Depression

Symptoms

  • Unhappy mood, insomnia, lethargy, loss of pleasure, interest, energy
  • Agitation
  • Lasting for several weeks or more
  • Experienced by ~7% Americans in any year
  • Prevalence (up to ~20% lifetime)
  • Females 2-3x males, higher 40+ years of age
    • postpartum anxiety and depression in 10-20% of mothers
  • MZ concordance ~60% vs. DZ ~20% suggests genetic component
[[@mahar_stress_2014]](http://doi.org/10.1016/j.neubiorev.2013.11.009)

(Mahar, Bambico, Mechawar, & Nobrega, 2014)

Neurobiology of Major Depressive Disorder (MDD)

Reduced sizes of brain regions

  • Reduced hippocampal volumes

Left Hippocampus

[[@Videbech2004-sm]](http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.161.11.1957)

(Videbech & Ravnkilde, 2004)

Right Hippocampus

[[@Videbech2004-sm]](http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.161.11.1957)

(Videbech & Ravnkilde, 2004)

[[@Palazidou2012-je]](http://dx.doi.org/10.1093/bmb/lds004)

(Palazidou, 2012)

Hypoactivity

  • Frontal and temporal cortex
  • Anterior cingulate
  • Insula
  • Cerebellum
[[@fitzgerald_meta-analytic_2008]](http://dx.doi.org/10.1002/hbm.20426)

(Fitzgerald, Laird, Maller, & Daskalakis, 2008)

[a] patients v. ctrls, [b] patients on SSRIs, [c] patients v. ctrls (happy stim), [d] patients v. controls (sad stim)

Hyperactivity

[[@Hamilton2012-iv]](https://doi.org/10.1176/appi.ajp.2012.11071105)

(Hamilton et al., 2012)

  • Both valence-specific and non-valence specific

(Hamilton et al., 2012)

[[@Hamilton2012-iv]](https://doi.org/10.1176/appi.ajp.2012.11071105)

(Hamilton et al., 2012)

Altered connectivity

[[@Sheline2010-nh]](http://doi.org/10.1073/pnas.1000446107)

(Sheline et al., 2010)

CCN (yellow); precuneus, part of DMN (pink); and affective division of the ACC (turquoise)

  • (Cheng et al., 2016)
  • Resting state fMRI (rsFMRI) in 421 patients with major depressive disorder and 488 control subjects.
  • Reduced connectivity between orbitofrontal cortex (OFC) and other areas of the brain
  • Increased connectivity between lateral PFC and other brain areas
[[@cheng_medial_2016]](http://doi.org/10.1093/brain/aww255)

(Cheng et al., 2016)

[[@cheng_medial_2016]](http://doi.org/10.1093/brain/aww255)

(Cheng et al., 2016)

Summary of areas implicated

[[@Palazidou2012-je]](http://dx.doi.org/10.1093/bmb/lds004)

(Palazidou, 2012)

Pharmacological factors

[[@Palazidou2012-je]](http://dx.doi.org/10.1093/bmb/lds004)

(Palazidou, 2012)

Measuring 5-HT

Treatments

Psychotherapy: Neural responses

  • increased rostral anterior cingulate cortex (rACC) activation vs. decrease in healthy controls
  • decreased activity in left precentral gyrus
[[@Sankar2018-yp]](http://doi.org/10.1016/j.pscychresns.2018.07.002)

(Sankar et al., 2018)

Fig. 2. Group by time interaction effects of psychological therapies. There was a significant group by time interaction in the left rostral anterior cingulate cortex, in which participants with major depression showed increased activity following psychological therapy while healthy participants showed a reduction in activity at the follow up scan. Sagittal (x), coronal (y), and axial (x) coordinates for each section are presented. Results are P < 0.05 FDR corrected.

[[@Sankar2018-yp]](http://doi.org/10.1016/j.pscychresns.2018.07.002)

(Sankar et al., 2018)

Fig. 3. Longitudinal changes following psychological therapies. There was a main effect of in the left precentral gyrus, which showed decreased activity following psychological therapy in major depression. The coronal (y) coordinate of each section is presented. There were additional regions which did not meet our threshold of 50 mm3 for significance. Results are P < 0.05 FDR corrected.

Electroconvulsive Therapy (ECT)

  • Last line of treatment for drug-resistant depression
  • Electric current delivered to the brain causes 30-60s seizure.
  • ECT usually done in a hospital’s operating or recovery room under general anesthesia.
  • Once every 2 - 5 days for a total of 6 - 12 sessions.
  • Remission rates of up to 50.9% (Dierckx, Heijnen, Broek, & Birkenhäger, 2012)
  • Seems to work via
    • Anticonvulsant (block Na+ channel or enhance GABA function) effects
    • Neurotrophic (stimulates neurogenesis) effects

Drugs

  • Monoamine oxidase (MAO) inhibitors
    • MAO inactivates monoamines in terminal buttons
    • MAO-I’s boost monoamine levels
  • Tricyclics
    • Inhibit NE, 5-HT reuptake
    • Upregulate monoamine levels, but non-selective = side effects
  • Selective Serotonin Reuptake Inhibitors (SSRIs)
    • Fluoxetine (Prozac, Paxil, Zoloft)
    • Prolong duration 5-HT in synaptic cleft
    • Also increase brain steroid production
  • Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

Drug effectiveness

  • STAR*D trial
  • On SSRI for 12-14 weeks. ~1/3 achieved remission; 10-15% showed symptom reduction.
  • If SSRI didn’t work, could switch drugs. ~25% became symptom free.
  • 16% of participants dropped out due to tolerability issues
  • Took 6-7 weeks to show response

Who benefits from drug therapy?

  • May depend on
  • Low-stress + low amyg reactivity -> > responding
  • High stress + high amyg reactivity -> > responding
[[@goldstein-piekarski_human_2016]](http://doi.org/10.1073/pnas.1606671113)

(Goldstein-Piekarski et al., 2016)

Problems with monoamine hypothesis

  • Too simplistic
  • NE, 5-HT interact
  • Drugs fast acting (min), but improvement slow (weeks)
  • “No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers.” (Tiger et al., 2015)
  • Monamine depletion studies…

“…we performed the first meta-analysis of the mood effects in ATD and APTD studies. The depletion of monoamine systems (both 5-HT and NE/DA) does not decrease mood in healthy controls. However, in healthy controls with a family history of MDD the results suggest that mood is slightly decreased…by [monoamine depletion]…”

Acute tryptophan depletion (ATD) targets 5-HT; phenylalanine/tyrosine depletion (APTD) targets DA; alpha-methyl-para-tyrosine (AMPT) targets NE/DA.

(Ruhé, Mason, & Schene, 2007)

Evaluating treatments

Ketamine, again

Putative pathway of pathology

  • Depression ~ chronic stress (Mahar et al., 2014)
  • Stress -> chronic HPA axis activity
  • Chronic HPA activity -> neuronal atrophy in hipp & PFC
  • Stress & cortisol decrease expression of brain-derived neurotrophic factor (BDNF)
  • BDNF boosts neurogenesis
  • SSRIs act via BDNF, as do NMDA receptor antagonists (e.g., ketamine)
[[@Duman2012-nz]](http://dx.doi.org/10.1016/j.tins.2011.11.004)

(Duman & Voleti, 2012)

[[@Frohlich2014-tq]](http://dx.doi.org/10.1177/0269881113512909)

(Frohlich & Van Horn, 2014)

Putting the pieces together

[[@Palazidou2012-je]](http://dx.doi.org/10.1093/bmb/lds004)

(Palazidou, 2012)

The disordered mind: Take home messages

References

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Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., … Duman, R. S. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329(5994), 959–964. https://doi.org/10.1126/science.1190287

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Medici, M., Direk, N., Visser, W. E., Korevaar, T. I. M., Hofman, A., Visser, T. J., … Peeters, R. P. (2014). Thyroid function within the normal range and the risk of depression: A population-based cohort study. J. Clin. Endocrinol. Metab., 99(4), 1213–1219. https://doi.org/10.1210/jc.2013-3589

Palazidou, E. (2012). The neurobiology of depression. British Medical Bulletin, 101, 127–145. https://doi.org/10.1093/bmb/lds004

Ruhé, H. G., Mason, N. S., & Schene, A. H. (2007). Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Molecular Psychiatry, 12(4), 331–359. https://doi.org/10.1038/sj.mp.4001949

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Sankar, A., Melin, A., Lorenzetti, V., Horton, P., Costafreda, S. G., & Fu, C. H. Y. (2018). A systematic review and meta-analysis of the neural correlates of psychological therapies in major depression. Psychiatry Research. Neuroimaging, 279, 31–39. https://doi.org/10.1016/j.pscychresns.2018.07.002

Sheline, Y. I., Price, J. L., Yan, Z., & Mintun, M. A. (2010). Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc. Natl. Acad. Sci. U. S. A., 107(24), 11020–11025. https://doi.org/10.1073/pnas.1000446107

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