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A recently released report by the Lancet Psychiatry Physical Health Commission highlights how prescribers and patients can make evidence-based decisions in maximising benefit and minimising side-effects from psychiatric medications.
Psychiatric medications are amongst the most widely prescribed medications in Australia, with 18% of the population prescribed a psychotropic according to 2023-2024 data from the Australian Institute of Health and Welfare. Antidepressants, antipsychotics, and mood stabilisers are core components of treatment for people living with severe mental illness, and their use is associated with decreased mortality for conditions such as schizophrenia and bipolar disorder at a population level. Despite their benefits, a diverse range of side-effects are associated with these medications. Experiencing side-effects can impact quality of life, adherence to treatment, and contribute to increased morbidity and mortality from physical health issues.
To address this pertinent clinical challenge, the Lancet Psychiatry Physical Health Commission has recently released a dedicated report on prevention and management of side-effects from psychiatric medications. Taking a systematic approach, this report summarises the propensity of antipsychotics, mood stabilisers, and antidepressants for side-effects, as well as detailing opportunities to intervene. This report is an expanded follow-up to the original high-impact 2019 Commission which has been cited over 1000 times, and has been published in parallel alongside a dedicated report on non-pharmacological management strategies to maximise physical health for people living with mental illness.
What We Did
This Commission report was produced through a global collaboration of experts in psychopharmacology from all UN regions in conjunction with the input of people with lived experience of mental illness. An initial advisory panel identified core side-effect domains of interest. We generally sought to cover side-effects that are affiliated with one or multiple classes, including both common side-effects, as well as those that are rare and severe. Of note, individuals with lived experience highlighted that weight gain and sexual dysfunction tend to be amongst the most distressing side-effects, often driving medication discontinuation.
We undertook an umbrella review of existing systematic reviews and meta-analyses of interventional studies to appraise existing interventions for side-effects. Given there are a number of psychotropic side-effects that do not have associated systematic review and meta-analytic evidence to guide intervention choice, we complemented this search through review of existing guidelines relevant to side-effect management. Where evidence was available, we prepared algorithms for stepwise management of specific side-effects. We also assessed the quality and rigour of the contributing evidence from the systematic reviews and guidelines contributing to the evidence synthesis.
What We Found
Through the umbrella review search process, we identified 69 systematic reviews and meta-analyses. A majority (77%) of the systematic reviews addressed antipsychotic related side-effects, whilst a smaller proportion of the literature was devoted to antidepressants (15%) and mood stabilisers (19%). Moreover, meta-analytic evidence was available to guide the treatment of cardiometabolic side-effects (particularly antipsychotic-induced weight gain), as well as tardive dyskinesia, akathisia, and hyperprolactinaemia. We also appraised 27 guideline and previous umbrella reviews, particularly for side-effects where data from systematic reviews were lacking.
Based on the above evidence synthesis, we structured the report by the following systems and domains: cardiometabolic, cardiac conduction, neurological, sexual and reproductive, endocrinological, gastrointestinal, anticholinergic, sleep, renal, haematological, and other side-effects. Given the greater availability of meta-analytic evidence, we prepared stepwise algorithmic management approaches for the cardiometabolic, neurological, sexual and reproductive, and anticholinergic side-effects. Two heatmaps that enable visualisation and ranking of side-effect propensity between different antipsychotics and antidepressants respectively are also featured in the report. These heatmaps are linked with a digital, free to use tool, PSYMATIK, that enables prescribers to select agents based upon their side-effect risk profile. This enables the user to weigh side-effects of concern based upon the patient’s preference and medical risks. To assist with individualised and tailored prescribing, the report also features sections on demographic considerations, relevant digital tools, and a side-effect monitoring schedule.
What Needs to Happen Next
In providing a summary of the current evidence-base, this report highlights several gaps. Firstly, compared to antipsychotics, there was limited interventional meta-analytic evidence available to guide the management of mood stabiliser and antidepressant related side-effects. Conversely, for side-effects where more effective management is possible (eg, use of GLP-1 receptor agonists for antipsychotic-induced weight gain), there are anticipated barriers to access and implementation of such evidence-based interventions.
Polypharmacy is ubiquitous in clinical practice, and many of the presented side-effects, such as weight gain or sexual dysfunction, are applicable to a variety of both psychotropic and non-psychotropic medications. Given much of the existing evidence-base on side-effect management is derived from monotherapy studies, there is a need for broader and nuanced research that contextualises both the impact and appropriate management of side-effects stemming from polypharmacy.
Considering the premature mortality faced by people with severe mental illness due to chronic physical disease and associated multimorbidity, this report highlights the need for integrated physical and mental health care. Whilst medications are not the only risk factor implicated here, they represent a significant modifiable risk factor where prescribers have a window of opportunity to intervene. Given the potential multisystem physical health sequelae of psychotropics — for example, olanzapine’s ability to drive metabolic syndrome, with downstream risks of ischaemic heart disease, diabetic nephropathy, and obstructive sleep apnoea — it is the responsibility of all doctors, not just GPs and psychiatrists, to be mindful of their impacts. Consequently, this report aims to empower all practitioners in providing holistic physical and mental health care.
Conclusion
Primum non nocere (first, do no harm) is a fundamental tenet of good medical care. Given the frequency at which psychiatric medications are prescribed both in Australia and worldwide, it is an imperative that these medications are used in a judicious and rationalised approach. It is also critical that prescribers make joint decisions with patients at all stages of treatment. We stress the importance of a preventative approach where choice of an initial psychotropic is guided by the potential side-effects that the patient is most concerned about developing, especially in light of any existing medical conditions and risk factors.
Medications have an important role to play in the treatment of severe mental illness, and the overwhelming evidence highlights that these medications reduce mortality on a population-level. This notwithstanding, medications are only one part of good psychiatric and medical care, and non-pharmacological approaches also have a critical role to play in the holistic treatment of both physical and mental health.
Sean Halstead is a psychiatry registrar and PhD candidate (University of Queensland) based in Brisbane.
Dan Siskind is a psychiatrist and Professor of Psychiatry at The University of Queensland. He works clinically at Metro South Addiction and Mental Health Services in Brisbane.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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