Introduction

The goal of this guideline is to improve the quality of care and treatment outcomes for patients with schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association 2013a). Since publication of the last American Psychiatric Association (APA) practice guideline (American Psychiatric Association 2004) and guideline watch on schizophrenia (American Psychiatric Association 2009a), there have been many studies on new pharmacological and nonpharmacological treatments for schizophrenia. Additional research has expanded our knowledge of previously available treatments. This practice guideline aims to help clinicians optimize care for their patients by providing evidence-based statements that are intended to enhance knowledge and increase the appropriate use of treatments for schizophrenia.

Schizophrenia is associated with significant health, social, occupational, and economic burdens as a result of its early onset and its severe and often persistent symptoms (American Psychiatric Association 2013a). Worldwide, schizophrenia is one of the top 20 causes of disability (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators 2018). Economic burdens associated with schizophrenia are high (Chapel et al. 2017; Jin and Mosweu 2017), with an estimated cost of more than $150 billion annually in the United States based on 2013 data (Cloutier et al. 2016). Lost productivity due to unemployment and caregiving each account for approximately one-third of total costs, and direct health care costs account for approximately one-quarter of total costs. The lifetime prevalence of schizophrenia is estimated to be approximately 0.7% (McGrath et al. 2008; Moreno-Küstner et al. 2018; van der Werf et al. 2014), although findings vary depending on the study location, demographic characteristics of the sample, the approach used for case finding, the method used for diagnostic confirmation, and the diagnostic criteria used.

Schizophrenia is also associated with increased mortality, with a shortened life span and standardized mortality ratios that are reported to be twofold to fourfold those in the general population (Hayes et al. 2017; Heilä et al. 2005; Hjorthøj et al. 2017; Laursen et al. 2014; Lee et al. 2018; Oakley et al. 2018; Olfson et al. 2015; Tanskanen et al. 2018; Walker et al. 2015). The common co-occurrence of other psychiatric disorders (Plana-Ripoll et al. 2019), including substance use disorders (Hunt et al. 2018), contributes to morbidity and mortality among individuals with schizophrenia. About 4%–10% of persons with schizophrenia die by suicide, with rates that are highest among males in the early course of the disorder (Drake et al. 1985; Heilä et al. 2005; Hor and Taylor 2010; Inskip et al. 1998; Laursen et al. 2014; Nordentoft et al. 2011; Palmer et al. 2005; Popovic et al. 2014; Saha et al. 2007; Tanskanen et al. 2018). Additional causes of death include other unnatural causes, such as accidents and traumatic injuries, and physical conditions, such as cardiovascular, respiratory, and infectious diseases and malignancies, particularly lung cancer (American Psychiatric Association 2013a; Hayes et al. 2017; Heilä et al. 2005; Hjorthøj et al. 2017; Laursen et al. 2014; Lee et al. 2018; Oakley et al. 2018; Olfson et al. 2015; Tanskanen et al. 2018; Walker et al. 2015). Increases in morbidity and mortality related to physical health in individuals with schizophrenia are likely associated with such factors as obesity, diabetes, hyperlipidemia, greater use of cigarettes, reduced engagement in health maintenance (e.g., diet, exercise), and disparities in access to preventive health care and treatment for physical conditions (Bergamo et al. 2014; De Hert et al. 2011; Druss et al. 2000; Janssen et al. 2015; Kisely et al. 2007, 2013; Kugathasan et al. 2018; Lawrence et al. 2010; Moore et al. 2015). Lack of access to adequate psychiatric treatment may also influence mortality (Schoenbaum et al. 2017).

This practice guideline focuses on evidence-based pharmacological and nonpharmacological treatments for schizophrenia. In addition, it includes statements related to assessment and treatment planning, which are an integral part of patient-centered care. Thus, the overall goal of this guideline is to enhance the treatment of schizophrenia for affected individuals, thereby reducing the mortality, morbidity, and significant psychosocial and health consequences of this important psychiatric condition.

The scope of this document is shaped by Treatments for Schizophrenia in Adults (McDonagh et al. 2017), a systematic review commissioned by the Agency for Healthcare Research and Quality (AHRQ) that serves as a principal source of information for this guideline on the basis of its methodological rigor and adherence to accepted standards for systematic reviews. This guideline is focused on the treatment of patients with schizophrenia, and, as such, the statements in this guideline will be relevant to individuals with a diagnosis of schizophrenia. The AHRQ review uses the DSM-5 definition of schizophrenia; however, many of the systematic reviews included studies that used earlier DSM or International Classification of Diseases (ICD) criteria for schizophrenia. Several studies, particularly those assessing harms and psychosocial interventions, also included patients with a schizophrenia spectrum disorder diagnosis. Consequently, discussion of treatment, particularly treatment of first-episode psychosis, may also be relevant to individuals with schizophreniform disorder.

Although many of the studies included in the systematic review also included individuals with a diagnosis of schizoaffective disorder, these data were rarely analyzed separately in a way that would permit unique recommendations to be crafted for this group of patients. In addition, this guideline does not address issues related to identification or treatment of attenuated psychosis syndrome or related syndromes of high psychosis risk, which were not part of the AHRQ systematic review.

Data are also limited on individuals with schizophrenia and significant physical health conditions or co-occurring psychiatric conditions, including substance use disorders. Many of the available studies excluded these individuals from the clinical trial or did not analyze data separately for these patient subgroups. Nevertheless, in the absence of more robust evidence, the statements in this guideline should generally be applicable to individuals with co-occurring conditions, including individuals who receive treatment using integrated collaborative care or inpatient or outpatient medical settings. Although treatment-related costs are often barriers to receiving treatment, and cost-effectiveness considerations are relevant to health care policy, few high-quality studies exist on the cost-effectiveness of treatments for schizophrenia. In addition, costs of treatment typically differ by country and geographic region and vary widely with the health system and payment model. Consequently, cost-effectiveness considerations are outside the scope of this guideline and its recommendations.

Since the publication of the Institute of Medicine (now known as the National Academy of Medicine) report Clinical Practice Guidelines We Can Trust (Institute of Medicine 2011), there has been an increasing focus on using clearly defined, transparent processes for rating the quality of evidence and the strength of the overall body of evidence in systematic reviews of the scientific literature. This guideline was developed using a process intended to be consistent with the recommendations of the Institute of Medicine (2011) and the Principles for the Development of Specialty Society Clinical Guidelines of the Council of Medical Specialty Societies (2012). Parameters used for the guideline’s systematic review are included with the full text of the guideline; the development process is fully described in the following document available at the APA website: www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines/guideline-development-process.

Development of guideline statements entails weighing the potential benefits and harms of each statement and then identifying the level of confidence in that determination. This concept of balancing benefits and harms to determine guideline recommendations and strength of recommendations is a hallmark of Grading of Recommendations Assessment, Development and Evaluation (GRADE), which is used by multiple professional organizations around the world to develop practice guideline recommendations (Guyatt et al. 2013). With the GRADE approach, recommendations are rated by assessing the confidence that the benefits of the statement outweigh the harms and burdens of the statement, determining the confidence in estimates of effect as reflected by the quality of evidence, estimating patient values and preferences (including whether they are similar across the patient population), and identifying whether resource expenditures are worth the expected net benefit of following the recommendation (Andrews et al. 2013).

In weighing the balance of benefits and harms for each statement in this guideline, our level of confidence is informed by available evidence, which includes evidence from clinical trials as well as expert opinion and patient values and preferences. Evidence for the benefit of a particular intervention within a specific clinical context is identified through systematic review and is then balanced against the evidence for harms. In this regard, harms are broadly defined and may include serious adverse events, less serious adverse events that affect tolerability, minor adverse events, negative effects of the intervention on quality of life, barriers and inconveniences associated with treatment, direct and indirect costs of the intervention (including opportunity costs), and other negative aspects of the treatment that may influence decision-making by the patient, the clinician, or both.

Many topics covered in this guideline have relied on forms of evidence such as consensus opinions of experienced clinicians or indirect findings from observational studies rather than research from randomized trials. It is well recognized that there are guideline topics and clinical circumstances for which high-quality evidence from clinical trials is not possible or is unethical to obtain (Council of Medical Specialty Societies 2012). For example, many questions need to be asked as part of an assessment, and inquiring about a particular symptom or element of the history cannot be separated out for study as a discrete intervention. It would also be impossible to separate changes in outcomes due to assessment from changes in outcomes due to ensuing treatment. Research on psychiatric assessments and some psychiatric interventions can also be complicated by multiple confounding factors such as the interaction between the clinician and the patient or the patient’s unique circumstances and experiences. The GRADE working group and guidelines developed by other professional organizations have noted that a strong recommendation or good practice statement may be appropriate even in the absence of research evidence when sensible alternatives do not exist (Andrews et al. 2013; Brito et al. 2013; Djulbegovic et al. 2009; Hazlehurst et al. 2013). For each guideline statement, we have described the type and strength of the available evidence as well as the factors, including patient preferences, that were used in determining the balance of benefits and harms.

The authors of the guideline determined each final rating, as described in the section “Guideline Development Process,” that is endorsed by the APA Board of Trustees. A recommendation (denoted by the numeral 1 after the guideline statement) indicates confidence that the benefits of the intervention clearly outweigh harms. A suggestion (denoted by the numeral 2 after the guideline statement) indicates greater uncertainty: although the benefits of the statement are still viewed as outweighing the harms, the balance of benefits and harms is more difficult to judge, or the benefits or the harms may be less clear. With a suggestion, patient values and preferences may be more variable, and this can influence the clinical decision that is ultimately made.

Each guideline statement also has an associated rating for the strength of supporting research evidence. Three ratings are used: high, moderate, and low (denoted by the letters A, B, and C, respectively). These ratings reflect the level of confidence that the evidence for a guideline statement reflects a true effect based on consistency of findings across studies, directness of the effect on a specific health outcome, precision of the estimate of effect, and risk of bias in available studies (Agency for Healthcare Research and Quality 2014; Balshem et al. 2011; Guyatt et al. 2006).

The APA Practice Guidelines are assessments of current (as of the date of authorship) scientific and clinical information provided as an educational service. The guidelines 1) should not be considered as a statement of the standard of care or inclusive of all proper treatments or methods of care, 2) are not continually updated and may not reflect the most recent evidence because new evidence may emerge between the time information is developed and when the guidelines are published or read, 3) address only the question(s) or issue(s) specifically identified, 4) do not mandate any particular course of medical care, 5) are not intended to substitute for the independent professional judgment of the treating clinician, and 6) do not account for individual variation among patients. As such, it is not possible to draw conclusions about the effects of omitting a particular recommendation, either in general or for a specific patient. Furthermore, adherence to these guidelines will not ensure a successful outcome for every individual, nor should these guidelines be interpreted as including all proper methods of evaluation and care or excluding other acceptable methods of evaluation and care aimed at the same results. The ultimate recommendation regarding a particular assessment, clinical procedure, or treatment plan must be made by the clinician directly involved in the patient’s care in light of the psychiatric evaluation, other clinical data, and the diagnostic and treatment options available. Such recommendations should be made in collaboration with the patient, whenever possible, and should incorporate the patient’s personal and sociocultural preferences and values in order to enhance the therapeutic alliance, adherence to treatment, and treatment outcomes.

For all of these reasons, APA cautions against the use of guidelines in litigation. Use of these guidelines is voluntary. APA provides the guidelines on an “as is” basis and makes no warranty, expressed or implied, regarding them. APA assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the guidelines or for any errors or omissions.