. 2023 Nov;10(11):860-876.

doi: 10.1016/S2215-0366(23)00262-6. Epub 2023 Sep 26.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK. Electronic address: toby.pillinger@kcl.ac.uk.
² Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK.
³ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, New York, NY, USA; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; Department of Child and Adolescent Psychiatry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴ Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany.
⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
⁶ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
⁷ Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Foundation Trust, London, UK; Institute of Pharmaceutical Science, King's College London, London, UK.
⁸ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 37774723
PMCID: PMC10878984
DOI: 10.1016/S2215-0366(23)00262-6

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development

Toby Pillinger et al. Lancet Psychiatry. 2023 Nov.

. 2023 Nov;10(11):860-876.

doi: 10.1016/S2215-0366(23)00262-6. Epub 2023 Sep 26.

Authors

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK. Electronic address: toby.pillinger@kcl.ac.uk.
² Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, UK.
³ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, New York, NY, USA; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; Department of Child and Adolescent Psychiatry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴ Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany.
⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
⁶ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
⁷ Pharmacy Department, Maudsley Hospital, South London and Maudsley NHS Foundation Trust, London, UK; Institute of Pharmaceutical Science, King's College London, London, UK.
⁸ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK.
⁹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.

PMID: 37774723
PMCID: PMC10878984
DOI: 10.1016/S2215-0366(23)00262-6

Abstract

Background: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation.

Methods: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS).

Findings: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap.

Interpretation: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes.

Funding: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

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Conflict of interest statement

Declaration of interests TP has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, Schwabe Pharma, ROVI Biotech, and Recordati. RAMcC has participated in advisory or speaker meetings organised by Otsuka, Karuna, Boehringer Ingelheim, and Janssen. TP and RAMcC are directors of Pharmatik that funds website hosting for Psymatik. Neither TP nor RAMcC have holdings or financial stakes in any pharmaceutical company. MH has received honoraria for advisory boards and lectures from Recordati. SJ has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, and Boehringer Ingelheim. FG has received honoraria from Lundbeck, Otsuka, Sunovion, and Boehringer Ingelheim. ODH has received investigator-initiated research funding from or participated in advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, Viatris (formerly Mylan), and ROVI Biotech. AHY has delivered paid lectures and advisory boards for the following companies: AstraZeneca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Pathways, Sage, Novartis, and Neurocentrx. CUC has been a consultant or advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, COMPASS Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen, Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a data safety monitoring board for COMPASS Pathways, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; has received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, MindPax, LB Pharma, and Quantic. All other authors declare no competing interests.

Figures

**Figure 1**
Methods summary First, evidence-based side-effect databases were created, one each for antipsychotics and antidepressants. Second, a digital tool was devised that allows the user to input side-effects of concern and the relative degree of concern for each side-effect. The input data are synthesised with the side-effect database using TOPSIS, the output of which ranks treatments from best to worst. Side-effect 1 represents the first side-effect of interest (eg, sedation), side-effect 2 represents the second side-effect of interest (eg, weight gain), and so on. Drug 1 represents the first antipsychotic or antidepressant of interest, drug 2 represents the second antipsychotic or antidepressant of interest, and so on. TOPIS=technique for order of preference by similarity to ideal situation.

**Figure 2**
Search process *Including consensus statements and one clinical guideline resource (UpToDate). †Including the UpToDate resource. ‡For antipsychotics, data were from five studies (constituting 11 meta-analyses) and four guideline documents; for antidepressants, data were from three guideline documents.

**Figure 3**
Meta-analyses included in umbrella review Colour coding shows groups of similar side-effects for those with more than one mention. HDL=high-density lipoprotein. IR=incidence rate. LDL=low-density lipoprotein. MD=mean difference. OR=odds ratio. QTc=corrected QT interval. RCT=randomised controlled trial. RR=relative risk. SMD=standardised mean difference. *Unless specified, no defined cutoff for change in parameter provided. †This number refers to the overall number of studies included in the network meta-analysis; study numbers for individual side-effect analyses (eg, weight gain or prolactin increase) were not provided. ‡This number refers to the overall sample size included in the network meta-analysis; sample sizes for individual side-effect analyses were not provided. §Selected for data extraction for the side-effect database. ¶Unpublished data provided by authors. ||Oral and injectable formulations of the same drug counted as a single drug.

**Figure 4**
National and international guidelines providing rankings of antipsychotic or antidepressant side-effects Colour coding shows groups of similar side-effects for those with more than one mention. See online for the UpToDate clinical resource. QTc=corrected QT interval. FDA=US Food and Drug Administration. *Selected for data extraction for the side-effect database. †Used for data imputation.

**Figure 5**
Heatmaps representing the Psymatik antipsychotic and antidepressant side-effect databases (A) Antipsychotic side-effect database. (B) Antidepressant side-effect database. Effect size magnitudes are normalised such that all values are between 0 and 1 inclusive; the higher the effect size, the greater the risk or magnitude of the side-effect for that drug. Effect sizes represent either the risk of a given side-effect happening or the magnitude of a given side-effect. Data are a combination of network meta-analytic, pairwise meta-analytic, imputed, and ordinal data. Data were imputed either because of uncertainty concerns regarding meta-analytic outcomes or because of absent meta-analytic data. QTc=corrected QT interval. *Including orthostatic hypotension.

See this image and copyright information in PMC

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Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development

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Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development

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Conflict of interest statement

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