Unit 3 - Antidepressants

Question 1

what is the biogenic amine hypothesis of mood disorders?

Answer 1

depression is too little CNS NE and/or 5-HT over amounts and/or activity
-thus, most antidepressant drugs block reuptake of both NE and 5-HT

Question 2

what is the discrepancy between pharmacological effect and clinical improvements of antidepressants?

Answer 2

PE happens within minutes to hours (increasing nt in synapse)
CI happens in 6-8 weeks (mech are matter of conjecture)
-receptor re-regulation?
-increasd BDNF gene trascription?
-induced synaptogenesis?

Question 3

what is the neurotrophic hypothesis?

Answer 3

brain derived neurotrophic factor (BDNF) drops in depression, so therapy should increase BDNF gene transcription and neurogenesis

Question 4

what is the Hamilton Depression Rating Scale?

Answer 4

8-13: mild depression
14-18: moderate depression
19-22: severe depression
>23: very severe depression

Question 5

what does MAO-A VS MAO-B do?

Answer 5

A: oxidizes mainly NE, 5-HT, tyramine
B: oxidizes mainly DA, phenyethylamine

Question 6

what drug class are Tranylcypromine and Phenelzine in?

Answer 6

MAOi

• inhibit both A and B for depression
• tranylcypromine is readily absorbed and persists in system for 7 days

Question 7

what drug class are Selegiline and rasagiline?

Answer 7

MAO-B selective for Parkinson’s

-Selegiline at high doses inhibits A and B for depression

Question 8

what are side effects of MAOi?

Answer 8

some anticholinergic, pronounced orthostatic hypotension, sexual dysfunction, weight gain, and sedation
-life threatening: potential hypertensive crisis if consume tyramine, as liver MAO is also inhibited

Question 9

what is serotonin syndrome?

Answer 9

potentially lethal effect from taking MAOi + SSRIs (drug-drug interaction)

• looks like malignant hyperthermia and potentially lethal
• hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs
• due to increased 5-HT and inhibited reuptake

Question 10

what are amine reuptake inhibitors? features?

Answer 10

tricyclics, SSRIs, and “atypicals”

1. drug-to-drug widely varying potencies and varying selectivity spectrum to inhibit reuptake transporter for NE or 5-HT or both
2. many have active metabolites (N-demethylated) which are usually much longer acting than the parent compound

Question 11

what are desipramine, imipramine, amitriptyline, and nortriptyline? what do they do?

Answer 11

TCAs

• inhibitors of NE and 5-HT reuptake to varying degrees of potency and selectivity (therapeutic effect from 8 to 100 hours)
• -depends on formation of active metabolites
• high protein binding and high lipid solubility, so very large Vd

Question 12

why are TCAs “dirty drugs”?

Answer 12

produce varying degrees of block at muscarinic, a-adrenergic, DA uptake pump, and histamien receptors, to cause many side effects

Question 13

what is the general reuptake inhibitor metabolism for TCAs?

Answer 13

N-demethylation followed by P450 oxidation followed by glucuronide conjugation

Question 14

what are adverse effects of TCAs?

Answer 14

1. anti-muscarnic: blurred vision, constipation, confusion, dry throat, hypotension
2. a-antagonistic: orthostatic hypotension
3. histamine antagonist: sedation (additive with alcohol)
4. sympathomimetic: tremor, insomnia
5. overdoses: cardiac arrhythmias, conduction defects

Question 15

which antidepressants are used more now? why?

Answer 15

SSRIs and atypicals are replacing MAOis and TCAs

• newer ones have less intense side effects (thus more compliance)
• although TCAs have higher efficacy per mg, their side effects are not manageable

Question 16

what are fluoxetine, paroxetine, sertraline, escitalopram, and citalopram? which one forms active metabolites?

Answer 16

SSRIs

-fluoxetine forms active metabolites

Question 17

what are duloxetine and venlafaxine?

Answer 17

SNRIs

Question 18

how are SSRIs different from TCAs?

Answer 18

1. SSRIs have longer duration of action
2. some inhibit P450 enzymes (esp. fluoxetine and paroxetine), so can interfere with metabolism of other drugs
3. much safer in OD (no seizures or cardiac arrythmias)
4. less side effects
5. more N/V and complaints of decreased sexual function

Question 19

what are adverse reactions of SSRIs?

Answer 19

potent inhibitors of P450 enzymes, and serotonin syndrome

Question 20

what are tetracyclics and unicyclics (bupropion, mirtazapine) and ketamine?

Answer 20

atypical antidepressants

Question 21

what are the unique things of bupropion?

Answer 21

1. notable selectivity for DA uptake transporter
2. potential side effect of lowering seizure threshold
3. improves nicotine abstinence in quitting smokers

Question 22

what is ketamine?

Answer 22

NMDA receptor antagonist with rapid antidepressant response (within hours) in treatment-resistant depressed patients
-rapidly increases synaptogenesis, including increased density and function of spine synapses in PFC

Question 23

how does Lithium work?

Answer 23

unclear mechanism, but causes depletion of IP3 and DAG second messengers in a-adrenergic and muscarinic-cholinergic transmission
-may cause selective depression of overactive circuits

Question 24

what are ASE of lithium?

Answer 24

low margin of safety

• drowsiness, weight gain, tremor, polydipsia, polyuria
• neurotoxicity, cardiac toxicity, renal dysfunction
• N/V is early awrning of OD

Question 25

what are carbamazepine and valproate?

Answer 25

anti-convulsants