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Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review
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Abstract: Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders ( DSM ) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry
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“However, preliminary data indicates community exercise can be beneficial and engaging for young people with mental illness, even for those with severe conditions.253,254”
From The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness (2019) · cites this paper as [253]
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Carvalho, A. F., Solmi, M., Sanches, M., Machado, M. O., Stubbs, B., Ajnakina, O., Sherman, C., Sun, Y. R., Liu, C. S., Brunoni, A. R., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0835-5 · Cited by 204
Self-citationVázquez, G. H., Bahji, A., Undurraga, J., Tondo, L., & Baldessarini, R. J. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211013579 · Cited by 95
Self-citationSolmi, M., Pigato, G., Kane, J. M., & Correll, C. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s133205 · Cited by 88
Medical Management of Eating Disorders: An Update
Voderholzer, U., Haas, V., Correll, C. U., & Körner, T. (2020) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000653 · Cited by 70
Self-citation
Metadata
- Authors
- Solmi, M., Murru, A., Pacchiarotti, I., Undurraga, J., Veronese, N., Fornaro, M., Stubbs, B., Monaco, F., Vieta, E., Seeman, M., Correll, C., & Carvalho, A.
- Affiliations
- University of Padua (IT)
- Hospital Clínic de Barcelona (ES)
- Universidad del Desarrollo (CL)
- New York State Psychiatric Institute (US)
- University of Toronto (CA)
- Northwell Health (US)
- ORCID
- Venue
- Therapeutics and Clinical Risk Management
- Publisher
- Informa UK Limited
- Published
- 2017-06
- Volume
- Volume 13
- Pages
- 757-777
- ISSN
- 1176-6336 (ISSN-L)
- 1178-203X
- PMC
- PMC5499790
- OpenAlex
- W2728473268
- Cited by
- 438
- References
- 285
- Citations by year
- 2026: 44 · 2025: 44 · 2024: 48 · 2023: 36 · 2022: 62 · 2021: 55 · 2020: 60 · 2019: 43 · 2018: 39 · 2017: 3
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Therapeutics and Clinical Risk Management (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion, cc-by-nc)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- Pfizer
- AstraZeneca
- Sanofi
- Sunovion
- Ministerio de Ciencia e Innovación
- Centro de Investigación Biomédica en Red de Salud Mental
- Servier
- H. Lundbeck A/S
- Comisión Nacional de Investigación Científica y Tecnológica (ACT1414)
- National Institute of Mental Health
- Fondo Nacional de Desarrollo Científico y Tecnológico (ACT1414, 1160736)
- Cilag
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- antipsychotic drugs, typical antipsychotics, atypical antipsychotics, drug safety, tolerability, adverse effects, severe mental illness, extrapyramidal symptoms, weight gain, metabolic abnormalities, negative symptoms, cognitive impairment, chlorpromazine, clozapine, olanzapine, amisulpride, aripiprazole
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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