Antipsychotic drugs: challenges and future directions
Open accessAbstract
Some sixty years on from the first use of chlorpromazine to treat schizophrenia, it is worth reflecting on where we have come from. Back in the 1950s, it was not known that dopamine was a neurotransmitter, how antipsychotics worked, what symptoms they worked on, or indeed if they worked at all1. Now we know that dopamine is a neurotransmitter, antipsychotics are all dopamine receptor blockers and, as Correll et al2 nicely review, large randomized, double-blind placebo-controlled trials have unequivocally demonstrated that they work both to treat acute psychotic episodes and to reduce relapse rates over the short to medium term. Recent meta-analytic data generated from over sixty years of placebo-controlled trials estimate the standardized mean difference (SMD) between antipsychotics and placebo to be 0.38, with a greater effect seen on positive symptoms (SMD=0.45) than negative symptoms (SMD=0.35), quality of life (SMD=0.35) or depression (SMD=0.27)3. Such effect sizes are comparable to or larger than those found for treatments used for many common physical health conditions, including angiotensin-converting enzyme (ACE) inhibitors for reducing cardiac events and mortality due to hypertension (SMD=0.16) and statins for reducing the risk of cardiac disease and stroke (SMD=0.15)4. Clearly, we have come a long way from the 1950s, but, despite these robust data on antipsychotics, many fundamental gaps in knowledge remain. One glaring gap highlighted in this Forum is that as of yet we are unable to say conclusively what the optimum length of treatment with antipsychotic medication should be, once a patient has recovered from an acute episode. In current practice, many patients are treated with antipsychotic medication long-term if not lifelong, in an attempt to prevent the frequency and severity of relapses that can be so disruptive to a person's life. Where patients are symptom free but experiencing side effects, such as weight gain, that may shorten life as well as affect its quality, the risk-benefit balance for relapse prevention is finely poised. Yet, as Correll et al highlight, there is little evidence from randomized, double blind controlled studies to support prophylactic treatment beyond two-three years. Whilst some naturalistic studies do provide support for treatment beyond this term, the inherent limitations of these designs mean that the question remains unresolved, and guidelines cannot be conclusive. This is a challenge to the field which needs to be met. We will need longer and, crucially, larger randomized controlled studies. This will not be easy, but other fields have risen to the challenge. For instance, in the case of the examples discussed above, statins and ACE inhibitors, there are now a number of randomized placebo-controlled trials with several thousand patients. These studies are roughly two orders of magnitude larger and five to ten times longer than the typical long-term randomized controlled study in schizophrenia. These large sample sizes give the power to have extended follow-up and account for treatment changes and drop-out. It is likely that we will need new ways of working, including international academic consortia as well as partnership with the pharmaceutical industry and governments, to achieve such large-scale studies. Correll et al also highlight heterogeneity in schizophrenia, something that is increasingly becoming apparent in the neurobiology underlying the disorder as well as its clinical manifestations, course and treatment response5. Treatment resistance is probably the most clinically important manifestation of heterogeneity in patients with schizophrenia, and remains a major issue that continues to provoke debate over its pathophysiology, diagnosis and clinical management6. About a third of patients are thought to have treatment resistant illnesses, and around 15% show treatment resistance from illness onset7. Moreover, we have no way to identify the individuals whose illness will benefit from antipsychotic treatment. Thus, large numbers of patients currently receive antipsychotic treatment although their illness is unlikely to respond to dopamine antagonists. The solutions to this will likely be found in part through identifying biomarkers that allow disease stratification, for example by the likelihood of response to dopamine receptor antagonists and, in the future, novel non-dopamine receptor blocking medication. As both trial data and clinical experience show, current antipsychotic treatment works most effectively in reducing the positive symptoms of schizophrenia, whereas the negative and cognitive symptoms often remain problematic. Cognitive symptoms in particular are associated with poor functional outcomes in schizophrenia8, yet our current treatments do nothing for them. In fact, there is evidence to suggest that dopamine antagonists may cause secondary negative and cognitive symptoms in people with schizophrenia9. Put simply, taking an antipsychotic may
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In schizophrenia and psychotic disorders, adherence to pharmacological treatments is frequently far from optimal.
“These latter aspects related to adherence are especially relevant in the setting of schizophrenia and psychotic disorders, where adherence to pharmacological treatments is frequently far from optimal and represents the main cause of relapse [16–18] and hospitalizations [19, 20].”
From The role of shared decision-making in improving adherence to pharmacological treatments in patients with schizophrenia: A clinical review (2020) · cites this paper as [18]
In schizophrenia and psychotic disorders, poor adherence to pharmacological treatments is the main cause of relapse and hospitalizations.
“These latter aspects related to adherence are especially relevant in the setting of schizophrenia and psychotic disorders, where adherence to pharmacological treatments is frequently far from optimal and represents the main cause of relapse [16–18] and hospitalizations [19, 20].”
From The role of shared decision-making in improving adherence to pharmacological treatments in patients with schizophrenia: A clinical review (2020) · cites this paper as [18]
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- Authors
- Howes, O. H., & Kaar, S. J.
- Affiliations
- Institute of Psychiatry, Psychology & Neuroscience, King's College London London UK
- King's College London (GB)
- ORCID
- Kaar, Stephen J.
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2018-05-24
- Volume
- 17
- Issue
- 2
- Pages
- 170-171
- ISSN
- 1723-8617 (ISSN-L)
- 2051-5545
- PMC
- PMC5980606
- OpenAlex
- W2806756628
- Cited by
- 24
- References
- 12
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 1
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- World Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Imperial College London
- King's College London
- Medical Research Council
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- antipsychotic drugs, schizophrenia, relapse prevention, long-term antipsychotic treatment, treatment duration, dopamine antagonists, antipsychotic adverse effects, weight gain, benefits and risks, naturalistic study, treatment guidelines, quality of life, depression in schizophrenia, chlorpromazine, positive and negative symptoms
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