Transcript No Slide Title

Mood Disorders
Bi / CNS 150
Lecture 26
Monday December 1, 2014
Bruce Cohen
Kandel Chap. 63: 1402-1418
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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,1520%)
– Bipolar disorder characterized by cyclical and exaggerated mood
swings between depression and mania that occur over a prolonged
period (prevalence, 1%)
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Depression has a significant economic impact
Disability Adjusted Life Years (DALY)
Unipolar depressive disorders
Alcohol use disorders
Schizophrenia
Iron-deficiency anemia
Bipolar affective disorder
Hearing loss, adult onset
HIV/AIDS
Chronic OPD
Data from United States, Canada and
Western Europe, 2008
15-44 year olds)
Osteoarthritis
Road traffic accidents
00
22
44
66
88
10
10
16
12
Percent of Total
Source: WHO – World Health Report
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Brain regions relevant to mood disorders
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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
Depressive episodes typically last 7-14 months and can recur throughout life
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Clinical signs of bipolar disorder (DSM-5)
•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.
Video of manic episode, University of Nottingham:
Psychiatric Interviews for Teaching: Mania - YouTube
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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
Disorder
Siblings
Identical
Twins
Bipolar
disorder
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60
Major
2-3
Depression
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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
Chemical structure of reserpine
Indole
•
Effects of these drugs suggest a role for 5-HT
and NE in depression
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Serotonergic neurons localized in Raphe nuclei
Rostral System
Midbrain Raphe nuclei
Caudal System
~ 15 serotonin receptor genes, one serotonin transporter gene
Feldman et al., Principles of Neuropsychopharmacology, ©Sinauer Associates, 1997
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Two Serotonergic Fiber Types in the Forebrain Demonstrated by
Immunocytochemical Labeling for Serotonin
10 µm
D-System - small arrows
M-System - large arrows
from Tork, Ann. N.Y. Acad. Sci., 1990
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SSRIs bind to, and stabilize, intermediate state(s) of the serotonin transporter.
Cao, Li, Mager, Lester. J Neurosci 1997
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Noradrenergic neurons localized in locus coeruleus
Locus coeruleus
from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997
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Primary objection to monoamine hypothesis
“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
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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
Berton et al. Nature Reviews Neuroscience 7, 137–151 (February 2006)
Neurotrophic Hypothesis of Mood Disorders
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.
From Berton and Nestler, Nature Reviews
Neuroscience, 7: 137, 2006
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Some antidepressants enhance adult neurogenesis
Samuels & Hen, Eur J. Neurosci, 2011
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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
Acute low-dose ketamine produces antidepressant effects within 2 hr
How?
The effects
(1) involve BDNF synthesis & release,
(3) require protein synthesis,
(2) occur in the dendrites,
(4) do not require gene activation.
Monteggia & Duman groups suggest . . .
Outside-in
NMDA Receptor
Ca2+
BDNF
secretion
Decreased
Ca2+ flux
Dendritic
Golgi
kinases↓
Dendritic
ER
BDNF↑
BDNF
mRNA
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Pharmacological treatment of bipolar disorder
Antidepressants are typically not used to treat bipolar patients because they can
cause manic episodes.
Drugs for BD
Li+ ion
Therapeutic effects begin in ~ 5 d, require several wk.
Li+ is toxic at higher doses
Valproic acid and other anticonvulsants
Also require several wk for full effects.
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Three exemplar patients in the early days of Li+
How does Li+ act?
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.
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Bruce Cohen’s office hours today 1:15 – 2 PM, 328 Kerckhoff
Bi / CNS 150
End of Lecture 26
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