Today I am bringing you a slightly different kind of blog. As a jobbing Psychiatrist I spend the majority of my time considering what medication to prescribe (or importantly not to prescribe) for people; a key element of this being patient preference and tolerability. However, if we aren’t aware of the range of side effects with each medication then how can we support the best choice for the patient?
The Lancet Psychiatry have published a range of Commission papers addressing key issues in mental health and in 2019 a Commission was published ‘A blueprint for protecting physical health in people with mental illness’ (Frith, et al., 2019). The paper is a very worthwhile read in itself, however what I am covering today is the follow-up paper, which relates to part 3 of the Frith paper: the interplay between psychiatric medications and physical health.
This 2nd Commission report provides ‘an expanded and structured systems-based overview of psychotropic side-effects and their management strategies relevant to the use of antipsychotics, mood stabilisers, and antidepressants in mental health globally’ (Halstead, et al., 2025). The authors have produced a comprehensive overview that I personally have found incredibly useful in my clinical practice and I hope you will too. It is a lengthy document and I have selected what I think are the key pieces of clinical information, but please do review the wider paper.
The Halstead et al paper is published today in parallel with the 3rd Report from the Commission which explicitly covers lifestyle interventions integral to the protection and promotion of physical health for people living with mental illness (Teasdale et al, 2025).
We must balance between the risks and benefits of psychotropic medications when prescribing
Methods
This paper is an umbrella review; a review of multiple systematic reviews and meta-analyses. In effect, it is a review of reviews to provide a helicopter view of the evidence base.
The main aims were to:
- characterise the risk of side-effects associated with psychotropics and
- synthesise evidence-based management approaches.
The group prioritised adverse drug reactions (ADRs) that are common and/or severe. They focussed on pharmacological treatments commonly used in the long-term management of mood and psychotic disorders, consistent with the original Commission paper (Frith, et al., 2019). Medications that were excluded were: stimulants, sedative medication and emerging agents that are not widely licensed.
The final recommendations were then reviewed by a global panel of experts, representing all United Nations regions and including people with lived experience.
Results
6,829 unique abstracts were identified; 400 full texts were assessed resulting in 69 systematic reviews with meta-analytic data being included. Guideline documents and umbrella reviews with management recommendations were included to clarify existing management approaches for psychotropic ADRs.
The review is structured mainly into body systems and then some additional side effects categories and I will take you through the key symptoms in each category and pertinent intervention suggestions. There are very useful management algorithms within the paper, which should be explored alongside this blog.
The categories include: cardiometabolic; cardiac conduction; neurological; sexual and reproductive; endocrinological; gastrointestinal; anticholinergic; sleep-related; renal; haematological; and ‘other’ side-effects.
Cardiometabolic
- Key symptoms: weight gain, dysglycaemia and dyslipidaemia. Blood pressure changes.
- Interventions:
- Olanzapine should be avoided as first line;
- Aripiprazole is recommended if no preference.
- Metformin should be commenced simultaneously when starting olanzapine or clozapine at antipsychotic initiation as a form of prevention.
- Management algorithm (link)
Cardiac conduction
- Key symptoms: QTc prolongation, sinus tachycardia
- Interventions:
- High risk abnormalities to be discussed immediately with cardiology and offending agent discontinued.
Neurological
- Key symptoms: neuromotor (akathisia, dystonia, parkinsonism, and tardive dyskinesia).
- Interventions:
- Dose reduction or switching
- Anticholinergic agents not recommended except for acute dystonia (masks parkinsonism, reduce cognitive abilities and increases risk of tardive dyskinesia)
- Management algorithm (link).
- Neuroleptic Malignant Syndrome (NMS):
- Not discontinuing offending antipsychotic increases risk of mortality from NMS
- No clear difference in mortality risk between oral and IM medication
- Re-challenge with slower titration and lower doses or less potent antidopaminergic agents may be possible in >90% cases.
Sexual and reproductive
- Key symptoms: impact on libido, pleasure, arousal, and orgasm, as well as breast tissue growth, lactation and menstruation.
- Interventions:
- Causes of sexual dysfunction can be multifactorial across physical, physiological, psychiatric, psychological, and interpersonal factors
- Assessment needs to consider all of these areas
- Management algorithm (link).
Endocrinological
- Key symptoms: hyperprolactinaemia, thyroid dysfunction.
- Interventions:
- Appropriate monitoring is key
- Adjunctive aripiprazole has demonstrated the largest meta-analytic effect sizes for reduction of prolactin levels
- If long term untreated hyperprolactinaemia, consider bone mineral density monitoring.
Gastrointestinal
- Key symptoms: nausea, vomiting, diarrhoea and constipation
- Intervention:
- For Clozapine associate constipation a proactive approach should be taken, monitoring bowel habits (including objective measures such as the Bristol Stool Chart)
- Stimulant laxatives should be used early in conjunction with osmotic laxatives (macrogol) with a low threshold for concern
- Bulk-forming laxatives should be avoided due to slow gut transit time.
Anticholinergic
- Key symptoms: confusion, blurred vision (and glaucoma in rare cases), dry mouth, constipation and urinary retention, nocturnal enuresis.
- Intervention:
- Reduction of anticholinergic burden and specific interventions
- Management algorithm (link).
Sleep-related
- Key symptoms: insomnia and sedation. Restless legs syndrome (RLS), periodic leg movements in sleep (PLMS), nightmares, REM sleep behaviour disorder (RBD) obstructive sleep apnoea (OSA)
- Intervention:
- Emergent RLS, PLMS, nightmares and RBD usually warrants medication discontinuation, and switching to an alternative agent
- Agents which can precipitate or exacerbate OSA should be avoided in those at risk of, or diagnosed with OSA.
Renal
- Key symptoms: nephrotoxicity, hyponatraemia.
- Intervention:
- Severe hyponatraemia of potential offending agents and consideration of hospital admission
- Potential for recurrence at re-challenge
- Slow dose titration with a lower risk agent recommended.
Haematological
- Key symptoms: Anaemia, neutropenia, thrombocytopenia, venous thromboembolism (VTE). Clozapine associated with an increased risk of lymphoma and leukaemia
- Intervention:
- Avoid NSAIDs with SSRIs to reduce risk of bleeding
- Monitoring for VTE in patients commenced on antipsychotics.
Other side-effects to note
- Hepatic injury
- Pneumonia – particularly with antipsychotics
- Skin reactions – Stevens Johnson Syndrome and Toxic Epidermal Necrolysis
- Congenital side-effects.
These other side-effect groups are expanded upon in further detail in the appendix of the paper (link).
Psychotropic medication can cause adverse affects within almost every system in the body.
Conclusions
There is a much wider range of side effects from psychotropic medications than might be first considered and as the authors have stated:
“…it is imperative that shared decision making is prioritised”
In addition, there are key factors to consider to help minimise side effects:
- Monitoring should be tailored to the individual in question (e.g. increased in frequency if needed)
- Demographic considerations of prescription and associated pharmacokinetic dosing consideration. Lower doses are generally advisable in people with first episode psychosis, females, children, and older people.
Lower doses are generally advisable in people with first episode psychosis, females, children, and older people.
Strengths and limitations
The process of identification of papers was robust, following standard guidelines and also included international experts and experts by experience to create the final guidelines and recommendations.
The paper itself highlights key limitations and these stem from the papers available for inclusion in the review:
- Most of the available data related to either risk or management of psychotropic ADRs, focussing on antipsychotics, with mood stabilisers and antidepressants, (lacking robust data and analysis)
- A majority of the included systematic reviews were rated as either low or critically low quality, underappreciating any high-quality trials that may be included in meta-analysis
- There was an absence of interventional data, meaning that many side-effect management protocols, particularly for antidepressants and mood stabilisers, could only be derived from consensus from existing international guidelines.
- Much of the antipsychotic side-effect literature is focussed on cardiometabolic and extrapyramidal side-effects. The imbalance in the literature can give the impression that psychotropics only have discrete side-effects in one or two systems, rather than a range of side-effects that can impact all major physiological systems
- Polypharmacy across different classes isn’t prevalent in the literature and can contribute in combination to common ADRs such as weight gain and sexual dysfunction.
- The exclusion of stimulants and sedative medication
- Newer agents and novel, emerging evidence was unlikely to be included in the systematic reviews reviewed
There is a lack of high-quality meta-analytic evidence relating to adverse drug reactions from psychotropic drugs.
Implications for practice
This paper provides an excellent reference tool for considering potential side effects when prescribing psychotropic medication and also how to manage them if they are to develop.
The authors aimed to produce a document that empower prescribers and patients to make informed and individualised decisions about psychotropic prescribing and side-effect management (with involvement of colleagues in other specialties as needed) and I think they have succeeded.
People living with severe mental illness have other pertinent risk factors, both genetic and environmental, for poorer physical health outside of psychotropic prescription and we need to minimise any potential additional harm that we cause.
It is important to remember that an absence of pharmacological treatment for severe mental illness can result in severe deterioration of symptoms, functioning, poor adherence to treatment for physical health conditions and ultimately premature mortality. Adverse effects are an all-to-frequent cause of non-adherence and need to be prevented and managed appropriately to optimise the individuals health and wellbeing.
Future research needs to address the identified current gaps:
- Antidepressants and mood stabiliser combination treatment
- Side effect domains which only have guideline-level management
- Other classes of psychotropic medication and new/emerging agents
- Polypharmacy
- Current quality of evidence
- Interventional studies for pertinent ADRs such as sexual dysfunction, which is repeatedly a key issue identified by people with lived experience and can result in non-adherence.
There are a range of digital tools available to assist with psychotropic prescribing and side-effect considerations, which are listed in appendix 4 (link) of the paper, however given the heterogeneous nature of ADRs, digital developments that improve side-effect risk stratification and prediction tools are needed.
There are many holes in the current evidence base that need to be addressed by future research.
As clinicians, the medications we prescribe can have far reaching effects on people’s lives; making them feel less like themselves…
Statement of interests
I have no conflicting interests to declare.
Links
Primary paper
Halstead, S. et al. (2025). Holistic prevention and management of physical health side-effects of psychotropic medication: second report of The Lancet Psychiatry Physical Health Commission. The Lancet Psychiatry. https://doi.org/10.1016/S2215-0366(25)00162-2
Other references
Frith, J. et al. (2019). The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness. The Lancet Psychiatry, Volume 6, pp. 675-712. https://doi.org/10.1016/s2215-0366(19)30132-4
Teasdale SB, Machaczek KK, Marx W, et al. (2025) Implementing lifestyle interventions in mental healthcare: third report from the Lancet Psychiatry Physical Health Commission. Lancet Psychiatry 2025). https://doi.org/10.1016/S2215-0366(25)00170-1
