What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?
Open accessAbstract
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.
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Psychotic relapse is associated with multiple downstream effects on disease course and brain structure, such as progressive decline in gray and white matter structure and volume.
“Psychotic relapse is extremely disruptive to patients and their families and is associated with multiple downstream effects on disease course and brain structure [2], such as progressive decline in gray and white matter structure and volume [8, 9].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [2]
Pharmacological and psychotherapeutic approaches do not result in full remission in all patients with mental disorders.
“whilst the pharmacological [35,36] and psychotherapeutic approaches [37,38] are helpful for many, they do not result in full remission in all patients.”
From Exercise as Medicine for Mental and Substance Use Disorders: A Meta-review of the Benefits for Neuropsychiatric and Cognitive Outcomes (2020) · cites this paper as [35]
Even in patients who respond well to traditional treatments, some continue to experience residual symptoms and/or risk of future relapse.
“Furthermore, even in those who respond well to traditional treatments, some continue to experience residual symptoms, and/or a risk of future relapse [35,36,38].”
From Exercise as Medicine for Mental and Substance Use Disorders: A Meta-review of the Benefits for Neuropsychiatric and Cognitive Outcomes (2020) · cites this paper as [35]
Antipsychotics and other psychotropic agents have adverse effects.
“adverse effects of antipsychotics 258,259 or other psychotropic agents”
From Preventive psychiatry: a blueprint for improving the mental health of young people (2021) · cites this paper as [259]
In schizophrenia and psychotic disorders, adherence to pharmacological treatments is frequently far from optimal.
“These latter aspects related to adherence are especially relevant in the setting of schizophrenia and psychotic disorders, where adherence to pharmacological treatments is frequently far from optimal and represents the main cause of relapse [16–18] and hospitalizations [19, 20].”
From The role of shared decision-making in improving adherence to pharmacological treatments in patients with schizophrenia: A clinical review (2020) · cites this paper as [16]
In schizophrenia and psychotic disorders, poor adherence to pharmacological treatments is the main cause of relapse and hospitalizations.
“These latter aspects related to adherence are especially relevant in the setting of schizophrenia and psychotic disorders, where adherence to pharmacological treatments is frequently far from optimal and represents the main cause of relapse [16–18] and hospitalizations [19, 20].”
From The role of shared decision-making in improving adherence to pharmacological treatments in patients with schizophrenia: A clinical review (2020) · cites this paper as [16]
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“93 In our opinion, 94 in agreement with other experts, 95 there is insufficient data to suggest that the benefits of antipsychotic drugs would disappear over time or that they would indeed become harmful.”
BackgroundIsohanni, M., Miettunen, J., Jääskeläinen, E., Moilanen, J., Hulkko, A., & Huhtaniska, S. (2018) · World Psychiatry · doi:10.1002/wps.20523 · Cited by 9 · see citing works
Psychiatric hospitalization following antipsychotic medication cessation in first episode psychosis
Hayes, J. F., Osborn, D. P., Lundin, A., & Dalman, C. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119827883 · Cited by 8 · see citing works
The long‐term treatment of schizophrenia with antipsychotics: a perennial debate
Fleischhacker, W. W. (2018) · World Psychiatry · doi:10.1002/wps.20542 · Cited by 6 · see citing works
- Authors
- Correll, C. U., Rubio, J. M., & Kane, J. M.
- Affiliations
- Northwell Health (US)
- Zucker Hillside Hospital, Psychiatry Research, Northwell Health Glen Oaks NY USA
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2018-05-24
- Volume
- 17
- Issue
- 2
- Pages
- 149-160
- ISSN
- 1723-8617 (ISSN-L)
- 2051-5545
- PMC
- PMC5980517
- OpenAlex
- W2806469814
- Semantic Scholar
- 1136679236bdeed2c728a21d56d0159539800118
- Cited by
- 324
- References
- 157
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 46 · 2023: 42 · 2022: 49 · 2021: 37 · 2020: 31 · 2019: 36 · 2018: 17
- FWCI
- 23.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- World Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Social Sciences › Psychology › Clinical Psychology › Psychiatric care and mental health services
- Keywords
- schizophrenia, long-term antipsychotic treatment, risk-benefit ratio, antipsychotic efficacy, antipsychotic adverse effects, tardive dyskinesia, metabolic disorders, mortality, medication adherence, psychosocial interventions, relapse, life expectancy
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