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.

THE PATHOPHYSIOLOGY OF MDD

A key to helping patients move beyond
partial response

With low response and remission rates in major depressive disorder (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. 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.1 The monoamine hypothesis proposes that depression is the result of deficiency in one or more monoamines1:

  • 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.1,3 Numerous pathways and biological processes may be implicated in MDD.1,3

THE PATHOPHYSIOLOGY OF MDD

A key to helping patients move beyond partial response

With low response and remission rates in major depressive disorder (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. 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.1 The monoamine hypothesis proposes that depression is the result of deficiency in one or more monoamines1:

  • 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.1,3 Numerous pathways and biological processes may be implicated in MDD.1,3

The endogenous opioid system and MDD

The endogenous opioid system plays an integral role in mood regulation.4

  • Numerous areas of the brain involved in mood regulation, including the prefrontal cortex and the limbic areas, receive input from endogenous opioid system4,5
  • Studies have suggested that dysfunctional signaling in the endogenous opioid system may occur in patients with MDD6

Achieving an antidepressant effect through modulation of the endogenous opioid system may involve the appropriate balance of this system's 3 receptors―the mu, delta, and kappa opioid receptors.7

The location of opioid receptors overlaps with brain regions responsible for emotional processing8
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.

FDR, false discovery rate.

Learn about the potential role of the endogenous opioid system in MDD. SEE MORE

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.9-11

  • Patients with MDD had a reduced number of synapses and synapse-related genes in the prefrontal cortex compared with healthy controls11
  • Interestingly, enhancement of neurogenesis and synaptogenesis is a common mechanism across antidepressants1
Number of dendritic branches was decreased in the dlPFC of patients with MDD11
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.11

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.4,9,12

  • Normal glutamatergic activity is thought to be involved in maintaining normal neuroplasticity9
  • Under conditions of stress or depression, glutamate signaling is impaired, leading to a reduction of neuroplasticity9

The cholinergic hypothesis

Increased cholinergic activity and decreased noradrenergic activity are thought to be involved in the development of depressive symptoms.1

  • Elevated acetylcholine levels have been observed in actively depressed patients13
  • Anticholinergic agents have been associated with antidepressant effects1
  • These antidepressant effects are thought to be mediated through a downstream increase in neuroplasticity1

Inflammation and depression

Inflammation is hypothesized to be involved in the etiology of depression.14 Stress can trigger a sequence of systemic events:

  • Activation of the sympathetic nervous system (fight-or-flight response) can induce systemic inflammation9,14
  • 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 depression9,14
Understanding the complexity of MDD may be the key to helping additional people achieve response and/or remission. EXPLORE MORE
EXPLORE THE OPIOID SYSTEM
REVIEW CHALLENGES OF PATIENT MANAGEMENT
VIEW RESOURCE LIBRARY

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. Chaudhury D, Liu H, Han MH. Neuronal correlates of depression. Cell Mol Life Sci. 2015;72(24):4825‐4848. 4. Stahl SM. Stahl's Essential Psychopharmacology Online. 2008. http://stahlonline.cambridge.org/essential_4th.jsf. Accessed July 7, 2017. 5. Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology. 2012;79(12):1288-1295. 6. Kennedy SE, Koeppe RA, Young EA, Zubieta J-K. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63(11):1199-1208. 7. Lutz P-E, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206. 8. Nummenmaa L, Tuominen L. Opioid system and human emotions [published online April 10, 2017]. Br J Pharmacol. 2017. 9. 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. 10. Zhao Y-J, Du M-Y, Huang X-Q, et al. Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis. Psychol Med. 2014;44(14):2927-2937. 11. 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. 12. 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. 13. 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. 14. Kim Y-K, Won E. The influence of stress on neuroinflammation and alterations in brain structure and function in major depressive disorder [published online April 22, 2017]. Behav Brain Res. 2017;329:6-11.

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