1 Mood Disorders Bi / CNS 150 Lecture 26 Monday December 1,
2014 Bruce Cohen Kandel Chap. 63: 1402-1418
Slide 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
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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)
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Brain regions relevant to mood disorders 4
Slide 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
Slide 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-20s 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
Slide 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)
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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
Slide 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
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Two Serotonergic Fiber Types in the Forebrain Demonstrated by
Immunocytochemical Labeling for Serotonin D-System - small arrows
M-System - large arrows 10 m from Tork, Ann. N.Y. Acad. Sci., 1990
10
Slide 12
SSRIs bind to, and stabilize, intermediate state(s) of the
serotonin transporter. Cao, Li, Mager, Lester. J Neurosci 1997
11
Slide 13
Noradrenergic neurons localized in locus coeruleus Locus
coeruleus from Feldman et al., Principles of
Neuropsychopharmacology, Sinauer, 1997 12
Slide 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.
SSRIs 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
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Berton et al. Nature Reviews Neuroscience 7, 137151 (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
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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
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16 Samuels & Hen, Eur J. Neurosci, 2011 Some
antidepressants enhance adult neurogenesis
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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
Slide 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
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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.
Slide 21
20 1. We dont 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
+
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21 Bi / CNS 150 End of Lecture 26 Bruce Cohens office hours
today 1:15 2 PM, 328 Kerckhoff