1. AFFECTIVE DISORDERS UNIPOLAR DISORDER ~ BIPOLAR 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 ~ times the rate among the general population

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

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

15. TREATMENT Bipolar 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
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 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

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

36. 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

37. Smith et al. (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 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 et al. 1996 of Depression The Stress-diathesis Model
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 et al. (1994, 1996)
Rats – Ladd et al. (1996)

44. 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

45. 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

46. Rosenblum et al. – cont. CSF CRF determined at 2 years of age
Results: CRF concentrations
- VFD infants pg/ml
- LFD infants pg/ml
- HFD infants pg/ml
Conclude:
Early-Life stressors sensitivity of
CRF neurons
Depression
Mild Stress in Adulthood

47. 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

48. 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

49. Ladd et al. (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?

51. 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)

52. Agid et al. (1999) – cont. RESULTS: -Rates of parental loss
Unipolar disorder 23/ %
Control group / %
Bipolar disorder / %
Control Group / %
-Separation more devastating than death
-Greater impact of loss in early childhood(<9 yrs)

53. 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

54. Can Enhanced Maternal Care Decrease CRF Response Sensitivity to Stress?

55. 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)

56. 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

57. 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

58. 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

59. persistent in CRF persistent in CRF
Prolonged, Uncontrollable Stress in Adulthood
Persistent amygdala activity
CRF
persistent in CRF persistent in CRF
release in hypothal release in other brain
paraventricular nucleus regions
hyperactive HPA axis chronic anxiety
increased GC levels depression

60. Is there evidence of increased activity in the amygdala during depression?
Drevets et al. (1992 ff.). A functional anatomical study of unipolar depression.

61. 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

62. 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