2017-11-10 14:29:59

Today's topic(s)

  • Depression
  • Planning for student-led presentations

Depression

  • Symptoms
    • Unhappy mood, insomnia, lethargy, loss of pleasure, interest, energy
  • Agitation
  • Lasting for several weeks or more

Depression

  • Experienced by ~7% Americans in any year
  • Prevalence (up to ~20% lifetime)
  • Females 2-3x males, higher 40+ years of age
  • MZ concordance ~60% vs. DZ ~20% suggests genetic component

Symptoms, (Mahar et al. 2014)

Neurobiology of Major Depressive Disorder (MDD)

  • Reduced sizes of brain regions
  • Hypoactivity
  • Pharmacological factors
  • Synaptic neurotrophic dysfunction

Neurological factors

(Videbech and Ravnkilde 2004b)

Left Hippocampus

(Videbech and Ravnkilde 2004a)

Right Hippocampus

Hypoactivity in

(Fitzgerald et al. 2008)

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

Baseline hyperactivity (Hamilton et al. 2012)

Valence-specific hyperactivity (Hamilton et al. 2012)

Increased connectivity between resting state network regions and dorsal PFC (Sheline et al. 2010)

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

Altered connectivity (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

Pharmacological factors

Pharmacological factors

  • Monoamine hypothesis
    • More: euphoria
    • Less: depression
    • Resperine (antagonist for NE & 5-HT) can cause depression
    • Low serotonin (5-HT) metabolite levels in CSF of suicidal depressives (Samuelsson et al. 2006)

Drug treatments

  • 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

Drug treatments

  • 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)

Cymbalta (SNRI)

How well do drugs work?

  • 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?

  • Depends on
    • Early life stress
    • Brain (amygdala) response to emotional faces
  • (Goldstein-Piekarski et al. 2016)
  • Low-stress + low amyg reactivity -> > responding
  • High stress + high amyg reactivity -> > responding

Problems with monoamine hypothesis

  • Too simplistic
  • NE, 5-HT interact
  • Drugs fast acting (min), but improvement slow (weeks)

What do drugs do, then?

Ketamine again

Pathway of pathology (Duman and Aghajanian 2012)

  • 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)

(Duman and Voleti 2012)

(Frohlich and Van Horn 2014)

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.

Electroconvulsive Therapy (ECT)

  • Remission rates of up to 50.9% (Dierckx et al. 2012)
  • Seems to work via
    • Anticonvulsant (block Na+ channel or enhance GABA function) effects
    • Neurotrophic (stimulates neurogenesis) effects

Take home messages

  • Multi-level, multi-method, multi-variate approaches essential to understanding mental illness
  • Developmental processes across the life span
  • Networks all the way down…

References

Berman, R M, A Cappiello, A Anand, D A Oren, G R Heninger, D S Charney, and J H Krystal. 2000. “Antidepressant Effects of Ketamine in Depressed Patients.” Biol. Psychiatry 47 (4): 351–54. https://www.ncbi.nlm.nih.gov/pubmed/10686270.

Burke, Heather M, Mary C Davis, Christian Otte, and David C Mohr. 2005. “Depression and Cortisol Responses to Psychological Stress: A Meta-Analysis.” Psychoneuroendocrinology 30 (9): 846–56. doi:10.1016/j.psyneuen.2005.02.010.

Cheng, Wei, Edmund T. Rolls, Jiang Qiu, Wei Liu, Yanqing Tang, Chu-Chung Huang, XinFa Wang, et al. 2016. “Medial Reward and Lateral Non-Reward Orbitofrontal Cortex Circuits Change in Opposite Directions in Depression.” Brain, October, aww255. doi:10.1093/brain/aww255.

Dierckx, Bram, Willemijn T Heijnen, Walter W van den Broek, and Tom K Birkenhäger. 2012. “Efficacy of Electroconvulsive Therapy in Bipolar Versus Unipolar Major Depression: A Meta-Analysis.” Bipolar Disorders 14 (2): 146–50. doi:10.1111/j.1399-5618.2012.00997.x.

Duman, Ronald S, and George K Aghajanian. 2012. “Synaptic Dysfunction in Depression: Potential Therapeutic Targets.” Science 338 (6103): 68–72. doi:10.1126/science.1222939.

Duman, Ronald S, and Bhavya Voleti. 2012. “Signaling Pathways Underlying the Pathophysiology and Treatment of Depression: Novel Mechanisms for Rapid-Acting Agents.” Trends Neurosci. 35 (1): 47–56. doi:10.1016/j.tins.2011.11.004.

Fitzgerald, Paul B., Angela R. Laird, Jerome Maller, and Zafiris J. Daskalakis. 2008. “A Meta-Analytic Study of Changes in Brain Activation in Depression.” Human Brain Mapping 29 (6): 683–95. doi:10.1002/hbm.20426.

Frohlich, Joel, and John D Van Horn. 2014. “Reviewing the Ketamine Model for Schizophrenia.” J. Psychopharmacol. 28 (4): 287–302. doi:10.1177/0269881113512909.

Goldstein-Piekarski, Andrea N., Mayuresh S. Korgaonkar, Erin Green, Trisha Suppes, Alan F. Schatzberg, Trevor Hastie, Charles B. Nemeroff, and Leanne M. Williams. 2016. “Human Amygdala Engagement Moderated by Early Life Stress Exposure Is a Biobehavioral Target for Predicting Recovery on Antidepressants.” Proceedings of the National Academy of Sciences 113 (42): 11955–60. doi:10.1073/pnas.1606671113.

Hamilton, J Paul, Amit Etkin, Daniella J Furman, Maria G Lemus, Rebecca F Johnson, and Ian H Gotlib. 2012. “Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data.” AJP 169 (7). American Psychiatric Publishing: 693–703. doi:10.1176/appi.ajp.2012.11071105.

Li, Nanxin, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, and Ronald S Duman. 2010. “mTOR-dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists.” Science 329 (5994): 959–64. doi:10.1126/science.1190287.

Mahar, Ian, Francis Rodriguez Bambico, Naguib Mechawar, and José N. Nobrega. 2014. “Stress, Serotonin, and Hippocampal Neurogenesis in Relation to Depression and Antidepressant Effects.” Neuroscience & Biobehavioral Reviews 38 (January): 173–92. doi:10.1016/j.neubiorev.2013.11.009.

Medici, Marco, Nese Direk, W Edward Visser, Tim I M Korevaar, Albert Hofman, Theo J Visser, Henning Tiemeier, and Robin P Peeters. 2014. “Thyroid Function Within the Normal Range and the Risk of Depression: A Population-Based Cohort Study.” J. Clin. Endocrinol. Metab. 99 (4): 1213–9. doi:10.1210/jc.2013-3589.

Samuelsson, M., J. Jokinen, A.-L. Nordström, and P. Nordström. 2006. “CSF 5-HIAA, Suicide Intent and Hopelessness in the Prediction of Early Suicide in Male High-Risk Suicide Attempters.” Acta Psychiatrica Scandinavica 113 (1): 44–47. doi:10.1111/j.1600-0447.2005.00639.x.

Sheline, Yvette I, Joseph L Price, Zhizi Yan, and Mark A Mintun. 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): 11020–5. doi:10.1073/pnas.1000446107.

Videbech, Poul, and Barbara Ravnkilde. 2004a. “Hippocampal Volume and Depression: A Meta-Analysis of Mri Studies.” American Journal of Psychiatry 161 (11). Am Psychiatric Assoc: 1957–66. doi:10.1176/appi.ajp.161.11.1957.

———. 2004b. “Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies.” Am. J. Psychiatry 161 (11): 1957–66. doi:10.1176/appi.ajp.161.11.1957.

Zarate, Carlos A, Jr, Jaskaran B Singh, Paul J Carlson, Nancy E Brutsche, Rezvan Ameli, David A Luckenbaugh, Dennis S Charney, and Husseini K Manji. 2006. “A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression.” Arch. Gen. Psychiatry 63 (8): 856–64. doi:10.1001/archpsyc.63.8.856.