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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