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Psychobiology of Mood Disorders
Biological – Genetic Factors
Psychological Factors
Environmental Factors
Psychobiology of Affective Disorders:
Major Theoretical Approaches
1. Monoamine theories
- Catecholamine hypothesis
- Indoleamine hypothesis
- Role of dopamine
2. Genetics
- Theoretical background
- Gene environment interaction
- Genome wide association studies
3. Neurohormonal theories
- Cortisol, CRF
- Neurokinins (substance P)
4. Neuroplasticity, Neural Atrophy and Neurogenesis
5. Psychosocial factors:
- Life events / environmental stress
- Personality / psychodynamic factors
- Cognitive theory / learned helplessness
Monoamine Theories
SEVERAL BRAIN AREAS involved in mood and other functions commonly
disturbed in depressed individuals--such as appetite, sleep, sexual desire
and memory--are highlighted. Except for the pituitary, all are broadly
considered to be part of the so-called limbic system, and all normally receive
signals from neurons that secrete serotonin or norepinephrine or from
neurons of both types. Reductions in the activity of circuits that use
serotonin and norepinephrine apparently contribute to depression in many
people. Some serotonin pathways (arrows) are indicated. Norepinephrineproducing cells project from the locus coeruleus.
Biological Factors: Other Neurotransmitters
•
•
•
•
Achetylcholine (Ach)
Gama-aminobutiric acid (GABA)
Glutamate
Glycine
Dopaminergic Pathways in the CNS
Neuroplasticity and Mood Disorders
Neuroplasticity
“Subsumes diverse processes of vital importance whereby the [adult] brain
perceives, adapts to and responds to a variety of external and internal stimuli.”
Manji et al., (Mol. Psychiatry 5:578-593; 2000.)
Manifestations of neuroplasticity:
- Alterations of dendritic function
- Synaptic remodeling
- Long term potentiation
- Axonal sprouting
- Neurite extension
- Neurogenesis
Neuroplasticity and mood disorder
Mood disorders may be the result of an inability to make the appropriate adaptive
responses to stress and other aversive stimuli. Mood stabilizing and
antidepressant treatments may act by facilitating or inducing the appropriate
response (After Duman et al., 1999).
Glucocorticoids and Hippocampal Atrophy
in Mood Disorders
Glucocorticoids (GC) promote acute adaptive responses to stress.
Chronic, excess GC secretion has deleterious effects in a number of systems:
Adverse effects of GC on hippocampus in animals
- Atrophy of dendritic processes
- Inhibition of adult neurogenesis
- Neurotoxic effects
Hippocampal atrophy in neuropsychiatric disorders
[Volumetric MRI scans]
- Cushing’s syndrome
- Depression
- Post-traumatic stress disorder
Loss of neurons and of glial cells observed in post-mortem prefrontal cortex.
Dentate gyrus--a region shaped like a backward C--lies in the lower, middle area
of the hippocampus (left). Neurogenesis (right) in this region begins when a
progenitor cell (green and red) proliferates to produce progeny, which migrate
outward and differentiate into neurons. These newly born cells send their
dendrites outward, whereas their cell processes go inward and follow paths to
other structures within the hippocampus, such as the CA3 cell fields.
In rat, hippocampal neuron (left) atrophies under repeated stress (shown at
right).
Hippocampus (indicated with arrows) in patient with high cortisol level (right) is
smaller than in patient with low cortisol level.
Neuroplasticity and Mood Disorders:
Effects of Antidepressants, ECT and Mood Stabilizers
Antidepressants
- Increase 5-HT and NA transmission
- Activate cAMP second messenger pathways
- Activate Ca+ dependent kinases
- Increase production of cAMP response element binding protein (CREB)
- Increase BDNF (brain derived neurotrophic factor)
gene expression
ECT
- Similar pattern of effects observed
- Increased sprouting of granule neurons in the hippocampus - mediated by BDNF.
- Increased neurogenesis
Lithium\Valproate
Neuroprotective effects by
- Increasing bcl-2, an anti-apoptotic protein.
- Li inhibits GSK-3b
Hippocampus
Stress
Depression
Neurogenesis
Environment
Antidepressants
Hippocampus
Neurogenesis
The rate of neurogenesis can be evaluated
by two immunohitochemical methods:
• Quantification of proliferating cells
• Quantification of newly formed neurons cell markers
Stress, Depression & Hippocampal Cell Loss
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in
recurrent major depression.
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3908-13
Stress, Depression & Hippocampal Cell Loss
Environmental Factors Increase Adult Neurogenesis
•
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice
living in an enriched environment.
Nature. 1997 Apr 3;386(6624):493-5
Antidepressant Treatment
Increases Adult Neurogenesis
•
Vaidya VA, Siuciak JA, Du F, Duman RS. Hippocampal mossy fiber sprouting
induced by chronic electroconvulsive seizures. Neuroscience. 1999
Mar;89(1):157-66
Antidepressant Treatment
Increases Adult Neurogenesis
MAOI
ECS
•
SSRI
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment
increases neurogenesis in adult rat hippocampus.
J Neurosci. 2000 Dec 15;20(24):9104-10
Requirement of Neurogenesis forAntidepressant
Effect of Fluoxetine
Santarelli L et al. Requirement of hippocampal neurogenesis for the behavioral effects of
antidepressants. Science. 2003 Aug 8;301(5634):805-9
Biological Factors:
Alterations of Hormonal Regulation
• Elevated HPA (hypothalamic-pituitary
adrenal) activity
• Thyroid axis activity
• Possible role of CRH antagonists and thyroid
hormones in the treatment of depression
Biological Factors:
Alterations of Sleep Neurophysiology
• Loss of deep
sleep
• Increased
nocturnal
arousal
• Shortened
REM latency
Biological Factors:
Possible Role of the Immune System
• Over activation of the proinflammatory
cytokine system
• Combined anti-inflammatory /
antidepressant treatment
Biological Factors:
Structural & Functional Brain Imaging
• CT & MRI: hyperintensities in subcortical
regions (periventricular, basal ganglia,
thalamus), ventricular enlargment, cortical
atrophy, sulcal widening, reduced
hippocampal / caudate nucleus volume
• PET: decreased anterior brain metabolism
(L>R), normalization by AD treatment
increased glucose metabolism in limbic
regions
The above images demonstrate a comparison of a clinically
depressed patient (right) compared to a matched control (left).
In the color scheme, blue represents less activity (glucose
metabolism) while red represents more (glucose metabolism).
Note the relative hypoactivity of the cortex on the right with
marked hypoactivity of the Prefrontal, Frontal and deeper
Basal Ganglia.
Genetic Factors
Family studies:
* MDD:
one parent – child risk 10-25%
two parents – child risk 20-50%
more relatives – higher risk
* Bipolar: – higher risk of BP & UP
Twin studies:
MDD concordance rate: MZ – 60%, DZ – 40%
BPD concordance rate: MZ – 70%, DZ – 20%
Adoption studies:
Bipolar biological relatives – X 3 UP, X 6 BP
MZ-DZ Twin Concordance Rates in
Depression and Bipolar Disorder
Genetic Factors
• Gene Identification:
- Linkage studies suggest loci on chromosome 18q and
20q and others
- No widely replicable findings in genome wide
association studies as yet
- Possible overlap between BPD and schizophrenia
susceptibility genes
Psychosocial Factors
- Personality / psychodynamic factors
- Life events / environmental stress
- Cognitive theory / learned helplessness
Rates of Early Parental Loss in Psychiatric
Patients and Matched Normal Controls
40
35
Percent
30
25
20
15
10
5
0
UP
“...it is evident that melancholia may be the
reaction to the loss of a loved object.”
S. Freud
Mourning and Melancholia
1917
Agid et al, Molecular Psychiatry, 1999
BP
SCZ
“…Processes of mourning occurring in
early years are more apt to take a
pathological course and leave the
individual prone to respond to further loss
in a similar way.”
John Bowlby, 1961
Adult Psychiatric Disorders Predicted by
Behavioral Observations at Age 3 Years
15
12
%
9
Well Adj
Undercon
Inhib
6
3
0
Alcohol
Suic Att
Antisoc
Pers
Undercontrolled children at increased risk for:
- Alcohol Dependence
(OR=2.2; p<.05)
- Suicide Attempts
(OR=16.8; p<.01)
- Antisocial Personality
(OR=2.9; p<.05)
Inhibited children at increased risk for:
- Suicide Attempts
(OR=6.5; p<.05)
Caspi et al, Arch Gen Psychiatry, 1996