing, 2020. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Clinical%20Practice%20Guidelines/APA-Draft-Schizophrenia-Treatment-Guideline-Dec2019.pdf
9.
Remington G, Addington D, Honer W, et al : Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry 2017 ; 62 : 604 – 616
10.
Galletly C, Castle D, Dark F, 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 2016 ; 50 : 410 – 472
11.
Tiihonen J, Mittendorfer-Rutz E, Majak M, et al : Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry 2017 ; 74 : 686 – 693
12.
Schreiner A, Aadamsoo K, Altamura AC, et al : Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res 2015 ; 169 : 393 – 399
13.
Stahl SM : Long-acting injectable antipsychotics: shall the last be first? CNS Spectr 2014 ; 19 : 3 – 5
14.
Correll CU, Rubio JM, Kane JM : What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 2018 ; 17 : 149 – 160
15.
Pietrini F, Albert U, Ballerini A, et al : The modern perspective for long-acting injectables antipsychotics in the patient-centered care of schizophrenia. Neuropsychiatr Dis Treat 2019 ; 15 : 1045 – 1060
16.
Kane JM, Correll CU : Optimizing treatment choices to improve adherence and outcomes in schizophrenia. J Clin Psychiatry 2019 ; 80 : IN18031AH1C
17.
Ereshefsky L, Mascarenas CA : Comparison of the effects of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics. J Clin Psychiatry 2003 ; 64 ( Suppl 16 ): 18 – 23
18.
Leucht C, Heres S, Kane JM, et al : Oral versus depot antipsychotic drugs for schizophrenia: a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 2011 ; 127 : 83 – 92
19.
Kishimoto T, Robenzadeh A, Leucht C, et al : Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull 2014 ; 40 : 192 – 213
20.
Ostuzzi G, Barbui C : Comparative effectiveness of long-acting antipsychotics: issues and challenges from a pragmatic randomised study. Epidemiol Psychiatr Sci 2016 ; 25 : 21 – 23
21.
Gentile S : Discontinuation rates during long-term, second-generation antipsychotic long-acting injection treatment: a systematic review. Psychiatry Clin Neurosci 2019 ; 73 : 216 – 230
22.
Hutton B, Salanti G, Caldwell DM, et al : The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 2015 ; 162 : 777 – 784
23.
Salanti G, Del Giovane C, Chaimani A, et al : Evaluating the quality of evidence from a network meta-analysis. PLoS One 2014 ; 9 : e99682
24.
Miura T, Noma H, Furukawa TA, et al : Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. Lancet Psychiatry 2014 ; 1 : 351 – 359
25.
Higgins JPT, Thomas J, Chandler J, et al. (eds): Cochrane Handbook for Systematic Reviews of Interventions, 2nd ed. Chichester, UK, John Wiley & Sons, 2019
26.
Higgins JPT, Deeks JJ, Altman DG (eds): Multiplicity in systematic reviews, in Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. Edited by Higgins JPT, Green S. Chichester, UK, John Wiley & Sons, 2011
27.
Gardner DM, Murphy AL, O’Donnell H, et al : International consensus study of antipsychotic dosing. Am J Psychiatry 2010 ; 167 : 686 – 693
28.
Leucht S, Samara M, Heres S, et al : Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull 2014 ; 40 : 314 – 326
29.
European Medicines Agency Committee for Medicinal Products for Human Use (CHMP): Assessment report: Abilify Maintena (EMA/737723/2013). 2013. https://www.ema.europa.eu/en/documents/assessment-report/abilify-maintena-epar-public-assessment-report_en.pdf
30.
Lambert TT : Antipsychotic Long-Acting Injections, 2nd ed. Oxford, UK, Oxford University Press, 2016
31.
Altman DG, Bland JM : Detecting skewness from summary information. BMJ 1996 ; 313 : 1200
32.
Furukawa TA, Barbui C, Cipriani A, et al : Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 2006 ; 59 : 7 – 10
33.
Wang D, Gopal S, Baker S, et al : Trajectories and changes in individual items of Positive and Negative Syndrome Scale among schizophrenia patients prior to impending relapse. NPJ Schizophr 2018 ; 4 : 10
34.
Leucht S, Rothe P, Davis JM, et al : Equipercentile linking of the BPRS and the PANSS. Eur Neuropsychopharmacol 2013 ; 23 : 956 – 959
35.
Correll CU, Kishimoto T, Nielsen J, et al : Quantifying clinical relevance in the treatment of schizophrenia. Clin Ther 2011 ; 33 : B16 – B39
36.
Furukawa TA, Cipriani A, Barbui C, et al : Imputing response rates from means and standard deviations in meta-analyses. Int Clin Psychopharmacol 2005 ; 20 : 49 – 52
37.
Lu G, Ades AE : Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004 ; 23 : 3105 – 3124
38.
Bucher HC, Guyatt GH, Griffith LE, et al : The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997 ; 50 : 683 – 691
39.
Higgins JP, Jackson D, Barrett JK, et al : Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 2012 ; 3 : 98 – 110
40.
Veroniki AA, Vasiliadis HS, Higgins JP, et al : Evaluation of inconsistency in networks of interventions. Int J Epidemiol 2013 ; 42 : 332 – 345
41.
Jackson D, Barrett JK, Rice S, et al : A design-by-treatment interaction model for network meta-analysis with random inconsistency effects. Stat Med 2014 ; 33 : 3639 – 3654
42.
Chaimani A, Higgins JP, Mavridis D, et al : Graphical tools for network meta-analysis in STATA. PLoS One 2013 ; 8 : e76654
43.
White I : Multivariate random-effects meta-regression: updates to mvmeta. Stata J 2011 ; 11 : 255 – 270
44.
White IR : Meta-Analysis in Stata: An Updated Collection From the Stata Journal, 2nd ed. Edited by Palmer TM, Sterne JAC. College Station, Tex, Stata Press, 2016
45.
Yu-Kang T : Node-splitting generalized linear mixed models for evaluation of inconsistency in network meta-analysis. Value Health 2016 ; 19 : 957 – 963
46.
Salanti G, Ades AE, Ioannidis JP : Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 2011 ; 64 : 163 – 171
47.
Egger M, Davey Smith G, Schneider M, et al : Bias in meta-analysis detected by a simple, graphical test. BMJ 1997 ; 315 : 629 – 634
48.
Nikolakopoulou A, Higgins JPT, Papakonstantinou T, et al : CINeMA: an approach for assessing confidence in the results of a network meta-analysis. PLoS Med 2020 ; 17 : e1003082
49.
Albert JM, Elie R, Cooper SF : Long term double-blind evaluation of pipotiazine palmitate and fluphenazine decanoate. Curr Ther Res Clin Exp 1980 ; 27 : 897 – 907
50.
Bai YM, Ting Chen T, Chen JY, et al : Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study. J Clin Psychiatry 2007 ; 68 : 1218 – 1225
51.
Barnes TR, Milavic G, Curson DA, et al : Use of the Social Behaviour Assessment Schedule (SBAS) in a trial of maintenance antipsychotic therapy in schizophrenic outpatients: pimozide versus fluphenazine. Soc Psychiatry 1983 ; 18 : 193 – 199
52.
Bechelli LPC, Iecco MC, Acioli A, et al : A double-blind trial of haloperidol decanoate and pipothiazine palmitate in the maintenance treatment of schizophrenics in public out-patient clinic. Curr Ther Res Clin Exp 1986 ; 37 : 662 – 671
53.
Berwaerts J, Liu Y, Gopal S, et al : Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2015 ; 72 : 830 – 839
54.
Bozzatello P, Bellino S, Mancini I, et al : Effects on satisfaction and service engagement of paliperidone palmitate compared with oral paliperidone in patients with schizophrenia: an open label randomized controlled trial. Clin Drug Investig 2019 ; 39 : 169 – 178
55.
Chai XSWJ, Liu XY, Ju HZ, et al : A comparison trial of pipotiazine palmitate, haloperidol decanoate and flupenthixol decanoate in treatment of schizophrenic patients. Chinese Journal of Psychiatry 1998 ; 31 : 218 – 221
56.
Chouinard G, Annable L, Campbell W, et al : A double-blind, controlled clinical trial of haloperidol decanoate and fluphenazine decanoate in the maintenance treatment of schizophrenia. Psychopharmacol Bull 1984 ; 20 : 108 – 109
57.
Chouinard G, Annable L, Kropsky M : A double-blind controlled study of pipothiazine palmitate in the maintenance treatment of schizophrenic outpatients. J Clin Pharmacol 1978 ; 18 : 148 – 154
58.
Chowdhury ME, Chacon C : Depot fluphenazine and flupenthixol in the treatment of stabilized schizophrenics: a double-blind comparative trial. Compr Psychiatry 1980 ; 21 : 135 – 139
59.
Chue P, Eerdekens M, Augustyns I, et al : Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol 2005 ; 15 : 111 – 117
60.
Cookson JC, Kennedy NM, Gribbon D : Weight gain and prolactin levels in patients on long-term antipsychotic medication: a double-blind comparative trial of haloperidol decanoate and fluphenazine decanoate. Int Clin Psychopharmacol 1986 ; 1 ( Suppl 1 ): 41 – 51
61.
Crawford R, Forrest A : Controlled trial of depot fluphenazine in out-patient schizophrenics. Br J Psychiatry 1974 ; 124 : 385 – 391
62.
Cuomo I, Kotzalidis GD, de Persis S, et al : Head-to-head comparison of 1-year aripiprazole long-acting injectable (LAI) versus paliperidone LAI in comorbid psychosis and substance use disorder: impact on clinical status, substance craving, and quality of life. Neuropsychiatr Dis Treat 2018 ; 14 : 1645 – 1656
63.
del Giudice J, Clark WG, Gocka EF : Prevention of recidivism of schizophrenics treated with fluphenazine enanthate. Psychosomatics 1975 ; 16 : 32 – 36
64.
Dencker SJ, Frankenberg K, Malm U, et al : A controlled one-year study of pipotiazine palmitate and fluphenazine decanoate in chronic schizophrenic syndromes: evaluation of results at 6 and 12 months’ trial. Acta Psychiatr Scand Suppl 1973 ; 241 : 101 – 118
65.
Dencker SJ, Giös I, Mårtensson E, et al : A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients. Psychopharmacology (Berl) 1994 ; 114 : 24 – 30
66.
Dencker SJ, Lepp M, Malm U : Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. I. A one year double-blind study of clopenthixol decanoate and flupenthixol palmitate. Acta Psychiatr Scand Suppl 1980 ; 279 : 10 – 28
67.
Detke HC, Weiden PJ, Llorca PM, et al : Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. J Clin Psychopharmacol 2014 ; 34 : 426 – 434
68.
Dotti A, Bersani G, Rubino IA, et al : Studio in doppio cieco della flufenazina decanoato versus placebo nella terapia ambulatoriale di mantenimento di pazienti schizofrenici cronici. Riv Psichiatr 1979 ; 5 : 374 – 383
69.
Eberhard G, Hellbom E : Haloperidol decanoate and flupenthixol decanoate in schizophrenia: a long-term double-blind cross-over comparison. Acta Psychiatr Scand 1986 ; 74 : 255 – 262
70.
Eklund K, Forsman A : Minimal effective dose and relapse: double-blind trial: haloperidol decanoate vs. placebo. Clin Neuropharmacol 1991 ; 14 ( Suppl 2 ): S7 – S12
71.
Eufe R, Wegener G : [Double-blind comparison of 2 depot neuroleptics (perphenazine enanthate and flupentixol decanoate) in chronic schizophrenia.] Nervenarzt 1979 ; 50 : 534 – 539 (German)
72.
Feng L : Double blind controlled trial of haloperidol decanoate and fluphenazine decanoate in chronic schizophrenia. Chinese Journal of Nervous and Mental Disorders 1990 ; 16 : 299
73.
Fleischhacker WW, Sanchez R, Perry PP, et al : Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study. Br J Psychiatry 2014 ; 205 : 135 – 144
74.
Fu DJ, Turkoz I, Simonson RB, et al : Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. J Clin Psychiatry 2015 ; 76 : 253 – 262
75.
Gaebel W, Schreiner A, Bergmans P, et al : Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology 2010 ; 35 : 2367 – 2377
76.
Gitlin M, Nuechterlein K, Subotnik KL, et al : Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001 ; 158 : 1835 – 1842
77.
Gitlin MJ, Midha KK, Fogelson D, et al : Persistence of fluphenazine in plasma after decanoate withdrawal. J Clin Psychopharmacol 1988 ; 8 : 53 – 56
78.
Glick ID, Marder SR : Long-term maintenance therapy with quetiapine versus haloperidol decanoate in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry 2005 ; 66 : 638 – 641
79.
Green AI, Brunette MF, Dawson R, et al : Long-acting injectable vs oral risperidone for schizophrenia and co-occurring alcohol use disorder: a randomized trial. J Clin Psychiatry 2015 ; 76 : 1359 – 1365
80.
Hirsch SR, Gaind R, Rohde PD, et al : Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: double-blind placebo trial: report to the Medical Research Council Committee on Clinical Trials in Psychiatry. BMJ 1973 ; 1 : 633 – 637
81.
Hirsch SR, Knights A, Okasha MS, et al : Maintenance therapy in out-patient schizophrenics: a report of a double-blind trial comparison of fluphenazine decanoate and flupenthixol decanoate (abstract). Br J Psychiatry 1978 ; 133 : 371
82.
Hogarty GE, Schooler NR, Ulrich R, et al : Fluphenazine and social therapy in the aftercare of schizophrenic patients: relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Arch Gen Psychiatry 1979 ; 36 : 1283 – 1294
83.
Hough D, Gopal S, Vijapurkar U, et al : Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2010 ; 116 : 107 – 117
84.
Hranov LG, Yanakiev N, Stefanov S, et al : Haloperidol decanoate and fluphenazine decanoate for schizophrenia: a comparative naturalistic medium-term study of efficacy and tolerability (abstract). Eur Neuropsychopharmacol 1998 ; 8 ( Suppl 2 ): S213
85.
Ishigooka J, Nakamura J, Fujii Y, et al : Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multicenter, randomized, double-blind, non-inferiority study versus oral aripiprazole. Schizophr Res 2015 ; 161 : 421 – 428
86.
Jain RC, Ananth JV, Lehmann HE, et al : A comparative study with pipothiazine palmitate and fluphenazine enanthate in the treatment of schizophrenic patients. Curr Ther Res Clin Exp 1975 ; 18 : 585 – 589
87.
Janssen Korea: An Efficacy and Safety Study of Long Acting Injectable Risperidone and Oral Risperidone in Participants With Schizophrenia or Schizoaffective Disorder. ClinicalTrials.gov identifier: NCT00992407 (https://clinicaltrials.gov/ct2/show/NCT00992407)
88.
Javed MA, Chaudhry MR : Double blind comparison of flupenthixol decanoate and fluphenazine decanoate in the treatment of chronic schizophrenia. Pakistan Journal of Clinical Psychiatry 1991 ; 1 : 69 – 74
89.
Jolley AG, Hirsch SR, Morrison E, et al : Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. BMJ 1990 ; 301 : 837 – 842
90.
Kamijima KI, Komada Y : Comparison study between risperidone long-acting injectable and risperidone tablets in patients with schizophrenia. Jpn J Clin Psychopharmacol 2009 ; 12 : 1199 – 1222
91.
Kane JM, Detke HC, Naber D, et al : Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry 2010 ; 167 : 181 – 189
92.
Kane JM, Eerdekens M, Lindenmayer JP, et al : Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003 ; 160 : 1125 – 1132
93.
Kane JM, Rifkin A, Quitkin F, et al : Low dose fluphenazine decanoate in maintenance treatment of schizophrenia. Psychiatry Res 1979 ; 1 : 341 – 348
94.
Kane JM, Sanchez R, Perry PP, et al : Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2012 ; 73 : 617 – 624
95.
Kaneno S, Okuma T, Yamashita T, et al : A double-blind comparative study on the efficacy and safety of fluphenazine decanoate (SQ10, 733) and oral haloperidol in the treatment of schizophrenic patients. Clinical Evaluation 1991 ; 19 : 15 – 45
96.
Kelly HB, Freeman HL, Banning B, et al : Clinical and social comparison of fluphenazine decanoate and flupenthixol decanoate in the community maintenance therapy of schizophrenia. Int Pharmacopsychiatry 1977 ; 12 : 54 – 64
97.
Keskiner A, Holden JMC, Itil TM : Maintenance treatment of schizophrenic outpatients with a depot phenothiazine. Psychosomatics 1968 ; 9 : 166 – 171
98.
Kissling W, Möller HJ, Walter K, et al : Double-blind comparison of haloperidol decanoate and fluphenazine decanoate effectiveness, side-effects, dosage and serum levels during a six months’ treatment for relapse prevention. Pharmacopsychiatry 1985 ; 18 : 240 – 245
99.
Koshikawa Y, Takekita Y, Kato M, et al : The comparative effects of risperidone long-acting injection and paliperidone palmitate on social functioning in schizophrenia: a 6-month, open-label, randomized controlled pilot trial. Neuropsychobiology 2016 ; 73 : 35 – 42
100.
Lapierre YD, von Frenckell R : AMDP psychopathology factors in chronic schizophrenia: a clinical trial of two long-acting neuroleptics. Mod Probl Pharmacopsychiatry 1983 ; 20 : 193 – 203
101.
Leong OK, Wong KE, Tay WK, et al : A comparative study of pipothiazine palmitate and fluphenazine decanoate in the maintenance of remission of schizophrenia. Singapore Med J 1989 ; 30 : 436 – 440
102.
Lundin L, Dencker SJ, Malm U : Community-based rehabilitation of schizophrenia. Nord J Psychiatry 1992 ; 46 : 121 – 127
103.
Macfadden W, Ma YW, Thomas Haskins J, et al : A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry (Edgmont) 2010 ; 7 : 23 – 31
104.
McCreadie R, Mackie M, Morrison D, et al : Once weekly pimozide versus fluphenazine decanoate as maintenance therapy in chronic schizophrenia. Br J Psychiatry 1982 ; 140 : 280 – 286
105.
McCreadie RG, Dingwall JM, Wiles DH, et al : Intermittent pimozide versus fluphenazine decanoate as maintenance therapy in chronic schizophrenia. Br J Psychiatry 1980 ; 137 : 510 – 517
106.
McEvoy JP, Byerly M, Hamer RM, et al : Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014 ; 311 : 1978 – 1987
107.
McKane JP, Robinson AD, Wiles DH, et al : Haloperidol decanoate v. fluphenazine decanoate as maintenance therapy in chronic schizophrenic in-patients. Br J Psychiatry 1987 ; 151 : 333 – 336
108.
McLaren S, Cookson JC, Silverstone T : Positive and negative symptoms, depression and social disability in chronic schizophrenia: a comparative trial of bromperidol and fluphenazine decanoates. Int Clin Psychopharmacol 1992 ; 7 : 67 – 72
109.
Mosolov SN, Tsukarzi EE, Potapov AV : [Comparative efficacy, tolerability and effect on the social functioning of the risperidone (Konsta) and olanzapine prolong with the long-term treatment of schizophrenia and schizoaffective disorder.] ТРУДНЫЙ ПАЦИЕНТ, 2008 (Russian)
110.
Odejide OA, Aderounmu AF : Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients. J Clin Psychiatry 1982 ; 43 : 195 – 196
111.
Pinto R, Bannerjee A, Ghosh N : A double-blind comparison of flupenthixol decanoate and fluphenazine decanoate in the treatment of chronic schizophrenia. Acta Psychiatr Scand 1979 ; 60 : 313 – 322
112.
Potkin SG, Loze JY, Forray C, et al : Multidimensional assessment of functional outcomes in schizophrenia: results from QUALIFY, a head-to-head trial of aripiprazole once-monthly and paliperidone palmitate. Int J Neuropsychopharmacol 2017 ; 20 : 40 – 49
113.
Quitkin F, Rifkin A, Kane J, et al : Long-acting oral vs injectable antipsychotic drugs in schizophrenics: a one-year double-blind comparison in multiple episode schizophrenics. Arch Gen Psychiatry 1978 ; 35 : 889 – 892
114.
Rifkin A, Quitkin F, Rabiner CJ, et al : Fluphenazine decanoate, fluphenazine hydrochloride given orally, and placebo in remitted schizophrenics. I. Relapse rates after one year. Arch Gen Psychiatry 1977 ; 34 : 43 – 47
115.
Rossi A, Volonté MV, Di Michele V, et al : Efficacia terapeutica e tollerabilità del Bromperidolo decanoato VS Flufenazina decanoato nel Distrubo Schizofrenico. Riv Sper Freniatr Med Leg Alien Ment 1990 ; 64 : 1379 – 1386
116.
Rossi P, Chini C, Casale A, et al : Azione del bromperidolo decanoato nel trattamento dei sintomi negativi della schizophrenia: confronto con l’aloperidolo decanoato. Riv Psichiatr 1992 ; 27 : 265 – 270
117.
Sampath GS, Shah A, Krska J, et al : Neuroleptic discontinuation in the very stable schizophrenic patient: relapse rates and serum neuroleptic levels. Hum Psychopharmacol 1992 ; 7 : 255 – 264
118.
Savitz AJ, Xu H, Gopal S, et al : Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol 2016 ; 19 : pyw018
119.
Schlosberg A, Shadmi M : A comparative controlled study of two long-acting phenothiazines: pipothiazine palmitate and fluphenazine decanoate. Curr Ther Res Clin Exp 1978 ; 23 : 642 – 654
120.
Schneider SJK, Kirby EJ, Itil TM : Clinical blood chemistry values and long acting phenothiazines. Pharmacopsychiatria 1981 ; 14 : 107 – 114
121.
Schooler NR, Levine J, Severe JB, et al : Prevention of relapse in schizophrenia: an evaluation of fluphenazine decanoate. Arch Gen Psychiatry 1980 ; 37 : 16 – 24
122.
Sharma SK, Jaigirdar SH : A comparison of fluphenazine decanoate and haloperidol decanoate in chronic schizophrenia. British Journal of Clinical Research 1991 ; 2 : 177 – 186
123.
Simon P, Fermanian J, Ginestet D, et al : Standard and long-acting depot neuroleptics in chronic schizophrenics: an 18-month open multicentric study. Arch Gen Psychiatry 1978 ; 35 : 893 – 897
124.
Singh AN, Saxena B : A comparative study of prolonged action (depot) neuroleptics: pipotiazine palmitate versus fluphenazine enanthate in chronic schizophrenic patients. Curr Ther Res Clin Exp 1979 ; 25 : 121 – 132
125.
Smeraldi E, Brancato V, Bellini L, et al : Bromperidol decanoate vs placebo in treating schizophrenia in the residual phase. New Trends in Experimental and Clinical Psychiatry 1990 ; 6 : 187 – 198
126.
Song Y : A double‐blind control study on the effect of pipotiazine palmitate and fluphenazine decanoate in the treatment of schizophrenia Chinese. J Neurol Psychiatry 1993 ; 26 : 137 – 140
127.
Steinert J, Neder A, Erba E, et al : A comparative trial of depot pipothiazine. J Int Med Res 1986 ; 14 : 72 – 77
128.
Subotnik KL, Casaus LR, Ventura J, et al : Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2015 ; 72 : 822 – 829
129.
Walker CA : A double-blind comparative trial of the decanoates of clopenthixol and fluphenazine in the treatment of chronic schizophrenic out-patients. Pharmatherapeutica 1983 ; 3 : 289 – 293
130.
Wistedt B, Koskinen T, Thelander S, et al : Zuclopenthixol decanoate and haloperidol decanoate in chronic schizophrenia: a double-blind multicentre study. Acta Psychiatr Scand 1991 ; 84 : 14 – 21
131.
Wistedt B, Persson T, Hellbom BA : A clinical double blind comparison between haloperidol decanoate and fluphenazine decanoate. Curr Ther Res Clin Exp 1984 ; 35 : 804 – 814
132.
Woggon B, Dick P, Fleischhauer HJ, et al : [Comparison of the effects of pipothiazine palmitate and fluphenazine decanoate: results of a multicenter double-blind trial.] Int Pharmacopsychiatry 1977 ; 12 : 193 – 209 (German)
133.
Zissis NP, Psaras M, Lyketsos G : Haloperidol decanoate, a new long-acting antipsychotic, in chronic schizophrenics: double-blind comparison with placebo. Curr Ther Res Clin Exp 1982 ; 31 : 650 – 655
134.
Zuardi AW, Giampietro AC, Grassi ER, et al : Double-blind comparison between two forms of haloperidol: an oral preparation and a new depot decanoate in the maintenance of schizophrenic inpatients. Curr Ther Res Clin Exp 1983 ; 34 : 253 – 261
135.
Taipale H, Mehtälä J, Tanskanen A, et al : Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia: a nationwide study with 20-year follow-up. Schizophr Bull 2018 ; 44 : 1381 – 1387
136.
Ostuzzi G, Papola D, Gastaldon C, et al : New EMA report on paliperidone 3-month injections: taking clinical and policy decisions without an adequate evidence base. Epidemiol Psychiatr Sci 2017 ; 26 : 231 – 233
137.
Misawa F, Kishimoto T, Hagi K, et al : Safety and tolerability of long-acting injectable versus oral antipsychotics: a meta-analysis of randomized controlled studies comparing the same antipsychotics. Schizophr Res 2016 ; 176 : 220 – 230
138.
Turner EH, Knoepflmacher D, Shapley L : Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS Med 2012 ; 9 : e1001189
139.
Cipriani A, Higgins JP, Geddes JR, et al : Conceptual and technical challenges in network meta-analysis. Ann Intern Med 2013 ; 159 : 130 – 137
140.
Papola D, Ostuzzi G, Gastaldon C, et al : Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies. Acta Psychiatr Scand 2019 ; 140 : 227 – 243
141.
Hui CLM, Honer WG, Lee EHM, et al : Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial. Lancet Psychiatry 2018 ; 5 : 432 – 442
142.
World Health Organization : World Health Organization Model List of Essential Medicines: 21st List. Geneva, World Health Organization, 2019

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 424 - 436
PubMed: 33596679

History

Received: 28 July 2020
Revision received: 27 November 2020
Accepted: 2 December 2020
Published online: 18 February 2021
Published in print: May 01, 2021

Keywords

  1. Antipsychotics
  2. Depot Formulation
  3. Network Meta-Analysis
  4. Relapse Prevention
  5. Maintenance Treatment

Authors

Details

Giovanni Ostuzzi, M.D., Ph.D. [email protected]
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Federico Bertolini, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Cinzia Del Giovane, Ph.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Federico Tedeschi, Ph.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Chiara Bovo, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Chiara Gastaldon, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Michela Nosé, M.D., Ph.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Filippo Ogheri, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Davide Papola, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Marianna Purgato, Psy.D., Ph.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Giulia Turrini, Psy.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Christoph U. Correll, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).
Corrado Barbui, M.D.
World Health Organization Collaborating Centre for Research and Training in Mental Health and Service Evaluation, and Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy (Ostuzzi, Bertolini, Tedeschi, Gastaldon, Nosé, Ogheri, Papola, Purgato, Turrini, Barbui); Institute of Primary Health Care, University of Bern, Bern, Switzerland (Del Giovane); University Hospital of Verona, Verona, Italy (Bovo); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., and Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin (Correll).

Notes

Send correspondence to Dr. Ostuzzi ([email protected]).

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share