Lecture 3: Basic Depression Flashcards
Mood Disorders are Serious
7 reasons
Start at early age.
Hard to diagnose in youth.
Confused with normal teenage behavior, drug use, or other psychiatric illnesses.
Mostly recurrent episodes or chronic illness.
High suicide risk.
Treatment is often started late and long-term compliance is poor.
Early treatment and episode prevention is better than responding to each new episode.
Serotonin and Dopamine
Pathways are involved
NE and DA broken down to variety of products through MAO and COMT
5HT is broken down by MAO to 5-HIAA
Major mechanism for terminating signal is neuronal reuptake
Monoaminergic Theories
Monoaminergic Theories
- Reserpine (early antihypertensive)
- Iproniazid (used to treat TB)
- Imipramine (originally studied as an antipsychotic)
- Drugs enhancing noradrenergic functioning were antidepressants (eg. stimulants)
Platelets Used as a Serotonin Neuron Model In Studies of Major Depression
Lots of serotonin-related abnormalities.
Serotonin uptake low.
Serotonin transporter sites are fewer.
More 5-HT2A receptors in association with suicidal acts.
5-HT2A signal transduction is blunted in suicidal cases.
Possible link to increased risk of death from myocardial infarction in major depression.
Serotonin 5-HT1A Receptors
Major part of serotonin communication in brain.
Both an autoreceptor and a terminal field post-synaptic receptor.
Role hypothesized in the pathobiology of mood disorders.
Role hypothesized in the action of antidepressants.
Can be studied in postmortem brain and in live patients using PET scanning.
Candidate Serotonin Genes in Depression
Serotonin transporter
Tryptophan hydroxylase
Receptors including 5-HT1A, 5-HT1B and 5-HT2A
Monoamine Oxidase
Results are promising but preliminary
Imply cause and mechanism
Norepinephrine System
Seems hyperactive in depressed patients. But since there are typically fewer noradrenergic neurons in these patients, there can be a deficiency.
Adverse childhood experiences can produce an over-active responsiveness in this system that persists into adulthood.
In situations that most people may not find too stressful,
the vulnerable depressed individual does feel very
stressed and may deplete NE. Depletion of NE with AMPT causes depression in recovered patients but not normals.
Restraint stress in animals causes NE depletion and
hopelessness. Hopelessness is a major part of depression.
Dopamine Function is Deficient in Major Depression
Parkinson’s Disease associated with depression.
CSF shows low homovanillic acid (HVA).
Neuroendocrine challenges: blunted responses to dopamine agonists
Depletion of dopamine with AMPT causes depression in recovered patients but not
normals.
Imaging: nothing found yet.
Postmortem brain: no data
Genes: TH, COMT & MAO
GABA in Major Depression
CSF levels of GABA are lower in depression.
Postmortem brain: fewer GABA neurons.
Imaging: low GABA in cortex.
Genes: N/A
Fewer GABA Neurons in Anterior Cingulate and Entorhinal Cortex in Bipolar Disorders
27% fewer GABA cells in layer II of bipolar group.
No statistically significant difference in pyramidal cells or glia.
No difference in size of pyramidal cells.
Indicates deficit in local circuit neurons or GABA cells in layer II of anterior cingulate in bipolar
disorders.
Similar results reported by others in entorhinal cortex.
Antidepressant increases neurogenesis in hippocampus
Section of the dentate gyrus of the hippocampus, showing
newly formed cells.
The histogram shows that various antidepressant
treatments increase the number of new labelled cells. The
treatments tested include electroconvulsive shock (ECS),
the MAOI tranylcypromine, the SSRI fluoxetine, and the selective norepinephrine reuptake inhibitor reboxetine.
Evidence Refuting the Monoamine Hypothesis
Neurogenesis Theory of Depression
Macrophage Theory of Depression
- Volunteers given cytokines (IL-1; INF-α; TNF) develop symptoms of a major depressive episode.
- IL-1 can account for hormonal abnormalities (e.g., ↑ ACTH; ↑ GH).
- Diseases and cohorts characterized by macrophage activation are associated with high rates of depression.
- Brain macrophages (microglia) secrete cytokines.
- Estrogen increases IL-1 secretion by macrophages.
- Sickness behavior (result of infection) strongly resembles depression
Stress Diathesis Models
Early Experience:
- Abuse
- Emotional Neglect
- Family Strife
- Harsh Discipline
> > > Individual differences in neural and endocrine responses to stress and thus vulnerability»_space;>
Health Risks: Depression Drug Abuse Anxiety Diabetes Heart Disease Obesity
Individual Difference in Glucocorticoid receptor levels lad to altered pituitary-adrenal responses to stress.
Hippacampus»_space;>
Hypothalamus»_space;> CRF»_space;>
Pituitary»_space;> ACTH»_space;>
Adrenals»_space;> Glusocoricoids
