Pharm of Antidepressant-Antimanic Agents

Question 1

Depressed mood

Answer 1

amygdala (A) and ventromedial prefrontal cortex (VMPFC) – innervated by NE-5HT-DA projections from brainstem nuclei

Question 2

Apathy

Answer 2

NE and DA

-PFC, hypothal, nuc accumb

Question 3

Sleep disturbances

Answer 3

Hypothal, thal, basal forebrain, diffuse areas of prefrontal cortex
-NE-5HT-DA

Question 4

fatigue

Answer 4

-deficient NE and DA

Question 5

Guilt

Answer 5

5HT

Question 6

Changes in weight/appetite

Answer 6

5HT

Question 7

Suicidal ideation

Answer 7

“emotional” brain regions such as amygdala, ventromedial prefrontal cortex, and
orbitofrontal cortex (OFC)

Question 8

Monoamine (biogenic amine) theory

Answer 8

-Initial observation that reserpine depleted brain NE / 5HT and induced depression
- drugs effective in treating depression shared the common
feature of enhancing availability of NE / 5HT at post syn receptor
-doesn’t totally explain etiology of depression
-LIKELY downstream effects rather than NT themselves (synaptic changes from antidep therapy can lead to alterations of gene expression that improve mood)

Question 9

Neurodegenerative hypothesis

Answer 9

-major depression is associated with neuronal loss in prefrontal cortex and hippocampus and
antidepressant therapies act by inhibiting-reversing this loss by stimulating neurogenesis
-Prodepressive pathways: stress induced activation of HPA axis that promotes neural apoptosis and also enhances excitotoxic actions of glutamate via NMDA receptors
-antidepressive pathways involve monoamines NE and 5HTacting on GPCR and BDNF acting on TrkB to switch on genes that promote neurogenesis as well as protecting against apoptosis

Question 10

Inhibition of NT reuptake

Answer 10

TCADs
SSRIs
SNRIs
NDRI
Mixed postsynaptic antag/serototin reuptake inhibitor

Question 11

Amitryptiline

Answer 11

TCAD

• block of serotonin and NE reuptake
• sedative action
• antimuscarinic action

Question 12

SSRI drugs

Answer 12

fluoxetine
Paroxetine
Escitalopram

Question 13

Venlafaxine

Answer 13

SNRI

Question 14

Buproprion

Answer 14

NE and DA reuptake inhibitor: NDRI

Question 15

Trazodone

Answer 15

Mixed postsynaptic antagonist-serotonin reuptake blocker

-Sedative action

Question 16

Phenelzine

Answer 16

MAOI
-block enzyme of major degradation pathway for NE and 5HT in neuron (allowing more presynaptic ccumulation and release) leading to chronic compensatory changes at synapse

Question 17

ECT

Answer 17

increases the amount and activity of rate limiting enzymes for synthesis of NE (tyrosine hyroxylase) and serotonin (typtophan hydroxylase)

Question 18

CNS stimulants

Answer 18

block reuptake pump and or increase release of NE, but also block DA reuptake or increase DA release

-cause mood elev in normals, NOT effective antidepressant as tolerance develops rapidly to mood elevating effects

Question 19

SE of SSRIs

Answer 19

acute: nausea, diarrhea, activation insomnia, restlessness, dry mouth
delayed onset: weight gain, sexual dysfunction, cognitive blunting

Very LOW likelihood of fatalities in overdose

Withdrawal: flu like–>severity related to t1/2 (shorter>longer; paroxetine>fluoxetine)

Question 20

SNRI SE

Answer 20

htn, anxiety

-more rapid appearance of withdrawal sx than SSRIs

Question 21

NDRI SE

Answer 21

(bupropion)

• anxiety
• potential for sz @ high doses

Question 22

Trazodone SE

Answer 22

drowsiness

Overdose: minor problems only

Question 23

TCAD SE

Answer 23

• poor SE profile leading to declining use
• sedation
• Antimuscarinic (blurred vision, constip, dry mouth, urinary hesitancy, fuzzy thinking)
• CV (orthostatic hypotension: alpha1 blockade), arrhythmias and sudden death in overdose
• Neuro: tremor, paresthesias, can see sz in overdose
• Metabolic: weight gain, sexual disturbances

Question 24

DDI for most agents

Answer 24

additive CNS depressant effects when used with other sedatives

Question 25

MAOIs DDI

Answer 25

hypertensive crisis with certain drugs and foods high in TYRAMINE (beer/wine/cheese)

Question 26

SSRIs + MAOIs

Answer 26

``` serotonin syndrome ([hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia)] ```

Question 27

SSRI DDI

Answer 27

Inhibition of P450 drug metabolizing enzymes by fluoxetine / paroxetine (CYP2D6)

Question 28

Pharmacokinetics TCADs/SSRIs/heterocyclic agents

Answer 28

Incomplete absorption, significant 1st pass effect, high protein binding/lipid solubility (high Vd) -->wide interpatient variations in plasma levels for a given dose

Question 29

Pharmacokinetics MAOIs

Answer 29

Inhibition is irreversible and occurs after drug no longer detectable in plasma (2 weeks)

Question 30

Bipolar storm

Answer 30

1. excessive activity in neuron A (2) widespread input from its dendrites triggers too much axonal flow, mediated by voltage-sensitive sodium channels (VSSC) (3) this in turn overly activates voltage-sensitive calcium channels (VSCC) linked to glutamate release (4) triggering excessive, chaotic, unpredictable neurotransmission from neuron A to neuron B (5) this “bipolar storm” is then by detected by postsynaptic NMDA receptors on neuron B (6) with subsequent excitation of its own VSSC and so on

Question 31

Lithium

Answer 31

-mech of antimanic action unclear - Requires 10-21 days for onset (effects greatest on cells with highest activity---use dependence) -eliminated via kidney -maintenance tx for manic and depressive episodes, commonly used in combination with other agents. adverse effects: - narrow therapeutic index - tremor, weakness, GI, decreased thyroid func, polyuria, polydipsia, confusion/sed/lethargy with mod toxicity - severe toxcity: sz, stupor coma - diuretics can decrease renal clearance by 25%--> increased Li levels (also with NSAIDs)