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Worsening stimulant use disorder outcomes coinciding with off-label antipsychotic prescribing: a commonly unrecognised side effect?
  1. Ruvini Amarasekera1 and
  2. Evan Wood1,2
  1. 1BC Centre on Substance Use, The University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Medicine, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Evan Wood; bccsu-ew{at}bccsu.ubc.ca

Abstract

Antipsychotic medications exert their effects via dopamine antagonism and are widely used off-label among persons with substance use disorders (SUD). While dopamine antagonists are recognised to stimulate food craving and weight gain, outside of possibly increasing nicotine craving and use, their impact on other SUD outcomes is poorly recognised. In this context, research has demonstrated that antipsychotic therapy can produce ‘supersensitivity’ to dopamine, enhancing the motivational effects of addictive drugs. Worsened drug craving and higher rates of substance use have also been observed in double-blind placebo-controlled trials. Nevertheless, widespread off-label antipsychotic prescribing among persons with SUD implies that the risks of worsening SUD outcomes are overall poorly recognised in both primary care and among specialists. We present a typical case of worsening stimulant use disorder in a patient prescribed antipsychotic medication for low mood and insomnia, highlighting that this is likely a widely under-recognised adverse effect of off-label antipsychotic therapy.

  • Drugs misuse (including addiction)
  • Unwanted effects / adverse reactions
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Background

Substance use disorders (SUD) have become an increasing issue in North America. In addition to known health harms secondary to nicotine and alcohol, illicit stimulants and opioids are increasing concerns. For instance, in the context of North America’s opioid overdose crisis, an increasing number of overdoses involve more than one drug, with stimulants playing an increasing role.1 Over the last several decades, licit and illicit drug deaths have been referred to as increasing ‘deaths of despair’, and have been contributing to a declining life expectancy in North America.2 Further, there is growing recognition of concurrent mental health consequences among those with SUD. While in some instances, mental health concerns may precede substance use, many substances of abuse can contribute to a full spectrum of concurrent mental health concerns from alcohol use attributable anxiety and depression through to substance-induced insomnia and psychosis.3 Some of these concerns are due to the neurobiological effects of substances themselves, whereas other mental health conditions may be caused or worsened by the social harms (eg, loss of relationships) secondary to SUD. To date, lack of proven pharmacotherapies and evidence-based guidelines to treat these concurrent mental health disorders has resulted in widespread off-label prescribing.4 5 In this report, ‘off-label’ refers to prescribing involving a physician prescription of a medication for an individual without an on-label or approved indication, but rather to alleviate other symptoms. For instance, while there are known benefits of antipsychotic treatment for psychiatric disorders such as schizophrenia, antipsychotic medications are known to be widely used off-label in many patients whereby medication side effects, such as drowsiness, are leveraged as treatments for certain conditions (eg, insomnia).

Specifically, antipsychotic medications are widely used off-label among persons with SUD, whereby their antidopaminergic effects may alleviate side effects or other symptoms of SUD including anxiety, low mood and insomnia.6 Additionally, some reports note that certain psychoactive medications, including antipsychotics, are diverted, and used outside of a normal prescribed medication for symptom management or for the perceived ability of certain medications to augment the ‘high’ of illicit drugs.7 In these contexts, the off-label prescribing of certain antipsychotic medications has become of increased concern.4

While dopamine antagonists are recognised to stimulate food craving and weight gain,8 outside of the possible role on increasing nicotine craving and use,9–11 their impact on other SUD outcomes is poorly recognised. Recognising that the neurobiology of addiction primarily involves the ‘reward pathway’ involving the neurotransmitter dopamine, research has demonstrated that antipsychotic therapy can produce ‘supersensitivity’ to dopamine which can enhance motivational effects of addictive drugs.12 This case report focuses on possible unintended consequences of dopamine antagonists, such as worsening stimulant cravings and stimulant use disorder. This case report also acknowledges that there may be clinical circumstances where off-label use may have benefit (eg, helping patients during severe agitation and anxiety in stimulant intoxication) or among individuals with severe concurrent disorders (eg, schizophrenia) where they are indicated.

Nevertheless, widespread off-label antipsychotic prescribing implies that the risks of worsening SUD outcomes is overall poorly recognised in primary care and among specialists. We present a typical case of worsening stimulant use disorder use in a patient prescribed antipsychotic medication for low mood and insomnia and highlight that this is likely a widely under-recognised adverse effect of antipsychotic therapy.

Case presentation

A man in his 20s with no prior psychiatric diagnoses presented with stimulant use disorder, reporting a 1 year history of methamphetamine and cocaine use. He reported increasing use, unsuccessful attempts to cut down on use, increasing time spent acquiring and using substances, strong craving, recurrent use despite negative impact on work, use despite physical harm, withdrawal from social activities, tolerance and withdrawal. When his stimulant use began contributing to mental health challenges including low mood and insomnia, he presented to his primary care physician. At this time, his primary care physician did not inquire about a substance use history and a urine drug screen was not done. As per the patient’s account, his primary care physician made a provisional diagnosis of bipolar disorder at this time and prescribed oral formulations of aripiprazole and later quetiapine (25–100 mg PO QHS). However, the patient reported several significant side effects of dopamine antagonism. Specifically, in addition to some unwanted daytime sedation, low libido, feelings of apathy and increasing low mood, this individual reported a significant increase in severe craving for substance use including both methamphetamine and nicotine and related compulsions for increasing use. Coinciding with these prescriptions, his stimulant use disorder escalated from weekly use and related to ‘party’ activities to daily use. During this time, he reported worsening craving which he attributed specifically to quetiapine.

Outcome and follow-up

An addiction medicine specialist evaluated the patient and recommended stopping the quetiapine and aripiprazole due to the absence of a clear on-label indication, a view that the patient’s original symptoms were likely attributable to stimulant use, and concern that dopamine antagonism was contributing to severe stimulant use disorder. This coincided with the individual being admitted to in-patient treatment including non-pharmacological management of his stimulant use disorder. As the patient with SUD was a health professional, the residential treatment programme involved a specialised programme for health professionals involving psychosocial treatment combining psychotherapy involving education about SUD, triggers for relapse and strategies to improve self-efficacy for avoiding returning to substance use supplemented by daily group work. He is presently in full remission of stimulant use disorder and has returned to work as a health professional.

Discussion

This case describes an individual with an emerging stimulant use disorder experiencing increased methamphetamine craving and ultimately the development of a severe stimulant use disorder coinciding with the introduction on antipsychotic medication. Here, the medication was started for a symptom complex inconsistent with a clear on-label indication and more likely symptoms secondary to stimulant abuse. While some harms of antipsychotic treatment are well-known among prescribers of this medication class, their potential harms among those with or at risk of SUD are largely under-recognised as reflected by current widespread prescribing to those with SUD.

For instance, one well-recognised harm of dopamine antagonists is weight gain. While some antipsychotics, such as olanzapine, may be worse than others,13–15 almost all antipsychotics can result in weight gain.15 16 While weight gain among users of dopamine antagonist medications may be multifactorial, enhanced food craving is a known side effect. Further, a well-known harm of antipsychotics specific to patients at risk of SUD is increased nicotine use, as demonstrated in patients with schizophrenia. While some have hypothesised that this may be related to an overlapping genetic risk of schizophrenia and risk of nicotine use disorder,12 17 controlled studies have clearly demonstrated a causal effect of dopamine antagonism on increased tobacco use.10 11 For instance, a controlled study that provided a dopaminergic antagonist (haloperidol) and a dopamine agonist (bromocriptine) found that dopamine antagonism increased tobacco use and concluded ‘nicotine mediates reinforcement from smoking via dopamine, and that smoking behaviour can be manipulated within the same subjects in opposite directions by alternately stimulating and blocking dopamine’.18

Antipsychotic-induced supersensitivity to dopamine has been long described in both humans12 19 and in laboratory animals.20–24 As described by Samaha, “Animals that have been rendered supersensitive to dopamine” when given dopamine antagonists “will work harder and longer to obtain these drugs compared to controls.”12

While prescribers cannot be expected to be up-to-date with basic science and animal research, observations from humans including randomised double-blind placebo-controlled trials have similarly demonstrated worsening of SUD with antipsychotic treatment.25–30 For example, a randomised controlled trial to evaluate the efficacy of olanzapine to treat cocaine dependence instead demonstrated that administering olanzapine significantly increased cocaine use, measured by urine benzoylecgonine tests, and reduced treatment retention compared with placebo-treated subjects.25 Similarly, a within-groups study in a laboratory setting evaluating aripiprazole’s influence on cocaine’s reinforcing effects demonstrated that administering aripiprazole increased self-administration of smoked cocaine among participants.26 Notably, another large randomised controlled trial comparing potential pharmacological agents for amphetamine dependance treatment was terminated prematurely as amphetamine-dependent subjects administered aripiprazole were more than three times more likely to have amphetamine-positive urine samples compared with placebo-treated subjects.27 Antipsychotics have demonstrated similar effects on alcohol relapse among persons with alcohol use disorder. For example, a randomised, double-blind, placebo-controlled, parallel-group study demonstrated that participants administered tiapride had a significantly worse relapse rate for alcohol use compared with the placebo group.28 Further, a prospective, randomised, double-blind, placebo-controlled trial demonstrated that flupentixol decanoate reduced the rate of alcohol abstinence among participants compared with the placebo-treated group.29 Secondarily, this study also demonstrated an increase in alcohol craving among antipsychotic-treated participants compared with the placebo group though this difference was non-significant.29 Of note, in a study evaluating the impact of quetiapine on cannabis withdrawal and relapse in daily cannabis users, quetiapine was shown to worsen marijuana craving and self-administration during relapse.30

As this current case report suggests, quetiapine may also worsen stimulant craving in individuals with stimulant use disorder. Research in this area would suggest that in some patients, quetiapine may induce dopamine supersensitivity within the brain’s dopamine-reward pathway due to its dopamine antagonist effects, causing stimulant craving and relapse.23 Past research has suggested that first generation rather than newer antipsychotics are of greater concern. Additionally, the patient described in this case may have been a poor metaboliser as the quetiapine dose was lower in comparison to a typical dose used to treat psychosis (eg, 400 mg). However, past studies of certain second-generation antagonists including olanzapine,25 aripiprazole27 and quetiapine30 have demonstrated increased craving and use of stimulants, cannabis and other substances of abuse suggesting that dopamine supersensitivity is not restricted to first-generation antipsychotics. As antipsychotics are commonly prescribed to individuals with SUD, it is increasingly important to be aware of their risks and engage in thoughtful prescribing. The above concerns must be considered alongside some research suggesting that antipsychotics may be beneficial to alleviate symptoms of SUD such as insomnia, anxiety and low mood.6 There are several relevant prescribing tools, such as the Maudsley Prescribing Guidelines In Psychiatry, that may aide in clinical decision making in the primary care setting.31

In this context, risks of dopamine supersensitivity have also been shown to be compounded with continuous versus intermittent antipsychotic exposure as well as with longer duration of antipsychotic prescribing.22 32 33 This illustrates the impact of prolonged exposure to dopamine antagonists promoting dopamine supersensitivity and may explain why short-term clinical trials have not more consistently demonstrated worsening SUD outcomes. Of note, this pattern was not borne out in nicotine literature and overall human research implies that both typical and atypical antipsychotics could pose a risk for dopamine supersensitivity.9

Existing research has clearly demonstrated that antipsychotic therapy can contribute to worsening of drug craving and higher rates of substance abuse in nicotine use disorder whereas the same impacts of dopamine supersensitivity are likely underappreciated in other SUD. This case of worsening stimulant use disorder brings this issue to attention, highlighting an under-recognised adverse effect of off-label antipsychotic use that may track with similar harms like weight gain and increased nicotine use in susceptible individuals.

Learning points

  • The neurobiological mechanism of substance use disorders (SUD) involves dopamine and research suggests that exposure to antipsychotics can induce dopamine ‘supersensitivity’, which can enhance the motivational effects of stimulants and other substances of abuse.

  • Through this mechanism, a number of randomised clinical trials have demonstrated that certain antipsychotics may worsen risk or symptoms of SUD though this has generally been understudied.

  • When considered, primary care physicians and specialists should be aware of the potential impacts of antipsychotics on worsening SUD outcomes, especially since benefits for off-label use are limited.

Ethics statements

Patient consent for publication

References

Footnotes

  • Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: RA and EW both interviewed the patient, reviewed the literature and drafted the manuscript. Both authors reviewed and approved the final version. The following authors gave final approval of the manuscript: Both authors approved the final version.

  • Funding This study was funded by Canadian Institutes of Health Research (950-232118).

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests Dr EW is a research physician and professor of medicine with some past and current consulting and employment activities unrelated to off-label antipsychotic prescribing. This case was written in his capacity as a research physician affiliated with a university rather than in other roles. Details available upon request.

  • Provenance and peer review Not commissioned; externally peer reviewed.