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.
Human neuroimaging shows mu-receptor activity in brain areas involved in emotions, including the nucleus accumbens, ventral pallidum, amygdala, anterior cingulate, and posterior thalamus.2 More detailed information comes from animal research using mice genetically engineered with inactive opioid receptors; micro-infusion of drugs into key sites such as the nucleus accumbens; and models such as learned helplessness, forced swim, and tail suspension.3 Mu-, delta-, and kappa-opioid receptors have central roles in many mood-related functions, including the dopamine reward system, serotonin and noradrenergic pathways, and the HPA axis. Opioids also influence the survival and growth of neurons in the hippocampus.
The Table summarizes some of the behavioral effects of opioids in animals. Mu-agonists relieve depression-like behavior acutely, but tolerance develops, and depression is worse on withdrawal from long-term administration. Delta-agonists appear to improve mood, while kappa-agonists worsen it.3-5 There is evidence that opioid dysfunction accounts for lack of pleasure in depression, while problems with dopamine impair motivation.6
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.
Yovell and colleagues1 report that ultra–low-dose buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varying levels of depression; the majority also had borderline personality disorder. The reduction in suicidality correlated only modestly with improvement in depressive symptoms. The investigators did not report any assessment of possible addictive responses to buprenorphine.
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, Panksepp8 has identified 7 basic emotional systems that underlie behavior, which he calls seeking, rage, fear, lust, care, panic/grief, and play. Each is associated with specific brain regions and neurotransmitters. Yovell, Panksepp, and colleagues1 hypothesized that patients’ depression, physical and mental pain, and suicidality were related to the panic/grief system and would be relieved by mu-opioid agonism.
In a second study, Fava and colleagues2 conducted an industry- sponsored trial in 105 patients with treatment-resistant depression. Buprenorphine at the much higher dosages of 2 mg and 8 mg daily was combined with the mu-antagonist samidorphan. (This strategy differs from co-administering naloxone, a mu-antagonist that is not absorbed orally, in the treatment of pain or addiction.) The lower-dosage group had modest reductions in depression scores, while the higher dosage was much less effective. The researchers administered questionnaires to assess subjective drug effects, which might predict addiction, with generally reassuring results. Similar to the Yovell study, symptoms improved over the 4-week period.
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.
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.
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.
1. Yovell Y, Bar G, Mashiah M, et al. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491-498.
2. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173:499-508.
3. Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36:195-206.
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. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537-555.
7. Venter JC, di Porzio U, Robinson DA, et al. Evolution of neurotransmitter receptor systems. Prog Neurobiol. 1988;30:105-169.
8. Panksepp J. The cross-mammalian neurophenomenology of primal emotional affects: from animal feelings to human therapeutics. J Comp Neurol. 2016;524:1624-1635.
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. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15:49-57.
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.