For years, the psychiatric community has sought to better understand why a significant portion of individuals with major depressive disorder (MDD) do not achieve relief of their symptoms after receiving treatment. Emerging research in the field is leading to new theories that broaden our understanding of what neural systems may be involved in MDD and that may help to explain this phenomenon.
The Pathophysiology of MDD
The exact etiology of MDD remains unknown, but the predominant focus to date has been on monoamine pathways. Over the course of the last several decades, the most commonly used therapies for the treatment of MDD have included selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and atypical antipsychotics, medicines that primarily target monoamine neurotransmitters in the brain (ie, serotonin, norepinephrine, and dopamine). However, research has shown that approximately two-thirds of people treated for MDD did not achieve symptom resolution with first-line antidepressants, and approximately one-third of these patients did not achieve full symptom relief, or remission, even after switching to a second, third, or fourth antidepressant.1,2 Additionally, the prospect of achieving remission declined with each new antidepressant regimen.2
With low response and remission rates in MDD, it is clear that an unmet need remains in a significant number of patients who fail to respond or only partially respond to current pharmacologic treatments.1,2
Research suggests that monoamine pathways may be just one part of a significantly more complex system of neural circuits involved in MDD. Numerous other neural pathways and biological processes may be implicated in MDD.1,3,4
Exploring Pathways That May Be Involved in the Biology of MDD
The endogenous opioid system
Multiple lines of evidence suggest that the endogenous opioid system is involved in the regulation of mood and may be dysregulated in MDD.1,4 Numerous areas of the brain involved in mood regulation, including the prefrontal cortex and the limbic areas, receive input from the endogenous opioid system. Studies have also suggested that dysfunctional signaling in the endogenous opioid system may occur in patients with MDD.
The neuroplasticity hypothesis
Neuroplasticity is the ability of the brain to adapt, change, and learn through mechanisms, including development and maturation of new neurons (neurogenesis) or synapses (synaptogenesis). Patients with MDD are thought to have a dysfunction in this important biologic process. Interestingly, enhancement of neurogenesis and synaptogenesis is a common mechanism across antidepressants.5
Dysfunction of glutamate signaling
Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory. Normal glutamatergic activity is thought to be involved in maintaining normal neuroplasticity. Under conditions of stress or depression, glutamate signaling may become impaired, leading to a reduction of neuroplasticity.5-7
GABA receptor signaling pathway
GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter, and the modulation of GABA receptors may be associated with modulation of stress and mood. Findings from clinical and preclinical studies have provided compelling evidence for associations between alterations in GABAergic transmission and specific stress-related psychiatric disorders, such as depression.8
A Deeper Dive Into the Biology of the Opioid System
The core symptoms of MDD are depressed mood and lack of interest or pleasure in normal activities.9 Evidence suggests that key areas of the brain, including the prefrontal cortex and the limbic areas, are involved in the processing of emotion, mood, and reward. Anatomical studies have shown that neurons containing endogenous opioids provide input to most of these key brain areas.6,10
An analysis of positron emission tomographic (PET) scans from 89 healthy volunteers showed that the location of opioid system receptors overlaps with brain regions responsible for emotional processing.11
Both animal models and human studies suggest that the natural opioid system in the brain is involved in mood regulation.12,13 Research in rodents with genetically modified opioid receptors revealed changes in behavioral models of depressive and anxious states. In a human study, patients with MDD showed reduced opioid-receptor activity in response to negative emotional stimuli indicating impaired system function vs healthy controls. Overall, these studies suggest that the opioid system must be functioning properly to maintain normal mood regulation.
The endogenous opioid system is a natural neurotransmitter system in your brain that includes 3 different peptide neurotransmitters — beta endorphin, enkephalin, and dynorphin — and 3 receptor types — the mu, delta, and kappa opioid receptors. Each of these receptors is involved in mood regulation as well as other functions.6,13 The most widely known endogenous opioid neurotransmitter is endorphin. Changes in endorphin levels have been associated with natural stimuli and experiences, such as exercise, meditation, laughter, and music.13-17
- Mu (μ-) opioid receptors: These receptors are known for their role in reward and analgesia. Overstimulation of these receptors can be associated with addiction. However, these receptors are intricately involved in mood regulation. Agonism, or activation, of these receptors is associated with improved mood, or what is considered antidepressant-like activity.6,13
- Delta (δ-) opioid receptors: Similar to mu opioid receptors, agonism of these receptors is linked to improved mood and antidepressant-like activity.18
- Kappa (κ-) opioid receptors: In contrast to the mu and delta receptors, agonism of the kappa receptors is associated with dysphoria, or prodepressive activity. However, antagonism, or inhibition of these receptors, is associated with a return to normal mood, or antidepressant-like activity.19-21
Achieving an antidepressant effect through modulation of the endogenous opioid system may involve the appropriate balance and modulation of these multiple receptors.13
Given that a substantial proportion of people do not achieve adequate symptom relief with available therapies, this new research provides new ways of thinking about this disease that could be meaningful for patients.
Craig Hopkinson, MD, is the chief medical officer and senior vice president, Clinical Development and Medical Affairs at Alkermes, a global biopharmaceutical company focused on central nervous system disorders.
- Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81-97.
- Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
- Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches [published online June 28, 2018]. Mol Psychiatry. doi: 10.1038/s41380-018-0117-2
- Chaudhury D, Liu H, Han M-H. Neuronal correlates of depression. Cell Mol Life Sci. 2015;72(24):4825-4848.
- Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249.
- Stahl SM. Stahl’s Essential Psychopharmacology Online. 2008. http://stahlonline.cambridge.org/essential_4th.jsf. Accessed July 7, 2017.
- Duric V, Banasr M, Stockmeier CA, et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol. 2013;16(1):69-82.
- Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D. GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response. Front Neuroendocrinol. 2015;36:28-48.
- American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4):1-45.
- Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology. 2012;79(12):807-814.
- Nummenmaa L, Tuominen L. Opioid system and human emotions. Br J Pharmacol. 2018;175(14):2737-2749.
- Hsu DT, Sanford BJ, Meyers KK, et al. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry. 2015;20(2):193-200.
- Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206.
- Arida RM, Gomes da Silva S, de Almeida AA, et al. Differential effects of exercise on brain opioid receptor binding and activation in rats. J Neurochem. 2015;132(2):206-217.
- Sharon H, Maron-Katz A, Ben Simon E, et al. Mindfulness meditation modulates pain through endogenous opioids. Am J Med. 2016;129(7):755-758.
- Dunbar RIM, Baron R, Frangou A, et al. Social laughter is correlated with an elevated pain threshold. Proc Biol Sci. 2012;279(1731):1161-1167.
- Tarr B, Launay J, Dunbar RI. Music and social bonding: “self-other” merging and neurohormonal mechanisms. Front Psychol. 2014;5:1096.
- Filliol D, Ghozland S, Chluba J, et al. Mice deficient for δ- and µ-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet. 2000;25(2):195-200.
- Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774-776.
- Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res. 1995;681(1-2):147-152
- Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305(1):323-330.