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Psychosocial Interventions for Adults With Schizophrenia: An Overview and Update of Systematic Reviews

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Cognitive adaptation training, cognitive-behavioral therapy, cognitive remediation, early intervention programs for treating first-episode psychosis, family interventions, illness self-management, psychoeducation, social skills training, supported employment, supportive therapy, box 1. future research recommendations to study interventions for patients with schizophrenia, conclusions, supplementary material, information, published in.

• Schizophrenia
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Open Access

Peer-reviewed

Research Article

A Systematic Review of the Prevalence of Schizophrenia

Affiliation Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Australia

Affiliations Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Australia, Department of Psychiatry, University of Queensland, St. Lucia, Australia

* To whom correspondence should be addressed. E-mail: [email protected]

• Sukanta Saha, 
• David Chant, 
• Joy Welham, 
• John McGrath

• Published: May 31, 2005
• https://doi.org/10.1371/journal.pmed.0020141
• Reader Comments

Understanding the prevalence of schizophrenia has important implications for both health service planning and risk factor epidemiology. The aims of this review are to systematically identify and collate studies describing the prevalence of schizophrenia, to summarize the findings of these studies, and to explore selected factors that may influence prevalence estimates.

Methods and Findings

Studies with original data related to the prevalence of schizophrenia (published 1965–2002) were identified via searching electronic databases, reviewing citations, and writing to authors. These studies were divided into “core” studies, “migrant” studies, and studies based on “other special groups.” Between- and within-study filters were applied in order to identify discrete prevalence estimates. Cumulative plots of prevalence estimates were made and the distributions described when the underlying estimates were sorted according to prevalence type (point, period, lifetime, and lifetime morbid risk). Based on combined prevalence estimates, the influence of selected key variables was examined (sex, urbanicity, migrant status, country economic index, and study quality).

A total of 1,721 prevalence estimates from 188 studies were identified. These estimates were drawn from 46 countries, and were based on an estimated 154,140 potentially overlapping prevalent cases. We identified 132 core studies, 15 migrant studies, and 41 studies based on other special groups. The median values per 1,000 persons (10%–90% quantiles) for the distributions for point, period, lifetime, and lifetime morbid risk were 4.6 (1.9–10.0), 3.3 (1.3–8.2), 4.0 (1.6–12.1), and 7.2 (3.1–27.1), respectively. Based on combined prevalence estimates, we found no significant difference (a) between males and females, or (b) between urban, rural, and mixed sites. The prevalence of schizophrenia in migrants was higher compared to native-born individuals: the migrant-to-native-born ratio median (10%–90% quantile) was 1.8 (0.9–6.4). When sites were grouped by economic status, prevalence estimates from “least developed” countries were significantly lower than those from both “emerging” and “developed” sites ( p = 0.04). Studies that scored higher on a quality score had significantly higher prevalence estimates ( p = 0.02).

Conclusions

There is a wealth of data about the prevalence of schizophrenia. These gradients, and the variability found in prevalence estimate distributions, can provide direction for future hypothesis-driven research.

Citation: Saha S, Chant D, Welham J, McGrath J (2005) A Systematic Review of the Prevalence of Schizophrenia. PLoS Med 2(5): e141. https://doi.org/10.1371/journal.pmed.0020141

Academic Editor: Steven E. Hyman, Harvard University, United States of America

Received: February 15, 2005; Accepted: March 29, 2005; Published: May 31, 2005

Copyright: © 2005 Saha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: LMR, lifetime morbid risk; NOS, not otherwise specified

Introduction

Schizophrenia is a disabling group of brain disorders characterized by symptoms such as hallucinations, delusions, disorganized communication, poor planning, reduced motivation, and blunted affect. While the incidence of the disorder is relatively low (median value 15.2 per 100,000 persons per year) [ 1 ], the condition is one of the major contributors to the global burden of disease [ 2 ]. The substantial burden of disease is a reflection of two features of schizophrenia: (a) the disorder usually has its onset in early adulthood, and (b) despite optimal treatment, approximately two-thirds of affected individuals have persisting or fluctuating symptoms [ 3 ].

Understanding the “epidemiological landscape” of schizophrenia requires many different types of descriptive studies [ 4 ]. Studies that estimate the incidence of schizophrenia are required in order to identify gradients across time and/or place. These gradients allow us to generate candidate risk factors that may underlie variations in the disorder. However, studies that report the prevalence of a disorder are also important. Estimating the proportion of a population affected with schizophrenia is central to health service planning. With respect to estimating the burden of disorder, prevalence proportions can provide insights into how incidence rates are refracted via different trajectories (e.g., recovery, chronicity, or early death). The statement “prevalence = incidence + course of illness” oversimplifies the dynamic matrix of factors influencing each component of the equation. Nevertheless, prevalence proportions can help us chart contours on the still-incomplete epidemiological map of schizophrenia.

Several scholarly narrative reviews of the prevalence of schizophrenia have been published in recent decades [ 4 – 8 ]. The sheer volume of data available on the prevalence of schizophrenia now requires a more systematic and orderly approach. As with many fields of medical knowledge, there is a growing appreciation that reviews should be based on data that are as complete and as free of bias as possible [ 9 ]. Systematic reviews have prespecified methods for locating studies and for extracting and synthesizing the data. Not all systematic reviews are accompanied by meta-analysis (i.e., pooling the data to provide one summary value) [ 10 ]. Even without pooling of data, the orderly sorting of data using meta-analytic techniques can provide useful insights into the structure of the relevant literature [ 11 ].

One systematic review of the prevalence of schizophrenia has been published to date [ 12 ]. This review (based solely on census and/or community survey data) identified 18 studies that provided estimates of either period and/or lifetime prevalence of schizophrenia. Goldner and colleagues reported pooled estimates for 1-y and lifetime prevalence of 3.4 and 5.5 per 1,000 persons, respectively. The authors commented on the heterogeneity of the data and suggested that this reflected “real variation” in the distribution of schizophrenia around the world.

Recently, we published a systematic review of the incidence of schizophrenia [ 1 ]. In brief, we found that the incidence of schizophrenia varied widely between sites (persons, media n = 15.2 per 100,000; 10%–90% quantiles = 7.7–43.0). In addition, the study identified that (a) males were more likely to develop schizophrenia than females (median male:female risk ratio = 1.4); (b) migrants were more likely to develop schizophrenia than native-born individuals (median risk ratio = 4.6); and (c) individuals in urban sites had a higher risk of developing schizophrenia than those in mixed urban/rural sites. Regardless of the factors that underpin these incidence gradients, would these same gradients also be found in the prevalence of schizophrenia? If so, then it might suggest, for example, that factors influencing the course of the illness were more evenly distributed across these groups than factors influencing the incidence of the disorder. If the prevalence gradients are not congruent with the incidence gradients, then we are faced with the challenging task of unraveling the factors that could influence the differential course of schizophrenia between risk groups.

In this paper we continue our cartography of the epidemiological landscape of schizophrenia by presenting a systematic review of the prevalence of this disorder.

Ways to Measure the Prevalence of Schizophrenia

Prevalence measures the proportion of individuals who manifest a disorder at a specified time, or during a specified period. Generally prevalence estimates are calculated as a proportion, by dividing the total number of individuals who manifest a disorder (the numerator) by the total population at risk, including those with the disorder (the denominator). Prevalence proportions vary according to temporal criteria (e.g., point, period, or lifetime), but are not reported as an index of events over time (i.e., they are not like incidence rates that report the number of new cases per background population per year). Prevalence proportions are often loosely referred to as “rates”; however, in this review we will refer to them as “prevalence estimates” or “estimates.” Tables S1 and S2 define the types of prevalence estimates used in this study, and provide descriptions of the variables that we have used to describe the studies.

Point prevalence is the proportion of individuals who manifest a disorder at a given point in time (e.g., 1 d or 1 wk), while period prevalence measures the proportion of individuals who manifest a disorder during a specified period of time (e.g., 1 y). Given that the course of schizophrenia extends over months to decades, estimates of point prevalence based on 1 d are comparable to those based on 1 mo [ 5 ]. Thus, in this review we have combined all estimates based on temporal criteria of 1 mo or less in “point prevalence,” while studies that reported prevalence estimates between 1 mo and 12 mo are included under the heading “period prevalence.”

“Lifetime prevalence” is the proportion of individuals in the population who have ever manifested a disorder, who are alive on a given day. It is important to emphasize that lifetime prevalence needs to be clearly distinguished from “lifetime morbid risk” (LMR; also described elsewhere as morbid risk or expectancy). LMR differs from lifetime prevalence in that it attempts to include the entire lifetime of a birth cohort both past and future, and includes those deceased at the time of the survey [ 13 ]. LMR is the probability of a person developing the disorder during a specified period of their life or up to a specified age. There are various ways to calculate LMR [ 14 , 15 ]. The reviews of Odegaard [ 15 ], and Larsson and Sjogren [ 16 ] noted that, for low-incidence disorders such as schizophrenia, summation of age-specific incidence rates gives almost the same result as other more complicated methods of calculation [ 17 ]. The World Health Organization ten-country study [ 18 ] used this so-called “summation method” for the approximation of LMR. If one were to apply Linnean principles in order to design a taxonomy of frequency measures of disease, prevalence measures such as point, period, and lifetime would be closely related species within the same genus. However, there is a case to allocate LMR to the Genus “Incidence” rather than the Genus “Prevalence.” Conceptually (but not mathematically), LMR is closely related to cumulative incidence proportions derived from birth cohort studies [ 19 ].

Traditional prevalence studies (henceforth referred to as “core” studies) generate an estimate based on the population residing within a defined catchment area. However, it should be noted that the boundaries chosen for epidemiological studies (e.g., health districts, cities, states, or nations) may not be optimal for the detection of variations of the disorder within or between various populations. Lumping populations into large but convenient administrative areas can obscure informative, fine-grained gradients. With respect to prevalence estimates, factors such as the age structure of the population, mortality rates, and migration patterns can influence the estimates, and these may vary within and between sites.

Apart from catchment-area-based studies of the general population, there are many studies that report prevalence estimates for subgroups of the population. These may include groups defined by narrow age strata (e.g., the elderly or children), migrant status, ethnic or religious status, or twin status, to name but a few. A recent paper has systematically reviewed the prevalence of schizophrenia in prison settings [ 20 ]; however, this will not be included in this review. Migrant studies will be collated separately for analysis , while the remaining subgroup prevalence estimates will be included in “other special groups.”

Some studies report inpatient census data over a period of time (e.g., 1 y) and use the count of unique individuals with schizophrenia to generate a proportion based on general population figures. While these studies may be useful for administrative purposes, it is important not to mistake these estimates as “true” prevalence proportions. Very few patients require prolonged and continuous inpatient care; therefore, prevalence proportions based on inpatient data alone grossly underestimate true prevalence proportions. This review will collate these studies separately (henceforth referred to as “inpatient-census-derived” data); however, they will not be included in any of the main analyses.

Key Research Questions about the Prevalence of Schizophrenia

First there is a need to examine the degree of variation in the prevalence estimates of schizophrenia between sites. The companion review on the incidence of schizophrenia [ 1 ] found that within the central 80% of incidence rates, the difference ranged from 7.7 to 43 per 100,000 (over a 5-fold difference). While there has been debate within the schizophrenia research community about whether this range of rates is “narrow” or “prominent” (see review [ 21 ]), variations in prevalence estimates have not been a focus of controversy. The World Health Organization ten-country study commented that the prognosis of schizophrenia [ 18 ] was better in developing than in developed nations, a finding that has been “clear and consistent” in general [ 22 ]. The present review will describe the distribution of the different types of prevalence rates, and specifically examine whether the “developed versus developing” status of the sites influences the distribution of estimates.

Are the gradients that were identified in the incidence of schizophrenia also reflected in the prevalence of the disorder? For example, based on the previous finding that males have a significantly higher incidence of schizophrenia [ 1 , 23 ], it would be predicted that this sex difference might also be reflected in prevalence estimates. In addition, a recent study from China [ 24 , 25 ] highlighted an apparently unusual higher prevalence of schizophrenia in females in this country. In light of this issue, the male:female prevalence ratio will also be compared when the sites are sorted by a measure of “developed versus developing” status. Similarly, the incidence review identified significantly higher rates for (a) urban place of residence when compared to mixed urban/rural sites, and (b) migrant groups when compared to native-born individuals. These gradients will also be explored regarding the prevalence of schizophrenia.

Finally, systematic reviews can explore possible sources of heterogeneity in data by sorting the data according to methodological features. We will compare the distributions of estimates based on the quality of the study (as assessed by design features and thoroughness of reporting).

Identification of Studies

This systematic review conforms to the guidelines outlined by the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) recommendations [ 26 ]. The search methodology for this review was identical to that of our previous review paper on incidence of schizophrenia [ 1 ]. As a first step, a broad (free text) search string ([schizo* OR psych*] AND [incidence OR prevalence]) was used in MEDLINE, PsychINFO, EMBASE, and LILACS. Potentially relevant papers (in all languages) were accessed in order to review the full text. The references cited by each potentially relevant paper, review, and book chapter were scrutinized in order to locate additional potential papers. Posters were presented at two international schizophrenia conferences [ 27 , 28 ] in order to encourage researchers to contribute studies, especially studies from the “grey literature” (e.g., conference reports, theses, government reports, and unpublished studies). Subsequently, letters or E-mails were sent to the senior authors of papers that met the inclusion criteria. These authors were provided with an interim list of included papers and asked to nominate missing studies.

Included Studies

We included studies that reported primary data on the prevalence of schizophrenia first published between January 1965 and December 2002. Where multiple publications presented identical data, the most “informative version” of the study was included. Studies published in a language other than English were translated, and relevant papers were included.

Excluded Studies

Studies that reported prevalence data on prison or forensic populations were excluded (see recent systematic review of these studies [ 20 ]). We did not include genetic epidemiological studies that reported prevalence estimates in family members of affected (index) probands. Some studies report the LMR within large, multiplex families. These were not included; however, if the prevalence estimates were based on the entire population within a catchment area (e.g., an isolated population living in a village), then they were included.

Potential studies that had not been located at the time of submission were allocated to the “awaiting assessment” category. Studies based on inpatient-census-derived proportions are presented in the tables and summarized for comparative purposes, but were excluded from the main analyses.

Data Extraction

Once a study was included, data were extracted and entered into a three-level normalized database (i.e., only the unique prevalence estimate identifier was allowed to occur in more than one level) that included study-level variables (e.g., authors, year of publication, and site), middle-level variables (e.g., urban/rural status, age group, recruitment duration, case finding method, and diagnostic criteria), and rate-level variables (e.g., sex-specific rates for persons, males, and females). Two or more of the authors checked all data used in the analysis. When disagreements arose, these were resolved by consensus. If required, we contacted the original authors for clarification of issues. The full electronic dataset is available as Dataset 1 .

Consistent with our previous systematic review of the incidence of schizophrenia [ 1 ], studies were given “quality points” based on operationalized features related to (a) optimal research design (e.g., higher scores for greater coverage, face-to-face interview versus chart diagnosis, and reliability of instruments), and (b) quality of reporting (e.g., provision of numerator and denominator, and description of diagnostic criteria). Details of the quality scores used in this review are provided in Table S3 .

Sorting Prevalence Estimates by the Application of Sequential Filters

In systematic reviews, it is important that individuals are not “double counted” by the same or different studies. Thus, a key feature of this study is the application of sequential filters in order to identify discrete prevalence estimates. We applied a similar sorting algorithm as in our previous review of incidence of schizophrenia [ 1 ]. Briefly, the first filter parsed prevalence estimates from the included studies into three groups: core, migrant, and other special groups. Next, as the second filter, the estimates were sorted into six main types: point (1 mo or less), period (between 1 and 12 mo), lifetime, LMR, not otherwise specified (NOS), and inpatient-census-derived data.

A third, study-level filter was applied in order to isolate discrete data from multiple studies that overlapped in both time and place. This third filter was used to select one representative prevalence estimate for inclusion in the cumulative distribution using the “most informative” rule. For example, if one study presented multiple overlapping estimates, the estimate based on the largest sample was preferred (e.g., the widest age range was preferred over narrower age strata). Furthermore, filter rules were defined in order to select discrete estimates such that they allowed the greatest number of estimates to be included.

Presentation and Analyses of the Data

Key details of the included studies are presented in tables sorted by country, year of publication and first author (Tables S4 , S5 , and S6 ). The distributions of prevalence estimates are presented in cumulative plots, with every estimate contributing to the distribution. The distribution of the data is shown in rank order for prevalence estimate (lowest to highest ranks) with the cumulative percent of estimates shown on the vertical axis. The plots show horizontal reference lines indicating the 50% (median), and 25% and 75% quantiles (between which lies the interquartile range). In order to aid visual interpretation, some plots have been truncated, excluding very high estimates. Key features of these distributions are presented in tables (e.g., median, mean, harmonic mean, standard deviation, and quantiles at 10%, 25%, 50%, 75%, and 90%). These summary characteristics are based on the entire distributions. Results are presented as prevalence estimates per 1,000. In plots of prevalence ratios (e.g., male:female ratio), a vertical reference at the line of unity is shown.

We wish to draw attention to several features of the graphs used in this review. First, the central, near-linear segment of the cumulative distributions may extend beyond the interquartile range (e.g., from the 10%–90% quantiles), thus shape features (where the tails start or the range of the linear central segment) can be more informative than traditional interquartile ranges. Second, steeper segments of the cumulative plots are underpinned by estimates that have a narrow distribution, while flatter (i.e., more horizontal) segments of the distribution are underpinned by data that are relatively more dispersed. Finally, some distributions are derived from more data than others. Regardless of slope (i.e., steep or flat), if many estimates underpin segments of the distributions, then inferences based on these segments are probably more reliable than those based on segments underpinned by less data.

Meta-analyses often display data points with confidence intervals, and formal tests of heterogeneity are usually applied before combining data. For several reasons, the data in this review do not lend themselves to this type of analysis. Among the discrete core studies (see below), no study provided confidence limits to accompany the prevalence estimate. One study, which was allocated to “other special groups,” did provide confidence limits [ 29 ]. Where studies provided the corresponding numerator and denominator for a prevalence estimate, we were able to derive standard errors. However, we were able to impute standard errors for only 26% of the prevalence estimates, which were drawn from less than half (45%) of the discrete core studies. Faced with such a restricted pool of standard errors, the ability to assess the heterogeneity of the estimates in a manner generalizable across all core studies is compromised. In addition, the issues that underlie the decision to combine data from randomized controlled trials or risk factor epidemiological studies are of less relevance to prevalence estimates, where estimates based on very large populations should not necessarily carry more weight than estimates based on small populations. Based on first principles, there is no reason to assume that prevalence estimates for a disease remain static across time or place. Thus, forcing individual prevalence estimates into one pooled estimate loses important information. In this review we wish to draw attention to several characteristics of the distribution of estimates (e.g., central tendency, shape and width of the distribution, and density of data), rather than provide one pooled estimate.

In keeping with our systematic review of the incidence of schizophrenia [ 1 ], we supplement the graphical presentation of the prevalence estimates with statistical analyses. These analyses take into account (a) the need to control for within-study variation (estimates drawn from the same study tend to be more alike than estimates drawn from different studies), and (b) the use of a log transformation of the data in order to analyze distributions that are often positively skewed. Note that the median value is more informative than the arithmetic mean to assess central tendency in a skewed distribution, as is the harmonic mean (which is calculated as the exponential of the arithmetic mean of the log-transformed data, also known as the geometric mean). The analyses were carried out in SAS 9.1 using proc univariate (for medians and other quantiles of the raw data) and proc mixed for comparisons of harmonic means (because one study may provide more than one estimate, it is important to control for within-study variation).

Faced with a large quantity of data, systematic reviewers need to keep a tight rein on the number of comparisons undertaken on the data [ 30 ]. While it is tempting to reanalyze data in the light of findings that emerge from the data, such reanalyses should be kept to a minimum. The analysis of prevalence estimates is particularly challenging because of the many different prevalence types (e.g., point, period, lifetime, and LMR). Thus, in order to minimize the number of statistical comparisons in the current review, we restricted the analyses to a limited set of planned sensitivity analyses, each with a priori directional hypotheses, and, for post hoc analyses, applied multiple comparison corrections to the nominal significance levels by a Bonferroni correction. Furthermore, these analyses were based on hybrid distributions, which merged four different prevalence estimate types (point, period, lifetime, and NOS; henceforth referred to as “combined prevalence estimates”). Apart from the specific analyses related to sex differences, we undertook these analyses on distributions for persons only (i.e., males and females combined).

Based on first principles, we predicted that the estimates for known prevalence types that include different temporal criteria would be significantly different. More specifically, we predicted the following: (a) prevalence estimates for persons would differ between lifetime, period and point (point being the lowest), and (b) LMR estimates would be higher than lifetime estimates.

There is now strong evidence that males have an increased risk of developing schizophrenia [ 1 , 23 ]. We compared the distribution for males versus females on the combined prevalence estimates, predicting that males would have distributions derived from higher estimates (i.e., distributions for males would be right-shifted compared to distributions for females).

In order to explore the influence of urbanicity of site on the prevalence of schizophrenia, we divided the combined prevalence estimates for persons into three categories (urban, rural, and mixed urban/rural). Allocation was based on the study descriptions of the area or, in the absence of these descriptors, the review authors' best estimate of this variable. There are several reasons to predict that the prevalence of schizophrenia would be higher in urban regions than in rural regions. First, the incidence of schizophrenia is higher in urban sites than mixed urban/rural sites [ 1 ]. Second, the “social drift” hypothesis suggests that the individuals with schizophrenia are more likely to move into urban regions in response to various factors related to poverty, the availability of services, and easier access to cheap accommodation [ 31 ]. Finally, some commentators suggest that less industrialized settings (e.g., rural regions and/or developing countries) may facilitate recovery via social connectedness and easier access to work [ 32 ]. Thus, we predicted that the prevalence of schizophrenia would be higher in urban sites than in rural or mixed urban/rural.

Migrants have a significantly increased risk of developing schizophrenia [ 1 , 33 ]. Assuming that the course of the illness does not vary according to migrant status, based on combined prevalence estimates for persons, we predicted that the prevalence of schizophrenia would be higher in migrants than in native-born individuals.

While there is a lack of evidence addressing whether the incidence of schizophrenia varies with the economic status of nations, there is solid evidence showing that people with schizophrenia from developing countries tend to have better outcomes than individuals in developed nations [ 18 , 22 ]. Mindful that there is a lack of consensus on how best to define the multidimensional concept of economic development, we have sorted prevalence estimates according to the per capita gross national product of the study site (2004 data) [ 34 ], and used standard World Bank definitions [ 35 ]: (a) least developed countries, = mean income of less than US$2,995; (b) emerging economy countries, = mean income between US$2,995 and $9,266; and (c) developed countries, = mean income of greater than US$9,266. Thus, based on combined prevalence estimates for persons, we predicted that the prevalence of schizophrenia would be significantly different across the three economic categories, and that the prevalence of schizophrenia would be significantly lower in least developed countries than in developed countries. Furthermore, a recent commentary drew attention to the apparent female excess in the prevalence of schizophrenia in developing nations, in contrast to the male excess thought to characterize the developed world [ 25 ]. Thus, based on combined prevalence estimates, we compared the male:female ratio when the prevalence estimates were classified by the three economic categories. We predicted that the ratio would be significantly different between the three economic levels, and specifically, that the male:female ratio in developed nations would be significantly higher than that of least developed countries.

Finally, methodological features can influence prevalence estimates. For example, studies that use comprehensive case ascertainment methods (e.g., “door-knock” surveys, inpatient and outpatient records, general practitioner surveys, and/or surveys based on other community sources), should identify more cases than those that rely on fewer recruitment sources. Based on the combined prevalence estimates for persons, we divided the estimates into quality score terciles. We predicted that the prevalence estimates would be significantly different when assessed by quality score. More specifically, we predicted that prevalence estimates from studies with the highest quality score tercile would be higher than those from the lowest tercile.

The “Epidemiology” of Prevalence Estimates

The results of the search strategy, including source of the studies, subsequent culling, and final distribution of the papers, are shown in Figure 1 . The electronic search identified 1,112 papers (85% of the total papers included in the study), while manual reference checking identified an additional 142 references (11%). We received responses from 31 authors (see Acknowledgments for full list), who provided an additional 53 references (4%). We identified 98 studies that were published in languages other than English. After translation 17 of these studies were included in this review.

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Double asterisk indicates exclusion categories (number studies excluded in parentheses). Double asterisk indicates numbers that are not mutually exclusive. A few studies provided rates for more than one group (11 studies provided data for both core and migrant [ n = 3] or both core and other special groups [ n = 8]; details in Results). LOTE, language other than English.

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The list of references arranged by various criteria can be found in Tables 1 – 4 . The systematic review identified 188 studies that provided prevalence estimates [ 18 , 29 , 36 – 223 ]. These studies provided 1,721 estimates and were drawn from 46 countries. There were 132 core studies, 15 migrant studies (of which three overlap with discrete core), and 41 studies that reported the prevalence of schizophrenia in other special groups.

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Key features of these core, migrant, and special groups are provided in Tables S4 – S6 . We excluded 26 studies that were completely overlapping by time and place, and 19 studies that reported prevalence data on prison populations (see Figure 1 ). However, ten partially overlapping studies were included that provided at least one discrete rate for this review [ 37 , 40 , 45 , 60 , 64 , 100 , 148 , 153 , 187 , 220 ].

The prevalence estimates were based on an estimated total of 154,140 potentially overlapping cases. The 132 core studies provided from one to 13 prevalence estimates per study. Four studies [ 59 , 120 , 169 , 224 ] reported prevalence only within narrow age strata without providing an overall rate. These studies were not included in the discrete core analyses.

Of the 132 core studies, we identified 21 studies for point prevalence, 34 studies for period prevalence, and 24 studies for lifetime prevalence. Thirty-two studies provided no information on the type of prevalence they reported—these were allocated to NOS prevalence. There were nine studies that reported LMR. Finally there were 44 studies that reported inpatient-census-derived data.

The Distribution of Prevalence Estimates

Figures 2 – 7 and Tables 5 – 7 show the distribution of the different types of prevalence estimates, and quantiles and moments for persons, males, and females.

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The median point prevalence for persons (based on 23 estimates) was 4.6 per 1,000, and the 10% and 90% quantiles ranged from 1.9 to 10.0 per 1,000 (a 5-fold difference). The median period prevalence for persons (based on 42 estimates) was 3.3 per 1,000, and the 10% and 90% quantiles ranged from 1.3 to 8.2 per 1,000 (a 6.5-fold difference). The median lifetime prevalence for persons (based on 29 estimates) was 4.0 per 1,000, and the 10% and 90% quantiles ranged from 1.8 to 11.6 per 1,000 (a 6.4-fold difference).

There were 32 prevalence estimates that could not be classified to the above criteria (NOS). Based on the distribution of these prevalence estimates, the median prevalence was 2.7 per 1,000 for persons, and the 10% and 90% quantiles ranged from 1.4 to 4.8 per 1,000 (a 3.4-fold difference).

The median LMR for persons (based on 27 estimates) was 7.2 per 1,000, and the 10% and 90% quantiles ranged from 3.1 to 27.1 per 1,000 (a 8.7-fold difference) (see Table 6 ).

https://doi.org/10.1371/journal.pmed.0020141.t006

The review identified 108 estimates based on inpatient-census-derived data. Based on the distribution of these estimates for persons, the median value was 2.4 per 1,000, and the 10% and 90% quantiles ranged from 0.07 to 10.0 per 1,000 (a 154-fold difference) (see Table 7 ). Inpatient-census-derived prevalence is not included for any subsequent analyses.

When point, period, and lifetime estimates were compared, the distributions were not significantly different ( F 2,75 = 2.48, p = 0.09) . Estimates based on LMR were significantly higher than estimates based on lifetime estimates ( F 1,25 = 4.53, p = 0.04).

Male Versus Female Prevalence

Table 8 shows the moments and quantiles for the combined prevalence estimates for persons, males, and females, and for a ratio derived from male:female estimates. Figure 8 shows the distribution of these data for males and females—these distributions were not significantly different ( F 1,72 = 0.68, p = 0.41). For the male:female estimate ratio (based on 57 ratios), the median value was 1.11, and the 10% and 90% quantiles were 0.50 to 1.70 (approximately a 3.4-fold difference) (see Figure 9 ).

https://doi.org/10.1371/journal.pmed.0020141.g008

https://doi.org/10.1371/journal.pmed.0020141.g009

https://doi.org/10.1371/journal.pmed.0020141.t008

Urbanicity of Sites

We identified 31 discrete-core studies with 73 rates from urban sites (see Table 4 ), 24 studies with 48 rates from rural sites, and 45 studies with 137 mixed urban/rural rates. There were four discrete-core studies providing rates for both urban ( n = 12) and rural ( n = 10) categories. Figure 10 and Table 9 show the distribution of overall prevalence based on rural, urban, and mixed urbanicity status for persons. While the mixed urban/rural estimates were higher than urban and rural rates, this difference was not statistically significant ( F 2,235 = 1.63, p = 0.20), nor were urban estimates significantly different from rural estimates ( F 1,120 = 0.95, p = 0.33).

https://doi.org/10.1371/journal.pmed.0020141.g010

https://doi.org/10.1371/journal.pmed.0020141.t009

https://doi.org/10.1371/journal.pmed.0020141.t010

https://doi.org/10.1371/journal.pmed.0020141.t011

Migrant Status

We identified 15 migrant studies from eight countries: Australia ( n = 2; [ 55 , 207 ]), Germany ( n = 1; [ 92 ]), India ( n = 1; [ 175 ]), Israel ( n = 1; [ 200 ]), Taiwan ( n = 1; [ 129 ]), the Netherlands ( n = 1; [ 173 ]); United Kingdom ( n = 7; [ 39 , 43 , 65 – 68 , 133 ]); and United States ( n = 1; [ 180 ]).

Table S5 presents a detailed list of migrant studies with key descriptive variables, prevalence rates, and within-study migrant:native-born estimate ratios.

The number of different migrant groups in one study ranged between one and 38. There were six studies that derived data from inpatient-census-derived prevalence [ 43 , 55 , 65 – 67 , 92 ] and thus could not used in this analysis. In addition, four migrant studies did not present data for native-born populations [ 92 , 133 , 173 , 200 ]. Therefore, our analysis was limited to five papers only [ 39 , 129 , 175 , 180 , 207 ]. Based on 22 prevalence ratios, the median migrant:native-born prevalence ratio was 1.84 and the 10% and 90% quantiles were 0.86 to 6.41 (approximately a 7.5-fold difference) (see Table 1 0; Figure 11 ). When the migrant versus the native-born prevalence estimates were compared, there was a significant difference ( F 1,2 = 5.57, p = 0.04).

https://doi.org/10.1371/journal.pmed.0020141.g011

Economic Status of Sites

Based on the three economic categories, we identified 19 estimates from least developed countries, 22 estimates from emerging economy countries, and 96 estimates from developed countries (see Table 1 1; Figure 12 ). When divided by this criterion, the prevalence estimate distributions were significantly different ( F 2,85 = 3.57, p = 0.03), with the difference attributed to the lower prevalence estimate distribution for the less developed economies (developed versus least developed, F 1,74 = 6.55, p = 0.04). Table 12 also shows the male:female prevalence estimate ratio when subdivided by economic status. The distributions of these ratios (see Figure 13 ) , were not significantly different ( F 2,42 = 0.44, p = 0.44).

https://doi.org/10.1371/journal.pmed.0020141.g012

https://doi.org/10.1371/journal.pmed.0020141.g013

https://doi.org/10.1371/journal.pmed.0020141.t012

Quality Score

When the combined prevalence estimates for persons were divided into quality score terciles, the prevalence estimate distributions were significantly different ( F 2,105 = 4.79 , p = 0.01), with the highest quality studies reporting significantly higher prevalence estimates than the other two terciles (highest versus lowest quality scores, p = 0.02) ( Table 13 ; Figure 14 ).

https://doi.org/10.1371/journal.pmed.0020141.g014

https://doi.org/10.1371/journal.pmed.0020141.t013

Other Special Group Studies

Details of these studies can be found in Table S6 . We identified 41 studies that reported the prevalence of schizophrenia in other special groups. These studies came from 14 countries: Australia ( n = 4), Canada ( n = 4), Denmark ( n = 3), Finland ( n = 1), Germany ( n = 3), India ( n = 2), Israel ( n = 1), Japan ( n = 3), Romania ( n = 1), Spain ( n = 1), Sweden ( n = 2), Taiwan ( n = 1), United Kingdom ( n = 2), and United States ( n = 5).

Prevalence estimates were obtained from a range of population subgroups including elderly individuals ( n = 10; [ 52 , 70 , 71 , 101 , 108 , 121 , 149 – 151 , 159 ]), ethnic groups ( n = 8; [ 58 , 134 , 139 , 140 , 166 , 199 , 213 , 218 ]), Aborigines ( n = 4; [ 105 , 106 , 115 , 164 ]), religious groups ( n = 5; [ 29 , 80 , 128 , 182 , 191 ]), homeless individuals ( n = 4; [ 118 , 161 , 192 , 194 ]), children and adolescents ( n = 3; [ 57 , 185 , 189 ]), students ( n = 2; [ 147 , 178 ]), twins ( n = 1; [ 61 ]), industrial workers ( n = 1; [ 172 ]), different castes ( n = 1; [ 145 ]), and an isolate pedigree ( n = 1; [ 99 ]).

The marked heterogeneity of these data does not make them suitable for combining. However, we note that prevalence estimates in some homeless populations were very high—300 per 1,000 persons for Sydney homeless individuals [ 194 ] and 131 per 1,000 persons for Los Angeles homeless individuals [ 118 ]. Conversely, some religious groups had very low prevalence estimates—0.36 per 1,000 persons for Amish individuals [ 80 ] and 1.29 per 1,000 persons for Hutterite individuals [ 29 ].

There is a wealth of data available on the prevalence of schizophrenia—a total of 1,721 estimates from 188 studies were identified in this systematic review. These estimates were drawn from 46 countries, and were based on an estimated 154,140 potentially overlapping prevalent cases.

The median prevalence estimates for persons were 4.6 per 1,000 for point prevalence, 3.3 for period prevalence, 4.0 for lifetime prevalence, and 7.2 for LMR. These estimates are congruent with an earlier narrative review of 70 studies by Torrey [ 8 ], who reported an overall prevalence estimate of 4.6 per 1,000. Key policy documents have correctly estimated the point prevalence of schizophrenia at about four per 1,000 [ 2 , 225 ]; however, the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) [ 3 ], reported that the lifetime prevalence of schizophrenia is “usually estimated to be between 0.5% and 1%.” This overestimate is often repeated in textbooks [ 226 ]. As with the misunderstandings about the incidence of schizophrenia [ 21 ], this is another example where the research community needs to review their belief systems in the face of data. It is reasonable to assume that lifetime prevalence estimates for schizophrenia would be higher than point estimates. Surprisingly, the data in this review do not support this assumption. While outside the scope of the current review, the findings raise interesting research questions about factors that may influence prevalence (e.g., recovery, suicide, or other forms of early mortality). Indeed, it is curious that the identification of the onset of psychotic disorders has received so much recent attention [ 227 , 228 ], while we still struggle to understand the offset of schizophrenia. Point and period prevalence estimates assume that we can identify when someone has recovered from an illness. Recovery from schizophrenia clearly occurs [ 229 – 231 ], but it is unclear whether those who are free of positive symptoms but who have mild residual disability should be counted as “active” cases or not. The definitions of recovery versus persistence are multidimensional, and future prevalence studies will benefit if these definitions can be operationalized.

The median LMR estimate was 7.2 per 1,000, which is consistent with two other narrative reviews. Fremming [ 232 ], who reviewed 18 studies conducted in central Europe between 1926 and 1938, reported a mean LMR of 7.4 per 1,000, while Gottesman and Shields [ 233 ] reported a mean LMR of 8.0 per 1,000 in their classic review. As predicted, LMR estimates were significantly higher than lifetime estimates, which reflects the different heritage of these two indices. It is reasonable to assume that the oft-quoted statistic that “schizophrenia affects about one in a hundred” derives from LMR data (see [ 234 ]). However, one in a hundred is an overestimate—our systematic review agrees with two previous reviews showing that the LMR for schizophrenia is between seven and eight per 1,000. While the arithmetic mean value of 11.9 per 1,000 is more consistent with the “one in a hundred” dogma, the median is a more appropriate measure of central tendency for this skewed distribution. If we wish to provide the general public with a measure of the likelihood that individuals will develop schizophrenia during their lifetime, then a more accurate statement would be that “about seven to eight individuals per 1,000 will be affected.”

While there has been considerable debate about whether or not the incidence of schizophrenia varies between sites [ 21 ], there is a tacit understanding that the prevalence of schizophrenia is variable. For example, in an earlier review by Eaton [ 5 ], a 12-fold variation in point and a 10-fold variation in lifetime prevalence were noted. A recent systematic review by Goldner et al. [ 12 ] also observed a 13-fold variation in lifetime prevalence of schizophrenia. Based on the central 80% of the estimates (10% to 90% quantiles), the present review found that the different types of prevalence estimates had from 3.4-fold (point) to 4.6-fold (period) variation. The use of the 10% and 90% quantiles to define the central segment of the distribution means that our reporting of the variability of estimates is more conservative than other commentators (i.e., we have ignored 20% of the distribution in the tails). If we had included all data points, the range of prevalence estimates would have been much higher. Regardless of whether this variability is labeled “narrow” or “prominent,” the task for the researchers is to determine how much of this variation is a function of measurement error versus “true” underlying variation. With respect to measurement error, it should be noted that this study found that quality of the study does significantly influence prevalence estimates. Future studies could explore the impact of quality on the variation in prevalence estimates.

Sex and Schizophrenia

One of the unexpected findings of this review was that there was no statistically significant difference in prevalence estimates between males and females. In our previous study of incidence of schizophrenia we found a male:female risk ratio of 1.40 [ 1 ]. Because narrative reviews conclude that the course of the illness tends to be more severe in men than in women [ 235 ], we assumed that this would be reflected in a higher prevalence in males than females. The lack of coherence between (a) the sex differences found in the incidence of schizophrenia, (b) the presumed difference in course of illness, and (c) the identified lack of difference in prevalence warrants closer scrutiny.

Economic Status and Schizophrenia

In keeping with our hypothesis, the prevalence of schizophrenia is lower in developing nations than in developed nations. However, we urge caution in the interpretation of these data. The use of a single economic variable is a crude way to assess a complex and multidimensional concept. Furthermore, the median prevalence estimates for emerging economies are numerically higher than those for the richest countries. While not statistically significant, the results did identify many prevalence studies from the developing world where females outnumbered males. Recently, a study from China examined whether this unexpected sex ratio was due to differential suicide rates in males with schizophrenia [ 24 ]; however, this did not seem to explain the female excess. Our findings lend weight to the commentary by Ran and Yu-Hai Chen [ 25 ], drawing attention to the different features of schizophrenia in the developing world. Overall, the findings suggest that factors that influence the course of illness of schizophrenia in men and women differ around the world. Regardless of the mechanisms underlying this possibility, the findings highlight the importance of using systematic techniques to identify data; 17 studies included in this review were only available in languages other than English. We speculate that the results of past narrative reviews may have been biased towards data from developed nations. From a wider perspective, the findings reinforce the importance of encouraging more research from poorer countries [ 236 ].

Urbanicity and the Prevalence of Schizophrenia

In the previous systematic review of the incidence of schizophrenia, we found that urban sites had significantly higher incidence rates of schizophrenia than mixed urban/rural sites (there were too few pure rural sites to make the direct urban versus rural comparison) [ 1 ]. Contrary to our expectations, the prevalence of schizophrenia did not differ according to urbanicity. While Figure 10 suggests that mixed urban/rural sites have higher prevalence estimates than pure urban and rural sites, this study found, in fact, that there was no significant difference between urban, rural, and mixed sites. Perhaps the inclusion of many sites from the developing world in this review has confounded the expected urban/rural gradient. This will be examined in more detail in future analyses.

Migrant Status and the Prevalence of Schizophrenia

As predicted, prevalence estimates for migrant groups tend to be higher than estimates for native-born populations. This finding is consistent with past systematic reviews of the incidence of schizophrenia [ 1 , 33 ]. Migrant studies are prone to a range of methodological issues (e.g., differential pathways to care, diagnostic inaccuracies due to language and cultural practices, and uncertainty about the denominator required for the calculation of proportions). While the prevalence estimates included in this systematic review may share common biases, the increased prevalence of schizophrenia in migrant groups found in this study adds weight to the argument that migrant status is an important risk factor for schizophrenia.

Quality Scores and Other Special Groups

Reassuringly, studies that had higher overall quality scores tended to identify more cases, and thus generate higher prevalence estimates than lower quality studies. Future studies will explore whether the findings based on the overall studies persist in the subgroup of studies in the highest quality tercile.

With respect to the studies included in the category “other special groups,” the estimates are not readily comparable, but it is interesting to note that these studies reported a wide range of prevalence estimates (e.g., high in homeless populations and low in certain religious groups). Future publications will examine these groups in more detail.

Based on our experience with previous systematic reviews, we acknowledge that we may have missed studies and/or made data entry errors. We encourage readers to inform us of missing studies or errors in the data. Updated lists of relevant studies and raw data will be available from the authors. Furthermore, in the absence of clear guidelines on how to synthesize descriptive studies [ 26 , 237 ], many of the rules we used to filter studies and extract data were necessarily ad hoc. In the future, researchers may wish to reanalyze the dataset using different criteria, and perform sensitivity analyses related to these choices.

Two of the prevalence types (LMR and inpatient-census-derived data) had distributions for persons that were higher than distributions for both males and females separately. This pattern, which is difficult to explain, was also noted in some of the previously published incidence distributions [ 1 ]. The impact of quality scores on this pattern will be assessed in future studies.

The planned sensitivity analyses were conducted on combined data, a strategy that reduced the number of comparisons substantially (one combined analysis versus five analyses on each of point, period, lifetime, LMR, and NOS data). However, the combined prevalence estimate included studies that contributed more than one prevalence type (e.g., one study could contribute both point and period prevalence estimates). Of the 94 studies, eight contributed more than one prevalence type to the combined prevalence estimates. While the analytic technique controlled for within-study variance, the combined dataset is not based on discrete data (in contrast to the prevalence-type-specific analyses).

It was disappointing that standard errors could be allocated to so few prevalence estimates (26%). Despite this, in the future we plan to undertake a traditional meta-analysis based on this subset of estimates in order to compare the pooled estimate values with those presented in the current study.

Concerning the analyses for urbanicity, the estimates from mixed urban/rural studies are likely to be very heterogeneous. Indeed, we allocated studies to the mixed category if there was any possibility that rural sectors were included. This bias would have made any true difference between urban versus mixed urban/rural more difficult to detect. There are good reasons to review the findings for both urbanicity and sex ratio more closely when categorized by economic status. Such analyses may help generate hypotheses for future analyses, but researchers need to be extremely cautious when systematic reviews are subjected to excessive data analyses (i.e., “data torturing” [ 238 ]). The contributing studies were not designed to test many of the hypotheses examined in this review, therefore researchers must be frugal in the use of planned sensitivity analyses, and cautious in the interpretation of the results. However, researchers are encouraged to freely explore the full data to examine additional research questions.

While there is substantial variation between sites, generally the prevalence of schizophrenia ranges from four to seven per 1,000 persons, depending on the type of prevalence estimate used. Countries from the developing world have a lower prevalence of schizophrenia. Overall, the prevalence of schizophrenia does not vary between the sexes; however, the data suggest that sex ratio of prevalence estimates may vary between sites more than previously believed. While the incidence of schizophrenia is higher in urban than rural settings, this is not reflected in the overall prevalence data. The prevalence of schizophrenia is higher in migrants than native-born individuals.

Regardless of the exact magnitude and precision of prevalence estimates, the numbers speak to a deeper, human dimension. Many people with schizophrenia have persisting symptoms, despite the best mix of interventions we can offer. This sobering reality has also emerged from research about “best buys” with respect to the cost of averting disability [ 239 ]. For schizophrenia, with the current mix of interventions we can only reduce 13% of the burden. If we improve efficiencies within the current services, we can do somewhat better (22%). In a utopian world, even if unlimited funding were available, three-quarters of the burden of schizophrenia would remain unavoidable [ 240 ]. This is a powerful argument for investing in applied and basic research.

As with its companion study on the incidence of schizophrenia [ 1 ], we hope that the current review will populate the “epidemiological landscape” with data, and that this enriched environment will select the fittest (most heuristic) hypotheses [ 21 ]. The epidemiological landscape of schizophrenia is no longer terra incognita—many of its contours have been mapped out. We can gain traction on this landscape and use the identified gradients to generate candidate risk factors for future research [ 241 ]. Equally, these systematic reviews have brought into focus the gaps in our knowledge—parts of the map “do not fit.” Paradoxes such as these can be powerful catalysts for advancing knowledge.

Supporting Information

Dataset s1. access dataset of prevalence studies.

https://doi.org/10.1371/journal.pmed.0020141.sd001

(272 KB ZIP).

Table S1. Definitions of Prevalence Estimate Types

https://doi.org/10.1371/journal.pmed.0020141.st001

(32 KB DOC).

Table S2. Definitions for the Variables Used to Characterize the Prevalence Studies

https://doi.org/10.1371/journal.pmed.0020141.st002

(43 KB DOC).

Table S3. Quality Score Criteria

https://doi.org/10.1371/journal.pmed.0020141.st003

(38 KB DOC).

Table S4. Characteristics of Core Prevalence Studies

https://doi.org/10.1371/journal.pmed.0020141.st004

(644 KB DOC).

Table S5. Characteristics of Migrant Prevalence Studies

https://doi.org/10.1371/journal.pmed.0020141.st005

(136 KB DOC).

Tables S6. Characteristics of Other Special Groups Prevalence Studies

https://doi.org/10.1371/journal.pmed.0020141.st006

(243 KB DOC).

Acknowledgments

The authors wish to express their gratitude to the following colleagues who assisted in the search for data and translation of the studies: R. C. Bland, D. Blazer, S. Caleo, G. Canino, B. Cooper, J. Copeland, J. Cullberg, H. Dominique, O. El Saadi, M. Fichter, R. Grawe, S. C. Gupta, H. Herrman, A. Isailovic, E. Jacko, F. Jacobi, H. Katchadourian, K. Kendler, B. Moreno-Kustner, I. Levav, C. MacCauley, D. McLean, R. McCreadie, P. Munk-Jorgensen, A. Preti, P. Rabins, J. Robertson, A. Robinson, S. Scheurer, P. Shrout, L. Teplin, P. Thomsen, E. F. Torrey, M. Von Korff, J. Waddington, A. Weeke, M. Weingarten, M. Weissman, Z. Welham, E. Wells, and H. Wittchen. The Stanley Medical Research Institute supported this project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Contributions

JM designed the study. SS, DC, JW, and JM analyzed the data and contributed to writing the paper.

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Patient Summary

Background..

Schizophrenia is a very serious mental illness and a major contributor to the global burden of disease. The topic of this study is the question of how common schizophrenia is among different groups and in different countries around the world. “Prevalence” means the number of people who have the disease at a particular time. The study itself is a so-called systematic review, which means the researchers used prespecified methods for finding individual studies and for extracting and summarizing the data from these individual studies in as objective a way as possible.

Why Was This Study Done?

Health care planning is based on prevalence estimates, and as a result, many studies on schizophrenia prevalence have been done by researchers around the world. The authors decided to do a systematic review of these studies to come up with a scientifically sound view of the big picture.

What Did the Researchers Do?

They looked at a total of 1,721 estimates of the prevalence of schizophrenia from 188 studies and covering 46 countries. They then calculated median prevalence estimates (that is, the middle value of all estimates) over a variety of time periods (see below).

What Did They Find?

The take-home message from their study is that about seven to eight individuals out of 1,000 will be affected by schizophrenia. To be more precise, the researchers found the following median estimates for the prevalence of schizophrenia: 4.6 out of 1,000 people have the disease at a specific time point; 3.3 per 1,000 have the disease within a surveillance period one to 12 months long; the lifetime prevalence (the number of people in the population who have ever manifested the disease) is 4.0 per 1,000; and the lifetime morbid risk (the likelihood that a particular individual will develop schizophrenia in their lifetime) is 7.2 per 1,000. While previous research has shown that men have a higher risk of developing schizophrenia, the researchers found that the prevalence of schizophrenia was the same in men and women (suggesting that the course of the illness differs between the sexes). The prevalence of schizophrenia was lower in poorer countries than in richer countries.

What Does This Mean?

Based on these estimates, our textbook numbers on lifetime prevalence and overall risk for an individual to develop schizophrenia are probably too high. Taken together with estimates on the incidence of schizophrenia (that is, the annual number of new cases), it is also clear that current treatments fail to cure most patients with schizophrenia.

More Information Online.

Additional information on schizophrenia can be found at the following sources.

United States National Institutes of Mental Health (search for “schizophrenia”): http://www.nimh.nih.gov/

Schizophrenia.com, a not-for-profit Web site providing information and education on schizophrenia: http://www.schizophrenia.com

For an explanation of systematic reviews: http://www.shef.ac.uk/scharr/ir/units/systrev/definitions.htm ; http://www.cochrane.org/index0.htm

For definitions of incidence and prevalence: http://www.wrongdiagnosis.com/admin/preval.htm

For more information about the systematic reviews of the incidence and prevalence of schizophrenia: http://www.qcmhr.uq.edu.au/epi/

• Open access
• Published: 13 April 2021

Effectiveness of community-based interventions for patients with schizophrenia spectrum disorders: a study protocol for a systematic review

• Soo-Yeon Kim 1 &
• Ah. Rim Kim 2  

Systematic Reviews volume  10 , Article number:  106 ( 2021 ) Cite this article

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Metrics details

Schizophrenia requires a community-based intervention approach combined with standard treatment to prevent relapses. A literature review is required to understand the effectiveness of community-based interventions and to enhance quality in countries where they have not been fully established. This is a protocol for a systematic review of the effectiveness of community-based interventions for patients with schizophrenia spectrum disorders.

We will search (from inception to January 2021) PubMed/MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL, and Research Information Sharing Service/Korean databases. Randomized controlled trials on community-based interventions for patients with schizophrenia spectrum disorders will be eligible. The comparison groups will include patients with schizophrenia spectrum disorders who are only receiving the usual care and those who also receive community-based interventions. The schizophrenia spectrum disorders referred to in this study are defined according to the DSM-5: delusional disorders, schizophrenic disorders, and schizoaffective disorder will be included. Relapse/re-hospitalization rates (primary outcome) and quality of life (secondary outcome) will be identified for each group. Two reviewers will independently screen study titles, abstract data, and full-text articles and perform the data extraction process. Potential conflicts will be resolved through discussion. The study risk of bias will be appraised using the Cochrane Risk of Bias 2.0 tool. Results will be descriptively synthesized and will be structured according to patients’ characteristics, intervention type and exposure, and outcome type. If feasible and appropriate, outcome data will be used to perform random effects meta-analyses. Discrete variables will be calculated via odds ratio, and continuous variables will be calculated via standardized mean difference using RevMan 5.3 software.

We will provide a summary of the available evidence on the effectiveness of community-based interventions and specific guidelines to improve their outcomes.

Systematic review registration

PROSPERO ( CRD42019145660 ).

Peer Review reports

Recently, in Korea, as violent crimes performed by patients with schizophrenia began to rise and became a social issue, the social atmosphere created a negative bias related to this mental illness [ 1 ]. Social issues related to patients with schizophrenia should be approached in a way that allows for the identification of blind spots in mental illness management, rather than just focusing on the crimes that occurred, and should also recognize the need for a closer look and care at the community level, which may ultimately help these individuals, when combined with regular treatment.

Schizophrenic episodes recur in patients at a high rate after diagnosis [ 2 ]. Relapse rates for schizophrenia are associated with the discontinuation of their respective antipsychotic drug treatments; therefore, symptoms such as violence are relatively well controlled―unlike social prejudice―when drug treatment is well adapted to the patient’s life [ 3 ]. Contrastingly, untreated schizophrenia tends to lead patients to repeated hospitalization due to frequent symptomatic relapses, a process that eventually leads to a general deterioration in individuals’ quality of life, provoked by difficulties related to cognitive skills, communication and interpersonal relationships, and significant social withdrawal [ 4 , 5 , 6 ].

Additionally, schizophrenia has been shown to have a higher requirement related to family care compared to other chronic conditions [ 7 ], mainly because it is difficult to maintain patients’ insight into their treatment and drug compliance, as well as manage their symptoms, which is represented by high relapse rates. Thus, schizophrenia requires long-term comprehensive care combined with standard treatment, to prevent recurrence and improve the individuals’ function on a daily basis.

Several studies have shown positive effects of interventions when used in parallel with the standard treatment for the management of schizophrenia. In groups who present low drug compliance and violent tendencies, symptoms were significantly reduced after more than 6 months of assisted outpatient treatment [ 8 ]. The results of a 2018 meta-analysis suggested that community-based interventions that are performed in the initial stages of the mental illness are effective to diminish the symptoms of schizophrenia, compared to the standard treatment [ 9 ]. Additionally, case management for more than 2 years has shortened the length of re-hospitalization [ 10 ].

Community-based interventions have shown to be effective not only in terms of the costs associated with hospitalization but also in terms of the quality of life and family burden of patients [ 11 ]. Particularly, it has been shown to help patients with schizophrenia in maintaining education and/or getting a job, which has resulted in their social reintegration and personal development [ 12 ].

Based on these positive effects of community involvement, many countries encourage community-based interventions. The National Institute of Clinical Excellence Guidelines in the UK emphasizes the need for community-based psychiatric intervention, such as cognitive therapy, counseling, and family intervention, in addition to standard treatment [ 13 ]. In Korea, since the enactment of the Mental Health Act in 1995, a policy of deinstitutionalization has been established with the help of the Mental Health Center, and community-based case management programs for various mental disorders have been developed and carried out [ 11 , 14 ]. However, to date, they have not been fully established, and community support systems are still vulnerable [ 15 ].

Thus, we deem that a systematic review on community-based intervention programs related to the treatment of schizophrenia is required. Similar studies were conducted in 2014 [ 16 ] and 2017 [ 17 ]; however, those studies were limited to low- and middle-income countries and they cannot be considered an international standard, thereby limiting the usefulness of their findings. The community-based interventions for schizophrenia spectrum patients were reviewed comprehensively in 2013 [ 18 ], but the effectiveness of the community program was not known because meta-analysis was not carried out.

This study protocol is not limited to a specific country or economic level, but plans an overall review, allowing the results to be presented in detail by type and duration of disease. Our review will cover patient categories in the schizophrenia spectrum disorders. These disorders look similar, with psychosis as a common symptom, but there are slight differences in duration and symptoms of the diseases, and finding suitable treatments is difficult considering these differences. For example, most schizophreniform disorders and brief psychotic disorders were thought to have fast remissions and retain this status relatively well [ 19 , 20 , 21 ]. In addition, depressive and manic dimensions are significantly higher in schizoaffective patients than in schizophrenia patients [ 22 ]. Delusional disorders cause no functional damage other than in the areas of life associated with delusions [ 19 ]; thus, general function is evaluated as being higher than that of schizophrenia patients [ 22 ]. If we can numerically determine which patients or symptoms each community-based intervention is particularly effective for, it will ultimately help patients, caregivers, and community-service providers identify the most suitable community services.

Analyzing the effectiveness of community-based intervention studies developed and applied worldwide to date through a comprehensive systematic review proves a necessary step in developing community-based intervention programs for patients with schizophrenia. This systematic review allows for the planning of community-based interventions in countries where foundations for community-based interventions have not yet been established. Furthermore, new evidence-based recommendations may be provided for countries where existing community intervention has been established. Thus, this review will aim to

Identify the relapse and remission rates for patients with schizophrenia who have participated in community-based intervention programs.

Identify the quality of life for patients with schizophrenia and their families who have participated in community-based intervention programs.

Materials and design

The present protocol has been registered within the PROSPERO database (registration number CRD42019145660) and is being reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews Meta-Analyses Protocols (PRISMA-P) statement [ 23 ] (see checklist in Additional file 1 ). This systematic review will be conducted in accordance with the Cochrane Handbook for Systematic Reviews of Intervention, 2nd edition [ 24 ]. As recommended by the handbook, we derived the review question through consultation with stakeholders, consisting of a community mental health center practitioner, a psychiatric nurse, and mental health policy experts. Finally, the search strategy was reviewed by search experts (medical librarians).

Review inclusion criteria

Participants.

This review will include all patients with schizophrenia spectrum disorders who received/were subject to a community-based intervention program. The patients considered in our study are diagnosed as having schizophrenia spectrum disorders as defined by the Diagnostic and Statistical Manual of Mental Disorder, 5th edition (DSM-5) [ 19 ]. Schizophrenia spectrum disorders include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and psychotic disorder not otherwise specified. Because psychotic symptoms are common characteristics, all diagnoses are included in the review literature, but the results are presented separately according to the individual diagnosis.

In addition to the differences inherent to their diagnosis, patients with these diagnoses may experience differences in treatment effects over the duration of the disease, so the results will be presented separately, based on the duration of the patients’ illness (divided into the first episode or chronic status).

Intervention

This review will consider studies that evaluate any type of intervention programs that originated from the community-based intervention program for patients with schizophrenia. Those interventions may include but are not limited to, case management, cognitive behavioral therapy, occupational rehabilitation, and physical intervention programs.

Comparators

The comparison groups will include one group of patients with schizophrenia spectrum disorders who are receiving the usual care (outpatient treatment that includes only medication) and a group who also receive community-based interventions in addition to the usual care.

Exploratory analysis will be conducted to identify the relapse, recovery, and/or remission rates of psychotic symptoms. In addition, the review will include the patients’ symptomatic severity and quality of life as outcomes of the community-based intervention. The patients’ conditions will be verified by the number and duration of hospitalizations after the community-based intervention, by their scores on the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Global Assessment of Functioning (GAF). Quality of life will be defined by the patients’ and their respective caregivers’ Quality of Life Scale scores. Thus, any studies that report any of the above outcomes will be included.

Study design

This review will only consider randomized controlled trials (RCT). Non-randomized controlled trials (non-RCT), cohort studies, case studies, and review articles will be excluded. It will report the specific characteristics of all included studies, using the inclusion criteria that the studies must be written in either English or Korean. We will not include data in the study results because it is difficult to extract data accurately for non-English or non-Korean written papers, but we will inform readers of ‘Studies Awaiting Classification’ through the PRISMA flowchart so that they can be used in other possibly-relevant reports. As community-based mental health services would have been implemented at various times in different countries, we will place no restrictions on the date of publication, and will consider any papers published until 6 January 2021. We will include not only peer reviewed papers but also gray literature (e.g., conference papers, reports, theses/dissertations, protocols) to reduce the bias in our research findings. Therefore, in cases of conference proceedings or protocols without data, we will manually search for full-text or contact the author to request unpublished data for systematic review.

Electronic bibliographic databases

Electronic searches will be conducted on the following databases from inception to 6 January 2021: MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Research Information Sharing Service (Korean database). To supplement these searches and reduce publication bias, we will expand our search for gray literature using System for Information on Grey Literature in Europe (SIGLE) and GreySource. We will search dissertations and theses by using Open Access Theses and Dissertations (OATD) and ProQuest Dissertations and Theses Global (PQDT). We will manually search the ClinicalTrials.gov website and International Clinical Trials Registry Platform search portal to identify relevant studies. Other avenues for identifying studies will be to use advanced search on Google Scholar, Scopus, and Web of Science. If only conference proceedings or trial protocols are in the search document, we will email the author to request the unreleased data.

Search strategy

The search strategy aims to find published or unpublished that are in accordance with the Population Intervention Comparison and Outcome Process. An initial search of PubMed will utilize text words related to the systematic review research question: “schizophrenia” and “community based” or “community mental health services.” Then, we will identify relevant keywords by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the relevant articles to refine our search. Draft search strategies are provided in Additional file 2 .

Study screening and selection

Search results will be downloaded using Endnote software, X9 version, and duplicate studies will be eliminated. In the first review, we will review the title and abstract of the selected studies to identify populations, intervention and outcome variables, and study designs to eliminate non-relevant literature; in the second review, a full-text review will identify the final literature of the selected studies. Each selected study will be independently reviewed by two researchers and will be cross-reviewed by both researchers. During the process, if opinions do not agree among researchers, the text will be reviewed together until the researchers reach an agreement.

Data extraction

Data extraction will include specificities about populations, types of interventions, study designs, and outcome variables. Researchers will select five articles to create a pilot-format data extraction tool, and this tool will use the EPPI reviewer version 4.11.5.2 ( http://eppi.ioe.ac.uk/ ).

In addition to the outcome data, descriptive details such as study designs (e.g., multicenter or cluster), participants’ characteristics (e.g., age, gender, diagnosis, disease status), methods used in the analysis, and methods of intervention (handling) will also be recorded and reviewed. The amount, duration, frequency, and intensity of each reported intervention will also be included in the record. The demographic characteristics and types of interventions will also be specified to enhance the study analysis and synthesis.

If there are any missing or unclear data, we will contact the author of the original research to clarify.

Assessing risk of bias

For RCT studies, we will use the Cochrane RoB 2.0 tool [ 25 ]. RoB is a tool that combines both the checklist method and area evaluation method, and it is an important tool because its area evaluation randomizes sequence generation, which blinds parts of the study and study personnel, blinds the outcome assessments, and does not include incomplete outcome data, which helps us avoid selective reporting and other possible types of biased selection. To avoid the risk of biases in each question, they will be judged as “high,” “low,” and “uncertified” bias, in accordance with the specific presented guidelines. Any disagreement will be resolved by discussion.

Descriptive analysis

Our review results will be descriptively synthesized and analyzed. The structure of the studies will be described, and they will be structured according to the following characteristics:

The characteristics of target populations

The type of intervention

Intervention exposure (e.g., intervention duration/times, individual or team approach)

The type of outcome

Statistical analysis

We will perform a meta-analysis that will first calculate summary estimates of individual studies. In this study, the results will be reported and divided into studies with discrete (hospitalization incidence rate) or continuous (hospitalization period; clinical scale involving PANSS, GAF, BPRS; quality of life) variables. The hospitalization rate will be calculated via odds ratio and other continuous variables (e.g., t, F, p), and the standardized mean difference will be used to calculate effect sizes, which will be calculated by merging the effect sizes of individual studies using the RevMan 5.3 software.

We will quantify statistical heterogeneity by estimating the variance between studies using I 2 statistic [ 26 ]. The I 2 is the proportion of variation in study outcomes between studies that is due to genuine variation rather than random error. I 2 ranges between 0% and 100% (with values of 0–25% and 75–100% taken to indicate low and considerable heterogeneity, respectively). If feasible and appropriate, outcome data will be used to perform random effects meta-analyses because of heterogeneity is expected a priori. The random effects model assumes the study level effect estimates follow a normal distribution, considering both within-study and between-study variation. Factors expected to contribute to heterogeneity include the clinical characteristics of the patients, including the severity of the disease, the comorbidity, the exact diagnosis, and the duration of the disease, which have all been reported to have an effect on treatment in previous studies [ 27 , 28 , 29 , 30 ]. Therefore, the subgroups will be set up in consideration of clinical characteristics and types of interventions, so that the likelihood of statistical errors is reduced. If quantitative synthesis is not appropriate due to high heterogeneity, we will only perform a descriptive synthesis.

Confidence in cumulative evidence

For strength of evidence related to all outcomes, we will assess evidence using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method, and it will be judged as “high,” “moderate,” “low,” and “very low” [ 31 ].

This systematic review of the effect of community-based interventions on patients with schizophrenia spectrum disorders will provide a detailed summary of the available evidence on the effectiveness of this type of intervention, and we intend to provide specific guidelines to help improve the outcomes of community mental health services. This will lay the groundwork for its role in enabling community centers to actively support patients diagnosed with the schizophrenia spectrum disorders. However, as this study focuses only on the effectiveness of community-based interventions, it is only discussed in patients who have already enrolled in community centers. In other words, it does not address direct strategies for connecting patients with schizophrenia spectrum disorders from hospital to community or finding untreated patients in the community. If the positive community-based intervention effect is known in detail through this systematic review, although it is expected to have a positive impact on making patient enrollment in the community center easier, follow-up study on effective ways to connect patients and community centers after discharge may also be considered. Findings of this study will be disseminated through publication in a peer-reviewed journal and conference presentations to mental healthcare providers in community center.

Among the final selected studies, it is used to derive effects by synthesizing the results of studies evaluated from risk of bias to ‘low’ or ‘some concerns.’ Since we only consider studies written in English and Korean, publication bias attributed to them may affect the results of the study.

The searched literature will be covered by January 2021, but if the systematic review is delayed due to the unexpected number of studies requiring full text review, the search period can be extended to add the latest literature. When conducting a review, all amendments made, including these further searches, will be outlined in PROSPERO and reported in the final manuscript.

Availability of data and materials

The study protocol does not include the dataset, but the search strategy is included.

Abbreviations

Brief Psychiatric Rating Scale

Cumulative Index to Nursing and Allied Health Literature

Global Assessment of Functioning

Grades of Recommendation Assessment, Development and Evaluation

Non-randomized control trials

Positive and Negative Syndrome Scale

Population Intervention Comparison and Outcome

Preferred Reporting Items for Systematic Reviews and Meta-analyses

Quality of Life Scale

Randomized control trials

Standardized mean difference

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Acknowledgements

We consulted on the research protocol by forming a group of stakeholders. The stakeholders are the Director of Community Mental Health Center (M.S.C), Research officers of National Center for Mental Health (M.K.J and S.J.R), and psychiatric nurse (M.H.L).

This research received no external funding.

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Conceptualization, S.Y.K; design, S.Y.K.; writing—original draft preparation, S.Y.K. and A.R.K; writing—review and editing, S.Y.K. and A.R.K. All authors have read and agreed to the published version of the manuscript.

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PRISMA-P 2015 Checklist

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Kim, SY., Kim, A.R. Effectiveness of community-based interventions for patients with schizophrenia spectrum disorders: a study protocol for a systematic review. Syst Rev 10 , 106 (2021). https://doi.org/10.1186/s13643-021-01662-0

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McDonagh MS, Dana T, Selph S, et al. Treatments for Schizophrenia in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 Oct. (Comparative Effectiveness Reviews, No. 198.)

Treatments for Schizophrenia in Adults: A Systematic Review [Internet].

Evidence summary.

• Condition and Treatment Strategies

Schizophrenia is a chronic mental health condition that most often presents in early adulthood and can lead to disabling outcomes. The most recent version of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders , 5th edition, ( DSM-5 ), 1 defines schizophrenia as: the presence of two or more of the five core symptoms (delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms), with at least one of the symptoms being delusions, hallucinations, or disorganized speech, and the presence of symptoms for at least 6 months. Differential diagnosis is broad, and includes delineation from mood disorders (bipolar disorder or major depressive disorder) with psychotic features and substance/medication-induced psychotic disorders. The course of schizophrenia varies. Approximately 20 percent of individuals may experience significant improvement including, in some cases, full recovery; however, the majority tend to experience some degree of social and occupational difficulty as well as need for daily living supports. 2 That said, more recent research and practice has focused on early intervention with first episode psychosis, demonstrating promise toward improving outcomes sooner and reducing longer-term disability. 3 , 4

Antipsychotic medications and nonpharmacological treatments are typically used together when treating individuals with schizophrenia. Both pharmacological and nonpharmacological treatments for schizophrenia can result in meaningful improvements in a variety of outcome areas, including psychiatric symptoms, functioning (e.g., employment, social), service utilization (e.g., hospitalization, crisis services), legal system involvement, quality of life, self-harm and aggressive behaviors, treatment engagement and retention, and co-occurring substance abuse. Ideally, improvements in symptoms translate to long-term, clinically relevant, positive changes in other outcome areas, with limited and manageable adverse effects.

Older, first-generation antipsychotics (FGAs), such as haloperidol, have proven efficacy but adverse effects, such as extrapyramidal symptoms and in some cases tardive dyskinesia, often limit long-term adherence. Second-generation antipsychotics (SGAs), beginning with clozapine, were introduced as having equal or better efficacy, particularly with negative symptoms, and lower risk of extrapyramidal symptoms and tardive dyskinesia. SGAs have potentially serious adverse effects (e.g., cardiovascular and endocrinologic effects) that make their overall risk/benefit profile less clear-cut than anticipated.

Although there are a large number of treatments for schizophrenia, it is not clear whether they afford long-term benefits on employment and social relationships and increase the likelihood of recovery, or what the most effective duration of treatment is. Equally important in selecting among competing interventions for a specific patient is consideration of patient-level characteristics that may affect the outcomes across a diverse group of possible interventions.

• Scope and Key Questions

Scope of the Review

This systematic review provides a comprehensive review of current evidence that can help in determining how to treat individuals with schizophrenia. The review synthesizes evidence on pharmacological treatments compared with each other and the general effectiveness of psychosocial and other nonpharmacological strategies compared with usual care for treating individuals with schizophrenia, and highlights areas of controversy and areas for future research. The analytic framework ( Figure A ) illustrates the population, interventions, and outcomes considered. Due to a very large body of research literature, the review has been focused in several ways (see Methods ).

Analytic framework. Pharmacological treatments: At least 90 percent of patients must have been diagnosed with schizophrenia. For studies specifically on harms of antipsychotic drugs, populations can be mixed-diagnoses, as the harms are not diagnosis-specific (more...)

Key Questions

What are the comparative benefits and harms of pharmacological treatments for adults with schizophrenia?

How do the benefits and harms of pharmacological treatments for adults with schizophrenia vary by patient characteristics? a

What are the benefits and harms of psychosocial and other nonpharmacological treatments for adults with schizophrenia?

How do the benefits and harms of psychosocial and other nonpharmacological treatments for adults with schizophrenia vary by patient characteristics? a

The methods for this systematic review follow the Methods Guide for Effectiveness and Comparative Effectiveness Reviews 5 and are reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist. 6 The scope of the report was developed with consultation with a group of key informants. The details of the inclusion criteria, including the prioritized list of outcomes, were developed with input from a group of technical experts. See the full report and the review protocol ( http://effectivehealthcare.ahrq.gov/index.cfm ) for additional details on methods.

Literature Search Strategy and Inclusion Criteria

A research librarian searched Ovid MEDLINE ® , the Cochrane Library, and PsycINFO ® . For Key Question 1 , recent high-quality systematic reviews were used as the starting point, such that our searches began in 2011 for FGA versus SGA drugs and in 2013 for SGA versus SGA drugs. For Key Question 2 , search dates were not restricted. Searches were conducted through February 1, 2017. Other standard search methods were also applied. Only English-language articles were included. A summary of the eligibility criteria and review methods are described below, and further details are in the full report.

Key Eligibility Criteria

Population(s): Adults with a diagnosis of schizophrenia

Interventions:

• Fluphenazine (Prolixin ® , Permitil ® )
• Haloperidol (Haldol ® )
• Perphenazine (Trilafon ® )
• Aripiprazole (Abilify ® , Aristada™)
• Asenapine (Saphris ® ),
• Brexpiprazole (Rexulti ® )
• Cariprazine (Vraylar™)
• Clozapine b (Clozaril ® , Fazaclo ® ODT , Versacloz™)
• Iloperidone (Fanapt ® )
• Lurasidone (Latuda ® )
• Olanzapine b (Zyprexa ® , Zyprexa Zydis ® ),
• Olanzapine Pamoate (Zyprexa ® Relprevv™)
• Oral paliperidone is marketed only as an extended-release product, and will be noted as paliperidone in the report because there is no immediate-release formulation.
• The extended-release formulation is noted as quetiapine ER in this report; the immediate-release formulation is not noted by a suffix to be consistent with the other immediate release formulations of SGAs.
• Risperidone b (Risperdal ® , Risperdal ® M-TAB ® ODT (oral dissolving tablet), Risperdal ® Consta ® )
• Ziprasidone b (Geodon ® )
• Assertive community treatment
• Cognitive adaptive training
• Cognitive behavioral therapy
• Cognitive remediation/training
• Co-occurring substance use and schizophrenia interventions
• Early interventions for first episode psychosis
• Family interventions
• Intensive case management
• Illness self-management training
• Psychoeducation
• Social skills training
• Supported employment
• Supportive therapy

Comparators:

• Key Question 1 : Head-to-head comparisons: FGAs versus SGAs, and SGAs versus SGAs.
• Usual care can consist of elements of medication treatment, medication management, case management, rehabilitation services, and psychotherapy. Both groups (treatment and usual care) received usual care, including drug treatment throughout the study.
• Evidence with active controls (other interventions with expected benefit, or attention controls which have minimal or no benefit but similar patient participation time) was considered where the evidence base with usual care comparisons for a given intervention is too small to draw conclusions (i.e., one or two trials, no systematic reviews).

Outcomes for each question (see also outcomes in Figure A ):

We limited the outcomes to those that are patient centered health outcomes (rather than intermediate outcomes), which were arranged according to their priority from the perspective of the patient, their family, and their clinicians. We considered advice from our experts in selecting and prioritizing this list of outcomes.

• Key Question 1 : Functional outcomes, quality of life, response and/or remission rate, mortality, reductions in self-harm, overall/any adverse events, improvements in core illness symptoms, and withdrawal due to adverse events.
• Rehospitalization was not included as an outcome because: (1) there is important variation in the indications for and length of psychiatric hospitalizations across time, in different localities, and with different financial contexts, and (2) there is important variation across trials in how rehospitalization is measured/evaluated, which may confound study interpretation. However, it was reported in addition to the prioritized outcomes for assertive community treatment because it is the target of this intervention for patients with a history of frequent hospitalization.
• Minimum duration of followup: 12 weeks.
• United States-relevant, such as countries listed as “high” or “very high” on the United Nations International Human Development Index ( HDI ), and applicable to United States practices.
• Excluded: inpatient setting.

Study designs

• Recent, comprehensive, good- or fair-quality systematic reviews, as well as randomized controlled trials (RCTs) published since the systematic reviews.
• Sample size of >50 for Key Question 2 .

Study Inclusion Decisions

Two independent reviewers assessed study eligibility and extracted data from included studies, with discrepancies resolved by consensus and involvement of a third reviewer, if necessary. Only English-language articles were included. We included trials with study populations of mostly outpatients and duration of at least 12 weeks, and systematic reviews that assessed the comparisons in Key Questions 1 and 2 that were deemed to be good or fair quality (see below). Whenever possible, systematic reviews were used as the primary evidence, with trials not included in reviews also fully evaluated and synthesized with the review evidence.

Risk of Bias Assessment of Individual Studies

Two investigators independently rated the risk of bias (quality) of each included study based on predefined criteria. Disagreements were resolved by consensus. Randomized controlled trials were evaluated with criteria developed by the Drug Effectiveness Review Project. 7 The quality of systematic reviews was assessed using the Assessing the Methodological Quality of Systematic Reviews quality (AMSTAR)-rating instrument. 8 These methods were used in accordance with the approach recommended in the chapter, “Assessing the Risk of Bias of Individual Studies When Comparing Medical Interventions” in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews . 5 Studies were rated as “good,” “fair,” or “poor.”

Data Synthesis

We synthesized results by summarizing study characteristics and investigating whether there were important differences in the distribution in characteristics that modified the treatment effects. Synthesis focused on the better-quality studies. Meta-analyses were conducted when studies were homogeneous enough to provide a meaningful combined estimate. We conducted pairwise meta-analyses, using the DerSimonian and Laird random-effects model. Statistical heterogeneity was assessed using the I 2 statistic or the Q-statistic chi-square. Network meta-analyses were conducted using a Bayesian hierarchical model.

Strength of the Body of Evidence

The strength of evidence ( SOE ) for each prioritized outcome was assessed by two reviewers using the approach described in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews . 5 , 9 We assigned an SOE grade of High, Moderate, Low, or Insufficient for the body of evidence for each outcome, based on evaluation of four domains: study limitations, consistency, directness, and precision. High, Moderate and Low ratings reflect our confidence in the accuracy and validity of the findings and whether future studies might alter these findings (magnitude or direction). We gave a rating of insufficient when we were unable to draw conclusions due to serious inconsistency, serious methodological limitations, or sparseness of evidence.

Peer Review and Public Commentary

Experts in treatments for schizophrenia were invited to provide external peer review of this systematic review; the Agency for Healthcare Research and Quality ( AHRQ ) and an associate editor also provided comments. In addition, the draft report was posted on the AHRQ Web site for 4 weeks to elicit public comment. We addressed the reviewer comments and revised the text as appropriate.

• Results Summary

Summary of Results of Literature Searches

For Key Question 1 on the benefits and harms of pharmacological interventions for schizophrenia, we reviewed 698 titles and abstracts and included one systematic review of 138 trials and 24 additional trials for SGAs versus SGAs, and one systematic review of 111 trials and five additional trials for FGAs versus SGAs. Some studies included comparisons of both intervention areas ( SGA vs. SGA and SGA vs. FGA ). The majority of new trials (71%) were fair quality, with 21 percent rated poor quality and 8 percent good quality.

For Key Question 2 on the benefits and harms of psychosocial and other nonpharmacological interventions for schizophrenia, we reviewed 2,766 titles and abstracts and included 13 systematic reviews of 271 trials and 32 additional trials. The included studies investigated 13 main intervention areas. Of these new trials, 20 were fair quality, four were good quality, and three were poor quality.

For each intervention area, we reported on the available evidence for prioritized outcomes, as described in the Methods section. Prioritized outcomes for which the evidence was insufficient or unavailable are not included in the Results Summary.

Summary of Results by Key Question

Key question 1. comparative evidence regarding antipsychotic drugs.

The findings on antipsychotic drugs came from one systematic review of 138 trials ( N =47,189) and 24 additional trials (N=6,672) for SGAs versus SGAs, and one systematic review of 111 trials (N=118,503) and five additional trials (N=1,055) for FGAs versus SGAs. In our review, we examined the prioritized outcomes: measures of functional abilities, quality of life, response and/or remission, mortality, self-harm, core illness symptoms, overall adverse events, and withdrawal from treatment due to adverse events. Overall, no drug intervention had high-strength evidence for any outcome of interest, but we found moderate-strength evidence for some outcomes. The evidence is divided into SGA versus SGA and FGA versus SGA according to traditional categorization of the drugs used in the two systematic reviews, although the drugs could be considered as one group with variations in effects associated with individual drugs.

Second-Generation Antipsychotics Versus Second-Generation Antipsychotics

We found the most evidence about the older SGAs (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone). We also found some evidence on the most commonly reported outcomes (e.g., core illness symptom improvement) for oral aripiprazole and paliperidone. Evidence for the newer drugs (asenapine, brexpiprazole, cariprazine, iloperidone, lurasidone, paliperidone, and long-acting injection [ LAI ] formulations of aripiprazole and paliperidone) is limited, with few studies, none finding a newer drug superior to an older SGA or each other on any outcome. Similarly, quetiapine and ziprasidone (older SGAs) were not found superior to any other SGA on any outcome.

Benefits Outcomes

Although functional outcomes were prioritized as most important, few studies of SGA versus SGA reported these outcomes. Very few differences were found among the older SGAs regarding effects on social, occupational, or global functioning (low SOE ). A single study found risperidone LAI to result in greater improvements in social function over 24 months compared with quetiapine. None of the studies of the newer SGAs reported on any type of functional outcomes. Findings on quality of life showed that there was no difference between olanzapine and risperidone or ziprasidone (moderate SOE); olanzapine or risperidone oral or LAI and quetiapine; or oral aripiprazole and aripiprazole monthly LAI (low SOE) in studies with up to 2 years of followup.

Symptom response and remission are dichotomous outcomes, which are measured as response or no response, remission or no remission. By definition, response and remission are outcomes that are meant to reflect clinically relevant improvement in core illness symptoms. However, response was defined in varying ways in the trials, although the most common definition was 20 percent improvement on a core illness symptoms scale, such as the Positive and Negative Symptoms Scale ( PANSS ). A network meta-analysis of 46 head-to-head trials found that olanzapine and risperidone were significantly more likely to result in response than quetiapine (low SOE ). Other comparisons and meta-regressions examining the influence of study duration, dose-level, populations (either treatment-resistant or first-episode status), and category of response definition did not result in any statistically significant differences between the SGAs (low SOE). Remission was reported too infrequently to assess comparatively, except in the group of studies on patients with a first episode of schizophrenia.

Improvement in core illness symptoms is a continuous outcome measured as the mean change in symptoms using a scale. A published network meta-analysis of 212 trials found that clozapine was superior to other oral SGAs except for olanzapine in improving core illness symptoms (low SOE ). Olanzapine and risperidone were not significantly different compared with each other, and both were superior to the other SGAs, except for paliperidone and clozapine (low SOE). Paliperidone also improved core illness symptoms more than lurasidone and iloperidone (low SOE). This analysis found that all of the drugs included were superior to placebo. In treatment-resistant patients, olanzapine improved core illness symptoms more than quetiapine. These findings are based on two published network meta-analyses (low SOE).

While infrequent, self-harm, including suicide, is a major cause of death among individuals with schizophrenia that antipsychotics, along with other interventions, are intended to help prevent. Although clozapine is often reserved for treatment-resistant patients, due to the serious adverse event profile and required monitoring, evidence supports its superiority over the other SGAs (primarily the older ones) in preventing self-harm (suicide-related outcomes) in both patients at risk for suicide-related outcomes (versus olanzapine) and in patients with unknown or mixed risk for these outcomes (versus olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) (low SOE ).

Harms Outcomes

Although SGAs have somewhat differing adverse event profiles, the evidence indicates no difference in the overall risk for adverse events between asenapine and olanzapine (moderate SOE ). Differences were also not found between quetiapine extended release ( ER ) versus quetiapine and risperidone; risperidone versus clozapine and aripiprazole; olanzapine versus paliperidone; risperidone LAI versus paliperidone and paliperidone palmitate monthly LAI; and aripiprazole versus aripiprazole monthly LAI (all low SOE). Given the variation in specific adverse event profiles across the SGAs, withdrawals due to adverse events is an outcome measure that has the advantage of measuring the seriousness and tolerability of adverse events experienced, including those that might be treated with another drug or dose reduction. Our network meta-analysis of 90 trials indicates that risperidone LAI had significantly lower risk of withdrawal due to adverse events than five other SGAs: clozapine, lurasidone, quetiapine ER, risperidone and ziprasidone (low SOE). Olanzapine had lower risk than five other SGAs: clozapine, lurasidone, quetiapine, risperidone, and ziprasidone (low SOE). Aripiprazole had lower risk than two SGAs: clozapine and ziprasidone, and cariprazine and iloperidone had lower risk of withdrawal due to adverse events than clozapine (low SOE). Comparative evidence on extrapyramidal symptoms, cardiovascular events, diabetes, weight gain, metabolic syndrome, and sexual function is summarized in the full report. Although these were secondary outcomes in this report, in general the evidence is not able to identify differences between drugs studied in cardiovascular adverse events, metabolic syndrome, and sexual function. Risk of diabetes and weight gain is greater with olanzapine, with increased risk of weight gain also found with clozapine and quetiapine. Findings on extrapyramidal symptoms are more mixed.

All-cause mortality is a rare event, but it is still an important outcome to evaluate as SGAs continue to be developed, approved, and marketed, and particularly as all SGAs carry an FDA Boxed Warning against their use in older patients with dementia due to increased risk of mortality. The mortality rate is low in SGA trials and cohort studies (0 to 1.17%), and there were no differences in mortality rates between olanzapine and risperidone or asenapine, risperidone and quetiapine, or paliperidone palmitate monthly LAI and risperidone LAI. There were also no differences in cardiovascular mortality among risperidone, olanzapine, and quetiapine (low SOE ). Comparative evidence on the risk of cardiovascular or all-cause mortality was not available for the other SGA drugs.

There are few differences among the SGAs in effects on several important outcomes, but in some cases the superior drug has serious adverse effects (e.g., clozapine’s risk of agranulocytosis [severe neutropenia] and olanzapine’s risk of weight gain and new onset diabetes). Therefore, it is especially important to consider how patient characteristics may affect outcomes. Evidence in subgroups was low strength.

In patients experiencing their first episode of schizophrenia, response and remission were not significantly different among olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, or paliperidone. Most studies also reported no difference in improvement in core illness symptoms, measured by symptoms scales, except that core illness symptoms were more improved with paliperidone than ziprasidone or aripiprazole, but response rates did not differ significantly. Response rates with olanzapine and risperidone were similar in patients with first-episode schizophrenia compared with patients with multiple previous episodes. These findings did not differ according to the duration of study, the specific drugs compared, in women, or whether or not studies were blinded. Evidence on SGA treatment discontinuation was more limited, with conflicting findings from five trials. An included systematic review reports that the incidence of clinically important weight gain is significant in first-episode patients, who have little previous exposure to antipsychotics, but differences among the SGA drugs has not been shown. These studies did not find a difference in benefits outcomes between risperidone and olanzapine over the first 3 years of treatment, but they found that that risperidone had higher risk of some specific adverse events (worsening akathisia, sexual dysfunction, and amenorrhea). Aripiprazole had either lower rates of or longer time to discontinuation due to adverse events than ziprasidone or quetiapine. Core illness symptoms were improved more with paliperidone than ziprasidone or aripiprazole, but response rates did not differ significantly.

In treatment-resistant patients (most commonly defined as having received an adequate course of at least two prior antipsychotics without achieving symptom response), a network meta-analysis of 40 trials indicated that olanzapine resulted in greater improvement in core illness symptoms, although the difference in mean change (−6 points) in the PANSS may not meet minimal clinically important difference criteria (−11.5 points for more severe symptoms), depending on the severity of the patient’s symptoms at baseline. A network meta-analysis of negative symptoms also found olanzapine significantly better than the other older SGAs, whereas response rates and all-cause discontinuations indicated no significant differences among the older SGAs. Clozapine had fewer discontinuations due to lack of efficacy than risperidone and quetiapine.

The evidence on other subgroups of patients is limited. Analysis of age subgroups did not find differences for comparisons of olanzapine with risperidone. Women had greater improvements than men in core illness symptoms with clozapine and in quality of life with olanzapine. Improvement in core illness symptoms was similar in Asian patients, compared with overall study populations for comparisons of aripiprazole and paliperidone with olanzapine, quetiapine, and risperidone. Among illicit drug users, differences between older SGAs were not found in rate or time to drug discontinuation. Response rates with olanzapine and risperidone were similar in patients with a history of cannabis use disorders and in those without such history.

First-Generation Antipsychotics Versus Second-Generation Antipsychotics

Although the SGAs were initially marketed as having multiple advantages over the FGAs, there has been concern that the evidence on first-generation versus second-generation antipsychotics was biased toward the SGAs in various ways (e.g., using higher than typical doses of the first-generation drugs). The Clinical Antipsychotic Trials of Intervention Effectiveness ( CATIE ) trial included one FGA along with five SGAs to test this theory. The trial found perphenazine to be noninferior to the other drugs, with the exception of olanzapine. However, the CATIE trial did not resolve the questions around the use of FGAs in current practice. The findings of the comprehensive systematic review of FGAs versus SGAs published in 2012 are not substantially changed with the additional consideration of five newer studies (2 good quality, 2 fair quality, and 1 poor quality). The 111 trials included in the previously published systematic review were rated as mainly fair quality (70 studies), with 41 rated as poor quality, and none rated as good quality. The FGA evidence was largely about haloperidol, with 108 studies, and only 7 of perphenazine and 4 of fluphenazine. The most common comparisons were risperidone (37 trials) and olanzapine (34 trials) versus haloperidol.

Quality of life, a highly prioritized outcome, was not different between the FGAs and SGAs, quetiapine and risperidone (low SOE ), and olanzapine (moderate SOE). Only ziprasidone was found better than haloperidol (low SOE). Evidence on functional outcomes was insufficient to draw conclusions. Risperidone is not different from haloperidol in response rates (moderate SOE). Symptom response and remission were better with olanzapine than haloperidol, but no differences were found in response between haloperidol and aripiprazole, quetiapine and ziprasidone, or in remission between haloperidol and ziprasidone (low SOE).

Comparative evidence on core illness symptoms is only available for haloperidol versus older SGAs. Core illness symptoms were improved significantly more with olanzapine and risperidone than haloperidol (moderate SOE ), but evidence on other comparisons did not show significant differences (low SOE). Olanzapine improved negative symptoms significantly more than haloperidol (moderate SOE), and risperidone and aripiprazole improved negative symptoms significantly more than haloperidol (low SOE).

Overall rates of patients reporting adverse events were 11 to 20 percent higher with haloperidol versus aripiprazole (moderate SOE ), risperidone, and ziprasidone (low SOE). Similarly, evidence indicates a higher rate of withdrawal from study (and treatment) due to adverse events with haloperidol versus aripiprazole, olanzapine, risperidone, and ziprasidone (moderate SOE). There were no differences in withdrawal due to adverse events between haloperidol and clozapine or quetiapine (low SOE).

Evidence comparing FGAs to SGAs in population subgroups is fairly limited, with unclear implications. In general, differences in outcomes were not found between FGAs and SGAs in patients with a first episode of schizophrenia. In treatment-resistant patients the effects on total core illness symptoms and negative symptoms mirrored the findings in the overall population. Response and core illness symptom improvement was similar in Asian populations and the overall study populations. In patients with co-occurring substance use disorder, core illness symptoms were improved more with olanzapine than haloperidol, but not with risperidone.

Key Question 2. Evidence on Psychosocial and Other Nonpharmacological Interventions

The studies included in our review reported that psychosocial and other nonpharmacological interventions were administered in addition to usual care, which typically includes treatment with antipsychotics, but could include other treatments. Therefore, the studies that make up the evidence base for this question compared (a) psychosocial and other nonpharmacological interventions plus usual care with (b) usual care alone. With usual care as the comparator, we did not include studies that provided direct evidence about head-to-head comparisons and therefore do not consider this a comparative effectiveness review. The evidence base is comprised of 13 systematic reviews (11 good quality, 2 fair quality) that included 271 trials ( N =25,050) relevant to this report. In addition, we included 27 trials that were not included in these reviews (N=6,404). Of these new trials, 4 were good, 20 were fair, and 3 were poor quality. Overall, no psychosocial intervention had high-strength evidence for any outcome of interest, but we found moderate-strength evidence for some outcomes.

Benefit Outcomes

Patients receiving assertive community treatment were more likely to be living independently and to be employed, and they were less likely to be homeless or to discontinue treatment compared with patients assigned to usual care (moderate SOE ). There were no significant differences in the degree of improvement in core illness symptoms or social functioning, and there were no differences in arrests, imprisonment, or police contacts compared with usual care (low SOE).

Cognitive behavioral therapy ( CBT ) resulted in improvements in global function and quality of life (low SOE ), and overall core illness symptoms (moderate SOE) compared with usual care during treatment and with up to 6 months of followup. In studies with longer-term followup after CBT ended, these differences were not significant, although there were few studies with a usual care control group. Low-strength evidence suggests that improvement in negative symptoms was not different between CBT and usual care.

Cognitive remediation resulted in small positive effects on social, occupational, and global function, core illness symptoms (low SOE ), and negative symptoms (moderate SOE) compared with usual care over 15 to 16 weeks of treatment.

Supported employment, specifically the individual placement and support model intervention, resulted in significantly better employment outcomes over 2 years compared with usual care. More patients gained either employment (competitive or any job), had more hours worked, were employed longer, and earned more money than those receiving usual care. Evidence with comparisons with other vocational training confirmed these findings.

Family interventions resulted in significantly lower relapse rates than usual care with up to 24 months treatment and at 5 years post-treatment followup; differences in relapse rates were not found from 25 to 36 months. Family interventions improved core illness symptoms, including negative symptoms. Unemployment, independent living, social functioning, or reduction in self-harm were not found to be different between groups (low SOE , except for reduced relapse from 7 to 12 months [moderate SOE]).

Intensive case management was not found to improve global function, quality of life, or core illness symptoms more than usual care.

Illness self-management training interventions reduced symptom severity (moderate SOE ) and relapse rates (low SOE). No significant difference was found for negative symptoms (low SOE). Fidelity to intervention was associated with better effects.

Psychoeducation had a greater effect than usual care on global function at 1 year and resulted in lower relapse rates at 9 to 18 months (moderate SOE ).

Social skills training improved social function at 6 months, 1 year, and 2 years, compared with usual care. Core illness symptoms and negative symptoms were also improved more with social skills training than usual care.

Supportive therapy was not significantly different from usual care in improving global or social function (low SOE ).

Clinical Subgroups

Early team-based multi-component treatment programs for patients with first episode psychosis resulted in significant improvements in global function with up to 2 years of treatment compared with usual care, but there were no significant differences in housing status (moderate SOE ). Quality of life was improved and participants in team-based multi-component treatment programs were less likely to relapse (moderate SOE), but there was no difference in total PANSS scores or rates of self-harm compared with usual care (low SOE).

In patients with co-occurring substance use disorder , there was low-strength evidence that assertive community treatment was not different from usual care in function, mortality, and substance use.

Demographic Subgroups

We found limited subgroup analyses across all psychosocial and nonpharmacological interventions to identify potential patient characteristics that might predict outcomes. Limited evidence on social skills training from one trial of a mixed population (about 50% diagnosed with schizophrenia or schizoaffective disorder) suggested that the intervention may be more effective in men than women for improving social function and core illness symptoms.

Four trials and seven systematic reviews assessed or reported any type of harms associated with psychosocial or other nondrug interventions. The few that did (e.g., studies of family interventions) resulted in insufficient evidence.

Key Findings and Strength of Evidence

This systematic review evaluated the evidence on treatments for schizophrenia, comparing drug treatments with each other and psychosocial and other nonpharmacological interventions with usual care. The purpose was to inform clinicians, patients and their families, and guideline authors with the ultimate goal of improving patient care. In the summary of the key findings and strength of evidence tables ( Tables A , B , and C ), we do not include findings where the evidence was insufficient to draw conclusions. (The full report presents additional detail on the findings.) There were no instances of high-strength evidence. This was primarily due to specific intervention comparisons having only fair-quality trials with few studies contributing evidence for a particular outcome, leaving moderate- and low-strength evidence. Tables showing the summary results for each drug, indicating magnitude, direction, and strength of evidence for an effect across all seven prioritized, patient-important, outcomes are included in Appendix I of the full report.

Summary of key findings and strength of evidence for Key Question 1: SGA versus SGA .

Summary of key findings and strength of evidence for Key Question 1: FGA versus SGA .

Summary of key findings and strength of evidence for Key Question 2: nonpharmacological interventions versus usual care .

Findings in Relationship to What Is Already Known

With regard to drug therapy, the findings of our review are generally consistent with prior systematic reviews that make comparisons among the SGAs and between SGAs and FGAs. 10 – 15 Although we incorporated the most relevant of these systematic reviews in our report, our findings differ to some extent from previous reviews because we consider outcomes prioritized with input from technical experts, incorporate newer evidence and the most recently approved drugs, and include three updated network meta-analyses. For example, in comparing SGAs, our network meta-analyses of response, withdrawal due to adverse events, and all-cause treatment discontinuation of treatment incorporate evidence on brexpiprazole and cariprazine, the two most recently approved oral drugs, and all of the long-acting injection SGAs, whereas the previously published network meta-analyses are limited to older oral drugs, included drugs not approved in the United States, and did not control for important potential effect modifiers. 10 , 11 , 13 , 15 – 18 Therefore, there are no existing reviews that cover the same scope as this report.

Our review is consistent with other reviews in the findings on the older SGAs. Clozapine, risperidone, and olanzapine have the most consistent evidence of superiority for specific outcomes (e.g., symptom improvement, response, self-harm, all-cause treatment discontinuations, and time to discontinuation), or populations (first-episode and treatment-resistant). 14 , 17 , 19 – 21 Other findings in this review are new, such as the finding that risperidone LAI and olanzapine result in significantly lower withdrawals due to adverse events than most other SGAs. Previous reviews did not assess key effectiveness outcomes, such as function, quality of life, and mortality.

A single comprehensive review on FGAs versus SGAs is available and serves as the basis of our review of FGAs versus SGAs, with nine new trials included. 22 , 23 Our findings are generally consistent with this review, which concluded that there were few differences of clinical importance for effectiveness outcomes, and that evidence on patient-important outcomes and adverse events were not well-studied. In adding new evidence, we found moderate-strength evidence of specific SGAs resulting in better symptom improvement (olanzapine and risperidone) and lower rates of overall adverse events (aripiprazole) and withdrawal due to adverse events (aripiprazole, olanzapine, risperidone, and ziprasidone) than haloperidol.

For the psychosocial interventions, our findings are consistent with some prior review findings and discordant with others. Key reasons for differing findings can be attributed to study eligibility criteria, outcomes included, inclusion of additional, newer studies, and review methodology. For example, we included trials with a usual care comparison group and excluded studies with sample sizes <50 patients and studies conducted in countries that were not United States-relevant (primarily studies conducted in China for certain interventions). Each of these criterion eliminated studies that were included in some other reviews.

The decision to focus our review of psychosocial interventions on comparisons with usual care was made as part of a set of decisions required to reduce the scope of the project. After identifying a large body of evidence for Key Question 2 , we determined that the funding and timeline required a reduction in scope. We first decided to use systematic reviews as the primary evidence, with subsequently published trials included as well. Examining those, we saw a large amount of heterogeneity in how control groups were defined and handled. In some reviews, all controls were lumped together, while in others “active” and usual care controls were assessed separately. Controls described as “active” varied widely, from competing interventions to attention controls, and these were not handled consistently across reviews. Interventions categorized as “active” in one review were evaluated separately as “passive” in another review. Many, however, reviewed usual care comparisons separately or exclusively. Therefore, within the systematic reviews, usual care was the most commonly reported comparison group. In the end we included well over 200 studies of the 12 psychosocial interventions that made comparisons with usual care. The implications of this choice certainly have been contemplated in the literature before 24 – 27 with no clear conclusion, although some have found little difference in analyses limiting to usual care comparisons and those including other comparisons. 24 The potential bias introduced by this decision depends on the usual care actually received by patients in the control group. For example, if no difference was found between an intervention and usual care controls, it could be attributed to better usual care; but where a difference was found it could be due to the intervention, lower quality usual care, or a combination of factors. In addition, the magnitude of difference could be affected. The difference in usual care received could occur at the patient level, at the study level, or at the body of evidence level for a given intervention.

The decision to eliminate studies conducted in China mainly affected the body of studies for family psychoeducation interventions. In this case, both a prior Cochrane review 28 and our own analysis indicate that the studies from China very likely overestimate treatment effects, which is consistent with the findings of other researchers in other clinical areas. Our decision to exclude rehospitalization as one of the prioritized outcomes was made after considering input from our technical expert panel, reflecting the lack of confidence that the findings are meaningful across time and different health care systems or settings. While studies of a few interventions regularly report this outcome, primarily as a proxy for relapse, we found that only assertive community treatment formally targets reducing rehospitalization. Hence, we reported rehospitalization as an outcome only for that intervention in the full report.

The other potential reasons for differences are to be expected—our searches are more recent, adding new evidence that could alter the prior findings, and we used the most up-to-date systematic review methodology, including assessing the strength of the body of evidence. Our finding that the strength of evidence for psychosocial interventions was moderate or low is consistent with our findings for antipsychotic drugs and with numerous reviews across other populations and interventions. This system of assessing the strength of evidence helps to make clear where future studies could alter findings, either in direction or magnitude, inform future research, and identify outcomes for which a given intervention is not effective. It does not, however, determine whether the intervention is useful or not in a broader sense, since the ratings are made on an outcome-by-outcome basis.

Below we summarize our findings in the context of key prior reviews for selected interventions for which differences in findings may be of particular interest. The Schizophrenia Patient Outcomes Research Team (PORT) 2009 publication is a highly regarded resource that assessed evidence and made recommendations on using several psychosocial interventions, and we discuss their findings as well as individual reviews of these specific interventions. 29

Cognitive Behavioral Therapy

Overall, our findings on CBT are consistent with prior findings, except that we found additional outcomes where CBT showed benefit over usual care and we did not find strong evidence regarding duration of effects. Consistent with other reviews, we found CBT to be effective at improving core illness symptoms with treatment durations of 8 weeks to 5 years and additionally for outcomes other than symptoms (e.g., functional outcomes), even when those outcomes were not the focus of the CBT. 29 – 31 With respect to the durability of these effects after CBT ends, there is less clarity. A 2011 meta-analysis found that the effects on symptoms were greater at followup that at the end of treatment, but only with comparisons to a diverse group of comparators, and with no specified duration of followup. Their findings for CBT compared with usual care are not statistically significant, so are similar to ours. 32 Results related to durability of treatment from individual trials with longer post-treatment followup have been mixed. One trial 33 of 9 months of CBT versus befriending found sustained benefit on overall and negative symptoms at 5-year followup with CBT, while a second trial 34 of 6 months of intensive CBT versus leisure activities found no difference between groups in negative symptoms after 5 years. Both studies had methodological limitations, which makes generalizable interpretation of these results difficult.

CBT in schizophrenia typically targets positive symptoms, with few studies targeting negative symptoms specifically. 30 , 35 Our findings regarding negative symptoms, based on two good-quality systematic reviews, 24 , 36 are somewhat in contrast with a 2008 review by Wykes et al. that found CBT associated with significant improvements in negative symptoms. 30 The Velthorst 2015 review found that studies published prior to 2003 reported larger and more positive effect sizes than studies published later. All three reviews found higher study quality to be associated with lower effect sizes, resulting in a nonsignificant effect on negative symptoms in favor of CBT.

Cognitive Remediation

Although the direct focus of cognitive remediation is on improving cognitive functioning, an outcome that is outside the scope of our review, there is some evidence that improvements in cognition can lead to improved global functioning. 37 Our review found that cognitive remediation improved functional outcomes, overall symptoms, and negative symptoms. Our findings differ from the conclusions of the 2009 PORT publication, which determined that the evidence base was inadequate to make recommendations, primarily due to a paucity of good-quality trials. Our findings are based on more than 39 trials included in two good-quality systematic reviews. 29

Family Interventions

Previous systematic reviews 38 and other reviews 39 and the 2009 PORT publication 29 report findings similar to our review. The 2001 systematic review by Pitschel-Walz and colleagues found that both short- and long-term family interventions are superior to usual care in prevention of relapse. 38 They also found that the effect remained regardless of the length of the followup period, but that the type of intervention (psychoeducation or therapeutic) made little difference in treatment effect (both better than usual care). These results are largely consistent with our findings. The Dixon update on family psychoeducation 39 concludes that family psychoeducation should be included as part of best practice guidelines for schizophrenia. The 2009 PORT publication recommends that family interventions should last between 6 and 9 months to reduce rates of relapse and hospitalization. 40 Similarly, we found the strongest evidence for interventions lasting 7 to 12 months. In addition, we found that the number of sessions was more predictive of reduction in relapse than was duration of treatment. The two studies with family interventions consisting of 10 or fewer sessions at 7 to 12 months were not different from usual care on risk of relapse. Pooled estimates for relapse in trials of 11 to 20 sessions, 21 to 50 sessions, and greater than 50 sessions were all statistically superior to treatment as usual. One difference between our review and some others is that we excluded trials conducted in China as we are not confident that the findings from Chinese studies are applicable to the United States population. Our review, and two other reviews, conducted sensitivity analyses (two analyses, one including the Chinese studies and a second excluding them) and found pooled effect estimates were reduced when Chinese studies were excluded. 41 , 42

Social Skills Training

Our inclusion criteria were considerably stricter than those of other recent reviews 43 , 44 in that we limited to larger trials ( N >50) with longer duration (>12 weeks) that utilized a usual care control group. Still, our findings for function, one of the primary targets of social skills training, were consistent with other reviews that found significant improvements in measures of function with social skills training. 43 – 45 Our findings for relapse, another target of social skills training, were also consistent with other reviews 43 , 45 that found social skills training reduced relapse; however, our estimates did not reach statistical significance, likely due to the low number of events and because the analysis in the other reviews included rehospitalizations as a surrogate for relapse. Our review also found social skills training significantly reduced negative symptoms, a finding that is consistent with one of these other reviews. 43 The addition of new trials provided information on additional outcomes or durations of followup, but did not change the prior findings. In 2009, the PORT publication reported that evidence for skills training supported benefits in community functioning, but that the studies were not adequate to show positive effects on symptoms or relapse. 29 Our findings are consistent with these findings.

Supported Employment

Our findings on supported employment are consistent with other reviews, such as the 2009 PORT recommendations and a review by Marshall, et al. 29 , 46 We found that supported employment, specifically the individual placement and support model intervention, resulted in significantly better employment outcomes over 2 years compared with usual care. More patients either gained employment (competitive or any job), had more hours worked, were employed longer, or earned more money than those receiving usual care. Because we found only one trial that met our criteria for inclusion in this review, we included a review and a study that included other comparison groups besides usual care. 47 , 48 In using this evidence, our findings are similar to PORT and Marshall, with the exception that our strength of evidence rating is moderate, while the Marshall rating is high. Our lower strength of evidence rating is due to our comparison group, i.e., usual care, where Marshall did not specify a comparison group. We note also, that the good quality Cochrane review 47 that we included rated the evidence as very low quality according to the Grading of Recommendations, Assessment, Development, and Evaluation working group (GRADE) 49 – 55 criteria for multiple reasons, including large amounts of missing data due to higher dropout rates in the control groups, skewed data for some outcomes, and concerns over the lack of blinding of outcome assessors.

Applicability

The applicability of the evidence in this review is limited to adult outpatients in United States-relevant settings. Applicability specific to the Key Questions is summarized in terms of the populations, interventions, comparisons, outcomes, timing, and study designs/settings (PICOTS).

Key Question 1. Comparative Effectiveness of Pharmacological Treatments

Populations.

Findings are applicable to adults (mean age 25 to 50 years), with mainly moderate and moderate-to-severe disease. There is heterogeneity in the relative predominance of specific symptoms of patients enrolled. For comparisons of SGAs, there is fairly robust evidence on first-episode patients, but less on treatment-resistant patients. The evidence is not clearly applicable to adolescents, older adults, patients with severe disease, or patients with multiple comorbidities.

Interventions/Comparisons

For the SGAs versus each other, the majority of the evidence is relevant to comparisons of the older SGAs, with very little evidence regarding drugs approved in the last 10 years. For the FGAs versus the SGAs, the evidence is almost entirely applicable to comparisons of the older SGAs and haloperidol. The evidence is less applicable to newer SGAs (i.e., brexpiprazole, cariprazine, iloperidone, lurasidone, and LAIs of paliperidone and aripiprazole). Evidence on clozapine may be less generalizable due to the potential effects of the required monitoring, which in essence insures adherence to treatment and may provide nonspecific support, encouragement, and even structure to the daily or weekly schedule through consistent interaction with a provider.

For the SGAs versus each other, there is evidence for all of the prioritized outcomes; however, again the majority of the evidence on effectiveness (long-term health outcomes) is mainly limited to the older drugs. The newer drugs primarily have evidence only for symptom-based outcomes and adverse events. For FGAs versus SGAs, the outcomes are more limited, with little good evidence on effectiveness outcomes. The evidence is less applicable to long-term outcomes, such as function, long-term quality of life, self-harm, and mortality, particularly for the comparison of FGAs versus SGAs and newer SGAs.

For all of the drug interventions, whereas the range of study durations was less than 1 day to 22 years, more studies were short term (6 to 12 weeks) than longer term (1 to 2 years). The evidence is not applicable to long-term followup (greater than 2 years).

For SGAs versus each other, the evidence applies only to outpatients. In the systematic review we included on FGAs versus SGAs, almost half the studies were in inpatients.

Key Question 2. Psychosocial and Other Nonpharmacological Interventions

Similar to the issues noted in Key Question 1 , the evidence base is limited in part by the scope identified for this review. For example, for Key Question 2 we added criteria that studies had to have at least 50 percent of patients diagnosed with schizophrenia, to reflect the fact that many of these interventions are aimed at patients with serious mental illness, as a group, rather than at specific diagnoses. Similar to our limiting FGAs to only the three drugs most commonly used today, we limited the Key Question 2 interventions also to those that are used commonly in clinical practice. We also limited to studies with a comparator of usual care across the 13 interventions included. Thus, this is not a traditional comparison of two active interventions.

Findings are applicable to adults ranging in age from 16 to 80 years (adolescents to older adults), mostly with a diagnosis of schizophrenia or a related disorder. The specific characteristics of patients varied somewhat by intervention category. For example, supportive therapy is most applicable to middle-aged men with schizophrenia and related conditions who were experiencing long-standing hallucinations and/or delusions. The evidence is not clearly applicable to patients with treatment resistance, or multiple comorbidities. Across the interventions it is not clear what level of disease severity was addressed.

The evidence in this review, by design, applies only to the comparisons with usual care, and the 13 intervention categories identified here. The evidence is not applicable to comparative effectiveness questions. For some interventions, such as family interventions and supportive therapy, a key limitation of the ability to understand the applicability of the evidence is varying or unclear definitions and descriptions of the elements of interventions and poor reporting of intervention and usual care details. As a result, specific description of the intervention applicability is limited. The evidence is less applicable to variations of these interventions, or emerging interventions.

The evidence is applicable only to a select group of outcomes that vary by intervention. Not all prioritized outcomes were reported consistently across studies. The evidence generally does not apply to long-term effectiveness outcomes that were highly prioritized (e.g., function, quality of life, mortality). For some interventions, outcomes reported were common, standard outcomes used in assessing individuals with schizophrenia, whereas for others there was wide variety and introduction of unique outcome measures.

Most of the interventions do not have evidence that is applicable to long-term followup (greater than 2 years).

The settings were mostly applicable to the United States, as evidence clearly not applicable was excluded from our review. The evidence is not exclusively applicable to the outpatient setting. Although the criteria for this review stipulated an outpatient setting, several of the systematic reviews used to provide evidence for Key Question 2 included inpatient studies as well, limiting the applicability based on setting.

Research Recommendations

Based on the research gaps and limitations identified in this review (see the full report for a more extensive discussion of limitations of the review and of the evidence base), we recommend the following:

Pharmacological Interventions

Trials should:

• Involve multiple newer SGA drugs (approved in the last 10 years), in comparison with one of the older SGAs (e.g., clozapine, olanzapine, risperidone LAI ) and haloperidol and compare fluphenazine and perphenazine with both older and newer SGAs.
• Ensure comparable dosing with the best dosing titration methods for all drugs included.
• Measure key health outcomes, using agreed-upon direct measures. For example, measuring functional outcomes using not only valid and reliable scales, but also actual measures of patient functioning. These measures need to be agreed upon by clinical and research experts and then used consistently across trials.
• Study durations must reflect real-life practice. Minimum study duration should be 1 year, with 3- to 5-year followup in order to measure the durability of effects, and truly long-term outcomes, including harms (e.g., metabolic changes and tardive dyskinesia). Long-term harms are not assessable in short-term studies, and relying on observational evidence has limitations.
• The concept of recovery should be incorporated into study designs, with testing of duration of effect and discontinuation of drug treatment following remission.
• Enroll subjects who reflect real populations. Studies exclusively of older patients, with multiple comorbidities and concomitant medications, and patients with severe disease, including treatment-resistance are needed. To better study other subgroups, such as minorities and women, specification and planning of subgroup analyses a priori and use of randomization methods that insure adequate distribution of these characteristics are needed to examine differences.
• Inpatients need to be studied separately from outpatients. Future reviews should evaluate treatments for inpatients.

Psychosocial and Other Nonpharmacological Interventions

The issues may vary by the specific intervention, but below are several key recommendations:

• Trials should have adequate sample sizes to address important health outcomes, rather than intermediate or surrogate outcomes and should adhere to the current standards for reporting, such as the Consolidated Standards of Reporting Trials (CONSORT) criteria. 56
• Future studies might consider using the National Institutes of Mental Health Research Domain Criteria 57 approach to categorizing patients.
• Future reviews should evaluate treatments for inpatients.
• Interventions should be clearly defined and described, including required components. Some interventions, such as cognitive remediation, have used expert groups to refine definitions and required components of interventions. Measurements of fidelity to the intervention model should be undertaken where possible.
• Trials need to evaluate and report patient-important health outcomes such as function, quality of life, self-harm, and adverse effects using standardized and easily interpretable methods. Studies should identify what constitutes clinically meaningful change in scale scores.
• Studies are needed to address the heterogeneity in usual care control groups. Usual care is highly variable; so studies using a usual care control group must report on the specific services and treatments received and standardize the comparison or control for attention effects.
• Studies should measure both intensity and duration of intervention required to achieve the best result and the duration of effect in relation to these.
• Additional well-designed long-term studies are needed. The long-term benefits versus risks and costs of treatments remain unclear, particular for individuals whose illness is resistant or only partially responsive to treatment.
• Include an evaluation of comparative effectiveness of psychosocial interventions compared with each other. Emerging methods of evaluating complex interventions may be helpful in such future studies. 58 , 59
• Include other nonpharmacological, device-based somatic treatments, such as electroconvulsive therapy and transcranial magnetic stimulation.
• Organize the evidence according to the patient characteristics that the intervention focuses on.
• Conclusions

The majority of the comparative evidence on pharmacotherapy to treat schizophrenia relates to the older SGAs (mainly clozapine, olanzapine, risperidone, quetiapine, and ziprasidone), with some evidence on paliperidone and aripiprazole, and the LAIs of risperidone, aripiprazole, and paliperidone. There is very little comparative evidence on newer SGAs (drugs approved in the last 10 years: asenapine, brexpiprazole, cariprazine, iloperidone, and lurasidone). Although there are some differences among the older SGAs on specific outcomes, no single drug was superior on multiple high-priority outcomes. However, clozapine, olanzapine, and risperidone oral and LAI did have superiority on more outcomes than other SGAs and quetiapine and ziprasidone were not superior to other SGAs on any outcome. No evidence found a newer SGA superior to older SGAs on any outcome. Evidence on FGAs versus SGAs indicates that olanzapine, risperidone, ziprasidone, and aripiprazole were similar to haloperidol on some outcomes of benefit, and were superior on overall adverse events and withdrawal due to adverse events.

In comparison with usual care, most of the psychosocial interventions to treat schizophrenia reviewed were more effective in improving two or more outcomes, including nontargeted but patient-important outcomes. Various functional outcomes were improved more with assertive community treatment, CBT , psychoeducation, social skills training, supported employment, and early team-based multi-component treatment programs for patients with first-episode psychosis than with usual care. Quality of life was improved more with CBT and early team-based multi-component treatment programs for first-episode psychosis than usual care. Core illness symptoms were improved with assertive community treatment, CBT, cognitive remediation, illness self-management, psychoeducation, social skills training, and early team-based multi-component treatment programs for patients with first-episode psychosis. Relapse was reduced with psychoeducation, illness self-management, family interventions, and early team-based multi-component treatment programs for patients with first-episode psychosis. Self-harm, response and/or remission, and adverse events were rarely reported.

Patient characteristics include age, sex, race, ethnicity, socioeconomic status, time since illness onset, prior treatment history, co-occurring psychiatric disorders, pregnancy, etc.

“Older” SGAs; approved up through 2001 and included in the Clinical Antipsychotic Trials of Intervention Effectiveness ( CATIE ) trials.

Limited to the most commonly used interventions relevant to U.S. practices.

• Cite this Page McDonagh MS, Dana T, Selph S, et al. Treatments for Schizophrenia in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 Oct. (Comparative Effectiveness Reviews, No. 198.) Evidence Summary.
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• Review Article
• Open access
• Published: 22 August 2024

All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis

• Claudia Aymerich   ORCID: orcid.org/0000-0003-0040-1608 1 , 2 , 3 , 4 ,
• Gonzalo Salazar de Pablo   ORCID: orcid.org/0000-0002-6992-0767 5 , 6 , 7 , 8 ,
• Malein Pacho 1 ,
• Violeta Pérez-Rodríguez   ORCID: orcid.org/0000-0002-2485-3054 9 ,
• Amaia Bilbao 10 , 11 ,
• Lucía Andrés 1 ,
• Borja Pedruzo 1 , 2 , 3 , 12 ,
• Idoia Castillo-Sintes 10 , 11 , 12 ,
• Nerea Aranguren 10 ,
• Paolo Fusar-Poli   ORCID: orcid.org/0000-0003-3582-6788 5 , 13 , 14 ,
• Iñaki Zorrilla 3 , 4 , 15 , 16 ,
• Ana González-Pinto 3 , 4 , 15 , 16 ,
• Miguel Ángel González-Torres 1 , 2 , 3 , 4   na1 &
• Ana Catalán   ORCID: orcid.org/0000-0002-0418-7904 1 , 2 , 3 , 4 , 5   na1  

Molecular Psychiatry ( 2024 ) Cite this article

Metrics details

• Prognostic markers
• Schizophrenia

Patients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear. To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics. Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95). Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44). Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia compared to oral antipsychotics. Better adherence to the medication and health services may explain this difference. Whenever possible, the use of LAIs should be considered from the FEP.

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Introduction.

Schizophrenia is a chronic and debilitating disorder characterized by positive, negative, and cognitive symptoms [ 1 ]. Individuals with schizophrenia experience a reduction in life expectancy of 15–20 years compared to the general population [ 2 ], with cardiovascular disease being the leading cause of death among this population [ 3 ]. This premature mortality is present even from the initial stages of the disorder [ 4 ], and has been consistently associated with modifiable factors, including poorer lifestyle conditions [ 5 ], limited access to healthcare services [ 6 ], and a high rate of comorbid disorders, both psychiatric [ 7 , 8 ] and physical [ 9 , 10 ].

While there has been some controversy on the potential increase in cardiovascular deaths caused by long-term use of antipsychotics [ 11 , 12 ], the protective effect of antipsychotic treatment has now been well-established, with a lower mortality rate in patients who received any antipsychotic treatment compared to those who did not [ 13 , 14 ]. Furthermore, consistently, long-term treatment with antipsychotic medication dramatically reduces the risk of relapse in multiple-episode and first-episode psychosis (FEP) [ 15 , 16 , 17 ], along with the associated risk behaviours and stress increase. However, a significant percentage of patients discontinue their oral antipsychotic medication, with non-adherence rates from 30% [ 18 ] to up 77% [ 19 , 20 ].

Long-acting injectable antipsychotics (LAI-AP), including first and second-generation antipsychotics, were introduced in the 1960s to overcome non-adherence in psychotic disorders. They have been shown to improve adherence, provide more stable antipsychotic blood levels and reduce relapses, all-cause hospitalizations and emergency department visits [ 21 , 22 ]. However, potential adverse effects are still important when starting long-term treatment with LAI-APs. Such medications are often initiated in large single doses, and there is no possibility of discontinuing them rapidly should a serious adverse effect appear. Moreover, some rare adverse events, such as post-injection syndromes [ 23 ], are produced exclusively by certain LAI-APs.

A meta-analysis of randomized controlled trials (RCTs) comparing LAI-AP and oral-AP pairs of the same antipsychotic in schizophrenia reported a lack of significant differences among the rate of most reported adverse events, including extrapyramidal side effects, weight gain, and sexual and reproductive functioning, among others [ 24 ]. Whether LAI antipsychotics can reduce more serious and infrequent adverse effects, including all-cause, suicidal and non-suicidal mortality, has yet to be addressed.

To fill these gaps of knowledge, a systematic review and meta-analysis were performed to try to answer the following research questions:

Do people with schizophrenia receiving LAI antipsychotics present lower all-cause, suicidal, and non-suicidal mortality than those receiving oral antipsychotics?

Is the difference in the all-cause mortality moderated by (a) the drug antipsychotic, age, sex, race, or type of sample (first-episode psychosis vs chronic schizophrenia), or (b) methodological factors, including the type of study (RCT vs cohort), length of follow-up, industry sponsorship, study quality, or publication bias?

This study protocol was registered on PROSPERO (registration number: CRD42023391352). The study was conducted in accordance with 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' (PRISMA) [ 25 ] (Supplementary Table  S1 ) and 'Meta-Analyses of Observational Studies in Epidemiology' (MOOSE) checklist [ 26 ] (Supplementary Table  S2 ), following 'EQUATOR Reporting Guidelines' [ 27 ].

Search strategy and selection criteria

A systematic literature search was carried out by two independent researchers (C.A. and B.P.). Web of Science database (Clarivate Analytics) was searched, incorporating the Web of Science Core Collection, the BIOSIS Citation Index, the KCI-Korean Journal Database, MEDLINE®, the Russian Science Citation Index, and the SciELO Citation Index as well as Cochrane Central Register of Reviews, and Ovid/PsycINFO databases, from inception until January 12th, 2023.

The following keywords were used: '(Antipsychotic OR neuroleptic OR aripiprazole OR bromperidol OR clopenthixol OR flupenthixol OR fluphenazine OR fluspirilene OR haloperidol OR iloperidone OR olanzapine OR paliperidone OR penfluridol OR perphenazine OR pipothiazine OR risperidone OR zuclopenthixol) AND (enanthate OR decanoate OR long-acting injection OR lai OR microsphere OR once monthly OR palmitate OR pamoate)'.

Articles identified were first screened as abstracts, and after excluding those that did not meet the inclusion criteria, the full texts of the remaining articles were assessed for eligibility and inclusion. Inclusion criteria for the systematic review and meta-analyses were: (a) individual studies with original data, (b) comparing patient groups receiving any long-action injectable antipsychotic with patient groups receiving any oral antipsychotic, being followed during the same amount of time, (c) patients meeting criteria for a schizophrenia spectrum disorder, according to DSM [ 28 , 29 , 30 ] or ICD [ 31 , 32 ] criteria, (d) including all-cause mortality data (e.g. number of deaths in each study group), (e) nonoverlapping samples (overlap was determined by looking at the inclusion dates, type of population and country in which the study was carried out), and (f) written in English or Spanish language. Exclusion criteria were (a) reviews, clinical cases, study protocols, conferential proceedings, letters, and commentaries, and (b) studies including patients receiving both oral and long-action injectable antipsychotics.

Data extraction

Three researchers (M.P., L.A., V.P.) independently extracted data from all the included studies. The three databases were then cross-checked, and discrepancies were resolved by a senior researcher (A.C.). A summary of selected variables included: first author and year of publication, country and city, sample size, age (mean ± standard deviation [SD]), sex (% female), LAI antipsychotic, setting (inpatient vs outpatient), type of study (cohort vs randomized controlled trial vs others), industry sponsorship of the study, number of deceases in each group and cause of death if specified, medical comorbidities, quality assessment (see below), and key findings.

Risk of bias (quality) assessment

Risk of bias was assessed using Newcastle–Ottawa Scale for cross-sectional and cohort studies [ 33 ] (Supplementary Table  S3 ).

Strategy for data synthesis and statistics

First, we provided a systematic synthesis of the findings from the included studies.

Second, we performed meta-analyses on all-cause mortality comparing LAI and oral antipsychotics. All LAI antipsychotics were pooled for a single analysis, and subgroup meta-analyses were subsequently conducted for each LAI antipsychotic where data allowed for it. Oral antipsychotics were pooled in all the performed analyses, as available data did not allow for analyzing each antipsychotic. We also conducted a secondary analysis to meta-analyze only those studies comparing LAI antipsychotics with the same oral antipsychotic. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using the number of deaths and sample sizes for each sample [ 34 ], without adjusting by any variable. An OR greater than 1 indicates that the LAI antipsychotic group have a higher risk of death than the oral antipsychotic group. The Mantel-Haenszel correction accounted for death as a rare, dichotomous event in this analysis [ 35 ]. Heterogeneity among studies was assessed using the Q statistic, with the proportion of the total variability in odds ratio estimates evaluated using the I 2 index, classifying the heterogeneity as low (I 2  = 25%), medium (I 2  = 50%), and high (I 2  = 75%) [ 36 ].

Next, we followed the same statistical procedure to separately meta-analyze the mortality due to suicide and the mortality due to any other cause for those articles that provided specific data in this regard. Additionally, we conducted a meta-analysis of all-cause mortality in those studies that offered a comparison between LAI and oral formulations of the same antipsychotic.

Meta-regressions were performed to determine the effect of the (a) age, (b) mean antipsychotic dose (calculated as their chlorpromazine equivalent dose), (c) % of females, (d) % of white race, and (e) follow-up length on the outcomes of interest where more than 7 articles were available. Sensitivity analyses were performed to determinate the differences depending on (a) design (cohort vs RCT), (b) type of sample (FEP versus chronic versus other), (c) drug (risperidone/paliperidone versus aripiprazole versus others), and (d) whether the study was industry-sponsored or not. As heterogeneity was expected to be high, the random-effects model was used. Publication bias was assessed by visually inspecting funnel plots and performing Egger’s test.

All analyses were conducted within Comprehensive Meta-Analysis Version 4 [ 37 ] and R 1.4.1106 [ 38 ]. The significance level was set at a p < 0.05, two-sided.

Sample characteristics

The literature search yielded 3077 non-duplicated citations through electronic database, which were screened for eligibility; 48 articles were assessed in full text, and 28 were excluded, mainly due to their design or lack of all-cause mortality data (n = 15), sample overlap (n = 5) or sample including affective psychosis patients (n = 3). The final systematic review and meta-analysis database included 20 studies, as seen in the PRISMA Flow Diagram (Fig.  1 ) [ 39 ]. Three articles meeting the inclusion criteria had to be excluded from the meta-analysis since they reported 0 deaths in the LAI-AP and oral AP groups and thus a reliable OR could not be calculated [ 40 , 41 , 42 ].

Prisma 2020 flow diagram.

Data were extracted for a total sample size of 12042 patients, including 5795 receiving any oral antipsychotic and 6247 receiving any LAI antipsychotic from over 75 countries across all continents. The median study follow-up was 100.0 (range = 20–729.4) weeks. Fifteen studies were RCT, and two were cohort studies. There were 18 studies involving second generation LAI-AP (risperidone = 8 [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], paliperidone = 4 [ 51 , 52 , 53 , 54 ], aripiprazole = 3 [ 55 , 56 , 57 ], olanzapine = 1 [ 58 ]) and 1 study including multiple LAI-APs [ 59 ]. 12 studies were sponsored by the industry, 13 included patients with chronic schizophrenia, 2 patients with a FEP, and 2 did not specify the phase of the psychotic illness. The mean age and SD of the sample was 38.3 ± 6.1 and ranged from 18 to 78 years. The mean proportion of females in the included studies was 41.5%. 51.5% were white. Study quality scores ranged from 6 to 9 in the NOS scale. The overall mean and SD quality score of the included studies was 7.2 ± 0.8. (Table  1 ).

All-cause mortality odds ratio

Altogether, 537 deaths were reported, 295 in the oral-AP group and 242 in the LAI-AP group. OR for all-cause mortality was 0.79 overall (95% CI = 0.66–0.95, k = 17, p = 0.01), implying a statistically significant lower risk of all-cause death for patients receiving LAI-AP. The OR was not altered after applying the Mantel-Haenszel correction (Fig.  2 ). When the analyses were repeated after removing the article with the most weight on the overall results [ 59 ], although the trend was maintained, the results were not powered enough to achieve statistical significance (OR = 0.66, 95% CI = 0.43–1.04, p = 0.056).

Values below 1 represent a lower mortality rate for LAI-AP group. LAI-AP Long-Acting Injectable Antipsychotic, AP Antipsychotic, OR Odds Ratio, CI Confidence Interval, MH Mantel-Haenszel.

Heterogeneity was non-significant with all the studies included in the analysis (Q = 5.57, I 2  < 0.01%, p = 0.992), which means estimated effects differ across studies due to random sampling error [ 60 ]. Publication bias was not identified neither by visual inspection of the funnel plot (Fig.  S1 ) nor by Egger’s test (p = 0.81).

Meta-regressions showed no significant effect of age, follow-up length, % of females, % of white race, mean LAI antipsychotic dose in chlorpromazine equivalents or quality (NOS score) (Table  2 ). When stratified by subgroups, studies not sponsored by the industry (OR = 0.79; 95% CI 0.66 – 0.95) and FEP samples (OR = 0.79; 95% CI 0.66 – 0.96) showed lower mortality when treated with LAI antipsychotics than with oral antipsychotics. No significant differences in all-cause mortality were found for any drug LAI antipsychotic; due to the number of articles included for each LAI antipsychotic the analyses were only powered to ascertain the effect on mortality of risperidone/paliperidone and aripiprazole (Table  3 ).

To verify that the difference between LAI and oral AP groups was due to the formulation (rather than differences between the active principals administered to each patient group), an additional meta-analysis was conducted, including only those studies where each LAI-AP was compared to the same oral-AP. 8 articles reporting on 8,169 patients [ 45 , 51 , 52 , 55 , 56 , 58 , 59 , 61 ] (4173 in the LAI-AP group and 3,996 in the oral-AP group) were included. OR for all-cause mortality was also 0.79 (95% CI = 0.66–0.95; k = 8; p = <0.01), thus confirming statistically significant lower mortality for the LAI formulation when the antipsychotic agent was the same for both study groups (Fig.  S2 ). Heterogeneity was non-significant (Q = 1.92, I 2  < 0.01%, p = 0.964) and publication bias was not identified neither by visual inspection of the funnel plot (Fig.  S3 ) nor by Egger’s test (p = 0.06). Meta-regressions showed no significant effect of % of females, % of white race, or quality score (Table  S5 ).

Suicidal and non-suicidal mortality odds ratio

13 articles provided stratified data for suicidal and non-suicidal deaths [ 43 , 44 , 45 , 46 , 48 , 49 , 50 , 54 , 55 , 56 , 58 , 61 , 62 ], including a total sample of 10,952 patients (5651 receiving LAI antipsychotics and 5301 receiving oral AP). However, in 5 of them reported 0 deaths in the LAI-AP and oral AP groups for both causes and had to be excluded from the meta-analyses.

110 deaths due to suicide were reported, 52 in the LAI-AP group and 58 in the oral group. OR for suicidal mortality was 0.86 (95% CI = 0.59–1.26; k = 8; p = 0.44), implying no statistically significant differences between the two groups (Fig.  S4 ). Heterogeneity was non-significant (Q = 2.41, I 2  < 0.01%, p = 0.934) and publication bias was not identified neither by visual inspection of the funnel plot (Fig.  S5 ) nor by Egger’s test (p = 0.75). Meta-regressions showed no significant effect of % of females or quality score (Table  S6 ). Not enough data was found to examine the effect of mean age, follow-up length, antipsychotic or % of white race.

As for non-suicidal mortality, 421 deaths were reported, 185 in the LAI-AP group and 236 in the oral group. OR for mortality due to causes other than suicide was 0.77 (95% CI = 0.63–0.94; k = 13; p = 0.01), indicating lower mortality in the LAI-AP group (Fig.  S6 ). Heterogeneity was non-significant (Q = 3.57, I 2  < 0.01%, p = 0.990) and publication bias was not identified neither by visual inspection of the funnel plot (Fig.  S7 ) nor by Egger’s test (p = 0.06). Again, meta-regressions did not find significant effect of mean age, follow-up length, % of females, % of white race, or quality score (Table  S7 ).

This systematic review and meta-analysis have identified, for the first time on a large scale and at a global level, a lower risk of all-cause mortality in schizophrenia patients receiving LAI-APs than in those receiving oral antipsychotics, with an OR of 0.79 (95% CI 0.66–0.95. This was more pronounced among first-episode psychosis patients than in chronic samples and in non-industry sponsored studies. When meta-analyzing only those studies where each LAI was compared to the same oral antipsychotic, the statistical significance was maintained, which indicates these results were due to the formulation, rather than potential differences between the antipsychotics administered to each study group.

The meta-analysis results seem to be largely driven by a large observational study [ 59 ]. However, after removing it from the analyses, the trend is maintained, and a lack of statistical power can easily explain its lack of statistical significance. Mortality, whether from suicidal or non-suicidal causes, requires large samples and lengthy follow-ups to study with precision. This can be a potential explanation for the fact that two previous meta-analyses did not identify significant differences in the mortality risk associated with LAI-APs compared with oral-APs [ 24 , 63 ]. In both cases, those meta-analyses only included RCTs, which may not be the best way to study mortality due to shorter follow-up periods and extremely exigent inclusion criteria. Patients enroled in RCTs may significantly differ from the general patient population in important ways, such as comorbidities, engagement with health care providers and adherence, substance use or risk of suicide, and may not reflect real-world practice and outcomes [ 64 , 65 ]. Moreover, mortality is a very infrequent event that relatively short follow-up periods fail to report adequately. Our work, besides including other study types like population cohorts, also includes a far greater sample of patients receiving both oral and long-acting injectable antipsychotics.

The results of our study are consistent with other large observational cohort studies in literature. Tang and Taipale identified in large national cohorts from Taiwan and Sweden, respectively, a significant lower risk of all-cause mortality in those patients receiving LAI-APs than in those receiving oral-APs [ 66 , 67 ]. Although the aforementioned studies were not included in our systematic review due to not meeting our inclusion criteria, their findings are consistent with ours. Furthermore, the Taipale study shows that antipsychotic use was associated with a 50% lower risk when compared with no use [ 66 ], with the lowest risk of death being observed with second-generation LAIs. First-episode psychosis might be a particularly vulnerable stage of the illness, where nonadherence is particularly high [ 68 ] and relapses are associated with a worse disease course and prognosis [ 69 ], including an increase in suicidality [ 70 ]. Therefore, it is not surprising that the results of our meta-analysis show even greater differences for FEP populations.

According to some studies [ 71 , 72 , 73 , 74 ], LAIs may improve treatment adherence, obtaining lower relapse and hospitalization rates (treatment discontinuation being the leading cause for relapse [ 75 ]). There is some controversy in this regard, with the recent randomized trial by Winter van Rossum et al. finding no significant differences in all-cause discontinuation between LAI-AP and oral AP. However, this conclusion is not supported by the totality of the data from their study, in which they found significant differences favouring LAIs in the discontinuation rate for very relevant reasons (including, among others, suicide attempts and all-cause death) [ 76 ].

Another important finding of our study is that, when separately analyzing suicidal and non-suicidal mortality, LAI antipsychotics only showed a statistically significant effect in reducing the latter, with an OR of 0.77 (95% CI = 0.63–0.94). Several reasons may explain the lower non-suicidal mortality risk among patients treated with LAI antipsychotics, including both the treatment of psychiatric symptoms and a stronger engagement to health services. Patients treated with LAIs periodically go to the health centre for treatment administration, allowing the possible diagnosis of other treatable comorbidities and early detection of the non-adherence [ 77 ]. Furthermore, individuals who maintain a sustained antipsychotic adherence present healthier lifestyle choices, including greater help-seeking behaviours and overall treatment adherence, including cardiometabolic medications [ 78 ]. Interestingly, in a recent article by Lieslehto et al. [ 79 ], general medical comorbidities were linked to primary nonadherence to antipsychotic treatment (which was also more pronounced for the oral antipsychotics), which could suggest an accumulation of poor lifestyle choices (including obesity or tobacco smoking) in a subgroup of a nonadherent patients, that could also lead to higher mortality.

On the other hand, no significant differences in suicidal mortality were found between LAI and oral antipsychotic-treated patients. Some authors suggest a decrease in the risk of consumed suicide in patients treated with LAI-AP [ 59 ]. It might be possible that our lack of statistical power could explain this contradiction. It is also important to note that, in clinical practice, patients receiving LAI-AP differ from those receiving oral antipsychotics, presenting higher symptom severity and a greater rate of previous hospitalizations [ 80 ], increased substance use [ 81 ], and higher rates of self-harming behaviours [ 82 ]. These differences are relevant regarding comorbidity and mortality and cannot always be effectively controlled in observational studies. Therefore, we believe that the superiority of LAIs in terms of mortality could be even more robust if these confounding factors could be controlled. Well-powered studies are needed to unravel which specific causes of death could be prevented or delayed by these medications.

Finally, it is important to notice that this study does not aim to explore the differences between specific antipsychotic drugs. Not all antipsychotics have LAI formulations available, and among those who have, important differences in terms of mortality have been found between first- and second-generation LAI antipsychotics [ 66 ]. The present work mostly includes data from atypical antipsychotics, which should be considered when extending these conclusions to all antipsychotic drugs.

Strengths and limitations

To the authors’ knowledge, this is the largest meta-analysis analyzing mortality risk in samples where schizophrenia patients receiving LAI-APs are compared to those receiving oral-APs. The study includes a large study sample from more than 75 countries on all continents. Unlike other previous meta-analyses, this one includes data from randomized controlled trials and observational studies with populations more representative of clinical practice. All of this supports the generalization of its findings.

Nevertheless, some limitations need to be considered. There were not enough data to perform meta-regressions to assess the effect of the combination of antipsychotics and other psychotropic drugs on all-cause mortality. Concomitant benzodiazepine use, for instance, has been previously linked with higher natural cause mortality in schizophrenia patients [ 83 ], whereas the combination of antipsychotics and antidepressants has been associated with lower mortality risk in the same group [ 51 ]. Finally, while the inclusion of RCT in our analyses increases the generalization of our findings, most RCTs present relatively short-term follow-up periods, which might not be ideal when studying rare events such as mortality. Some do not include mortality data, and when they do, they rarely mention the specific cause of death. This further complicates the establishment of relationships between medications and specific outcomes.

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This research received funding from the Biobizkaia Health Research Institute for publication fees.

Author information

These authors contributed equally: Miguel Ángel González-Torres, Ana Catalán.

Authors and Affiliations

Department of Psychiatry, Basurto University Hospital, Bilbao, Spain

Claudia Aymerich, Malein Pacho, Lucía Andrés, Borja Pedruzo, Miguel Ángel González-Torres & Ana Catalán

Biobizkaia Health Research Institute, Barakaldo, Spain

Claudia Aymerich, Borja Pedruzo, Miguel Ángel González-Torres & Ana Catalán

CIBERSAM. Centro Investigación Biomédica en Red de Salud Mental, Madrid, Spain

Claudia Aymerich, Borja Pedruzo, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres & Ana Catalán

University of the Basque Country, UPV/EHU, Leioa, Spain

Claudia Aymerich, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres & Ana Catalán

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Gonzalo Salazar de Pablo, Paolo Fusar-Poli & Ana Catalán

Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Gonzalo Salazar de Pablo

Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Madrid, Spain

South London and Maudsley NHS Foundation Trust (Southwark CAMHS), London, UK

Violeta Pérez-Rodríguez

Osakidetza Basque Health Service, Basurto University Hospital, Research and Innovation Unit, Bilbao, Spain

Amaia Bilbao, Idoia Castillo-Sintes & Nerea Aranguren

Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), Bilbao, Spain

Amaia Bilbao & Idoia Castillo-Sintes

Kronikgune Health Services Research Institute, Barakaldo, Spain

Borja Pedruzo & Idoia Castillo-Sintes

National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), London, UK

Paolo Fusar-Poli

Outreach and Support in South London (OASIS) service, South London and Maudsley NHS Foundation Trust, London, UK

Bioaraba, Mental Health and Childhood Research Group, Vitoria-Gasteiz, Spain

Iñaki Zorrilla & Ana González-Pinto

Osakidetza Basque Health Service, Araba University Hospital, Psychiatry Department, Vitoria-Gasteiz, Spain

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CA (Conceptualization and protocol writing, original draft, methodology, systematic search); GSP (Conceptualization, original draft, methodology); MP (Systematic search, data extraction, writing—review and editing); VPR (Systematic search, data extraction, writing—review and editing); AB (Statistics, writing—review and editing); LA (Systematic search, data extraction); ICS (Statistics, writing—review and editing); NA (Statistics, figure design); PFP (Conceptualization and protocol writing, supervision, writing—review and editing); IZ (Methodology, writing—review and editing); AGP (Methodology, writing—review and editing); MAGT (Conceptualization and protocol writing, supervision, writing—review and editing); AC (Conceptualization and protocol writing, supervision, writing—review and editing)

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Correspondence to Claudia Aymerich .

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CA received personal fees or grants from Janssen Cilag and Neuraxpharm outside the current work. GSP has received honoraria from Janssen Cilag, Lundbeck and Angelini outside the current work. PFP has received grant support from Lundbeck and honoraria fees from Angelini, Menarini, and Lundbeck outside the current work. AGP has received grants and served as consultant, advisor or CME speaker for the following entities: Jannsen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Exeltis, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), and the Basque Government. AC received personal fees or grants from Lundbeck, ROVI, and Janssen Cilag outside the current work. The rest of the authors reported no biomedical financial interests or potential conflicts of interest.

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Aymerich, C., Salazar de Pablo, G., Pacho, M. et al. All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02694-3

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Received : 18 October 2023

Revised : 01 August 2024

Accepted : 05 August 2024

Published : 22 August 2024

DOI : https://doi.org/10.1038/s41380-024-02694-3

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The Relationship between Oral Health and Schizophrenia in Advanced Age-A Narrative Review in the Context of the Current Literature

Affiliation.

• 1 Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY 14620, USA.
• PMID: 37892634
• PMCID: PMC10607055
• DOI: 10.3390/jcm12206496

Schizophrenia is a psychiatric disorder that makes patients incompetent to perform day-to-day activities due to their progressing mental illness. In addition to disturbances with thoughts, behavioral changes, and impaired cognitive functions, oro-systemic health also becomes compromised. Even though the population with schizophrenia is primarily made up of older people, little is known about this group's oral health treatment. The present review explores the relationship between oral healthcare and elderly patients with schizophrenia. Our literature search included databases, like PubMed, Embase, and Google Scholar, for appropriate and evidence-based information. Preventive and management strategies outlined in the included articles and future research perspectives in this field are discussed. To the best of our knowledge, this is the first review that looked at dental care and related characteristics in older schizophrenia patients. The findings highlight the necessity for targeted dental interventions to address the dental health challenges faced by this vulnerable population. Integrating dental health into the overall medical management of elderly individuals with schizophrenia is crucial. Although specific therapies remain limited, the emphasis is on preventive dentistry to reduce the occurrence and progression of oral diseases in this group.

Keywords: antipsychotics; elderly; geriatric; oral health; schizophrenia.

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Conflict of interest statement

The authors declare no conflict of interest.

A flow diagram of the…

A flow diagram of the search strategy conducted (PRISMA flow of study selection…

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