I.       Depression is the “common cold” of psychopathology

A.       5-20% of us will suffer a major incapacitating depression at some point in our lives.

B.        Devastating, suicidal—not just “feeling depressed”

II.    The symptoms

A.       Anhedonia—inability to feel pleasure

B.        Great grief and guilt

C.       Thought disorder: see the world in distorted, negative way:  glasses always half empty.

1.        Aaron Beck: flash 2 pictures, rapidly or simultaneously: dinner table vs. funeral.  Depressives see mostly funeral scene.

D.       Psychomotor retardation or psychomotor agitation

E.        Vegetative symptoms: decreased eating and sleeping

1.        Sleep “architecture” changes: 90-min rhythm of slow-wave sleep and REM

2.        Elevated glucocorticoids:  “tightly coiled spool of wire, tense, straining, active…”

F.        Multiple types

1.        Unipolar: fluctuates between extreme depression and near normalcy

2.        Bipolar (manic-depressive disorder)”: p. 234: woman in emergency room, on welfare, bought 3 Cadillacs, and can’t drive. 

a.       Also: irrational grandiosity, lack of sleep, vastly distractable.

b.      Rhythmic cycles

3.        SAD—seasonal affective disorder

III.   The biology of depression

       A.       Neurochemistry

1.        Norepinephrine (NE) & serotonin (5-HT, 5-hydroxytryptophan)

2.        Tricyclics—reuptake inhibitors

3.        MAO (monoamine oxidase) inhibitors

4.        SSRIs—selective serotonin reuptake inhibitors

5.        (St. John’s wort:  also inhibits reuptake of NE and 5-HT, not clear how effective it is and whether it has fewer side effects.)

6.        Problem of timing:  drugs act quickly at synapse and slowly on symptoms.

a.         Maybe there’s too much transmitter at first, and adding extra transmitter REALLY down-regulates the postsynaptic receptors.  (more than compensates)

b.         Maybe there really is too little transmitter:  drugs may down-regulate autoreceptors more than postsynaptic receptors.  (ECT decreases the number of NE autoreceptors in animals.)

7.       Why NE and 5-HT?  (good question!)

a.         NE linked to arousal and, inversely, to psychomotor retardation.

b.         5-HT linked inversely to impulsivity and obsessive-compulsive disorder

8.       Dopamine (DA)  (Olds & Milner:  “pleasure pathway”)  (Bupropion aka Wellbutrin=DA agonist)

       B.       Neuroanatomy

1.        The limbic system

2.        Cingulotomy: used on hopelessly depressed patients.  May also interfere with pleasure.  (Also affects working memory!)

C.       Endocrinology

1.        Excess glucocorticoids—feedback resistance on the dexamethasone suppression test.

2.        Hypothyroid

3.        Incidence rates:  more women than men.               

a.         Cognitive theory: Women ruminate, men exercise, get drunk, or start wars.

b.         Psychosocial theory: Women lack power and control over their lives.

c.         However, the sex difference holds only for unipolar, not bipolar, disorder.

d.         Women are at more risk during premenstrual, menopausal, and postpartum times: E to P ratio? (conversion of P to pregnanolone, which is anxiolytic—increases GABA binding)

IV.  Stress and the onset of depression

A.       Stress = trigger only for first few depressions; after that they have a rhythm of their own.

B.        Lab rats: Stress increases the threshold for pleasure stimulus.

C.       Chronic stress à dexamethasone resistance in animals and humans

1.        So can glucocorticoids.  (Cushing’s syndrome and people treated with glucocorticoids à clinical depression.

D.    Anti-glucocorticoids can in some cases be antidepressants.

1.        Maybe typical antidepressants work by normalizing glucocorticoid levels.

2.        Some, but not all, researchers find rapid regulation of glucocorticoid receptors by antidepressants.

3.        This can’t be the whole story, since half of depressed people have normal glucocorticoids levels.

V.    Stress and the psychodynamics of major depressions

A.       Freud: Major melancholic depression: simultaneous, irreconcilable nature of conflict of intense love with intense hatred.

1.        You lose both the loved individual and the chance to resolve the difficulties.

2.        This may explain the guilt.  If there were only anger, you should feel relief to get it over.  It’s aggression turned inward.

VI.  Stress, learned helplessness, and depression

A.       Learned helplessness: yoked pairs of rats: one has control, the other doesn’t. It’s the yoked animal that becomes helpless. (Martin Seligman & Steven Maier)

B.        Characteristics

1.        Can’t learn simple escape or avoidance task.

2.        Motivational problem—don’t even try.

3.        Cognitive problem—Don’t perceive that occasional random response affects the shock. (Learned not to pay attention.)

a.         In some ways similar to “spoiled brat” syndrome (“learned laziness”): Free rewards

b.         Beck:  Depression = Overgeneralizing from one awful thing: cognitive distortion

4.        Rat’s equivalent of anhedonia: stops grooming, loses interest in sex and food.

5.        Psychomotor retardation???

a.       Lack of learning sometimes also seen in passive avoidance—therefore not just motor problem.  However, Jay Weiss does not see a deficit in passive avoidance: there IS a motor problem. (Also, “overlearning” a helplessness task by daily repetition over 10 or 14 days à NO HELPLESSNESS. Therefore, not just learning, but NE levels.)  

6.        In some cases “helpless” rats self mutilate, have sleep loss and disorganized sleep, & elevated glucocorticoid levels. 

7.        NE depletion in brain.  Learning is normalized by antidepressant drugs and ECS.

C.       Humans: Donald Hirohito: escapable or inescapable loud noises: inescapable group less capable of learning response to turn off noise; also less able to solve simple word puzzles.

1.        Similar experiment: had to pick cards according to learnable or unlearnable rules.  Those with unlearnable rules were worse at simple tasks and social coping situations.

2.        Some people are more vulnerable than others: external vs. internal locus of control.

3.        Sapolsky:  “learned cooking helplessness”

4.        Schoolkids with severe reading problems:  teach them Chinese!

5.        Loss of a parent early in life à increased risk for depression later.

VII. Attempting an integration

A.       Why does the stress-depression link uncouple after 3 or so bouts of major depression?

B.        Why don’t we all get depressed?

1.        In most of us stress not only depletes NE in the limbic system, but also increases tyrosine hydroxylase, the rate-limiting enzyme of its synthesis.

2.        In some people, a big enough stressor seems to overwhelm the defenses.

C.       So, why are some people more prone toward depressions than others?

1.        Genetic vulnerability: perceive stressor as stressful; more glucocorticoids; defect in feedback;     

NE, 5-HT (and/or DA?) systems may be vulnerable; less able to activate a restorative defense.