[139] How well do you know your dopamine antagonists?

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29 Nov 2022 [139] How well do you know your dopamine antagonists?

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Posted at 07:00h in Podcasts & Videos, Therapeutics Letter by

illustrationMost Therapeutics Letters analyze evidence to draw conclusions about average drug effects in defined groups of people. This Letter takes a clinical pharmacological approach to review how individuals may be harmed by dopamine (DA) receptor antagonists. Using these drugs safely requires that clinicians and patients appreciate their important adverse effects, which are not always well understood.1 The online version links to videos of patient experiences that illustrate problems arising from dopamine blockade. Patients provided informed consent in the hope that health professionals and students can better appreciate potential harms, after watching and hearing about their experiences.

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.

Excessive prescribing of antipsychotics

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 (see Table below)

Table
* Outpatients dispensed DA antagonists in 2021.4
PharmaNet statistics exclude First Nations Benefit plan and Military/RCMP (federally insured).

Dopamine’s role in the brain

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

Profound effects of DA blockade 

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. 

  • Drug-induced Parkinsonism includes decreased or slowed movements, rigidity, tremor, unsteadiness, and loss of facial expression. (watch videos 1, 2 below)

  • Akathisia refers to intense internal restlessness or a constant desire to move. To diagnose “restless leg syndrome”, drug-induced akathisia must be excluded.12–13 (watch video 3 below)

  • Acute dystonic reaction is a sudden, involuntary, and often painful muscle spasm that can affect the neck, eyes, back (causing painful posturing), or vocal cords (making it hard to breathe). (watch video 4 below)

  • Dyskinesia, whether early or later onset (tardive dyskinesia, TD) is of special concern, because it is so hard to treat and can be permanent.  TD consists of repetitive, involuntary movements that can be associated with cognitive decline.14 (watch videos 5, 6, 7 below)

  • 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

Are “atypical antipsychotics” different?

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

Avoiding serious neurological harms

EPS are dose-related, but also occur at low doses and with short or even single exposures. (watch videos 3, 4, 5 above) 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.

Conclusions

  • Learn and teach the symptoms and signs of dopamine blockade. Exclude causation by DA antagonists before applying terms like “flat affect” or “restless legs” to patients.
  • During treatment, re-examine patients frequently. Look and listen for EPS including drug-induced Parkinsonism, akathisia, and movement disorders.
  • When renewing or dispensing a prescription, also reassess dose and duration of treatment.
  • Videos embedded above may help health professionals and students understand potential harms of DA receptor blockade.
Multiple experts and primary care clinicians reviewed the draft of this Therapeutics Letter for factual accuracy, and to ensure it is relevant to clinicians.
The UBC TI is funded by the BC Ministry of Health to provide evidence-based information about drug therapy. We neither formulate nor adjudicate provincial drug policies.
ISSN: 2369-8691 (Online) || ISSN: 2369-8683 (Print)
International Society of Drug Bulletin LogoThe Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.

References

  1. Salem H, Nagpal C, Pigott T, Teixeira AL. Revisiting antipsychotic-induced akathisia: Current issues and prospective challenges. Current Neuropharmacology 2017; 15(5):789-98. DOI: 10.2174/1570159X14666161208153644
  2. BC Patient Safety & Quality Council. CLeAR Wave 2 final evaluation report 2017. https://bcpsqc.ca/wp-content/uploads/2018/07/2017-CLeAR-Wave-2-Evaluation-Report-Aug-3-2017_FINAL.pdf
  3. Bethany Lindsay. B.C. care homes need cultural shift from ‘default’ use of antipsychotics, seniors’ advocate says. CBC News; 14 September 2022. https://www.cbc.ca/news/canada/british-columbia/bc-care-homes-antipsychotic-drug-use-seniors-1.6574113
  4. Healthideas. British Columbia Ministry of Health [creator] (2022): Claims History. BC Ministry of Health [publisher]. Data Management & Stewardship Branch (2017). https://www2.gov.bc.ca/gov/content/health/conducting-health-research-evaluation/data-access-health-data-central
  5. Goodman and Gilman. The Pharmacological Basis of Therapeutics. 14th edition, Chapters 15 and 16. McGraw Hill 2023. https://www.mheducation.ca/goodman-and-gilman-s-the-pharmacological-basis-of-therapeutics-14th-edition-9781264258079-can
  6. Deniker P. Introduction of neuroleptic chemotherapy into psychiatry. in: Ayd FJ, Blackwell B (eds). Discoveries in Biological Psychiatry. p. 155-64. Lippincott, 1970. https://books.google.ca/books/about/Discoveries_in_Biological_Psychiatry.html?id=auBsAAAAMAAJ&redir_esc=y
  7. Cunningham Owens D, Johnstone EC. The development of antipsychotic drugs. Brain and Neuroscience Advances. 2018; 2:1-6. DOI: 10.1177/2398212818817498
  8. Hornykiewicz O. L-DOPA (Review). Journal of Parkinson’s Disease 2017; 7(S1):S3-S10. DOI: 10.3233/JPD-179004
  9. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: From biology to symptoms. Trends in Neurosciences 2019; 42(3): 205-20. DOI: 10.1016/j.tins.2018.12.004
  10. Moncrieff J. A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry 2009; 17(3):214-25. DOI: 10.1080/10673220902979896
  11. Moncrieff J. What do psychiatric drugs really do and how can we use them rationally. Lecture at UBC TI Best Evidence Course, Oct. 5, 2019. https://nexuswebcast.mediasite.com/Mediasite/Play/48339d6d886d4002a0a981039ba6959e1d
  12. Stowe RC. Acute drug-Induced symptoms of restless legs syndrome in an emergency department: What’s in a name? Journal of Clinical Sleep Medicine 2019; 15(9):1381. DOI: 10.5664/jcsm.7948
  13. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria – history, rationale, description, and significance. Sleep Medicine 2014; 15(8):860-73. DOI: 10.1016/j.sleep.2014.03.025
  14. Waddington JL, Youssef HA. Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years and its longitudinal relationship to the emergence of tardive dyskinesia. Psychological Medicine 1996; 26(4):681-88. DOI: 10.1017/s0033291700037697
  15. Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Annals of Pharmacotherapy 2018; 52(7):662-72. DOI: 10.1177/1060028018760296
  16. Rissardo JP, Caprara ALF. The link between amitriptyline and movement disorders: Clinical profile and outcome. Ann Acad Med Singapore 2020; 49(4):236-51. Medline: 32419008
  17. Cornett EM, Novitch M, Kaye AD, et al. Medication-induced tardive dyskinesia: A review and update. Ochsner Journal 2017; 17(2):162-74. Medline: 28638290
  18. Revet A, Montastruc F, Roussin A, et al. Antidepressants and movement disorders: a postmarketing study in the world pharmacovigilance database. BMC Psychiatry 2020; 20(1):308. DOI: 10.1186/s12888-020-02711-z
  19. Kanzaki A, Tada H, Otsuka A, Nakamura T. Severe tardive dyskinesia induced by domperidone in presenile and non-dementia type 2 diabetes man with alcohol misuse showing albuminocytological dissociation and white matter hyperintensity. BMJ Case Reports 2019; 12(5):e228789. DOI: 10.1136/bcr-2018-228789
  20. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatrica Scandinavica 2006; 114(1):3-13. DOI: 10.1111/j.1600-0447.2006.00787.x
  21. Cosci F, Chouinard G. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychotherapy and Psychosomatics 2020; 89(5):283-306. DOI: 10.1159/000506868
  22. Choosing Wisely Canada. Psychiatry (2021). https://choosingwiselycanada.org/recommendation/psychiatry
  23. Therapeutics Initiative. Therapeutics Letter 20 (Jul-Aug 1997); 26 (Sep-Oct 1998); 74 (Apr-Jun 2009); 79 (Sep-Dec 2010); 95 (Jul-Aug 2015).
  24. Owens DC. How CATIE brought us back to Kansas: a critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia. Advances in Psychiatric Treatment 2008; 14(1):17-28. DOI: 10.1192/apt.bp.107.003970
  25. Kendall T. The rise and fall of the atypical antipsychotics. Br J of Psych 2011; 199:266–68. DOI: 10.1192/bjp.bp.110.083766
  26. Leucht S, Davis JM. Are all antipsychotic drugs the same? Br J of Psych 2011; 199:269–71. DOI: 10.1192/bjp.bp.111.095323
  27. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382(9896):951-62. DOI: 10.1016/S0140-6736(13)60733-3
  28. Abi-Jaoude E, Stall NM, Rochon PA. Psychotropic drugs for the behavioural and psychological symptoms of dementia: no free ride. CMAJ 2018; 190(47):E1374-75. DOI: 10.1503/cmaj.181486
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5 Comments
  • Chris Rauscher
    Posted at 09:18h, 29 November Reply

    I recommend these additional precautions when prescribing dopamine receptor antagonists:

    1. 1. Always start with low doses, unless control of dangerous behaviour is urgent.
    2. 2. Always define a review date when one starts an antipsychotic or other dopamine antagonist (or any symptomatic drug, for that matter).
    3. 3. Consider additive adverse effects from other medications – not only other neuroleptics, but particularly other drugs with anticholinergic effects.
    4. 4. Remember the limited positive effect of antipsychotics on sleep, for which quetiapine is too often prescribed.

    Chris Rauscher MD, FRCPC
    Retired geriatrician/general internist, Vancouver BC
    Dr. Rauscher declares no relevant conflict of interest. He was a consultant to the BC Shared Care Polypharmacy Risk Reduction Project and is a consultant to Northern Health Authority (BC) on use of antipsychotics in long-term care homes.

  • Elia Abi-Jaoude
    Posted at 09:26h, 29 November Reply

    Thank you for this useful Therapeutics Letter. The use of antipsychotic drugs has increased dramatically with the arrival of the so-called “atypicals”(1), which were very heavily pushed to expand into markets beyond psychosis, specifically targeting mood disorders, disruptive behaviour in children, and agitation in the elderly(2).
    While the focus on extrapyramidal symptoms is crucial, it’s also important to understand other significant harms caused by antipsychotic drugs, including metabolic effects, cognitive effects, apathy, and gynecomastia/galactorrhea. Metabolic effects are especially common and striking.
    Some of the newer antipsychotics have been marketed with the misleading claim of being “metabolically neutral.” However, an older antipsychotic, molindone, known to be weight neutral, was already available – it had performed well in a major National Institute of Mental Health-funded study, particularly with regards to its favorable weight and metabolic profile(3). However, shortly thereafter, it was pulled from the market. In response to our inquiry with the company that issued the notice, we were informed the reason was that molindone was no longer manufactured by the supplier, a major pharmaceutical company. This same company had just brought to market a new antipsychotic which it was positioning as weight-neutral(4). With no hint of irony, the American Journal of Psychiatry published a commentary lamenting the loss of molindone, while the same issue of the journal contained a glossy 12-page advertisement for yet another new antipsychotic with a purportedly favorable metabolic profile.(5)
    Another issue that deserves attention is the current heavy push to get patients quickly onto long-acting depot antipsychotics. Again, this only started once new, on-patent, very expensive depots became available, and before there was any good evidence to support this practice(6); in fact, an entire supplement issue of the Canadian Journal of Psychiatry, sponsored by Pharma, was devoted to the topic. Marketing experts are being paid millions by the pharmaceutical industry for market research specifically aimed at persuading prescribers to use depot antipsychotics. Is this evidence-based or money-based medicine? We would strongly urge the Therapeutics Initiative to evaluate the current evidence to support the current heavy reliance on depot antipsychotics.

    Elia Abi-Jaoude MD, MSc, PhD, FRCPC
    Assistant Professor
    Department of Psychiatry, University of Toronto

    Daniel Gorman MD, FRCPC
    Associate Professor
    Department of Psychiatry, University of Toronto
    —
    Dr. Abi-Jaoude and Dr. Gorman declare no conflicts of interest.

    1. 1. Kendall T. The rise and fall of the atypical antipsychotics. Br J Psychiatry J Ment Sci. 2011 Oct;199(4):266–8.
    2. 2. Spielmans G, Parry P. From evidence-based medicine to marketing-based medicine: Evidence from internal industry documents. [References]. J Bioethical Inq. 2010;7(1):13–29.
    3. 3. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L. Double-Blind Comparison of First- and Second-Generation Antipsychotics in Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study. Am J Psychiatry. 2008;165:1420–31.
    4. 4. Thompson A, Lavedan C, Volpi S. Absence of weight gain association with the HTR2C −759C/T polymorphism in patients with schizophrenia treated with iloperidone. Psychiatry Res. 2010 Feb 28;175(3):271–3.
    5. 5. Neimark G. Farewell, Moban. Am J Psychiatry. 2010 May;167(5):501–501.
    6. 6. Weiden PJ. Why Are Canadians Complacent about Long-Acting Injectable Antipsychotic Therapies? Come on, Canada, You Can Do Better! Can J Psychiatry. 2013 May 1;58(5_suppl):3–4.
  • David Cunningham Owens
    Posted at 09:34h, 29 November Reply

    One needs some caution about stopping antipsychotics, even when they may not appear medically necessary. This is because of the increased risk of tardive dyskinesia (TD) that emanates from ‘on/off’ exposure, postulated as a kindling effect.

    So if one believes that a patient has a relapsing-remitting type of illness, one must consider not only short-term but also long-term treatment implications and discuss these with the patient.

    Also, while it may appear that some EPS are “dose-related”, it is also not strictly so! The extent to which dopamine balance is disrupted in terms of daily dose, drug potency, cumulative antagonist burden and a whole range of drug-related variables, in the context of personal susceptibility is key. Some of this may relate to variability of drug metabolism by CYP450 isoenzyme genotype, as opposed to dopamine receptor mutations. Antipsychotic “dose” may be a convenient short-hand, but dopamine antagonist “burden” is probably closer to what determines EPS.

    I’ve never been convinced by the “rebound” or “withdrawal” argument, except (possibly) with clozapine, which I think is the clue. Rebound/withdrawal is probably a muscarinic phenomenon restricted to drugs (or active metabolites) with potent anti-muscarinic actions, and hence not generalisable. Others disagree.

    The mantra with antipsychotic use is “primary prevention”. Limit indications, limit doses, and remove where possible. We have had ample evidence for 20 years that “atypicals” are not different, and need no more!

    David C. Owens MD(Hons), FRCP, FRCPsych.
    Professor Emeritus of Psychiatry, University of Edinburgh
    Dr. Owens reports no relationships with the pharmaceutical industry since 2000. He is a member of the expert advisory group, Central Nervous System, for the UK regulator MHRA and previously for the European Medicines Agency.

    Reference: Cunningham Owens, D. (2014). A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs (2nd ed.). Cambridge: Cambridge University Press. DOI: 10.1017/CBO9781139149112

  • Rokuro Hama
    Posted at 17:06h, 29 November Reply

    Thank you for this useful Therapeutics Letter.
    I would like to add some points:

    Acute extrapyramidal symptoms include
    1) dystonic reactions especially in infants and young adults
    2) akathisia especially in adolescent and young or middle aged adults
    3) Parkinsonism especially in older people

    However, if causative agents were not stopped, these symptoms may develop to the following more severe stage with complicated symptoms[1,2]:

    4) Catatonia with hyper kinetic state or with akinetic state as the next step of akathisia and Parkinsonism or even dystonic reactions. This stage may develop to the following stage:

    5) Malignant syndrome (neuroleptic malignant syndrome): rigidity, pyrexia, increased CK, impaired mental state (agitation, confusion, delirium and coma) and various autonomic symptoms (hypertention, hypotension, tachicardia, diaphoresis etc)

    Rokuro Hama MD
    Director, Japan Institute of Pharmacovigilance publishing independent Drug Bulletin “MedCheck”
    —
    Dr. Rokuro Hama declares no conflict of interest.

    References：
    1) Hynes AF et al. Case Study: Neuroleptic Malignant Syndrome without Pyrexia. J American Acad Child Adlesc Psychiatry 1996: 35: 959-961, https://www.ncbi.nlm.nih.gov/pubmed/8768358

    2) Woodbury MM & Woodbury MA, Case Study: Neuroleptic-induced Catatonia as a Stage in the Progression toward Neuroleptic Malignant Syndrome.J American Acad Child Adlesc Psychiatry 1992: 31: 1161-4 https://www.ncbi.nlm.nih.gov/pubmed/1429421

  • Christine Martin
    Posted at 09:53h, 01 December Reply

    Thank you to all the TI members involved in putting together this very important, and very informative information for us consumers, regarding the consequences of prolonged and overuse of these types of medications. Once prescribed, they often are not monitored adequately, and the adverse effects are not well communicated, if at all.

    As was the case with my Mom, the serious harms that can result are often not recognized or reported by the patient, or misunderstood. While I acknowledge that there are many good medications that save lives, some antidepressant, antianxiety and antipsychotic medications are ineffective, harmful, or overprescribed.

    I would like to thank one of your team for helping my late mother, who suffered from tardive dyskinesia. What she experienced was much more impactful than can be described in the written words in your Letter (or elsewhere). Fortunately, even after years of treatment with trifluoperazine, my mother was able to slowly taper off the causative antipsychotic medication, over 11 months. Because of a diagnosis given to her in the mid-1950’s, doctors originally believed that she could never discontinue this (or an equivalent) medication. That was a time when mental illness was very poorly understood.

    My mother’s tardive dyskinesia symptoms were not recognized, but interpreted instead as a worsening of the original diagnosis. So more medications were added. These just worsened her symptoms, that had now manifested into tremor and shuffling gait that were thought to be symptoms of Parkinson’s disease. She was also thought to have dementia, because of her deteriorating mental condition.

    Fortunately one of the TI physicians was asked to evaluate her before she started any medications to treat Parkinson’s disease or dementia. Were it not for that intervention to deprescribe trifluoperazine, my Mom would have been misdiagnosed, and unknowingly given more inappropriate medications, just worsening her condition.

    If caught early, and if appropriate information is made available, tardive dyskinesia can be prevented. There seems to be very little awareness in the community about this adverse effect of antipsychotic drugs.

    Your organizations’s motto of “Better Prescribing, Better Health.” is exactly that, from my experience. I am forever grateful for the help my Mom received.

    Christine Martin
    North Vancouver, BC, CANADA
    (Christine Martin advises that she has no conflict of interest)

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