- Major issue is loss (i.e. parental deprivationÞ ß immune function, Ý cortizolemia and other signs)
Chronic childhood emotional depravation
Þ low self-esteem and poor emotional developmentÞ poor ability to cope with stress
in adulthood reawakens latent poorly integrated feelings Þ feelings of sadness
Instead of expressing feelings, rigid defenses emerge, enabling patient to avoid dealing with chaotic early life experiences
- negative illogical thinking Þ depression, so it can be overcome by more logical thinking
negative illogical thinking continues to adulthood by coping mechanisms that do not adequately deal with major stress
sadness results from low self-esteem/respect; patient negatively distorts and personalizes neutral statements of others
- explains depression in terms of neuroanatomy of the limbic/hypothalamic systems
can be a relief to patients and
Ý compliance if illness is explained in biological terms. This is important because compliance in taking medication (regardless if it is placebo) is major predictor of positive treatment outcome
Schildkraut introduced the Biogenic Amine Hypothesis of Depression in 1965.
Permissive Hypothesis: serotonin and norepinephrine are
ß in depression (Ý norepinephrine normalizes depression); mania if norepinephrine too high
Neurotransmitters are important in Affective Disorders
based on the info that:
(1) 15% of HTN patients on biogenic amine depleting drug (reserpine), become depressed
(2) norepinephrine metabolite (MHPG) is
ß in depression (urine, CSF, Plasma)
(3) Location of function of norepinephrine in CNS supports this theory
remember that norepinephrine is the neurotransmitter of the Locus Ceruleus which projects throughout Limbic system (hypothalamus, hyppocampus and parts of cortex) and controls the peripheral secretion of NE. Also remember that LC functions in wakefulness and is inhibited by GABA from VLPO in sleep.
(1) Serotonin (5-HT)
: Evidence for its role in depression include
decreased metabolites (5-HIAA: 5-Hydroxyindoleacetic acid) found in CSF in depression.
5-HT uptake 3H-imipramine binding sites especially in bipolar, psychotic depressives.
5-HT precursor (Trp) in some patients
5-HT may explain Ý 5-HT type 2 receptors in brains of suicide victims.
therefore treatment with 5-HT precursors and antidepressants should help (it can). Lithium and ECT
Ý serotonergic activity.
(2) Norepinephrine (NE)
: considered significant because antidepressives ß b -adrenergic receptors within 2 weeks
linked to 5-HT because antidepressives won’t work if 5-HT system is not working well
dysregulation Hypothesis may be explained by down subsensitivity of presynaptic
a Þ ß inhibition of norepinephrine release resulting in depleted stores of norepinephrine and problems modulating its activity
Ý levels of MHPG have been found in mania
: concentration of its major metabolite, homovanilic acid, is inversely correlated to severity of depression.
dopamine agonists (bromocryptine) have antidepressive effects.
abuse of dopamine depleting drugs (cocaine, amphetamines) is followed by depression.
: 20 yr ago was thought to play a role in depression: - Thought was that Ach agonist caused depression (syllabus says "in manic patients and enhances symptoms in depressed patients")
: widespread CNS inhibitory NT. Not understood (can’t be explained by effect on LC): relieves depression in animal models
depression caused by abnormalities of hypothalamus, which controls vegetative functions (feeding, sex, circadian rhythms), and/or hypothalamic-releasing hormones. Explains why depressed people either loss appetite or overeat; decrease in sexual energy (which is increased in hypomania); etc.
Hypercortisolism: most consistent neuroendocrine finding; Pseudo Cushing’s Disease; reflects a defect in CRH
ß CSF somatostatin; ß CSF Arg vassopresin; ß GH response to clonidine; ß TSH response to TRH
: makes CRH and coordinates fight/flight (stimulates locus ceruleus to produce norepinephrine): uncovers genetically vulnerable
(1) Circadian Rhythm Hypotheses
Biorhythmic evidence: recurrent nature (1x =50% chance; 3x = 90%); change in rest activity; change in sleep architecture; phase shifts of circadian rhythm (notice that staying up all night causes marked but transient antidepressive effect)
Sleep architecture abnormalities
- Ý sleep latency; ß arousal threshold; early morning awakening = most specific form of insomnia for depression
- ß REM latency; redistribution of REM to first half of night
(2) Kindling and Behavior Sensitization
: Idea comes from experiments where rats were stimulus trained to have seizures, eventually the seizures become uncoupled from the stimulus. The parallel thought in depression would be that stress is stimulus for depression which eventually becomes uncoupled from the stress stimulus and is constant
predisposition provided by stressful early life experiences
gradual worsening of affective episodes over time at expense of well intervals (Uncoupling)
progressively shorter latency between episode onset and peak severity