In general, how is unipolar depression different from bipolar disorder?
unipolar depression is characterized by episodes of depression, separated by periods of euthymia
bipolar disorder is characterized by episodes of depression (briefer) followed by episodes of mania
What is the prevalence of depression?
1 in 10 patients seen in primary care!
it's the 4th most common compaint
***Note that 70% of medical care over-utilizers have at some time in their lives had a diagnosis of major depression
What hypothesis is the make idea fo neurochemical basis of affective disorders?
the amine hypothesis
Describe the amine hypothesis for affective disorers.
certain levels of amine NTs and receptor sensitivity are necessary for normal mood
(NE, 5HT, DA)
Depression occurs if receptors are insensitive or if amine synthesis, storage, or release is deficient
Mania occurs if there is an excess of NT or a receptor hypersensitivity
What ist he major issue with the amine hypothesis of mood disorders?
there's a mismatch between the time course of treatment:
neurochemical effects can occur in 1-2 days, while clinical improvement takes 10-21 days
What are the two general drug classes for treatment of mood disorders?
What percentage of patients do not respond to initial antidepressant therapy?
What effects do tricyclic antidepressants cause in normal, non-depressed, subjects?
NO stimulation of mood elevating effect
you get antimuscarinic effects: dry mouth, blurred vision, constipation, urinary retention, sleepiness and light headedness
What is the effect of TCAs in depressed subjects?
elevation of mood only after 2-3 weeks
50% experience dry mouth and tachycardia
What is the mechanism of the TCAs
block the reuptake of NE and/or 5HT by nerve terminals
some are NE selective and others are NE/5HT mixed action
This results in higher concentration of the NTs at their receptors
What are the adverse effects of the TCAs
antimuscarini effects (especialy in elderly patients): acute confusional state, constipation, glaucoma
tachycardia and increased tendency for arrhythmias with high doses
What are some drug interactions you'll see with the tricyclic antidepressants?
1. they'll potentiate central depressants like alcohol, sedatives, and opioids
2. the antimuscarinic effects may delay gastric emptying time, so you get increased inactivation of levodopa in treating parkinsonism
What do MAOIs do?
they irreversibly block the oxidative deamination of monoamines like NE and 5HT
What's the difference between MAOa and MAOb?
MAOa metabolizes NE and 5HT in the brain and gut
MAOb metabolizes DA in the blood platelets
How long do you have to wait for changes to be seen with MAOIs?
the NTs change in 24-48 hours, but it takes 3+ weeks for clinical effect
Why are MAOIs used more for treating symptomatically?
the therapeutic index is very low - only 5!
usually hospitalize 1 week too
What is the major concen for drug interaction with the MAOIs?
They will potentiate sympathomimetic amins
especially indirect acting amines like tyramine
tyramine is usually metabolized by hepatic MAO, but ifyou take an MAOI, tyramine will build up and enter systemic circulation
it enhances release of catecholamines from peripheral and central nerve terminals and the adrenal medulla
this results in massive adrenergic stimulation that can cause a hypertensive crisis
What option is available in Europe to lower the incidence of interaction with tyramine?
they have approved selective and reversible MAOa inhibitors called Brofaramine and maclobemide
they don't inhibit all the MAO, so you don't get the interaction
What are some major examples of SSRIs?
fluoxetine = prozac
sertraline = zoloft
citalopram = celexa
escitalopram = lexapro
What are the adverse effects of SSRIs and how are they different from the TCAs and MAOIs?
nausea, diarrhea, weight LOSS, sexual dysfunction
stimulation - anxiety, nervousness, insomnia
They are unusual in that they're NOT sedating
What is the black box marning for fluoxetine?
they can increase suicidal thinking in children, adolescence and young adults
Which serotonin receptor probably contributes to the clinical improvement seen with SSRIs?
What is the difference between an autoreceptor and a heteroreceptor?
autoreceptors are acted on by 5HT to inhibit the addition release of 5HT
Heteroreceptors are acted on by NE to inhibit the release of 5-HT
What are hte 4 major atypical antidepressants?
What is the mechanism of action for venlafaxine (effexor)?
it's a selective 5HT and NE reuptake inhibitor (SNRI)
If Venlafaxine also blocks serotonin and norepinephine reuptake, why is it different than the TCAs?
Venlafaxine does NOT affect the adrenergic receptors, histaminergic receptors or cholinergic receptors
this means it has far fewer side effects
Although efficacy of most antidepressants doesn't increase with increasing dose, it does with venlafaxine. Why?
because it affects different NTs at different doses
lowest = serotonin
middle = norepinephrine
hihest = dopamine
What is desvenlafaxine (pristiq) and is it more effective than venlafaxine (effexor)?
It's an active metabolite of venlafaxine
it's not any more effective- the patent for venlafaxine was up in 2010, so they played the system
What's the mechanism of action for mirtazapine (remeron)?
It blocks presynaptic alpha2 receptors on adrenergic and serotonergic neurons, so you increase NE and 5HT levels
What is the mechanism of action for buproprion (wellbutrin)?
it affects boht NE and DA transport in th eneurons
How is ketamine used for depression treatment?
It's an injectable NMDA receptor antagonist
using a single dose of ketamine significantly improved symptoms of depression in treatment-resistant patients in LESS THAN 2 HOURS AND LASTS AT LEAST ONE WEEK!
What is the first string drug for bipolar disorder?
What is the mechanism of lithium?
We actually don't really know
Most likely involves effect on postsynaptic rather than presynaptic neurons - interferes with produciton and release of IP3 and DAG, may uncouple receptor recognition site from GTP binding protein, may affect several cell or nuclear regulatory factors
How is lithium absorbed and excreted?
readily absorbed form GI
95% excreted by kidneys, but 70-80% is reabsorbed by proximal renal tubule
What does lithium compete with for reabsorption in the renal tubule and how does this play into a toxicity?
it competes with sodium for eabsorption
sodium deficiency (because of low sodium diet or a diuretic) will increase lithium toxicity, because more will be reabsorbed
What are some of the adverse side effects of lithium?
fatigue, musculr weakness, slurred speech,a taxia, fine tremor, excessive thirst and urination
note: tolerance develope sto many of the side effects, but not to the tremor or excessive urination and thirst
What anticonvulsants are used for bipolar?
Valproic acid and sodium valproate (depakene and depacon)
What aspect of bipolar disorder are anticonvulsants better at?
acute manic episodes
not that great at long-term management of the disorder
What is the main atypical antispychotic to remember?
quetiapine - seroquel
What is the mechanism of action for the atypical antipsychotics?
they block the 5HT 2a receptor to have antimanic properties and mood stabilization
may has DA antagonism too
Why should SSRIs NEVER be used as a monotherapy in patients with bipolar disorder?
they can cause rapid onset mania, so they need to receive prophylactic mood stabilizer therapy to prevent this from occurring
What is a drug to specifically treat bipolar DEPRESSION?
it's an atypical antipsychotic
What is wake therapy?
You keep people awake during the night and prevent them from sleeping during the day
it alleviates the signs of depression
patients typically relapse within following 24 hours, usually when they resume sleep
it may "jump-start" the effectiveness of antidepressant drugs