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AFFECTIVE DISORDERS

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

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AFFECTIVE DISORDERS

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  1. AFFECTIVE DISORDERS • UNIPOLAR DISORDER ~ • Major Depression • BIPOLAR DISORDER ~ • Depression and Mania

  2. 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

  3. SYMPTOMS OF DEPRESSION • MELANCHOLIA • ANXIETY • DELUSIONS/HALLUCINATIONS

  4. 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

  5. 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:

  6. UNIPOLAR DEPRESSION ~ Subtypes • PSYCHOTIC • MELANCHOLIC • ATYPICAL • SEASONAL AFFECTIVE DISORDER • POSTPARTUM ONSET

  7. UNIPOLAR DEPRESSION ~ Subtypes • PSYCHOTIC • delusions and hallucinations are present • 15 % of all depressives fall into this subtype • MELANCHOLIC • ATYPICAL • SEASONAL AFFECTIVE DISORDER • POSTPARTUM ONSET

  8. UNIPOLAR DEPRESSION ~ Subtypes • MELANCHOLIC • Psychomotor retardation • Lack of pleasure • Worse in a.m. • Early morning wakenings • ATYPICAL • SEASONAL AFFECTIVE DISORDER • POSTPARTUM ONSET

  9. UNIPOLAR DEPRESSION ~ Subtypes • ATYPICAL • Overeat, oversleep • weight gain • marked anxiety • difficulty falling asleep • heaviness in arms and legs • SEASONAL AFFECTIVE DISORDER • POSTPARTUM ONSET

  10. UNIPOLAR DEPRESSION ~ Subtypes • SEASONAL AFFECTIVE DISORDER • Regular temporal relationship with time of year • related to sunlight • POSTPARTUM ONSET

  11. 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

  12. 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

  13. BIPOLAR DISORDER • Affects men and women equally • 2.0 million Americans suffer from BIPOLAR disorder

  14. TREATMENTSUnipolar Depression • Psychotherapy • Monoamine Oxidase (MOA) inhibitors • Tricyclic Antidepressants • Selective Serotonin Reuptake Inhibitors (SSRI’s) • Electroconvulsive Shock Therapy (ECT) • Lithium

  15. TREATMENTBipolar Depression • Lithium

  16. BIOLOGICAL BASIS OF AFFECTIVE DISORDERS Genetics - Concordance rate among twins • Monozygotic(identical) twins = 60% • dizygotic twins(fraternal) = 15% Pharmacology - Drugs

  17. Concordance Rate • 100 sets of twins with one twin diagnosed with depression • 48 sets in which both diagnosed with depression • Concordance Rate = 48%

  18. BIOLOGICAL BASIS OF AFFECTIVE DISORDERS • Pharmacology - Drugs

  19. How do these drugs work? Monoamine Oxidase (MAO)Inhibitors • IPRONIAZID, PARGYLINE • MAO = ENZYME located in terminal boutons • Found in NOREPINEPHRINE and SEROTONIN-containing neurons • Degrades excess neurotransmitter • MAO inhibition Transmitter availability for storage/release

  20. How do these drugs work?TRICYCLIC ANTIDEPRESSANTS • IMIPRAMINE (TOFRANIL™), DESIPRAMINE • Block re-uptake of NOREPINEPHRINE and SEROTONIN (MONAMINES) • More transmitter available in synapse

  21. 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”

  22. THE MONAMINE THEORY OF DEPRESSION Insufficient activity of monoamine neurons, particularly, NOREPINEPHRINE and SEROTONIN neurons.

  23. 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!

  24. THE MONAMINE THEORY OF DEPRESSION Why the time lag?

  25. 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.

  26. Dendritic Release of Serotonin dendritic autoreceptors 5-HT released when cell is active. Binds to auto- receptors to inhibit activity 5-HT neuron Prozac increases 5-HT inhibitory effect by blocking 5-HT dendritic re-uptake

  27. At the Serotonin Terminal Bouton • Less release of 5-HT at bouton due to Prozac-induced inhibition at dendritic autoreceptor • With less release Prozac has less of an effect at terminal bouton little therapeutic effect

  28. 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

  29. QUESTION: Why don’t terminal bouton postsynaptic receptors become desensitized like autoreceptors? ANSWER: They are a different type of receptor than the dendritic receptors

  30. 5-HT1a dendritic receptors: desensi- tize over time 5-HT neuron post-synaptic receptors 5-HT2a, 5-HT3 receptors: no desensitization

  31. CRITICAL EXPERIMENT TO TEST THIS HYPOTHESIS: • Administer PROZAC PLUS dendritic autoreceptor antagonist (PINDOL) • RESULTS: Reduction of depressive symptoms within ONE WEEK!

  32. Is There Direct Evidence for Deficient Serotonin Function in Depression?

  33. Dietary Depletion of Serotonin and Depression Serotonin Synthesis tryptophan (amino acid) 5–hydroxytryptophan 5–hydroxytryptamine (Serotonin)

  34. Delgado etal. (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

  35. Delgado etal. – cont. • RESULTS - Rapid serotonin depletion - Rapid onset of depression (within hours) - Return to normal diet depression subsides within 24 hours

  36. Smith etal. (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

  37. Smith etal. (1997)- cont. • Rate mood hourly for next 7 hrs. • Blood samples to determine tryptophan levels • RESULTS: - 75% reduction in tryptophan with tryptophan- free 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

  38. Hormonal Abnormalities in Depression • Dysregulation of the hypothalamic-pituitary-adrenal (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

  39. 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

  40. Nemeroff etal. 1996 The Stress-diathesis Model of Depression The interaction between experience(stress) and inborn predisposition (diathesis)

  41. 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

  42. In adulthood -persistent increase in sensitivity of CRF neurons -mild stressors vigorous activation of CRF neurons Symptoms of Depression

  43. What’s the evidence for the model? • Primates - Rosenblum etal. (1994, 1996) • Rats – Ladd etal. (1996)

  44. Rosenblum etal. (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

  45. Rosenblum etal.-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

  46. Rosenblum etal. – 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

  47. Ladd etal.(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

  48. Ladd etal. (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

  49. Ladd etal. (1996) • CONCLUDE: Early Stress (maternal deprivation) Persistent increase in sensitivity of CRF neurons into adulthood Depression Chronic mild stress

  50. Does early trauma in humans predispose to depression in adulthood?

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