pharmacology of depression

Question 1

Which neurotransmitters play a role in: depressed mood, apathy, sleep disturbance, fatigue, guilt, changes in weight/appetite

Answer 1

Depressed mood: NE-5HT-DA projections from brainstem nuclei. Apathy: NE and DA. Sleep disturbances: NE-5HT-DA. Fatigue: NE and DA. Guilt: 5HT. Changes in weight or appetite: 5HT

Question 2

Monoamine theory of depression

Answer 2

Proposes that depleted brain NE and 5HT induce depression. Depression is due to dysregulation of pre and post synaptic control of NE-5HT neurotransmission.

Question 3

Monoamine theory of depression limitations

Answer 3

Does not totally explain etiology of depression b/c drugs that enhance NE-5HT-DA availability in synapse work immediately, while mood elevating effect is delayed 2-3 weeks.

Question 4

Describe acute and chronic changes following antidepressant therapy

Answer 4

acute: inhibit 5HT or NE reuptake/breakdown. Chronic: increased transcription of genes which promote function and survival of cells

Question 5

neurotrophic hypothesis of antidepressant therapy

Answer 5

stress causes increased glucocorticoids which leads to decreased Brain derived neurotrophic factor (BDNF) gene expression causing neuronal atrophy in the CA3 region of brain (prefrontal cortex and hippocampus). Antidepressive pathways involve monoamines NE and 5-HT acting on G protiein receptors, and BDNF acting on TrkB to turn on genes that promote neurogenesis and protect against apoptosis

Question 6

Tricyclic antidepressants MOA

Answer 6

Acutely blocks reuptake of NE and/or 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse. Used as 2nd line agents due to poor side effect profile

Question 7

List Tricyclic antidepressants

Answer 7

amitriptyline, imipramine, desipramine (only blocks NE reuptake)

Question 8

Tricyclic antidepressants side effects

Answer 8

sedation [Amitriptyline > Desipramine], antimuscarinic such as dry mouth, urinary hesitancy [Amitriptyline > Desipramine-Nortriptyline], cardiovascular such as orthostatic hypertension (a1 blockade) and sudden death in overdose, neurologic such as seizures during overdose

Question 9

Serotonin selective reuptake inhibitors (SSRIs) MOA

Answer 9

Acutely blocks reuptake of 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse

Question 10

List Serotonin selective reuptake inhibitors

Answer 10

fluoxetine, paroxetine, sertraline

Question 11

SSRIs side effects

Answer 11

Acute: Nausea-diarrhea [5HT3] (increased serotonin effects in GI tract), activation-insomnia (commonly), restlessness [5HT2] (akathisia), somnolence (occasionally); dry mouth. Delayed onset: weight gain, sexual dysfunction [5HT3], cognitive blunting. LOW likelihood of fatalities in overdose

Question 12

SSRIs drug interactions

Answer 12

SSRI + MAOI or SSRI + opioids causes serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia). Also Inhibition of P450 drug metabolizing enzymes by fluoxetine. St. Johns Wort induces P450 drug metabolizing enzyms

Question 13

Serotonin and norepinephrine reuptake inhibitors (SNRIs) MOA

Answer 13

Acutely blocks reuptake of NE and 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse

Question 14

List Serotonin and norepinephrine reuptake inhibitors (SNRIs)

Answer 14

venlafaxine

Question 15

Venlafaxine side effects

Answer 15

Hypertension, anxiety

Question 16

Bupropion MOA

Answer 16

Norepinephrine and dopamine reuptake inhibitor

Question 17

Bupropion side effects

Answer 17

anxiety, seizures at high doses

Question 18

Trazadone MOA

Answer 18

Mixed postsynaptic antagonist-serotonin reuptake inhibitor

Question 19

Trazadone side effects

Answer 19

drowsiness. Overdose only leads to minor problems

Question 20

Mirtazapine MOA

Answer 20

Acute effect is inhibition of presynaptic a2 adrenergic receptor that decreases NE release, such a block results in increased NE release

Question 21

Mirtazapine side effects

Answer 21

weight gain

Question 22

MAOIs MOA

Answer 22

Block enzyme of major degradation pathway for NE and 5HT in neuron, presumably allowing more presynaptic accumulation and subsequent release into the synapse and again leading to chronic compensatory changes at the synapse

Question 23

MAOIs examples

Answer 23

Phenelzine and Selegiline

Question 24

MAOIs side effects

Answer 24

postural hypotension, seizures, shock, hyperthermia in overdose

Question 25

MAOIs drug interactions

Answer 25

Hypertensive crisis with certain drugs (meperidine, decongestants) or with foods high in tyramine (beer/wine/cheese) [results from acute increase in norepinephrine displacement].

Question 26

Electroconvulsive therapy MOA

Answer 26

Increases the amount and activity of the rate-limiting enzymes for synthesis of norepinephrine (tyrosine hydroxylase) and serotonin (tryptophan hydroxylase) resulting in increased levels of these neurotransmitters

Question 27

MAOIs pharmacokinetics

Answer 27

•Inhibition is irreversible – continues after drug no longer detectable (2 weeks)

Question 28

SSRIs / Heterocyclic agents / TCADS pharmacokinetics

Answer 28

Wide interpatient variations in Cp for given dose

Question 29

Describe neurotransmission during a bipolar storm

Answer 29

(1) excessive activity in neuron An(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 30

Pharmacotherapy to stabilize mood in bipolar

Answer 30

lithium and valproate

Question 31

Pharmacotherapy for mania in bipolar

Answer 31

atypical antipsychotics

Question 32

pharmacotherapy for depression in bipolar

Answer 32

lamotrigine or antidepressants

Question 33

Pharmacotherapy for acute manic symptoms in bipolar

Answer 33

with BDZs (alprazolam, lorazepam) or atypical antipsychotic agents

Question 34

MOA of valproate

Answer 34

Blocks voltage sensitive sodium channels

Question 35

MOA of lamotrigine

Answer 35

block voltage sensitive calcium channels

Question 36

Lithium MOA

Answer 36

Enhance 5HT action and/or diminish NE and DA effect by interfering with PIP recycling. PIP recycling is required for G protein actions Use dependent

Question 37

Lithium side effects

Answer 37

interference with Gs and Gi in thyroid leads to hypothyroidism and in kidney leads to polyuria-polydipsia

Question 38

Lithium pharmacokinetics

Answer 38

competes with Na for reabsorption, so increased Na leads to decreased Lithium plasma levels

Question 39

lithium drug interactions

Answer 39

Diuretics can decrease renal clearance by as much as 25%. This increase in plasma lithium levels is also seen with NSAID analgesic agents.