Objective Treatment resistance complicates the management of schizophrenia. Research and clinical translation is limited by inconsistent definitions. To address this we evaluated current approaches and then developed consensus criteria and guidelines. Method A systematic review of randomized antipsychotic clinical trials in treatment resistant schizophrenia was performed. Definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed by a working group of researchers and clinicians through i) a multi-phase, mixed methods approach; ii) identifying key criteria via an online survey; and iii) meetings to achieve consensus. Results 42 studies met inclusion criteria. Of these, 21 (50%) studies did not provide operationalized criteria, whilst in others, criteria varied considerably, particularly regarding symptom severity, prior treatment duration and antipsychotic dose thresholds. Important for the inability to compare results, only two (5%) studies utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) ≥moderate functional impairment; 3) prior treatment consisting of ≥2 different antipsychotic trials, each for a minimum duration and dose; 4) adherence systematically assessed and meeting minimum criteria; 5) ideally at least one prospective treatment trial; 6) criteria that clearly separated responsive from treatment resistant patients. Conclusions There is considerable variation in current approaches to defining treatment resistance in schizophrenia. We present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment and treatment response in schizophrenia, providing a benchmark for research and clinical translation.

he Clinical Challenge 1 in this issue of JAMA Psychiatry describes a patient who clinicians will be familiar with: a young woman who develops auditory hallucinations, unusual beliefs, and a deterioration in cognitive abilities and social function and is diagnosed with schizophrenia in early adulthood. The diagnosis of schizophrenia is based on a clinical assessment. In response to concerns regarding diagnostic reliability, early narrative descriptions of the disorder have been replaced with codified criteria (Box). Positive symptoms, such as delusions and hallucinations, are often the reason the patient presents to the clinician. However, the disorder is also associated with negative symptoms, such as amotivation and social withdrawal, and cognitive symptoms, including deficits in working memory, executive function, and processing speed. While more recent descriptions emphasize positive symptoms (Box), earlier conceptualizations saw negative symptoms as core features of the disorder, 2 and negative and cognitive symptoms contribute substantially to the long-term burden associated with the disorder. 3 The disorder typically appears in early adulthood, and a prodromal period frequently precedes the first psychotic episode (Figure 1).Schizophrenia has a lifetime prevalence of about 1% 4 and accounts for a huge health care burden, with annual associated costs in the United States estimated to be more than $150 billion. 5 The fact that a disorder affecting around 1% of the population is associated with such costs is attributable to the fact that typical onset is in early adulthood and the long-term impairments in social and occupational function associated with the disease (Figure 1). 6 The disorder is also associated with reduced life expectancy: someone with schizophrenia has a mean life expectancy about 15 years shorter than the general population and a 5% to 10% lifetime risk of death by suicide. 7 In this review, we discuss findings from epidemiological, genetic, neuroimaging, and preclinical research to provide an overview of schizophrenia and consider the gaps in knowledge that remain. Theme 1: Convergence of Genetic and Early Environmental Risk Factors on NeurodevelopmentThe patient in the Clinical Challenge 1 case has a history of perinatal complications. Although schizophrenia typically appears in early adulthood, multiple strands of evidence indicate that its pathogenesis begins early in neurodevelopment. 8 This evidence includes increased rates of in utero adversity, such as maternal infections and starvation during pregnancy, and obstetric complications, including preterm birth and preeclampsia. [9][10][11] There is also evidence consistent with disrupted early neurodevelopment, such as skin markers of altered ectodermal development and mild cognitive and motor impairments in childhood. 9,12 Such impairments may manifest as IMPORTANCE Schizophrenia is a common, severe mental illness that most clinicians will encounter regularly during their practice. This report provides an overview of the clinical...