In both studies, low dosages of buprenorphine were effective, which suggests that fine-tuning the mu-system may be a good strategy.2,3 But buprenorphine is also a kappa- and delta-opioid antagonist. Because kappa-antagonism is associated with antidepressant effects, it will be important to clarify whether symptom improvement resulted from mu-agonism, kappa-antagonism, or some combination.
Because mammals develop tolerance to mu-antidepressant effects, longer-term studies are necessary. A fixed-dose combination to fine-tune a complex neurobiological system may be problematic because of individual variations in drug actions and metabolism. A further concern is that an antidepressant that relies on mu effects might disturb the reward system and affect motivation—a major problem for depressed patients—or put them at risk for addiction.
If the combination of buprenorphine and samidorphan turns out to be an effective antidepressant, would substituting naltrexone, a mu-blocker available generically, for the new drug, samidorphan, be equally effective? The buprenorphine-naltrexone combination showed antidepressant properties in a mouse model of depression,9 but there are no published human data.
Psychiatrists have discussed treating depression with buprenorphine ever since it became available, but the only previous study is a small open-label trial from 1995.10 Some may be tempted to try low-dose buprenorphine for depressed or suicidal patients11 by cutting the 2 mg/0.5 mg buprenorphine-naloxone tablet and, perhaps, combining it with naltrexone. Because the short- and long-term efficacy, appropriate dose, safety, and potential for triggering addiction of such off-label use have not been studied in detail, it cannot be recommended at this time.
Panksepp’s8 animal work suggests that most basic emotions are nonconscious and not necessarily accessible to verbal understanding. In humans, prefrontal circuitry exerts top-down control over emotions, which may account for the efficacy of psychodynamic interpretations and cognitive therapy. But we shouldn’t be surprised when reasoning and insight don’t work, and we need to consider relational, behavioral, pharmacological, or environmental interventions.
When it comes to anhedonia—DSM’s “loss of interest or pleasure”—animal research distinguishes interest, or motivation, from pleasure, since they involve different, though overlapping, brain systems.6 Interest is associated with dopamine, and pleasure with endogenous opioids. Taking a “pleasure history,” trying to connect depressed patients with activities they have enjoyed in the past, and nurturing any happiness they are capable of feeling are strategies worth trying. The overlap of the brain systems involved in pain and depression is a reminder to ask depressed patients about their experiences of pain. And Yovell and colleagues’1 finding that suicidality correlated only modestly with depression confirms the counterintuitive reality that not all suicidal patients are depressed.
These trials of buprenorphine for suicidality and depression move us forward. Opioid systems contribute to depression, though the details are complex and also involve monoamines, stress, and hippocampal damage. Medications and probably nonpharmacological treatments that adjust the mu-opioid system, block kappa-activity, or modify other opioid functions are potential new therapies that may improve outcomes.
This article was originally posted on 10/12/2016 and has since been updated.
Dr. Woodward is Assistant Clinical Professor of Psychiatry at Boston University School of Medicine. He is in private practice in Newton, MA. He reports no conflicts of interest concerning the subject matter of this article.
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