Transcript Etiology and Pathogenesis of Depressive Disorders

Chapter 4
Etiology and Pathogenesis of Depressive
Disorders
Copyright © 2011. World Psychiatric Association
Overview
Depression is a heterogeneous disorder with complex and mutifactorial
factors ranging from genes to environment.
Many hypotheses have been advanced about the etiology and
pathogenesis of depressive disorders.
The overview that follows summarizes the findings about the role of
genetic, and neurochemical factors, and brain imaging studies.
In addition, psychosocial factors, premorbid personality, in the
occurrence and course of depressive disorders are explained.
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Genetics of Depression-1
• Family, twin, and adoption studies provide ample evidence of the
importance of genetic and familial factors in the development of mood
disorders.
• Comparisons of the within-pair correlations for the two sets of twins
will result in rough estimates of the variance due to genes (a), shared
environment (c) and unique environment (e) (Kendler et al 1987;
Kendler & Prescott 1999; Thapar & McGuffin 1998).
• These studies all show the same thing: shared family environment
has no contribution whatever, genetic factors account for around 40%
of the variance, and environment unique to the individual accounts for
a large part of the rest.
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Genetics of Depression-2
• However, the genes that control depression are almost the same as
those that control anxiety (Kendler et al 1987). About half of this
genetic variance is associated with “neuroticism” measured in adult
life (Kendler et al, 1993).
• Linkage studies seek candidate genes for depression, which include
serotonin and dopamine receptor genes, G protein, and CREB gene
(Taylor and Fink, 2006), but the results are not yet conclusive
(Levinson, 2006).
• More recent studies on candidate genes have focused on the genes
involved in the neurotrophic and neurotoxic processes, inflammation,
the regulation of the HPA axis, sleep and circadian rhythms.
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Gene-Environment Interactions: the
serotonin transport gene
• It can both be long, both short, or heterozygous. This gene appears
to modulate the serotonergic response to stressful events.
• In a cohort study of children born in Dunedin, New Zealand, Caspi
and his colleagues (2003) have shown that those with the
homozygous long version (31% of this population) are relatively
resilient in that they tend not to develop depression even when they
have experienced several stressful events.
• This results were well replicated by many other studies.
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major depression episode（％）
Correlation b/w Stress and 5-HTT Genotype
Caspi et al., Science 2003
40
35
30
25
20
15
10
5
0
0
n=184
s genotype
(n = 581)
１
138
２
104
３
64
stress
４＋
91
ｌ genotype
40
35
30
25
20
15
10
5
0
0
n=79
(n = 264)
１
73
２
57
３
26
４＋
29
stress
• Heterozygous people (51%) are more likely to become depressed if they
experience events, while those who are homozygous short (17%) have a very
strong relationship.
• Without stress, the gene does not manifest itself, but in the presence of stress
one’s genetic make-up will determine how likely you are to become depressed.
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Neurochemical Hypotheses
• Psychoactive drugs have provided researchers with powerful tools for
studying the biochemical basis of behavior.
• One hypothesis based primarily on pharmacologic data is that a
disturbance in biogenic amine metabolism is the predisposing factor
in mood disorders.
• In its simplest form, “the monoamine hypothesis” postulates that
depressive disorders are associated with a relative deficit of one or
more of the biogenic amines, while mania is linked to a relative
excess.
• It is now considered that a diversity in the pathophysiology underlying
depressive disorders may exist, thus suggesting that there may be no
single common mechanism for antidepressants.
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Hippocampal Dysfunction and
Neuroendocrine Dysregulation
• A more consistent finding in depression is the
hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis, which is revealed by the
dexamethasone suppression test (DST)
Hypothalamus
(Carroll et al, 1982).
• A major drawback of the DST has been
reported to be its modest sensitivity to
depression.
Hippocampus
• Subsequently, a more accurate test was
introduced by which DST was combined with
a CRF challenge (Holsboer et al, 1987).
• Depressed patients displayed higher ACTH
and cortisol responses to CRF when
pretreated with dexamethasone.
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CRF
-
+
Pituitary
Amygdala
ACTH
Glucocorticoids
Dexamethasone
Adrenal
cortex
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Hippocampal Neurogenesis is Associated
with Depressive State
Granular
Cell
Layer
SGZ
Hilus
• An exciting finding that the birth of new neurons, namely “neurogenesis”, occurs in the hippocampus
throughout the lifespan (Eriksson et al, 1998) has changed the way we think about the pathogenesis
of psychiatric disorders.
• Many studies have indicated that antidepressants and ECT increase neurogenesis (Malberg, 2004).
• While acute and chronic stressors produce a down-regulation of neurogenesis, antidepressants can
reverse the stress-induced down-regulation of neurogenesis.
• One way in which antidepressants may produce neurogenic effects is by increasing neurotrophic
factors such as brain-derived neurotrophic factor (BDNF).
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BDNF, Depression, Antidepressants
• BDNF is downregulated in MDD
and increased with
antidepressant treatment
• BDNF has a hypothetical
neurotrophic effect that
influences regulation of mood
and perception of pain in clinical
and animal studies
• 5-HT and/or NE are believed to
play roles in the modulation of
BDNF
• Increase in BDNF promotes
neuroplasticity, neurogenesis,
and neuroprotection (cellular
resilience)
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Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Brain Imaging of Depression
Brain Atrophy in Depression?
• Coinciding to these basic mechanisms of antidepressants, imaging
studies carried out in chronically depressed patients have reported a
reduction in the hippocampal volume and the cortex (Sheline et al,
1996; Botteron et al, 2002), thus indicating that the change in the
hippocampal volume and/or the cortex may be caused by depression.
• Furthermore, antidepressant treatment can reverse the depressioninduced decreases in the hippocampal volume (Vermetten et al, 2003).
• However, it is still not clear whether such changes appeared before the
onset of the disease or whether they were a direct cause of the disease.
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Brain Imaging of Depression
• In structural neuroimaging studies in depression, well replicated
findings include an increased rate of deep white matter
hyperintensities, and the smaller frontal lobe, hippocampus,
cerebellum, caudate, and putamen (Steffens and Krishnan, 1998).
• Functional imaging studies have indicated both the metabolism and
blood flow in the dorsolateral prefrontal cortex, left hippocampus are
decreased in depressed patients
• In addition, a reduction in the volume and metabolism of the
subgenual prefrontal cortex (SGPFC) has also been reported (Drevet
et al, 1997).
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Environmental Factors-2/II
The Importance Of Secure Attachment
• Maternal separation increases HPA sensitivity, as does maternal
depression.
• Severe chronic deprivations, such as being brought up in an
orphanage since birth, are also associated changes in the sensitivity
of the HPA axis - with cortisol hypersecretion frequently reported.
• In children, early parental loss from death or separation engenders
an increased risk for developing future psychiatric illnesses, such as
major depression and anxiety (Mireault and Bond, 1992).
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Environmental Factors-1/II
The Importance Of Secure Attachment
• Secure attachment to the care-giver (usually the mother) in the first few
months is of critical importance in modifying the excitability of the
hypothalamo-pituitary axis (HPA), and thus the vulnerability to later
life stress.
• Attachment theory proposes that infants develop ‘internal working
models’ of relationships that serve as a psychological blueprint for
interpersonal functions with others in childhood and later life.
• Insecure attachment produces a baby with poor social development
and more anti-social behaviour, which in the presence of negative
experiences leads on to anxious traits.
• Thus, maternal attachment is the first life experience that can modify –
in either direction – the excitability of the HPA axis.
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Premorbid Personality
• Individuals with certain personality types are at greater risk for
depressive disorders.
• An example is the hypothesized association between unipolar
depressive disorder and a trait pattern described as Shimoda’s
Shuuchaku Kishitu (Shimoda, 1941) or the melancholic type
(Tellenbach, 1961).
• This pattern includes features such as orderliness, conscientiousness,
rigidity, obsessiveness, meticulousness, placing a high value on
achievement, and dependency on close personal relationships. In
recovered patients, passivity, interpersonal dependence, and low
scores in emotional stability increase the risk of relapse (Hirschfeld et
al, 1983).
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Premorbid Personality is Genetic
• A longitudinal study performed in Zurich identified the premorbid
personality trait for unipolar disorder to be neuroticism (Clayton et al.
1994).
• There is a substantial genetic component to the experience of
stressful life events, but this is mediated by personality variables.
• About half the variation in normal personality is genetically
determined.
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Summary-1
1.Genetic study suggests that depression is multifactorial disease, and
gene-environment correlation is important, eg. 5-HTT gene
2.Neurotrophic factors (BDNF etc), neuronal damage, and
neurogenesis may be involved
3.Immunoneurological process involved
4.Antidepressant/ECT are neuroprotective
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Summary-2
5.Coincidely, volume reduction is observed in hippocampus, cortex,
basal ganglia
6.In activation study, elevation is observed in amygdala, ventolateralposterior orbital cortex. Subgenual preforontal cortex is reduced.
7.Biological bases of secure attachment
8.Biological bases of premorbid personality
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