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Ther Clin Risk Manag. 2017 Jun 29;13:757-777. doi: 10.2147/TCRM.S117321. eCollection 2017.

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.

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Neuroscience Department, University of Padua.
Institute for Clinical Research and Education in Medicine, Padua, Italy.
Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
Department of Psychiatry, Faculty of Medicine, Clínica Alemana Universidad del Desarrollo.
Early Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile.
National Research Council, Ageing Section, Padua.
Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "Federico II", Naples, Italy.
New York State Psychiatric Institute, Columbia University, New York, NY, USA.
Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London.
Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London.
Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK.
Institute of Medical Science, Toronto, ON, Canada.
Department of Psychiatry Research, Zucker Hillside Hospital, Northwell Health, Glen Oaks.
Department of Psychiatry and Molecular Medicine Hempstead, Hofstra Northwell School of Medicine, Hempstead, NY, USA.
Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil.


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.


antipsychotics; psychiatry; psychosis; safety; side effects; tolerability

Conflict of interest statement

Disclosure AM has received Continuing Medical Education-related honoraria or consulting fees from Adamed, AstraZeneca, Bristol-Myers-Squibb, Janssen, Lundbeck, and Otsuka. IP has received CME-related honoraria or consulting fees from Adamed, Janssen-Cilag, and Lundbeck. EV has received grants and served as a consultant, advisor, or CME speaker for the following entities: AB-Biotics, Allergen, AstraZeneca, Bristol-Myers-Squibb, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefonica, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (Centro de Investigación Biomédica en Red de Salud Mental), the Seventh European Framework Programme (European Network of Bipolar Research Expert Centres), and the Stanley Medical Research Institute. CUC has received grant or research support from the National Institute of Mental Health, the Patient-Centered Outcomes Research Institute, the American Academy of Child and Adolescent Psychiatry, The Bendheim Foundation, Takeda, and the Thrasher Foundation. He has served as a member of advisory boards/the Data Safety Monitoring Boards for Alkermes, Forum, IntraCellular Therapies, Lundbeck, Otsuka, Pfizer, and Sunovion. He has served as a consultant to Alkermes, the Gerson Lehrman Group, IntraCellular Therapies, Janssen/Johnson and Johnson, Lundbeck, Medscape, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, and Takeda. He has presented expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He has received honorarium from Medscape. He has received travel expenses from Janssen/Johnson and Johnson, Lundbeck, Otsuka, Pfizer, ProPhase, Sunovion, and Takeda. MS, JU, NV, MF, BS, FM, MVS, and AFC report no conflicts of interest in this work.

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