Opioids in Psychiatric Disorders: Back to the Future?

The article by Yovell and colleagues in the May issue (1) points to the potential use of low doses of a buprenorphine, a mu-opioid partial agonist, to decrease suicidal ideation in psychiatric patients. The findings are in keeping with earlier workofBodkinetal. (2),who foundthatbuprenorphinecould provide relief to patients with refractory depression, and the more recent work of Ehrich et al. (3), who found that buprenorphine in combinationwith amu-opioid antagonist— samidorphan—may be effective in refractory major depression. The Yovell et al. data are intriguing on several counts. For one, they offer a possible approach to helping acutely suicidal patients, particularly those with borderline personality disorder, for whom we have little in the way of effective treatments. For another, they point to a possible role for opioids in the treatment of depressed or suicidal patients, particularly those whose illness has been refractory to standard therapy. The latter is in some ways encouraging but presents a number of important issues that we need to address for the sake of our patients, our profession, and the society at large. In these pages, the concern has been raised that the rapid benefits of intravenous ketaminemight reflect its mu agonist properties and that ultimately could pose problems for our patients and the field (4). The present report that low oral doses of amupartial agonist results in relief of suicidal ideation only reinforces our need to begin to address a number of issues that will arise from the use of potential drugs of abuse to treat psychiatric disorders. As Yovell et al. remark, opioids were commonly used for the treatment of depression before the introduction of effective antidepressant agents, and they were abandoned in favor of effective agents that didnot connote risk for addiction. And for many of our patients, these second-generation agents have provided great relief of suffering. Unfortunately, many patients do not respond to them, and suicide remains a major public health problem onwhichwe havemade little progress. Some compounds with abuse potential offer considerable acute relief,muchas anopioidwouldhelppostoperativepain. The problem is that patients generally require ongoing therapy, and with that comes the potential risk of dependence, withdrawal, and other ill effects. We have already witnessed this with the epidemic opioid use often stemming from legitimate medical uses (5). In the Yovell et al. study, withdrawal symptoms were not formally evaluated, although they were not elicited after 4 weeks, and the buprenorphine dosages used were very low, ranging from 0.2 to 0.8 mg/day. Butwhat of patientswho require higher dosages or for longer periods in maintenance treatment? Are we putting patients at risk for addiction with longer-term use at higher dosages? If so, can we justify this approach in some patients, much as we would in a terminally ill patient? Can guidelines be promulgated to help here? Does the potential use pose a threat to the society at large because of diversion to others? What is the relative risk-benefit ratio for an individual patient versus for the society at large? Some of the potential risk may be mitigated by the approach one company has pursued that involves combining buprenorphine with samidorphan (3). This approach may limit the risk of dependence andwithdrawal andmay reregulate the opioid system by combining a so-called driver with a brake. Another potential mechanism heremay involve kappa antagonism properties of buprenorphine that may emerge more clearly after blocking the drug’s mu partial agonismwhen combining it with a mu antagonist. Kappa receptor agonism itself is thought to be depressogenic. Clinical trials are under way to address efficacy and safety of the buprenorphine-samidorphan combination approach. What do the findings of Yovell et al. tell us regarding the opioid system in major depressive disorder and borderline personality disorder?We know that endogenous opioids play key roles in the modulation of physical pain but also in social rejection, a clinical dimension of particular relevance in borderlinepersonality disorder. Zubieta’s group (6, 7)has elegantly described alterations in basal opioid activity in borderline personality disorder or major depression using positive emission tomography (PET), and their findings suggest that activity of the system may not be entirely homologous across the two disorders. For one, basal activity is relatively high in borderline personality disorder and low in major depression. Moreover, the two groupsmaydiffer in response to social rejection stress, with depression patients demonstrating relative blunting of the opioid response (7). The Yovell et al. data suggest greater response in patients with borderline personality disorder, although the relatively small number of subjects with major depression may account for the differences. Study of buprenorphine directly in refractory major depression without borderline features and rejection sensitivity across disorders would be useful, as would be PET changes with the drug to The field needs to study the use of the drug not only acutely but over the long term to assess efficacy and safety before it is widely adopted.