Long-term Continuity of Antipsychotic Treatment for Schizophrenia

A Nationwide Study

Jose M. Rubio; Heidi Taipale; Antti Tanskanen; Christoph U. Correll; John M. Kane; Jari Tiihonen


Schizophr Bull. 2021;47(6):1611-1620. 

In This Article

Abstract and Introduction


Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for "within-participant" risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3–11) with a median duration of 11.4 months (IQR = 5.3–25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89–30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75–9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20–0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27–0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia.


Schizophrenia is most often a chronic disorder, requiring long-term treatment.[1] Despite the demonstrated efficacy of antipsychotics in preventing relapse,[2] most guidelines do not make recommendations for treatment beyond 2 years, since this is the longest period of time for which there are randomized data.[3] However, there is no evidence that the risk of relapse associated with interrupting antipsychotic treatment decreases after 2 years of antipsychotic treatment. Instead, long-term national registry data indicates that this risk may indeed increase.[4] Interruption of antipsychotic treatment has been consistently associated with worse psychiatric and medical outcomes. In a systematic review and meta-analysis of risk factors for relapse following the initial treatment of schizophrenia, interrupting antipsychotic treatment was the predictor with the largest effect, with 4-fold risk compared to treatment continuation, surpassing other risk factors such as co-occurring drug use.[5] Lack of antipsychotic treatment in individuals with schizophrenia has also been associated with premature mortality due to medical comorbidities and suicide.[6]

The general consensus favoring long-term antipsychotic maintenance treatment for relapse prevention in schizophrenia has been questioned, however, by some authors. The Dutch MESIFOS study found that individuals randomized to treatment discontinuation did have greater rates of long-term functional recovery,[7] which has prompted some authors to caution against the universal long-term antipsychotic maintenance treatment for schizophrenia.[8] However, this finding was not replicated in a study from Hong Kong with a similar design and larger sample.[9] Additionally, given their naturalistic designs, other studies cited in support of better prognosis associated with treatment discontinuation[10] may have been exposed to selection and attrition bias (ie, including and retaining disproportionately individuals with better prognosis) and confounder by indication (ie, treatment discontinuation is consequence but not cause of better prognosis). Thus, some degree of controversy remains on this important area, although we would argue that most evidence supports the recommendation of continuous long-term antipsychotic treatment in most individuals with schizophrenia.[1] In a recent systematic review of treatment guidelines, 5 out of 6 advised against discontinuation of treatment in multiepisode schizophrenia, and 9 out of 9 converged recommending against intermittent/targeted use of antipsychotic drugs.[3] Given this important discussion about the long-term treatment of schizophrenia at the level of supporting evidence and recommendations, it is relevant to study the actual utilization of antipsychotic medication over the long-term. Understanding such patterns of treatment utilization is essential to inform policies aimed at closing the gap between actual and recommended use.

It is well known that that there is a high rate of interruption in long-term antipsychotic treatment. For example, a study from the veteran affairs (VA) system in the United States (n = 2138) found that 84% of patients discontinued antipsychotic treatment during a follow-up of up to 33 months.[11] Also in a VA cohort, another group found that 61% of individuals had difficulty with consistent adherence over a 4-year period, with younger age, non-white race, co-occurring substance use, and previous hospitalizations contributing to greater risk for poor adherence over this period of time.[12] Similarly in Europe, the SOHO study (n = 7728) reported treatment discontinuation rates between 34% and 66% over 36 months of follow-up.[13] Thus, it is well established that most individuals will interrupt antipsychotic treatment during their course of illness. What is less understood, and what this study intends to address, is how such a high rate of treatment interruption evolves over the long term and what factors might contribute. To our knowledge, there are no studies that measure treatment utilization in a representative cohort starting from the early treatment and continuing to the chronic phase of illness.

In this study, we aim to measure the continuity of antipsychotic treatment over a significant portion of the course of illness in a national cohort of individuals with early phase schizophrenia followed for up to 18 years. In particular, we use a within-participant analysis to examine the risk factors associated with the interruption of each treatment period for any given participant, which mitigates residual confounding and reverse causation by comparing treatment episodes for each individual participant, instead of comparing between groups of participants.