Watch a video on evolving theories in MDD pathophysiology and patient management.

NEW THEORIES CHALLENGE OUR UNDERSTANDING OF MDD

Andrew J. Cutler, MD, discusses going beyond the current pathways to seek a deeper understanding of MDD.

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THE PATHOPHYSIOLOGY OF MDD

A key to helping patients move beyond partial response

With low response and remission rates in major depressive disorder (MDD), an unmet need remains. Gaining a deeper understanding of MDD pathophysiology is essential to address this challenge.1,2

Looking outside the monoamine system

The exact etiology of MDD remains unknown, but the predominant focus to date has been on monoamine pathways.3 The monoamine hypothesis proposes that depression is the result of deficiency in one or more monoamines3:

  • Serotonin
  • Norepinephrine
  • Dopamine

However, research suggests that monoamine pathways are just one part of a significantly more complex system of neural circuits involved in MDD.1,4 Numerous pathways and biological processes may be implicated in MDD.1,4

THE PATHOPHYSIOLOGY OF MDD

A key to helping patients move beyond partial response

With low response and remission rates in major depressive disorder (MDD), an unmet need remains. Gaining a deeper understanding of MDD pathophysiology is essential to address this challenge.1,2

Watch a video on evolving theories in MDD pathophysiology and patient management.

NEW THEORIES CHALLENGE OUR UNDERSTANDING OF MDD

Andrew J. Cutler, MD, discusses going beyond the monoamine pathways to seek deeper understanding of MDD.

Looking outside the monoamine system

The exact etiology of MDD remains unknown, but the predominant focus to date has been on monoamine pathways.3 The monoamine hypothesis proposes that depression is the result of deficiency in one or more monoamines3:

  • Serotonin
  • Norepinephrine
  • Dopamine

However, research suggests that monoamine pathways are just one part of a significantly more complex system of neural circuits involved in MDD.1,4 Numerous pathways and biological processes may be implicated in MDD.1,4

The endogenous opioid system and MDD

The endogenous opioid system and its 3 receptors—mu, kappa, and delta—are believed to play an integral role in the expression of mood, emotion, reward, and motivation.5-10

  • Numerous areas of the brain involved in mood regulation, including the prefrontal cortex and the limbic areas, receive input from endogenous opioid system3, 11-16
  • Studies have suggested that dysfunctional signaling in the endogenous opioid system may occur in patients with MDD17

A study of PET scans from 89 healthy volunteers showed that the location of opioid system receptors overlaps with brain regions responsible for emotion processing.18

image of PET scans showing mu opioid receptor in the brain

Distribution of mu opioid receptors in the brain.

image of PET scans showing the overlap between the human emotion circuit

Brain regions known to be involved in emotional experience and perception.

Reproduced with permission from Nummenmaa and Tuominen.18
FDR, false discovery rate.

Learn about the potential role of the endogenous opioid system in MDD
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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.19,20

  • Patients with MDD had a reduced number of synapses and synapse-related genes in the prefrontal cortex compared with healthy controls20
  • Interestingly, enhancement of neurogenesis and synaptogenesis is a common mechanism across antidepressants17
Number of dendritic branches was decreased in the dlPFC of patients with MDD20
Chart showing the number of dendritic branches was decreased in the dlPFC of patients with MDD.

Postmortem cortical brain slices stained with MAP2 (antibody used to label dendrites) show plentiful dendritic branches in a healthy individual while barely any neuronal processes are visible in an individual with MDD.
dlPFC, dorsolateral prefrontal cortex; MAP2, microtubule-associated protein 2.
Reproduced with permission from Kang et al.20

Dysfunction of glutamate signaling

Glutamate is an excitatory neurotransmitter involved in many functions, including synaptic plasticity, learning, and memory. Numerous studies have shown regional changes in glutamate receptors, as well as elevated levels of glutamate in the brains of patients with MDD.19,21,22

  • Normal glutamatergic activity is thought to be involved in maintaining normal neuroplasticity19,21
  • Under conditions of stress or depression, glutamate signaling is impaired, leading to a reduction of neuroplasticity19,21

The cholinergic hypothesis

Increased cholinergic activity and decreased noradrenergic activity are thought to be involved in the development of depressive symptoms.23,24

  • Decreased acetylcholine receptor levels have been observed in actively depressed patients23
  • Anticholinergic agents have been associated with antidepressant effects25
  • These antidepressant effects are thought to be mediated through a downstream increase in neuroplasticity25

Inflammation and depression

Inflammation is hypothesized to be involved in the etiology of depression.3,26 Stress can trigger a sequence of systemic events:

  • Activation of the sympathetic nervous system (fight-or-flight response) can induce systemic inflammation3,26
  • The resulting inflammation is believed to cause neurotoxic effects in regions of the brain responsible for regulation of emotion; this can present as symptoms of depression3,26
Understanding the complexity of MDD may be the key to helping additional patients achieve response and/or remission.
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References: 1. Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81-97. 2. 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. 3. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013. 4. Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci (Landmark Ed). 2009;14:5291-5338. 5. Filliol D, Ghozland S, Chluba J, et al. Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses. Nat Gen. 2000;25(2):195-200. 6. Peppin JF, Raffa RB. Delta opioid agonists: a concise update on potential therapeutic applications. J Clin Pharm Ther. 2015;40(2):155-166. 7. Jutkiewicz EM, Rice KC, Traynor JR, Woods JH. Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats. Psychopharmacology (Berl). 2005;182(4):588-596. 8. 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. 9. Nguyen AT, Marquez P, Hamid A, et al. The rewarding action of acute cocaine is reduced in β-endorphin deficient but not in μ opioid receptor knockout mice. Eur J Pharmacol. 2012;686(1-3):50-54. 10. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774-776. 11. Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206. 12. George SR, Zastawny RL, Briones-Urbina R, et al. Distinct distributions of mu, delta and kappa opioid receptor mRNA in rat brain. Biochem Biophys Res Commun. 1994;205(2):1438-1444. 13. Fazio L, Logroscino G, Taurisano P, et al. Prefrontal activity and connectivity with the basal ganglia during performance of complex cognitive tasks is associated with apathy in healthy subjects. PLoS One. 2016;11(10):e0165301. doi: 10.1371/journal.pone.0165301. 14. Monosov IE, Hikosaka O. Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex. J Neurosci. 2012;32(30):10318-10330. 15. Bishop SJ. Trait anxiety and impoverished prefrontal control of attention. Nat Neurosci. 2009;12(1):92-98. 16. Cooney RE, Joormann J, Eugène F, Dennis EL, Gotlib IH. Neural correlates of rumination in depression. Cogn Affect Behav Neurosci. 2010;10(4):470-478. 17. 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. 18. Nummenmaa L, Tuominen L. Opioid system and human emotions [published online April 10, 2017]. Br J Pharmacol. 2017;175:2737-2749. 19. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants [published online March 11, 2015]. Nat Med. 2016;22(3):238-249. 20. Kang HJ, Voleti B, Hajszan T, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18(9):1413-1417. 21. 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. 22. Choudary PV, Molnar M, Evans SJ, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA. 2005;102(43):15653-15658. 23. Saricicek A, Esterlis I, Maloney KH, et al. Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder. Am J Psychiatry. 2012;169(8):851-859. 24. Gonzalez MM, Aston-Jones G. Light depreivation damages monoamine neurons and produces a depressive behavioral phenotype in rats. Proc Natl Acad Sci USA. 2008;105(12):4898-4903. 25. Yu H, Lv D, Shen M, et al. BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1. Psychiatry Res. 2019;271:328-334. 26. Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21(10):1356-1365.

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