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AFFECTIVE DISORDERS UNIPOLAR DISORDER ~ – Major Depression BIPOLAR DISORDER ~ – Depression and Mania SYMPTOMS OF DEPRESSION ANHEDONIA ~ lack of pleasure Feelings of WORTHLESSNESS PSYCHOMOTOR RETARDATION Loss of ENERGY (FATIGUE) VEGETATIVE SYMPTOMS – appetite disturbances – weight gain/loss – sleep disturbances SYMPTOMS OF DEPRESSION MELANCHOLIA ANXIETY DELUSIONS/HALLUCINATIONS UNIPOLAR DISORDER ~ Major Depressive Disorder Endogenous - usual onset in mid 20’s-30’s 50% will have another episode Most untreated episodes last from 6-24 months Treatment more effective in early stages of an episode Women are 2-3 times more likely to suffer than men UNIPOLAR DISORDER ~ Major Depressive Disorder Afflicts 13-20% of American population at any one time 80% of all suicide victims are profoundly depressed A number of subtypes exist: UNIPOLAR DEPRESSION ~ Subtypes PSYCHOTIC MELANCHOLIC ATYPICAL SEASONAL AFFECTIVE DISORDER POSTPARTUM ONSET UNIPOLAR DEPRESSION ~ Subtypes PSYCHOTIC – delusions and hallucinations are present – 15 % of all depressives fall into this subtype MELANCHOLIC ATYPICAL SEASONAL AFFECTIVE DISORDER POSTPARTUM ONSET UNIPOLAR DEPRESSION ~ Subtypes MELANCHOLIC – – – – Psychomotor retardation Lack of pleasure Worse in a.m. Early morning wakenings ATYPICAL SEASONAL AFFECTIVE DISORDER POSTPARTUM ONSET UNIPOLAR DEPRESSION ~ Subtypes ATYPICAL – Overeat, oversleep – weight gain – marked anxiety – difficulty falling asleep – heaviness in arms and legs SEASONAL AFFECTIVE DISORDER POSTPARTUM ONSET UNIPOLAR DEPRESSION ~ Subtypes SEASONAL AFFECTIVE DISORDER – Regular temporal relationship with time of year – related to sunlight POSTPARTUM ONSET UNIPOLAR DEPRESSION ~ Subtypes POSTPARTUM ONSET – 50-80% of women experience some depressive symptoms within 1-5 days of delivery – related to changes in hormones but not sure – can be mild or severe BIPOLAR DISORDER Episodes of depression and mania/hypomania are equally frequent Mean age of onset = early 20’s Untreated MANIC episode is 6 months Depressive episode is 8-10 months 10-15% of untreated commit suicide ~ 15-20 times the rate among the general population BIPOLAR DISORDER Affects men and women equally 2.0 million Americans suffer from BIPOLAR disorder TREATMENTS Unipolar Depression Psychotherapy Monoamine Oxidase (MOA) inhibitors Tricyclic Antidepressants Selective Serotonin Reuptake Inhibitors (SSRI’s) Electroconvulsive Shock Therapy (ECT) Lithium TREATMENT Bipolar Depression Lithium BIOLOGICAL BASIS OF AFFECTIVE DISORDERS Genetics - Concordance rate among twins Monozygotic(identical) twins = 60% dizygotic twins(fraternal) = 15% Pharmacology - Drugs Concordance Rate 100 sets of twins with one twin diagnosed with depression 48 sets in which both diagnosed with depression Concordance Rate = 48% BIOLOGICAL BASIS OF AFFECTIVE DISORDERS Pharmacology - Drugs How do these drugs work? Monoamine Oxidase (MAO)Inhibitors IPRONIAZID, PARGYLINE MAO = ENZYME located in terminal boutons Found in NOREPINEPHRINE and SEROTONINcontaining neurons Degrades excess neurotransmitter MAO inhibition Transmitter availability for storage/release How do these drugs work? TRICYCLIC ANTIDEPRESSANTS IMIPRAMINE (TOFRANIL™), DESIPRAMINE Block re-uptake of NOREPINEPHRINE and SEROTONIN (MONAMINES) More transmitter available in synapse How do these drugs work? SSRI’s Fluoxetine (PROZAC™) SELECTIVE SEROTONIN REUPTAKE INHIBITORS Kramer ~ “Listening to Prozac” “You take Prozac to treat a symptom, and it transforms your sense of self. The pill seems to give social confidence to habitually timid, to make the sensitive brash, to lend the introvert the social skills of a salesman” THE MONAMINE THEORY OF DEPRESSION Insufficient activity of monoamine neurons, particularly, NOREPINEPHRINE and SEROTONIN neurons. THE MONAMINE THEORY OF DEPRESSION BIG PROBLEM w/ THEORY THE TIME-LAG FACTOR TAKES 2-3 HOURS FOR DRUGS TO EXERT EFFECTS ON SYNAPSE BUT… IT TAKES 2-3 WEEKS FOR DRUGS TO EXERT EFFECTS ON DEPRESSION! THE MONAMINE THEORY OF DEPRESSION Why the time lag? THE MONAMINE THEORY OF DEPRESSION EFFECTS OF PROZAC: INCREASE 5-HT at terminal bouton (the desired THERAPEUTIC effect), but also… INCREASE inhibition at dendritic autoreceptors. Dendritic Release of Serotonin dendritic autoreceptors 5-HT neuron 5-HT released when cell is active. Binds to autoreceptors to inhibit activity Prozac increases 5-HT inhibitory effect by blocking 5-HT dendritic re-uptake At the Serotonin Terminal Bouton Less release of 5-HT at bouton due to Prozacinduced inhibition at dendritic autoreceptor With less release Prozac has less of an effect at terminal bouton little therapeutic effect Over time (2-3 weeks)... Inhibition of SEROTONIN neurons by autoreceptors subsides (receptor desensitization to excess serotonin) Activity of neurons increase Increased 5-HT at terminal bouton synapse Prozac can now work to increase 5-HT at terminal bouton synapse Therapeutic Effect QUESTION: Why don’t terminal bouton postsynaptic receptors become desensitized like autoreceptors? ANSWER: They are a different type of receptor than the dendritic receptors 5-HT1a dendritic receptors: desensitize over time 5-HT neuron post-synaptic receptors 5-HT2a, 5-HT3 receptors: no desensitization CRITICAL EXPERIMENT TO TEST THIS HYPOTHESIS: Administer PROZAC PLUS dendritic autoreceptor antagonist (PINDOL) RESULTS: Reduction of depressive symptoms within ONE WEEK! Is There Direct Evidence for Deficient Serotonin Function in Depression? Dietary Depletion of Serotonin and Depression Serotonin Synthesis tryptophan (amino acid) 5–hydroxytryptophan 5–hydroxytryptamine (Serotonin) Delgado et al. (1990) Depressed patients Antidepressant drugs(2-3 weeks) Feeling well Low tryptophan diet for 24 hours - Amino acid “cocktail” 1. contained no tryptophan 2. promotes protein synthesis 3. causes further depletion of tryptophan Delgado et al. – cont. RESULTS - Rapid serotonin depletion - Rapid onset of depression (within hours) - Return to normal diet depression subsides within 24 hours Smith et al. (1997) 15 women with history of recurrent depression - in remission - drug free Two Trials Trial 1 - Tryptophan-free amino acid cocktail Trial 2 (one week later) - Tryptophan-containing amino acid cocktail Smith et al. (1997)- cont. Rate mood hourly for next 7 hrs. Blood samples to determine tryptophan levels RESULTS: - 75% reduction in tryptophan with tryptophanfree cocktail - Tryptophan-free trial 10 of 15 women experienced temporary, significant depression - Tryptophan-containing trial no mood changes Conclude: A key role for deficient serotonin function as a cause for depression Hormonal Abnormalities in Depression Dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis Many depressives have an overactive HPA axis - high cortisol levels - enlarged adrenals - enlarged pituitary gland - high CRF concentrations in cerebrospinal fluid - enhanced expression of CRF gene CRF = Corticotropin Releasing Factor CRF-containing neurons in several brain areas -hypothalamic paraventricular nucleus, amygdala Intracerebroventricular CRF injections in rats Behaviors similar to depression in humans - insomnia - decreased appetite - decreased sexual drive - anxiety Nemeroff et al. 1996 The Stress-diathesis Model of Depression The interaction between experience(stress) and inborn predisposition (diathesis) Genetic Predisposition for Depression Genetic traits lower threshold for depression - diminish monoamine levels - increase reactivity of HPA axis to stress EXAMPLE: stress (e.g., early childhood abuse/neglect) persistent increase in sensitivity of CRF-containing neurons to stress in predisposed individuals In adulthood -persistent increase in sensitivity of CRF neurons -mild stressors vigorous activation of CRF neurons Symptoms of Depression What’s the evidence for the model? Primates - Rosenblum et al. (1994, 1996) Rats – Ladd et al. (1996) Rosenblum et al. (1994, 1996) Stress in infant monkeys Foraging demand paradigm Three conditions for mothers Low foraging demand condition (LFD) - minimal search for food in foraging device Variable foraging demand condition (VFD) - unpredictable access to food - required search for food in foraging device - 3 mos. duration during first 3-6 mos. of infant life High foraging demand condition (HFD) - considerable work effort for food, but predictable Rosenblum et al.-cont. Effect on mothers’ behavior: VFD mothers - more anxiety behaviors than LFD and HFD mothers - less responsive to infants than LFD and HFD mothers Effect on infants’ behavior: VFD infants - first year - less independent of their mothers than LFD and HFD - more frightened by novelty than LFD and HFDs VFD infants > four years later (young adults) - more timid - less social - more subordinate Rosenblum et al. – cont. CSF CRF determined at 2 years of age Results: CRF concentrations - VFD infants 110 pg/ml - LFD infants 77 pg/ml - HFD infants 82 pg/ml Conclude: Early-Life stressors sensitivity of CRF neurons Depression Mild Stress in Adulthood Ladd et al.(1996) Neonatal rats Separated from mothers vs. controls (not separated) - 6 hours daily - Days 2-20 of life Measure ACTH and CRF concentrations at 3 months of age (young adult rat) - basal and stress levels Four groups: 1. Non-deprived/no stress 2. Non-deprived/stress 3. Deprived/no stress 4. Deprived/stress Ladd et al. (1996) RESULTS: Deprived rats - higher basal and stress ACTH levels - higher basal and stress CRF concentrations in two areas 1. median eminence – receives paraventricular nucleus CRF projections 2. parabrachial nucleus –receives amygdala CRF projections Ladd et al. (1996) CONCLUDE: Early Stress (maternal deprivation) Persistent increase in sensitivity of CRF neurons into adulthood Chronic mild stress Depression Does early trauma in humans predispose to depression in adulthood? Agid et al. (1999) Early trauma before the 17th year - death of a parent - physical separation from one parent Groups - unipolar depressive disorder (n=79) - bipolar disorder (n=79) - control groups (ns=79) Agid et al. (1999) – cont. RESULTS: -Rates of parental loss Unipolar disorder 23/79 Control group 6/79 29.1% 7.6% Bipolar disorder 14/79 17.7% Control Group 6/79 7.6% -Separation more devastating than death -Greater impact of loss in early childhood(<9 yrs) Agid et al. - cont. Control groups those who experienced EPL demonstrated 1. lower incomes 2. more physical illness 3. greater divorce rate 4. more likely to be living alone 5. stronger lifetime history of smoking Can Enhanced Maternal Care Decrease CRF Response Sensitivity to Stress? Liu et al. (1997) Neonatal handling changes in mother-pup (first 10 days) interactions - increased licking and grooming by mother - higher incidence of arched-back nursing (ABN) Pup handling reduces HPA response to stress in adulthood (Less ACTH and GC response) Liu et al. – cont. Observed behavior of mothers of non-handled pups Divide mothers into two groups - High groomers - Low groomers Measured HPA axis sensitivity in pups as adults RESULTS: 1. Decreased HPA stress response in high groomed pups 2. Decreased CRF synthesis in paraventricular nucleus in high groomed pups Stress-induced Depression in Adulthood Human -Stressful events can precede depression a. Inability to predict b. Inability to control Animal Models Uncontrollable Stressful Events Depression-like characteristics A Potential Brain Circuit for Depression Acute fear/anxiety provoking stimulus (bear) activates the amygdala CRF hypothalamic other brain paraventricular n. areas activate the HPA axis acute anxiety Prolonged, Uncontrollable Stress in Adulthood Persistent amygdala activity CRF persistent in CRF release in hypothal. paraventricular nucleus persistent in CRF release in other brain regions hyperactive HPA axis chronic anxiety increased GC levels depression Is there evidence of increased activity in the amygdala during depression? Drevets et al. (1992 ff.). A functional anatomical study of unipolar depression. Drevets et al. Melancholic depressives with a family history of depression (familial depressive disorder) Melancholic depressives in remission Matched control group PET scan at rest to assess metabolic activity RESULTS: - enhanced amygdala activity in depressed patients - some increase in remission group - the greater the depression the greater the amygdala activity Drevets et al. – cont. In depressives, the greater the amygdala activity, the greater the cortisol level Antidepressive drugs decrease depression and amygdala activity toward normal Tryptophan-free cocktail to depressive patients in remission - those who relapse had higher amygdala activity during remission CONCLUDE: Amygdala may contribute to symptoms of, and vulnerability to, depression