Exam 4: Treatment for Affective Disorders Flashcards
reserpine
reduces high blood pressure
induces depression as a side effect
prevents packaging of neurotransmitters into vesicles, leaves in synapse whereMAO can degrade them
it reduces levels of DA, NE and 5-HT
serotonin and depression
significant influence on sensitivity to pain, emotionality, response to negative consequences or reward
- having low levels of serotonin does NOT cause depression, except in vulnerable individuals
- tryptophan challenge
tryptophan challenge
tryptophan is what gets converted into serotonin
if give drink that dec tryptophan in ppl with a history of depression it will cause depression symptoms
5-HIAA levels
the serotonin metabolite
low levels of 5-HIAA found in postmortem brains of depressed individuals
-low levels associated with 5 fold inc in suicide risk
MDD patients have low levels of what in cerebral spinal fluid (spinal tap)
5-HT, TPH, 5-HIAA
lowered serotonin is problem in people with depression but does not mean the person will become depressed
brains of unmedicated individuals with mood disorders have inc what
inc density of postsynaptic 5-HT2 receptors (with hallucinogens too)
this is compensatory response to low serotonergic activity
-more receptors to try to recapture as much serotonin as possible
-antidepressants reduce 5-HT2A receptor binding
examples of tricyclic antidepressants
amitriptyline, chlorimipramine, imipramine
what is NE involved in
neuroendocrine function, reward, attention and arousal, response to stress
NE and depression
dowwn regulation of B-receptors with chronic antidepressant treatment
-takes 7-21 days of treatment to see effects - delay
types of antidepressant drugs
MAOIs, TCA, second generation antidepressants(SSRIs)
nondrug therapies
sleep deprivation electroconvulsive therapy (shock) transcranial magnetic stimulation vagal nerve stimulation deep brain stimulation
exercise
dopamine
involved in motivational deficits associated with depression
anhedonia (loss of pleasure)
does anxiety or depression come first
anxiety
anxiety vs depression neurochemistry
anxiety = too much serotonin, NE, DA
depression= not enough serotonin, NE< DA
anxiety increases SERT…more SERT =
less serotonin
ROA of antidepressants
typically oral
transdermal gel or patch - longer lasting actions
- ex: selegiline: MAOI with transdermal patch
Absorption of antidepressants
max blood concentrations:
- TCA: 1-2hrs
- MAOIs: 2-3hrs
- SSRIs/SNRIs: 4-8hrs
1st pass metabolism dec bioavailability - oral drugs
-inhibited by alcohol - slows breakdown of drugs
depot binding!!!
-SSRI Fluoxetine has over 95% depot binding - longer time of peak levels in blood, longer half life
distribution of antidepressants
most cross BBB and placental barrier
concentrate in lungs, liver, kidneys, brain
lipid soluble
metabolism of antidepressants
inhibition of MAO in liver (normally MAO breaks down dietary tyramine)
dietary tyramine
formed as byproduct of fermentation in cheeses, meats, pickled products, other foods
people on MAOIs given list of foods they should avoid bc they can cause a dangerous spike in BP
what does elevated tyramine do
releases higher than normal stores of NE at nerve endings, causing dangerous increases in BP
MAOIs inhibit CYP450s
effects of alcohol, barbiturates, opiates, aspirin all intensified in presence of MAOIs (enzyme inhibition)
competition for enzymes!
side effects of MAOIs
changes in BP
sleep disturbances - interesting bc sleep disturbances is problem with depression and this is going to cause it
overeating/weight gain
how do most antidepressants increase 5-HT
blocking reuptake or inhibiting MAO
-prevent 5-HT breakdown or prevent it from being repackaged
acute effects of increased serotonin
gives cell more opportunity to activate the 5-HT1A autoreceptor to slow cell firing and reduce synaptic serotonin
chronic serotonin treatment results in
down regulation of 5-HT1A sutoreceptors and synaptic 5-HT increases
this inc is just initial step, other changes required like hippocampal neurogenesis and functional remodeling of corticolimbic circuits
MAOIs increase amount of…
serotonin, NE, DA available
action of TCAs
bind to presynaptic transporter proteins and inhibit reuptake of neurotransmitters - prolongs duration of transmitter action at synapse
diff TCAs have diff NE and 5-HT reuptake blocking potencies
inc in synaptic activity first step but NEED neuronal adaptation
side effects of TCAs
also block histamine, acetylcholine, and a1 receptors
anticholinergic effects of TCAs
dry mouth constipation urine retention dizziness confusion impaired memory blurred vision
a1 receptor blockade of TCAs
coupled with NE reuptake blocking leads orthostatic hypotension, tachycardia, arrhythmias
- overdose causes cardiovascular depression, delirium, convulsions, respiratroy depression, coma
- heart arrythmias can produce ardia arrest
histamine receptor blockade - TCAs
causes sedation and fatigue that limit the drugs usefulness - positive effect for people with sleep dysfunction
for patients with agitation these side effects help
do TCAs have a high or low therapeutic index
low!
- fatalities occur at approximately 10 times the normal dose
- can also get overdoses if take TCAs with alcohol
SSRIs
block 5-HT reuptake transporters more than NE transpoters
-used to treat panic and anxiety disorders, OCD, obesity, alcohol use disorder
serotonin syndrome
SSRIs have potentially life-threatening effects when combines with other serotonergic agonists or drugs that interfere with metabolism of the SSRIs
mild symptoms serotonin syndrome
how to manage
mydriasis
shivering
sweating
tachycardia
manage: observe for at least 6 hrs and BENZOS
moderate symptoms of serotonin syndrome
how to manage
altered mental status (agitation, disorientation)
rigidity, tachycardia, hyperthermia
tremor, hypereflexes
manage: hospital
cardiac monitoring, cyproheptadine
life threatening symptoms of serotonin syndrome
how to manage
delirium, hypertension, hyperthermia, muscle rigidity, tachycardia
manage: ICU, esmolol or nitroprusside, cooling measures, ventilation, SkM paralysis, sedation
is it more beneficial to enhance both NE and 5-HT function or just one
both
mirtazapine
antagonist for a2 autoreceptors
inc synaptic NE and a2 heteroreceptors on serotonergic cells
inc 5-HT release
also antagonist for 5-HT2 receptors
what is the most effective medication for patients with bipolar disorder
lithium carbonate
- flattens extremes of emotion
- has no effect on healthy ppl but reduces manic episodes without causing depression or producing sedation
- effective in dec suicides in bipolar
lithium ROA
oral
absorption and distribution of lithium
readily absorbed by GI tract
peak plasma conc 30min-3hr
brain peak conc 18-24 hrs
no depot binding, no 1st pass metabolism
metabolism and excretion of lithium
NO metabolism
100% excreted unchanged in urine
half life: 18-30 hrs
side effects of lithium
low therapeutic index
blood levels of lithium must be monitored regularly
mild but can include inc thirst and rination, impaired conc and memory, fatigue, tremor, weight gain
lithium pharmacodynamics
many system - 5-HT, DA, GABA, glutamate
2nd messenger systems
lithium downregulates NMDA and DA receptors (dec Ca ion influx through NMDA receptors)
lithium enhances 5-HT actions (elevates brain tryptophan, 5-HT, 5-HIAA and inc 5-HT release
lithium inc GABA levels and inc GABA B receptors
what does lithium downregulate
NMDA and DA receptors
reduces Ca ion influx
treatment for bipolar disorder
anticonvulsant drugs
-valproate and carbamazepine
valproate (depakote)
bipolar anticonvulsant treatment
- inc GABA levels in brain
- dec glutamate in brain
carbamazepine (tegretol)
anticonvulsant for bipolar
resembles TCAs and inhibits NE reuptake
-blocks adenosine receptors in sleep
addiction and withdrawal
no euphoria
little to no abuse liability for SSRIs, TCAs, MAOIs
but can cause physical dependence
physical dependence and antidepressants
-sudden discontinuation of high dose TCAs - restlessness, anxiety, chills muscle aches, akathisia
SSRI withdrawal
dizziness, insomnia, fatigue, anxiety, nausea
withdrawal from NE targeting drugs
heart palpitations, psychiatric symptoms - delusions
