Download 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
– 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
