AFFECTIVE DISORDERS Flashcards
what are affective disorders
disorders of mood rather than cognitive function
unipolar // bipolar (low-high manias)
endogenous (no obvious reason) // reactive (post trauma)
animal models of depression
- forced swim test (mouse will give up and drown)
- tail suspension test (give up fighting urger quicker)
- learned helplessness (stop looking for food)
- olfactory bulbectomy (removal of sensory neurons)
- maternal deprivation
- chronic mild stress
Monoamine Hypothesis
mood disorders result from an imbalance in signals generated by NE + 5-HT (serotonin) dependent pathways
anxiety - too much // depression - less activity
evidence of Monoamine Hypothesis
. TCAs - block NE + 5-HT reuptake =(+) mood
. MAOI - increase storage or NE + 5-HT =(+) mood
. tryptophan - increases 5-HT synthesis =(+) mood
. ECT - increases CNS repsonses to NE + 5-HT =(+) mood
. Reserpine - inhibits NE + 5-HT storage =(-) mood
. a-Methyltyrosin - inhibits NE synthesis =(-) mood
. Methyldopa - inhibits NE synthesis =(-) mood
Tryptophan depletion = decreases brain 5-HT synthesis
- induces relapse in SSRI treated patients
counterevidence to Monoamine Hypothesis
. amphetamines inhibit reuptake of NE + Dopamine
= no effect on depression
. antidepressant actions of MAOI, TCAS, SSRIs
=delayed effects
. some antidepressant drugs have no effects on adrenergic/serotonergic transmission
.ECT has in some cases shown to reduce NE+5-HT in CNS of patients = improves depression
what keeps cells alive
BDNF - brain-derived neuro factor
potential targets for treatment of affective disorders
- (+)enzymes involved in NE + 5-HT synthesis
- (-)enzymes involved in NE + 5-HT metabolism
- (+) transporters of vesicular storage of NE + 5-HT
- (-) NE + 5-HT reuptake transporters
- postsynaptic receptors (activate agonists)
- autoreceptors
what route does all uptake happen via
uptake 1
drugs used to inhibit unipolar depression
- MAOI
- TCAs
- SSRIs
- SNRIs
monoamine oxidase
metabolizes NE + 5-HT + dopamine
A = specifity for NE + 5-HT
B = degrades dopamine
most MAOI are nonspecific - bind to both // actions on A responsible for therapeutic action of drugs in treating depression
MAOIs
PHENELZINE
noncompetitive IRREVERSIBLE inhibition of MAO
= increases 5-HT, NE, Dopamine
side effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia, arrhythmias, orthostatic hypotension
why are interactions of MAOIs with SSRIs/food fatal
tyramine breakdown product of amino acid degredation
Tricyclic Antidepressants (TCAs)
AMITRIPTYLINE
inhibits uptake 1 for both NE + 5-HT
side effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia, arrhythmias, orthostatic hypotension + sedative effect
Selective Serotonin Reuptake Inhibitors (SSRIs)
FLUOXETINE
. selective inhibition of serotonin reuptake receptors in presynaptic 5-HT neurons
. advantage over MAOI/TCAs - lack of noradrenergic PNS effect = no tyramine toxicity
side effects: nausea, diarrhea, anorexia, insomnia, sexual dysfunction, increased sweating
Other uses: anxiety disorders, panic attacks, PTSD, OCD
MAOI interaction: hypothermia, muscle rigidity, cardiovascular collapse
where are 5-HT1 R found
on cell body/dendrites = somatodendritic receptors
= inhibitory - limit opening of Na+ channel = slow AP
- less release of serotonin
take SSRI - increase amount of serotonin = more stimulation // opposite effect: increase somatodendritic 5-HT1 = decrease activity of AP
Serotonin - NE Reuptake Inhibitors (SNRIs)
DULOXETINE
. selective inhibition of serotonin + NE reuptake receptors in presynaptic neurons
. advantage over TCAs -more selective = fewer side effects
. other uses: anxiety disorders, chronic nerve pain
side effects: nausea, diarrhea, anorexia, insomnia, sexual dysfunction, increased sweating
what are the roles of other antidepressants:
. mirtazapine
. L-tryptophan/5-HT
. St John’s wort
. blocks inhibitory actions caused by alpha2 heteroreceptors/5-HT = increasing NE + 5-HT release
fewer side effects / faster acting than TCAs
. increases synthesis of serotonin
. contains hyperforin - Uptake 1 Inhibitor
fewer side effect // serious drug interactions - ability to induce drug-metabolizing liver enzymes in P450
what is the most effective drug treatment for BIPOLAR Disorder
LITHIUM
- inhibits inositol synthesis – IP3 dependent pathways
- blocks 5-HTa1 autoreceptors = prevent inhibition
- enhance glutamate reuptake (too much =mania)
- inhibit activity of glycogen synthase kinase 3 (effects on neurite outgrowth/axonal spreading
LOW TI = kidney damage, thyroid enlargement, muscle tremors, vomiting, diarrhea, weigh gain, hair loss
what are 4 antimania drugs
- lamotrigine
- carbamazepine
- valproate
- gabapentin
- also used to treat epilepsy
why do we use drug cocktails
attempt to improve depression/mania when one medication is not enough
aripiprazole: D2 partial agonist, 5HT1a partial agonist
antipsychotic
side effects: restlessness, uncontrolled movements
