Antipsychotic Discontinuation: Two Decades Later

Dr Miller is Associate Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Editor for Psychiatric Times.

RESEARCH UPDATE

An important question that patients might ask clinicians is, “How long should I continue antipsychotic treatment after the first episode of schizophrenia?” Many current treatment guidelines recommend 1 to 5 years of antipsychotic treatment if relapse does not occur.¹ A classic study found that antipsychotic discontinuation was associated with a 5-fold higher risk of relapse over 5 years following a first episode of psychosis.² However, it is not known whether relapse risk remains elevated after 2 to 5 years of stability.

Tiihonen and colleagues³ used a large electronic database to assess risk of treatment failure (rehospitalization or death) as a function of the duration of antipsychotic treatment prior to discontinuation in a nationwide cohort of patients with first-episode schizophrenia. They first identified all persons hospitalized for schizophrenia (ICD-8, -9, and -10 diagnoses) in Finland from 1972 to 2014 using the Finnish Hospital Discharge register.

Next, they identified 8719 persons with a first hospitalization for schizophrenia between 1996 and 2014, based on no previous hospitalizations and no antipsychotic exposure in the year preceding hospitalization (from the Finnish Prescription register). After hospital discharge, a 30-day definition period was applied to identify users (n = 4217) and non-users (n = 3217), based on initiation of antipsychotic use. A total of 1714 subjects discontinued antipsychotic use during the follow-up period because of rehospitalization, death, or the end of the study period, and were considered discontinuers. Clozapine was used as a proxy for treatment resistance, and long-acting injectable medication as a proxy for poor treatment adherence.

Subjects were followed until the outcome event (rehospitalization or death), until they started using antipsychotics, or until the end of the follow-up period. Patients who discontinued antipsychotic treatment were matched to an antipsychotic user. For mortality analyses, antipsychotic nonusers were matched with patients who discontinued use after less than 1 year. Antipsychotic use was modeled with the PRE2DUP method from purchases recorded in the Finnish Prescription register.⁴

The composite measure, “treatment failure,” which included psychiatric rehospitalization or death, was the primary outcome to evaluate the net effect of antipsychotic use. Secondary outcome measures were rehospitalization (as a proxy for relapse) and mortality. Covariates included age, sex, and duration of index hospitalization (as a proxy for illness severity). Data were analyzed using Cox proportional hazards models, comparing risk of treatment failure between discontinuers (stratified by 0; 1-2; 2-5; and > 5 years) and matched users, adjusting for age and sex. In separate Cox analyses, nonusers were compared with antipsychotic users.

The median age of subjects in the cohort was 35 years; 57% of subjects were male. The majority of patients who discontinued antipsychotic treatment did so during the first year. Treatment failure occurred in 57% of antipsychotic nonusers compared with 34% of antipsychotic users. Of those who discontinued antipsychotics, 38% experienced treatment failure compared with 29% of matched antipsychotic users. Interestingly, the risk of treatment failure significantly increased with the duration of antipsychotic treatment before discontinuation. Subjects with antipsychotic discontinuation after more than 5 years were 7-fold more likely to experience treatment failure compared with matched antipsychotic users (HR = 7.0). Similarly, subjects with antipsychotic discontinuation after more than 5 years also had the highest risk of psychiatric rehospitalization compared with matched users (HR = 4.5). Compared with antipsychotic users, antipsychotic nonusers had a 214% higher risk of death (HR = 3.1), and early discontinuers had a 174% higher risk of death (HR = 2.7).

The authors reported that theirs is the first study of how risk of relapse in first-episode schizophrenia is modified by the duration of antipsychotic treatment (ie, the later the antipsychotic is discontinued, the greater the risk of treatment failure). Study findings suggest that there is no “safe” timepoint for discontinuation following initiation of antipsychotic treatment. One potential explanation is that long-term antipsychotic exposure modifies brain homeostasis, making discontinuation more difficult.

Study strengths included nationwide coverage of first-episode schizophrenia and follow-up based on register data, as well as the long follow-up period. One limitation is not knowing whether antipsychotic discontinuation was a patient decision or guided by the treating physician.

The bottom line

If antipsychotic treatment has been used continuously for several years, it is risky to discontinue treatment. Risk of illness relapse does not decrease as function of time during the first 8 years of illness. Continuous use of antipsychotics for up to 20 years is associated with lower mortality than no use or early discontinuation. Long-lasting continuous antipsychotic treatment appears to be beneficial for the majority of patients with first-episode schizophrenia.

This article was originally published on 8/7/18 and has since been updated.

References:

1. Takeuchi H, Suzuki T, Uchida H, et al. Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res. 2012;134:219–225.

2. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56:241–247.

3. Tiihonen J, Tanskanen A, Taipale H. 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia. Am J Psychiatry. 2018;175:765-773.

4. Tanskanen A, Taipale H, Koponen M, et al: From prescription drug purchases to drug use periods: a second generation method (PRE2DUP).BMC Med Inform Decis Mak. 2015;15:21.