Affective Disorders

Question 1

There are two types of affective disorders, both characterized by

Answer 1

extreme and inappropriate exaggeration of mood (affect):

A) Bipolar disorder
B) Major depression

Question 2

Bipolar disorder

Answer 2

moods swing from depression to mania over time.

Question 3

Major depression

Answer 3

recurring episodes of dysphoria and negative thinking

Question 4

Reactive depression

Answer 4

state of sadness in response to situations like loss of a loved one.

Question 5

Pathological depression

Answer 5

resembles an emotional state we have all experienced but differs significantly in intensity and duration

Question 6

Biological Bases for Affective Illness

Answer 6

-strongest theory is the monoamine hypothesis; affective illnesses are due at least in part to an impairment in the function of two different monoamine neurotransmitters, norepinephrine and serotonin.

• idea supported by fact that reserpine (blocks vesicular
  transporter) can lead to depression… or can be used to treat mania.
• in general, antidepressant drugs alter NE and 5-HT synapses in the nervous system
• 5-HT may be key; low 5HT levels may lead to NE levels determining mood.
• HIGH NE = Mania; LOW NE = Depression.
• this might explain why lithium may be effective in manic-depressives, as it stabilizes 5HT synthesis.

Question 7

Key problem in treatment

Answer 7

start-up phenomena; clinical effects may take weeks to be expressed.

Question 8

The first antidepressant drugs were…..

Answer 8

The first antidepressant drugs were MAO-I’s;

Question 9

MAO-I’s

Answer 9

• they acutely block MAO, elevate levels of NT, and ultimately produce long-term changes in the postsynaptic cell (eg, receptor down-regulation) that underlie startup of therapeutic effect.
• limited therapeutic usefulness due to side effects. Most often used when other drugs fail, or in treatment of atypical depression.
• currently 3 in regular use; best known is tranylcypromine (Parnate), which irreversibly inhibits monoamine oxidase.
• lipid soluble and rapidly absorbed (1 hr peak); short half-life (about 1-4 hr); metabolized in liver by CYP-450 enzymes (often affects other drugs)
• takes 2-3 weeks for clinical effect to appear, also takes about 2 weeks to wear off (classic “start-up” seen with many monaminergic drugs).
• in all cases, clinical usefulness limited by extreme toxicity, including hypertension (TI ~5-10).Hypertension can also result from other drugs (decongestants, psychostimulants) or due to “cheese effect”.
• transdermal MAO-I patch (Eldapril) has been developed; low peak levels lead to reduced side effects
• all MAO-I’s have low abuse potential.

Question 10

Tricyclics

Answer 10

replaced MAO-Is; remain the benchmark; named for 3-ringed structure

• may block 5HT reuptake , or NE reuptake, or both…and DA reuptake; D-2 antagonist; 5-HT2 antagonist; block Na+ and Ca2+ channels
• includes imipramine (Tofranil) and metabolite DMI (Norpramin).
• take 1-3 weeks work; most effective against chronic unipolar affective illness.
• well absorbed; peak levels w/in 1 hr; long half-life w/ huge variability (e.g. about 48 hr for DMI); metabolized in liver by CYP-450 enzymes.
• low TI ~10…25% of all OD’s are w/ tricyclics.
• side effects due to antagonism of histamine and ACh receptors (dry mouth; constipation; heart arrythmias; blurred vision. These often tolerate…
• little abuse potential.

Question 11

SSRI’s:

Answer 11

2nd generation of antidepressants; favored due to lack of side effects, though therapeutic effects often no better.

• specifically block 5-HT reuptake carrier; a modified tricyclic.
• pioneer was Prozac (fluoxetine); has long half-life (96-144 hrs) and active metabolites (norfluoxetine) so….

…it takes a long time to ramp up plasma levels of the drug; can be administered ONCE A WEEK; metabolized in liver by CYP 450 enzymes

• better TI than traditional tricyclics, but overdose can lead to serotonin syndrome (altered cognition, agitation, diarrhea, myoclonus).
• no clear abuse potential.

Question 12

NSRI’s

Answer 12

-most recently, NSRI + SSRI drugs developed to affect both systems at once

Question 13

Novel Treatment of Affective Illness:

Answer 13

-focuses on abnormal stress response and effects of CRH on brain

-corticosteroids/CRH both increase excitability of
LC (NE) and raphe nuclei (5-HT); leads to anxiety, loss of control, etc. that may lead to depression.

• also activate amygdala (fear center) and kill hippocampal neurons (cognitive impairments?).
• CRH antagonists block development of depressive symptoms; research ongoing to develop drugs for humans.

Question 14

Pharmacotreatment of Mania:

Answer 14

lithium salts are overwhelming drug of choice; effective in about 70% of cases.

• mechanism of action unknown but may stabilize neural membrane; reduced Ca2+ dependent release of catecholamines (but not 5-HT!); stabilize synthesis of 5-HT.
• readily absorbed, very small; low TI (~3); can kill if patient has heart or kidney problems; long half-life (about 24 hr) so several small doses taken each day; eliminated by kidneys without being metabolized (as Lit+); must watch NaCl intake as increased Na+ levels reduce amount of Li+ that can be excreted, and NaCl levels too low cause toxic levels of Li+ to be retained.

-Carbamazepine/oxacarbazapine and valproate also used as adjuncts or primary treatment; mechanism of action unclear; GABA indirect agonists;
decrease neural excitability (block “kindling” effect?).