Role of Endogenous Opioids in Depression

Role of Endogenous Opioids in Depression

 

cell-1740543_1280

 

The roles of opioid receptors in pain and addiction is well known, but their function in mood disorders has received less attention. Opioid receptors are a group of inhibitory G protein-coupled receptors with following subtypes and functions:

  1. Mu-receptors: role in Analgesia, Reward, and Dependence. (1)
  2. delta-receptors: role in Anti-depressant and Anti-anxiety. (2) 
  3. kappa receptors: role in Anti-reward, Dysphoria and Pro-depression. (3)

 

This post will summarize important trials in depression of following three medications acting on opioid receptors:

  1. Buprenorphine
  2. ALKS 5461 (Buprenorphine + Mu Antagonist ALKS 33)

  3. CERC 501 (Selective Kappa Antagonist)

 

BUPRENORPHINE

Mechanism:

  • Partial mu opioid agonist
  • Kappa antagonist

 

Article published by Yovell et al in Am J Psychiatry in May 2016, tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation.

Design: multisite randomized double-blind placebo-controlled trial.

Results:

  • Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3).
  • Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine.
  • No withdrawal symptoms were reported after treatment discontinuation at the end of the trial.

 

ALKS 5461 (Buprenorphine + Mu Antagonist ALKS 33)

Mechanism:

  • Developed by Alkermes as a potential treatment for patients with MDD not responding to SSRIs or SNRIs: Combination of Buprenorphine + Mu Antagonist ALKS 33.
  • Buprenorphine (Partial mu opioid agonist + Kappa antagonist)
  • ALKS 33: Mu Antagonist- added to reverse the known side effects induced by the Mu opioid component of buprenorphine.

 

Article published by Fava et al in Am J Psychiatry in May 2016 conducted this study in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment.

Design:

  • Multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study.
  • Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/ALKS 33 (2/2 dosage group), 8 mg/8 mg of buprenorphine/ALKS 33 (8/8 dosage group), or placebo.

 

Results:

  • Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1).
  • There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance.
  • Overall, buprenorphine/ALKS 33 combinations were well tolerated.
  • There was no evidence of opioid withdrawal on treatment discontinuation.

 

CERC501

Mechanism:

  • Selective Kappa Antagonist

 

No studies are published to date- in progress.

CERC501 is developed based on following study showing depressive like effects of Kappa opioid receptor agonist (Salvinorin A) on behavior and neurochemistry in rats: William A. Carlezon et al 2004.

  • Systemic administration of salvinorin A produced depressive like effects in the forced swim test (FST) and intracranial self stimulation (ICSS) test, which are behavioral models often used to study depression in rats.

 

Thus emergence of Kappa Antagonist and ALKS 5461 in addition to Buprenorphine seems promisingly for those with treatment-resistant depression responding poorly to at least two antidepressants.

 

SOURCE:

 

  1. Moles et al. Science 2004.
  2. Filliol et al. Nat Genet 2000.
  3. Lutz and Kieffer. Trends Neurosci. 2013.
  4. Fava et al. Am J Psychiatry May 2016.
  5. Yovell et al. Am J Psychiatry May 2016.
  6. William A. Carlezon et al. 2004.

Please do post your questions or comments below. 


Dr. Harvinder Singh, M.D. (Admin)


Enroll in our online course to have access to all important clinically relevant psychiatry topics in one place.


Related Articles