First Episode Schizophrenia: Intervening Early and Well

SPECIAL REPORT: SCHIZOPHRENIA/PSYCHOSIS

Schizophrenia affects only 1% of the population yet it is among the top 20 causes of disability in the US.¹ Schizophrenia is also associated with a 20-year decrease in life expectancy² and a 4-fold increase in all-cause mortality.³ Moreover, despite treatment advances, long-term prognosis is limited: At 25 years, only 13% of individuals with schizophrenia are in recovery, and only 5% are in remission.⁴ Given the significant long-term impact of schizophrenia, there has been a focus on early intervention with comprehensive treatment for the first episode, as early treatment is generally associated with better outcomes throughout medicine. In psychosis, there is a prognostic benefit from keeping the duration of untreated psychosis (DUP) short once the psychotic threshold has been crossed.⁵

The first episode of schizophrenia is typically preceded by a prodromal or clinical high-risk (CHR) period occurring several months to years before the onset of frank psychosis. This prodromal period often includes nonspecific symptoms such as depression, anxiety, and social and cognitive deficits, all of which contribute to gradual functional impairment.⁶ Specific criteria for CHR include attenuated psychotic symptoms, full-blown psychotic symptoms that are brief and self-limiting, or a significant decrease in functioning in the context of a genetic risk for schizophrenia.⁷ Among patients with this constellation of symptoms, it is estimated that only 22% will convert to psychosis.⁶ Although interventions to prevent conversion to the first psychotic episode are an area of active research,⁶ cannabis use is an important risk factor that should be addressed in treatment.⁸ Although most individuals identified as CHR will not convert to psychosis, they do continue to have impaired social and role functioning, and many develop other psychiatric disorders, particularly depression and anxiety.⁹

The transition to the first episode of schizophrenia is characterized by the full onset of positive symptoms (eg, hallucinations, delusions, disorganized speech), negative symptoms (eg, flat affect, anhedonia, amotivation, asociality), and ongoing functional impairment. An important contributor to this functional impairment is declining cognition, which typically begins in the CHR period and progresses through the early stages of schizophrenia.¹⁰

Because positive psychotic symptoms are not pathognomonic for schizophrenia and can be present in multiple disorders, a broad differential diagnosis must be considered. This differential diagnosis includes mood disorders with psychotic features, substance-induced psychosis, complex posttraumatic stress disorder, schizophrenia spectrum disorders, and nonpsychiatric illnesses causing secondary psychosis. The presence of significant mood symptoms or substance use before the onset of psychosis may provide diagnostic clues, as would the combination of positive and negative symptoms occurring in the context of a gradual and chronic functional impairment. An abrupt onset of symptoms, atypical age of symptom onset, vital sign abnormalities, and neurologic symptoms would all suggest a nonpsychiatric etiology causing secondary psychosis. Given the potential for secondary psychosis, patients experiencing a first episode of psychosis deserve a thorough medical evaluation, although the specific components of the assessment may be dictated by the individual clinical presentation.¹¹

Treatment Options

Psychiatric treatment should be initiated rapidly after the emergence of psychosis because the DUP affects prognosis.⁵ Early intervention is associated with a lower risk of relapse and hospitalization,¹² greater symptomatic improvement,¹² improved functioning and quality of life,¹² and a lower suicide rate.¹³ Coordinated Specialty Care (CSC), a comprehensive treatment delivered in a coordinated fashion as pioneered in the seminal RAISE study,¹⁴ is an evidence-based treatment recommended for all individuals experiencing a first episode of schizophrenia.¹¹ The CSC core components are specialized psychopharmacology, individual therapy, family psychoeducation, case management, and supported employment and education. These services are delivered by a single recovery-oriented multidisciplinary team that promotes easy access to comprehensive care and coordinated shared decision-making between patients, families, and health care providers. The benefits of CSC include improved quality of life, better functioning, and greater symptomatic improvement.¹⁴

The cornerstone of specialized psychopharmacology is antipsychotic medication. Efficacy across most individual antipsychotic drugs is similar, including both first-generation antipsychotics (FGA) and second-generation antipsychotics.¹⁵ Among agents available in the US, only clozapine, olanzapine, and risperidone have superior efficacy for overall symptoms, with a smaller effect size for olanzapine and risperidone.¹⁵ Thus, antipsychotic selection must be based on other factors, including adverse effect profile, particularly extrapyramidal adverse effects and metabolic impact, and long-acting injectable (LAI) availability. FGAs have a higher risk of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) and may have lower tolerability and a higher risk of discontinuation in first-episode patients.^16,17 Although all antipsychotic medications cause some degree of weight gain, the overall metabolic impact varies between agents. Lumateperone has a negligible risk of weight gain,¹⁸ lurasidone and ziprasidone have a very low risk of weight gain,¹⁹ and clozapine and olanzapine have the highest risk.^18,19 When possible, a lower metabolic risk antipsychotic should be selected, although some patients may require medications with a higher metabolic impact due to increased efficacy. LAI availability should also be considered. LAIs increase adherence and allow for easier detection of nonadherence.²⁰ They may be particularly beneficial in the first episode; they are correlated with improved positive symptoms, fewer relapses, and hospitalizations.²⁰ In addition, LAIs are associated with a 33% lower risk of all-cause mortality and a 47% lower suicide mortality risk.²¹ Prescribers and patients must consider these factors together with individual preferences, comorbid health conditions, and treatment goals through shared decision-making to select the ultimate antipsychotic agent.

Patients with first-episode schizophrenia are more sensitive to the adverse effects of antipsychotic medication¹⁶ and more responsive to medication than multiepisode patients.²² Therefore, they often are best treated with doses on the lower end of the therapeutic antipsychotic dose range.¹⁶ Quetiapine is the one exception where doses must approach what is given for multiepisode patients (500-600 mg/d).¹⁶

Even in the first episode, 20% of individuals will not respond to first-line antipsychotics.¹⁷ Patients with 2 failed trials of antipsychotics that are adequate for dose, duration, and adherence should be offered a trial of clozapine. Clozapine is the only FDA-approved medication for treatment-resistant schizophrenia. Although clozapine has significant adverse effects, it also has lower all-cause mortality compared to all other antipsychotics.²³ Despite well-established superior efficacy,¹⁵ clozapine is underutilized; many patients, including those experiencing a first episode who are treatment resistant, would benefit from earlier consideration of a clozapine trial.¹¹

All individuals taking antipsychotics need adverse-effect monitoring and management to prevent antipsychotic-associated morbidity and mortality. Almost all antipsychotics show weight gain and associated metabolic problems like diabetes after extended use.¹⁹ This weight gain may be more pronounced in antipsychotic-naive first- episode patients.²⁴ Weight gain occurs rapidly after medication initiation and then plateaus¹⁹; thus, early monitoring and intervention are important. Monitoring should include body mass index (BMI), waist circumference, blood glucose, hemoglobin A_1C, and lipids regularly. However, monitoring alone is insufficient. Prevention of metabolic changes is paramount, and emerging abnormalities require intervention. In addition to nutritional counseling and regular exercise, metformin is an (off-label) method of prevention for antipsychotic-induced metabolic problems. Metformin is a safe and relatively well-tolerated medication; the most common adverse effects are gastrointestinal. It is associated with a significant decrease in BMI and hemoglobin A_1C.²⁵ Metformin often requires robust dosing, with a daily target of 2000 mg for adults.²⁵ If metformin is ineffective, weight loss medications, including glucagon-like peptide-1 receptor agonists, can be considered.

Antipsychotic medications also cause EPS, including early-onset dystonia, akathisia, and parkinsonism, as well as later-onset TD. Patients thus require motor adverse-effect monitoring, including regular Abnormal Involuntary Movement Scale evaluations, the frequency of which is determined by individual patient risk factors.¹¹ Other adverse effects, including sedation, hyperprolactinemia, and constipation, require monitoring as well.

Once the acute episode of psychosis has been stabilized, the focus of treatment transitions to the critical goal of relapse prevention. The consequences of early relapse are significant: After relapse, it takes longer to respond to medication, higher doses are often needed, and fewer individuals have a favorable treatment response, including the development of treatment resistance.²⁶ An important component of relapse prevention is antipsychotic medication. Although many patients who experience a first episode of schizophrenia wish to stop medication, those who do are at high risk of relapse¹¹ and other associated poor outcomes, including persistent psychosis²⁷ and an increased risk of death.²⁸ Thus, current treatment recommendations for schizophrenia encourage long-term treatment with the lowest effective dose of antipsychotic medication, although some individuals with a brief episode of psychosis or an uncertain diagnosis may not require ongoing antipsychotic treatment.¹¹ Unfortunately, there are no biomarkers or other clinical measures to prospectively identify this select group. The ultimate decision regarding medication continuation must be made through a shared decision-making process in which the prescriber and patient consider individual recovery goals, the benefits of long-term medication, and the risks of adverse effects, dose reduction, and discontinuation. Family members or other support people should also be included in this discussion.

Concluding Thoughts

The first episode of schizophrenia is a critical period of illness. Although long-term recovery in schizophrenia remains suboptimal, the best opportunity for recovery lies in early intervention with comprehensive treatment of the first episode, including CSC and the use of clozapine for treatment-resistant patients. Prevention of morbidity and mortality is an integral aspect of psychopharmacology. Until novel treatment advances change the prognostic landscape, our focus must be on optimal treatment of the first episode.

Dr Donovan is the director of the first episode and early psychosis program; director of clinical services, psychosis clinical and research program; director of child psychiatry emergency services; and associate director of the acute psychiatry service at Massachusetts General Hospital in Boston. She is also an assistant professor of psychiatry at Harvard Medical School, also in Boston.

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