
- Vol 33 No 12
- Volume 33
- Issue 12
Opioids to Treat Depression: The Jury Is Out
Two recent clinical trials of opioid medication for depression and suicidality highlight the role of brain opioid systems in depression.
SCIENCE AND CLINICAL PSYCHIATRY
Two recent clinical trials of opioid medication for depression and suicidality highlight the role of brain opioid systems in depression.1,2 Opioids treat pain, but depression and pain are often comorbid, and some antidepressants relieve neuropathic pain even in the absence of depression. Depression involves dysfunction in monoamine systems, the hypothalamus-pituitary-adrenal (HPA) axis, and hippocampal neurogenesis, but could it also be rooted in a deficit of endorphins, or even an endopharmacological withdrawal state?
Before the modern antidepressant era, depression was often treated with opiates-with a sometimes heavy price of addiction. Would psychiatrists be contributing to the epidemic of opioid addiction if we started to treat depression with opioids?
Brain opioid systems
The best-understood endogenous opioids are the endorphins, which, like morphine, bind preferentially to mu-opioid receptors. Enkephalins bind to the delta-receptor, and dynorphins to the kappa-receptor. The less-studied endomorphins and nociceptin are structurally related to opioids; they also contribute to pain, anxiety, stress responses, and reward, and are targets for drug development.
The
Opioid systems, then, participate in many mood-related functions. They are examples of evolutionary repurposing of neurotransmitters that originally evolved for one purpose to meet a variety of other needs.7,8 Like monoamines, opioids are neuromodulators; they affect excitability by slower second messenger effects.
Recent research
The mean buprenorphine dosage in the study was only 0.44 mg daily, which is in the range used to treat pain. In mammals, such ultra-low dosages reduce separation distress. Below 2 mg, agonist effects predominate, and abuse can occur. At the much higher dosages of 8 mg to 24 mg daily used to treat addiction, buprenorphine is a mu-partial agonist, exerting mild mu-agonist effects while blocking other opioids from the receptor.
This intriguing study originated in theoretical work by the neuroscientist Jaak Panksepp. Drawing on animal research,
In a second study,
Pharmacological implications
In both studies, low dosages of buprenorphine were effective, which suggests that
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.
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.
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.
Nonpharmacological treatment
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
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.
Disclosures:
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.
References:
1. Yovell Y, Bar G, Mashiah M, et al.
2. Fava M, Memisoglu A, Thase ME, et al.
3. Lutz PE, Kieffer BL.
4. Pradhan AA, Befort K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011;32:581-590.
5. Lalanne L, Ayranci G, Kieffer BL, Lutz P-E. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry. 2014;5:170.
6. Treadway MT, Zald DH.
7. Venter JC, di Porzio U, Robinson DA, et al. Evolution of neurotransmitter receptor systems. Prog Neurobiol. 1988;30:105-169.
8. Panksepp J.
9. Almatroudi A, Husbands SM, Bailey CP, Bailey SJ. Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice. J Psychopharmacol. 2015;29:812-821.
10. Bodkin JA, Zornberg GL, Lukas SE, Cole JO.
11. Moore BA. Buprenorphine for suicidality? Maybe. The Carlat Report: Psychiatry. Research Update. August 2016:8-9. http://thecarlatreport.com/research/buprenorphine-suicidality-maybe. Accessed September 30, 2016.
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