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Long-term treatment of schizophrenia: The up-to-date evidence-base

By Prof Brendan Kelly - 22nd Oct 2023


This article looks at some recent evidence about the benefits of treatment in this population, especially antipsychotic medication

Schizophrenia is a common, challenging mental illness. Treatment is often protracted, involving both primary care and specialist mental health services over many years. Often, GPs are to forefront of management: Administering long-acting antipsychotics, dealing with physical health problems, and supporting families.

Bio-psycho-social care

The bio-psycho-social model of health, illness, and healthcare was described by George Engel, a Professor of Psychiatry and Medicine, in Science in 1977.1 The essence of this framework lies in its acknowledgement of biological, psychological, and social dimensions to health, illness, and healthcare. In other words, while each illness, such as schizophrenia, might have a physical cause (known or unknown), there are also psychological and social aspects to risk, causation, symptoms, treatments, and outcomes. As humans, we are complex actors in complicated environments, subject to a range of different forces and influences which shape our experiences in profound ways over time. All these factors – biological, psychological, and social – must be considered for a full understanding of the causes of illness, its manifestations, preventive paradigms, treatment approaches, and therapeutic outcomes. This is especially true in schizophrenia, which is a complex condition that presents evolving challenges over time.

From a social perspective, the distribution of symptoms and illnesses across populations is far from random, as multiple factors determine who gets which illness, how it manifests, when it is treated (if at all), and what the likely outcome will be. This is also the case in schizophrenia, in which long-term outcomes are substantially shaped by social factors. These include poverty, inequality, living arrangements, socio-economic circumstances, access to preventive programmes (eg, cancer screening), and other matters. Access to care is similarly patterned by social forces, economic conditions, and political contexts, as are the efficacy of interventions which are offered, and outcomes. In short, we are social creatures living in societies, and, as such, the social landscape inevitably has a determinative effect on health, healthcare, and illnesses such as schizophrenia.

This bio-psycho-social model of psychiatry is often articulated in contradistinction to what is described as a ‘biomedical model’, a term which suggests an approach that is based solely on biology and does not take account of psychological or social determinants. The term ‘biomedical model’ is often used as a strawman in discussions about models of care, especially in psychiatry. It is, at best, an over-simplification or an exaggeration, and, at worst, an unjust mischaracterisation of medical approaches to illness and treatment, which have always recognised psychological and social dimensions. It is simply impossible for anyone involved in the care of someone with schizophrenia to be unaware of the psychological and social aspects of the condition, or to have a purely ‘biomedical’ approach in practice.

In 2022, Bolton, writing in BJPsych Bulletin, suggested that “we can make use of the term ‘biopsychosocial model’ as a shorthand for methodological assumptions that causes and/or cures of specific conditions at specific stages, including matters of adjustment and quality-of-life, will generally – across a wide range of conditions – include biological, psychological and social factors, and interactions between them” (p229).2 In psychiatry, there is strong evidence that ‘biological’ treatments such as psychiatric medications are no less effective than medications in other areas of medicine and are sometimes more efficacious,3 but combinations of medication, psychological care, and/or social support are the most effective ways to relieve symptoms and improve outcomes. One size does not fit all, and the bio-psycho-social framework has sufficient flexibility to reflect this in practice, especially in prolonged conditions such as schizophrenia.

Antipsychotic medication

Chlorpromazine, the first effective antipsychotic medication for schizophrenia, was developed in the 1950s and followed by a number of related medications in tablet and injected forms.4 These agents alleviated psychotic symptoms (eg, delusions and hallucinations) and made it possible for some long-term patients with schizophrenia to leave large psychiatric institutions and live with greater independence in the community. These ‘first-generation’ or ‘typical’ antipsychotics included fluphenazine, trifluoperazine, flupentixol, haloperidol, zuclopenthixol, sulpiride, and pimozide.

It was soon apparent that these medications, despite their benefits, can have significant adverse effects, including movement disorders (such as restlessness or Parkinsonism), dry mouth, constipation, sedation, effects on the heart (increasing risk of sudden cardiac death), and various other effects (eg, dizziness, sexual dysfunction). A number of strategies were introduced to manage these issues and research focused on developing new treatments that would combine good clinical effects with fewer side-effects. A series of ‘second-generation’ or ‘atypical’ antipsychotics was duly developed and introduced to clinical practice.

As a result, there is now a broad range of antipsychotic medications available, with different combinations of benefits and potential adverse effects. “Atypical” antipsychotics include risperidone, olanzapine, quetiapine, aripiprazole, amisulpride, ziprasidone, and paliperidone. Some of these agents combine therapeutic efficacy with concerning side-effects such as weight gain and other impacts on metabolism. Clozapine, another antipsychotic, is generally reserved for treatment-resistant schizophrenia. A more detailed consideration of individual medications, their profiles, and their individual roles is provided elsewhere.5 For now, it is sufficient to say that each antipsychotic has its own combination of benefits and side-effects, and each has a different role in the treatment of various forms of psychosis and severe mental illness.6

But, given that some of the antipsychotics can have significant adverse effects, what is the evidence that they are helpful overall? Are the potential negative effects justified by the positive ones?

Leucht and colleagues published a meta-analysis of the comparative efficacy and tolerability of 15 antipsychotics for the treatment of schizophrenia in The Lancet.7 This research group identified 212 trials suitable for inclusion in the study, with data for 43,049 participants. All 15 antipsychotics were significantly more effective than placebo. The medications differed substantially in side-effects, and there were small but robust differences in efficacy. In addition, the data challenged a simple classification into ‘first-generation’ and ‘second-generation’ agents. Instead, the authors found that hierarchies in different domains could help clinicians to match antipsychotic drug choice to the needs of individual patients, rather than simply categorising these medications into two ‘generations’.

Balancing adverse effects with benefits

But what about the side-effects of antipsychotic medication? In particular, some “second-generation” antipsychotics are associated with weight gain. Might this lead to poor physical health, cardiovascular illness, and increased mortality? Many people with schizophrenia are on antipsychotic medication for years or even decades, so might certain long-term adverse effects have a cumulative impact over time? Are these medications worth it?

In 2020, Taipale and colleagues published a follow-up study of physical morbidity and mortality in the context of antipsychotic treatment among 62,250 patients with schizophrenia in Finland.8 After following-up these patients for a median of 14 years, this research group found no increase in risk of hospitalisation for physical illness, including cardiovascular disease, among people with schizophrenia while on antipsychotics. This provides strong evidence that, despite metabolic and other side-effects, antipsychotics do not increase risk of serious physical illness requiring hospitalisation among those taking them. But what about risk of death?

Taipale and colleagues found that the adjusted hazard ratio for all-cause mortality was 0.48 (95 per cent confidence interval (CI): 0.46-0.51) among people with schizophrenia while on antipsychotics (compared with not being on antipsychotics).8 There were similar reductions in cardiovascular mortality (0.62; 95 per cent CI: 0.57-0.67) and mortality from suicide (0.52; 95 per cent CI: 0.43-0.62). To put these findings another way, mortality rates during 14 years of follow-up were 46.2 per cent for people with schizophrenia who were not on an antipsychotic, 25.7 per cent for those taking any antipsychotic, and 15.6 per cent for those taking clozapine. These mortality benefits persisted even after adjustment for gender, age, time since diagnosis, previous psychiatric hospitalisations, other medication use, non-adherence, previous suicide attempt, substance abuse, physical comorbidities, and various other factors.


For GPs, psychiatrists, and others involved in long-term care of people with schizophrenia, recent research indicates that long-term antipsychotic use does not increase risk of serious physical illness requiring hospitalisation. In fact, antipsychotics are associated with substantially decreased mortality among people with schizophrenia, especially those on clozapine. Similar results were reported by Correll and colleagues in World Psychiatry in 2022, in their extensive systematic review and meta-analysis of relative risk and aggravating or attenuating factors for mortality in people with schizophrenia: Antipsychotics are protective against all-cause mortality, compared to no antipsychotics, despite their side-effects.9

Again, the adverse effects of these medications must be considered in each individual case when prescribing, not least because some people find the metabolic effects of certain medications so disturbing that they would prefer a different treatment, despite any benefits. Communication and flexibility are vital in this process, including articulating the substantial benefits of antipsychotics in the long-term. Recent evidence supports the position that antipsychotics offer many advantages to physical health as well as mental health, once they are used with care and consideration, treatment is reconsidered at regular intervals, and other forms of support are offered as appropriate, consistent with a bio-psycho-social approach to care.

Prof Kelly is author of Asylum: Inside Grangegorman (Royal Irish Academy, 2023).


1.   Engel GL. The need for a new medical model: A challenge for biomedicine. Science. 1977; 196: 129-36

2.   Bolton D. Looking forward to a decade of the biopsychosocial model. BJPsych Bulletin. 2022; 46: 228-32

3.   Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: Review of meta-analyses. British Journal of Psychiatry. 2012; 200: 97-106

4.   Kelly BD. Mental health in Ireland: The complete guide for patients, families, healthcare professionals, and everyone who wants to be well. Dublin: The Liffey Press, 2017

5.   Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (14th Edition). Hoboken, NJ and Chichester: Wiley Blackwell/John Wiley & Sons, Inc, 2021

6.   Gulati G, Cullen W, Kelly BD. Psychiatry algorithms for primary care. Hoboken, NJ and Chichester: Wiley Blackwell/John Wiley & Sons, Inc, 2021

7.   Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet. 2013; 382: 951-62

8.   Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry. 2020 Feb;19(1):61-68

9.         Correll CU, Solmi M, Croatto G, Schneider LK, Rohani-Montez SC, Fairley L, et al. Mortality in people with schizophrenia: A systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022; 21: 248-71

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