Antidepressants PT1 Flashcards
Types of Depression
- Symptoms
Types:
- Persistant Depressive Disorder (dysthymia)
- Major depression (unipolar)
- Bipolar 1 + 2 (manic-depressive)
Symptoms:
- depressed mood, diminished interest in normal actives, pessimistic worry, guilt and worthlessness
Antidepressant Drugs
USE: treatment of major depression Other Conditions: - panic disorders - PTSD - OCD - Generalized anxiety disorder
Patho Of Major Depression
- Monoamine hypothesis
- Problems with monoamine theory
- Reserpine is associated with depression and depletes monoamine stores in CNS.
- Elevated MAO-A in most brain regions of depressed patients
- antidepressants increase levels of NE and/or 5-HT in synaptic cleft
Problems:
- cocaine: brockets NET, SERT, DAT–> not an effective antidepressant
- amphetamine: increase NE/DA levels in synapse
- some antidepressants do not act directly on the monoamine system
- clinical efficacy: antidepressants only effective after long term
Presynaptic Regulation of NE release
- Synthesized within nerve termini and released upon depolarization
- Presynaptic alpha2-adrenergic receptors inhibit NE release
- NE taken up into presynaptic nerve termini by NE transporters
NE Pathways
- Predominantly produced by neurons from the locus coeruleus
- Important for mood, cognitive function, behavior fxn, behavioral arousal, memory and emotion, and endocrine responses
Dopamine DA Pathways
Mesolimbocortical pathway: important for reward and executive functions
- VTA to nucleus accumbent and cortex
Nigrostriatal pathway (mesostriatal): important for movement - substantia nigra to basal ganglia
Indolamine Synthesis (serotonin and melatonin)
Tryptophan –(tryptophan hydroxyls–> 5-HTP—(5-HTP decarboxylase)–> serotonin
Presynaptic Regulation of Serotonin (5-HT) release
- 5-HT synthesized within nerve termini and released upon depolarization
- presynaptic 5-HT receptors inhibit 5-HT release
- presynaptic alpha2-adrenergic heteroreceptors inhibit 5-HT release
- 5-HT taken up into presynaptic nerve termini by 5-HT transporters
Serotonin (5-HT) Pathways
- Predominantly released from raphe nucleus
- important for mood, arousal, sleep, anxiety, temperature regulation
Neurotrophic Hypothesis of Major Depression
Cortisol down regulates BDNF:
- decrease BDNF negatively affects neuronal survival
- decrease neuronal survival reduce monoamine NTs
- decrease number of dendritic sprouts
Problems with Neurotrophic Theory
- BDNF knockout mice do not always exhibit depressive-like behaviors
- some animal studies show increased BDNF levels after some types of social stress
- some studies show increase in depressive behaviors with lateral ventricle inj of BDNF
What drugs bind on the serotonergic neuron?
Fluoxetine and trazodone
what drugs bind on the noradrenergic neuron?
desipramine, maprotiline
MAO Inhibitors
First generation: irreversibly bind to and inhibit MAO-A and -B
- isocarboxazid, phenelzine, and tranylcypromine
- effects last about 2 weeks
Second generation: reversible inhibitors of MAO-A (RIMAs)
- moclobemide
- effects last 2-5 days; not available in the US
Third generation: selectively, irreversibly inhibits MAO-B
- selegiline
- used for Parkinson disease
- transdermal patch formulation approved
MAOI MOA and AE
-PK?
- Tyramine found in fermented foods; take up into nerve terminals by NET causes release of catecholamines
- -> can cause hypertensive crisis; “cheese reaction”
PK:
- well absorbed from GI tract; first pass effect
- short half life
