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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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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). Copyright © 2011. World Psychiatric Association 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) Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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). Copyright © 2011. World Psychiatric Association 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). Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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). Copyright © 2011. World Psychiatric Association 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. Copyright © 2011. World Psychiatric Association 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 Copyright © 2011. World Psychiatric Association 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 Copyright © 2011. World Psychiatric Association