What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?

Abstract

The long-term benefit-to-risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically examine the literature on the long-term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors that affect the risk-benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following stabilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not all, of the long-term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive, given the extensive risk of bias, including increasing non-adherence. On the other hand, long-term studies based on national registries, which have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless, chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evidence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psychosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated with undesirable neurologic and metabolic side effects, the evidence supporting its long-term efficacy and effectiveness, including impact on life expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit-to-risk ratio. However, the finding that a minority of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treatment, calls for further research on patient-level predictors of positive outcomes in people with an initial psychotic presentation.

Long‐term antipsychotic treatment of schizophrenia: does it help or hurt over a 20‐year period?

“…Correll et al argue for a positive view of the risk‐benefit ratio for long‐term continuous antipsychotic treatment of schizophrenia. They claim that studies of long‐term outcome which show negative results are not convincing because of confounding factors.…”

“…They claim that studies of long‐term outcome which show negative results are not convincing because of confounding factors. Their chief argument is that in “non‐randomized, uncontrolled studies… there is a high risk of confounding by indication and reverse causation, in that greater illness severity could be the cause of continued antipsychotic treatment, rather than being the effect”. The other argument is that long‐term continuous use of antipsychotics does not involve significant morbidity from dopamine supersensitivity psychosis.…”

Antipsychotic maintenance treatment in schizophrenia and the importance of preventing relapse

“…First, it appears difficult to explain why one of the best documented findings in psychiatric treatment research, namely the fact that continuous intake of antipsychotics prevents relapses with a numberneeded-to-treat of 3 1 , a success rate which must be seen with envy from the perspective of other medical specialties, is questioned on the basis of a handful of studies of suboptimal methodological rigor 2 . Second, one wonders why historical hypothetical constructs, such as "supersensitivity psychosis" 3 , which have not proven reasonably valid ever since they were originally put forward, experience a sudden renaissance.…”

Increasing expectations and knowledge require a more subtle use of prophylactic antipsychotics

“…In recent years, concern has been raised about the risk/benefit ratio of prophylactic antipsychotics. The paper by Correll et al is the second of two responses from the psychopharmacological establishment, and takes a less dogmatic approach than its predecessor.…”