2. 1 Mood Disorders Bi / CNS 150 Lecture 26 Monday December 1, 2014 Bruce Cohen Kandel Chap. 63: 1402-1418

3. Overview Mood (affect) is emotional state over time Because it is based on emotion, mood can be characterized by its valence and intensity (similar to emotion) Mood disorders are characterized by extreme and inappropriately exaggerated moods that last for prolonged period of time Two broad categories of affective disorders –Major (unipolar) depression characterized by recurring episodes of dysphoria (unhappiness) and negative thinking (prevalence,15- 20%) –Bipolar disorder characterized by cyclical and exaggerated mood swings between depression and mania that occur over a prolonged period (prevalence, 1%) 2

4. Depression has a significant economic impact Unipolar depressive disorders Alcohol use disorders Schizophrenia Iron-deficiency anemia Bipolar affective disorder Hearing loss, adult onset HIV/AIDS Chronic OPD Osteoarthritis Road traffic accidents 024 6 81016 Source: WHO – World Health Report Disability Adjusted Life Years (DALY) 3 Data from United States, Canada and Western Europe, 2008 15-44 year olds)

5. Brain regions relevant to mood disorders 4

6. Clinical signs of major (unipolar) depression Reactive depression is state of sadness in response to loss of loved one, failure to achieve goals, or disappointment in love. Major (unipolar) depression includes 5 or more of symptoms below that persist for > 2 weeks and impair normal function 5 Depressive episodes typically last 7-14 months and can recur throughout life

7. 6 Manic episodes alternate with depressive episodes Manic episode is abnormally elevated, expansive, or irritable mood that lasts for week or more Initial episode often occurs in mid-20’s and can lead eventually to suicide. Clinical signs of bipolar disorder (DSM-5) Video of manic episode, University of Nottingham : Psychiatric Interviews for Teaching: Mania - YouTube

8. Genes contribute to mood disorders Recurrence risk ratio ( ) measures relative lifetime risk of developing a disease as a function of relatedness For mood disorders, is significantly greater for identical twins than that for siblings or unrelated individuals Increased for identical twins indicates genetic contribution to mood disorders for bipolar disorder is much greater than that for major depression Despite increased, no single dominant gene has emerged as a risk factor for mood disorders Data suggest environmental and developmental influences also contribute to mood disorders DisorderSiblingsIdentical Twins Bipolar disorder 760 Major Depression 2-316 7 Recurrence Risk Ratios ( ) for Mood Disorders. Measures relative increase in lifetime risk of developing a disorder (compared to general population) as a function of relatedness (from Table 63-2, Kandel)

9. Monoamine hypothesis of Mood Disorders Reserpine is an indole alkaloid isolated from the plant Indian snakeroot It inhibits monoamine vesicular transport and depletes monoamines from synaptic vesicles in presynaptic terminal Patients given reserpine for high blood pressure frequently experienced depression as a side effect Two early antidepressants, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants also increase serotonin (5-HT) and norepinepherine (NE) in synapse Effects of these drugs suggest a role for 5-HT and NE in depression 8 Chemical structure of reserpine Indole

10. Serotonergic neurons localized in Raphe nuclei Midbrain Raphe nuclei Feldman et al., Principles of Neuropsychopharmacology, ©Sinauer Associates, 1997 Rostral System Caudal System ~ 15 serotonin receptor genes, one serotonin transporter gene 9

11. Two Serotonergic Fiber Types in the Forebrain Demonstrated by Immunocytochemical Labeling for Serotonin D-System - small arrows M-System - large arrows 10 µm from Tork, Ann. N.Y. Acad. Sci., 1990 10

12. SSRIs bind to, and stabilize, intermediate state(s) of the serotonin transporter. Cao, Li, Mager, Lester. J Neurosci 1997 11

13. Noradrenergic neurons localized in locus coeruleus Locus coeruleus from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997 12

14. “ The mood-elevating effects of fluoxetine [Prozac] are not evident after initial exposure to the drug but require its continued use for several weeks. This delayed effect suggests that it is not the inhibition of serotonin transporters per se, but some adaptation to sustained increases in serotonin function that mediates the clinical actions of fluoxetine. However, where these adaptations occur in the brain, and the nature of the adaptations at the molecular level, have yet to be identified with certainty.” SSRI’s help ~ 50% of major depressive disorder patients From S. E. Hyman, E. Nestler, R. Malenka, 2008 Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition Primary objection to monoamine hypothesis 13

15. Berton et al. Nature Reviews Neuroscience 7, 137–151 (February 2006) Glucocorticoid Hypothesis of Mood Disorders Postulates that sustained release of glucocorticoid stress hormones such as cortisol causes depression In response to stress, hypothalamic neurons (PVN) release corticotropin-releasing factor (CRF) CRF triggers adrenocorticotropic hormone (ACTH) release from anterior pituitary (Pit) ACTH stimulates release of glucocorticoid stress hormones from adrenal cortex Cortisol feeds back to hypothalamic neurons to shut off CRF release Failure of cortisol to suppress CRF release causes depression

16. Neurotrophic Hypothesis of Mood Disorders From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 Role of Brain-derived Neurotrophic Factor (BDNF) in depression Low BDNF reduces dendritic branches and spines in hippocampus and prefrontal cortex Loss of spines and branches in these areas causes depression possibly by deregulating stress response Antidepressant treatments prevent stress-induced reduction in BDNF and neuronal atrophy. Antidepressants ameliorate structural effects of depression. 15

17. 16 Samuels & Hen, Eur J. Neurosci, 2011 Some antidepressants enhance adult neurogenesis

18. Neurogenesis in the SGV In adult animals, new neurons are formed continuously from progenitor cells located in the subgranular zone (SGV) Those neurons differentiate and become incorporated into neuronal circuits in the dentate gyrus Warner-Schmidt and Duman (2006) Hippocampus 16: 239 17

19. 18 Acute low-dose ketamine produces antidepressant effects within 2 hr How? Monteggia & Duman groups suggest... (1) involve BDNF synthesis & release, (2) occur in the dendrites, (3) require protein synthesis, (4) do not require gene activation. The effects NMDA Receptor kinases↓ BDNF secretion BDNF mRNA BDNF↑ Dendritic Golgi Outside-in Ca 2+ + Decreased Ca 2+ flux Dendritic ER

20. 19 Pharmacological treatment of bipolar disorder Drugs for BD Li + ion Therapeutic effects begin in ~ 5 d, require several wk. Li + is toxic at higher doses Antidepressants are typically not used to treat bipolar patients because they can cause manic episodes. Valproic acid and other anticonvulsants Also require several wk for full effects.

21. 20 1. We don’t know, but there are now some good guesses. 2.All ideas about Li + assume an intracellular target. Li + enters cells freely through several channels and ion-coupled transporters that normally serve for Na +. Intracellular concentrations of Li + are probably several mM. 3.Most ideas about Li + involve enzyme inhibition. Most of the suspected enzymes manipulate high-energy phosphate bonds, and Li + would compete for Na + binding sites. How does Li + act? Three exemplar patients in the early days of Li +

22. 21 Bi / CNS 150 End of Lecture 26 Bruce Cohen’s office hours today 1:15 – 2 PM, 328 Kerckhoff