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Perry T, editor. Therapeutics Letter. Vancouver (BC): Therapeutic Initiatives; 1994-.
Therapeutics Letter 139 aims to provide clinicians with an understanding of dopamine (DA) antagonists and their potential side effects. Dopamine antagonists are a class of drugs commonly used to treat various psychiatric disorders, such as schizophrenia and bipolar disorder.
The authors reviewed the literature on dopamine antagonists and their side effects, summarized the mechanism of action of dopamine antagonists, their clinical uses, and the different classes of dopamine antagonists. A clinical pharmacological approach was used to review how people may be harmed by DA antagonists. Videos included with this Letter may help clinicians and students better understand the potential harms of this drug class.
The article highlights the different types of DA antagonists and their respective side effects. It notes that some dopamine antagonists can cause metabolic disturbances, such as weight gain and hyperglycemia. Movement disorders, such as Parkinsonism and tardive dyskinesia, are also common side effects. Moreover, some dopamine antagonists can have cardiac effects, such as QT prolongation and torsades de pointes.
Clinicians should be aware of the potential harms associated with these drugs, especially metabolic, movement, and cardiac effects and should learn and teach the symptoms and signs of dopamine blockade. The potential benefits and risks of dopamine antagonists should be carefully weighed when considering their use and patients should be re-examined frequently during treatment, with dose and duration of treatment re-assessed when renewing prescriptions.
Dopamine receptor antagonists are widely prescribed in Canada. They include all antipsychotic drugs, the common anti-emetics metoclopramide and prochlorperazine, and domperidone (used to promote lactation or stomach emptying). Haloperidol, methotrimeprazine, and olanzapine are also used to control nausea in palliative care.
Deprescribing initiatives have reduced inappropriate use of antipsychotics for people with dementia living in long-term care;2 yet over 25% of BC long-term care residents still received them in 2021.3 We know little about avoidable prescriptions in outpatients, but during 2021 over 172,000 community living British Columbians were dispensed at least one DA antagonist: 3.3% of BC’s population, versus 2.7% in 2011.4 (Table)
Dopamine (DA) is a predominant neurotransmitter in brain, influencing arousal, motivation and reward, emotion, cognition, memory, motor control, and regulation of prolactin release from the anterior pituitary. Five distinct receptor types are now grouped into two families: D1-like and D2-like DA receptors.5
In 1952 French Army surgeon Henri Laborit described a calming effect of chlorpromazine, a recently synthesized drug related to the first antihistamines. It was soon found to reduce “positive symptoms” of schizophrenia such as hallucinations and disturbing behaviour. Availability of a drug that spared psychotic patients from straitjackets, frontal lobotomy, ECT, or insulin coma jump-started the science of psychopharmacology.6–7
With new pharmacological techniques, it was recognized in the 1950’s that these beneficial effects were in some way related to dopamine. Appreciation that dopamine is a neurotransmitter led to discovery of its deficiency in Parkinson’s disease, and breakthrough treatment with the oral DA precursor l-DOPA.8 The “dopamine hypothesis of schizophrenia” arose from the observation that drugs which block D2 dopamine receptors in vitro were associated with improvements in symptoms of psychosis. This working hypothesis continues to evolve in complexity, but has been criticized for the lack of supporting evidence.9–11
But chlorpromazine and subsequent competitors also caused serious adverse effects. Patients experienced a range of symptoms and movement disorders collectively termed “extrapyramidal symptoms” (EPS), probably due to dopamine blockade. Videos embedded in the online version show patients affected by quetiapine, metoclopramide, and prochlorperazine.
Drugs from other classes that target the brain, including many antidepressants and domperidone (a DA antagonist with poor brain penetration) can cause similar symptoms and signs.15–19
Withdrawal symptoms, including psychosis, were recognized later as a consequence of stopping long-term antipsychotic treatment.20–21 Antipsychotic drugs have other important adverse effects: cognitive (including sedation and apathy), gynecomastia/galactorrhea, weight gain, type 2 diabetes, increased cardiovascular disease, and increased mortality in nursing home patients.22
Clozapine, the original putative “atypical antipsychotic”, causes fewer EPS, but other toxicities limit use to the most treatment refractory patients. Olanzapine, quetiapine, risperidone, and many later competitors were promoted as “atypical” or “second generation”.23 These marketing terms imply mediation of effects through mechanisms different from DA blockade.24 But while some patients tolerate one drug better than another, newer drugs retain the potential to cause serious neurological, metabolic, and other problems.25–27
EPS are dose-related, but also occur at low doses and with short or even single exposures. (videos 3, 4, 5) Avoidance starts by prescribing DA antagonists only when essential, at the lowest effective dose, and shortest duration. Cautious time-limited prescribing is appropriate for people with psychotic disorders including schizophrenia, psychotic depression, or bipolar mania, and for some long-term care residents only after non-drug interventions are exhausted.28 The same considerations apply for control of nausea, to promote stomach emptying, or to enhance breast feeding.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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