Commentary on Aubin et al.: Could combination medication approaches target mental health comorbidity in the context of alcohol use disorder?

Combination pharmacological targets for alcohol use disorder may play a role in improving mental health and post-traumatic stress disorder symptoms. Alcohol use is a leading risk factor for global burden of disease, contributing to over 5% of disease and injury and nearly 3 million deaths annually [1]. Medications play a key role in alcohol use disorder (AUD) treatment approaches, but there are only three approved medications in the existing repertoire, with few advances in pharmacological targets [2]. Therefore, the combination treatment approach proposed by Aubin and colleagues [3], who report on the first trial of a combination of α-1b blocker prazosin and 5HT-2A blocker cyproheptadine, represents a significant innovation by targeting different pathways concurrently. These authors found a significant effect of high-dose combination treatment on change in total alcohol consumption in individuals with AUD, which raises a range of questions in considering external validity and extrapolation of study findings in broader populations. A point of interest in this study is the potential role of mental health comorbidity in driving potential treatment response, through improvement of mental health symptoms that underpin alcohol use. Untreated mental health symptoms contribute substantially to the precipitation and perpetuation of AUD. For a large proportion of treatment-seeking individuals with AUD, the course of their illness and attempts at recovery from AUD, are complicated by comorbid mental health disorders [4]. Comorbidity presents a major clinical challenge, associated with an even higher degree of clinical impairment, poorer prognosis and treatment attrition [5]. This is particularly the case for comorbid post-traumatic stress disorder (PTSD), estimated to be prevalent in up to one in two individuals who seek AUD treatment [4]. Treatment for substance use disorder is typically less effective without concurrent management of PTSD, as untreated symptoms (nightmares, sleep dysfunction and emotion dysregulation) precipitate relapse to alcohol use. The combination approach from Aubin and colleagues [3] uses two medications that have an evidence base for the treatment of PTSD and trauma-related sleep dysfunction. Prazosin, an α-1b antagonist, has shown some promise in individual observational studies and six RCTs as a potential treatment for PTSD, particularly for nightmares [6]. There are also several case reports suggesting that cyproheptadine, a 5HT2-A blocker, may improve management of nightmares and sleep dysfunction in PTSD [7]. The combination blockade of these two mechanistic pathways could potentially ameliorate both PTSD and AUD symptoms. However, the presence of comorbidity was not measured in this study, and there is no report of the prevalence of mental disorders or associated symptoms. This remains a common gap across the existing AUD treatment literature, despite acceptance of high rates of comorbidity within clinical populations worldwide. Important risk considerations raised by Aubin and colleagues [3] also need to be further explored. These specifically include the interaction of heavy alcohol consumption with potentially sedative medications, and the risk of cumulative sedation both within therapeutic dose ranges and in overdose. Self-reported sedation was reported by over 10% of participants on active medication in this study, although the over-time evolution of sedative scores was comparable between placebo, low dose and high dose groups. This remains a risk in broader clinical populations, particularly in the context of other sedative or drug use. Alcohol use will also enhance the risk of orthostatic hypotension, contributing to the known adverse effects of dizziness, light-headedness and falls; risks relevant for both prazosin and cyproheptadine. These risks are partially mitigated in this study by the use of an extended-release formulation of prazosin, with <10% of study participants affected by orthostatic hypotension; however, extended release formulations of prazosin are not widely available internationally, with immediate release requiring careful, gradual titration in routine practice. Weight gain is a further major consideration in future studies. This is a recognised adverse effect of cyproheptadine, and in this study, weight gain was reported in both active treatment groups compared to placebo (mean of 2.5 kg weight gain in lower dose, and 2.4 kg weight gain in higher dose, over the 3-month treatment period). Finally, it will be important that future studies further investigate the risk of diversion and aberrant use. Nonetheless, these findings do show promise of recoupling the noradrenergic and serotonergic systems by simultaneously blocking α-agonist and serotonergic receptors, and potentially ameliorating a range of mental health comorbid symptoms in the process. It is well recognised that medications are under-prescribed and under-used in the AUD treatment response internationally, so the study from Aubin and colleagues [3] brings much-needed innovation to the field. We look forward to phase 3 clinical trials in broader populations to investigate the promise of this approach. Shalini Arunogiri prepared the first draft of the commentary. Shalini Arunogiri and Kirsten C. Morley contributed to edits and the final draft of the article. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians. None. There are no funders to report.