Depression and Drugs

Question 1

Half life of drug associated with probability of experience discontinuation syndrome

Answer 1

The shorter the half-life, the greater probability (short so gets removed fast, so more dramatic drop)

Most common with Venlafaxine and Paxil (Paroxetine)

Question 2

SSRIs vs TCAs

Answer 2

SSRIs are much safer than TCAs

• not lethal on overdose
• no anticholinergic and other autonomic effects)
• minimal sedation (Because no histamine activity)
• no cardiac toxicity

Question 3

Explain the actions of a tricyclic antidepressant (imipramine)

Answer 3

TCAs are hydrophobic so they are not very selective, thus they interact with many targets. There is a narrow theraputic index, and can become toxic quickly.

At low [] it inhibits neuronal uptake of NE, but then it blocks alpha receptors, histamine receptors, Ach receptors, and 5HT receptors and its uptake.

Question 4

Side effects associated with TCAs: cardiotoxicity

Answer 4

conduction block, arrhythmias, can be lethal

Question 4

Why is mirtazapine generally not used as first line treatment?

Answer 4

Causes a lot of NE release. Also nonspecific for inhibiting other post synpatic serotonin receptors. Biggest problem is ++++ sedation.

[Also causes reduction in white blood cells in small in small number of patients, produces appreciable sedation and weight gain due to antihistamine properties.]

Question 5

Side effects associated with TCAs: blockage of histamine H1 receptors

Answer 5

sedation, weight gain (causes increase in appetite)

Question 5

What are some potential side effects of SSRIs? (6)

Answer 5

• sexual dysfunction
• GI disturbances
• weight gain on long term use
• metabolic syndrome
• liver toxicity
• increased hemorrhage during surgery

Question 5

What is akathisia?

Answer 5

Movement disorder -inner restleness, need to be in constant motion. Symptom of Serotonin syndrome (mild)

Question 5

Which drugs inhibit Cytochrome p450 isozyme CYP2D6? (4 main ones)

Answer 5

Fluoxetine, Paroxetine, Sertraline, and Vortioxetine.

CYP2D6 metabolizes antidepressant, antipsychotics, antiarrhythmias, B-blockers, opiates, and many other drugs. Thus you get drug interaction

Question 6

What is the percentage of patients with major depressive disorder that respond to an inidtal anti depressant (with adequate dose and duration)?

Answer 6

50-60%

Question 6

What is a drug good for weakly blocking serotonin reuptake and sedatitve effect?

Answer 6

Trazodone - weak blocker and potent anti-histamine. Sometimes you desire thie effect if pt has trouble sleeping (“trazure your sleep”)

Question 7

1) Treatment for serotonin syndrome
2) treatment for abrupt serotonin discontinuation

Answer 7

1) remove the drug
2) put pt back on drug and slowly taper off

Question 8

What is the new drug that doesnt inhibit cytochrome p450 isozyme

Answer 8

Escitalopram (escited that its such a good drug)

Question 10

Etiology of Depression: What is the Monoamine Deficiency Hypothesis?

Answer 10

• deficiency of NE and/or serotonin causally related to symptoms
• depletion of brain amine by reserpine or reduction in braine NE can precipitate depressive episodes

Question 11

What do you need to monitor with ongoing care with SNRIs?

Answer 11

BP

Question 12

what is unique about bupropion

Answer 12

blocks dopamine reupta,e and has an active metabolite that weakly blocks NE reuptake. But it has NO ABILITY to block serotonin reuptake pump.

Question 13

What are the classes of antidepressants used to treat unipolar depression?

Answer 13

1. TCAs (tricyclic antidepressants)
2. MOAIs (monoamine oxidase inhibitors)
3. Serotonin Selective Reuptake Inhibitors (SSRIs)
4. Combine Serotonin-Norephinephrine Reuptake Inhibitors (SNRIs)
5. 2nd and 3rd generation heterocyclic atypical antidepressants

Question 14

Even though SSRIs are first line therapy, what are its side effects? (6)

Answer 14

1. sexual dysfucntion
2. GI disturbances
3. weight gain on long term use
4. metabolic syndrome
5. liver toxicity
6. increased hemorrhage during surgery

Question 16

The two main tricyclic antidepressants

Answer 16

Imipramine

Desipramine

Question 17

What are the four targets that cause side effects associated with TCAs use? (4)

Answer 17

1. blocks alpha 1 adrenergic receptors
2. Blocks histamine (H1) receptors
3. Blocks muscarinic acetylcholine receptors
4. Cardiotoxicity

Question 18

what causes serotonin syndrome?

Answer 18

too high of sertonin when on an SSRI and an MAOI. These extremely elevated levels of serotonin

Question 19

Currently approved SSRIs -most known one

Answer 19

Fluoxetine (Prozac)

Question 20

What are 4 pieces of evidence for serotonergic dysfunction in depression?

Answer 20

1. low serum tryptophan (makes serotonin)
2. reduced platelt uptake of 5-HT
3. low CSF 5-HIAA (5-HIAA is main metabolite of serotonin)
4. reduced 5-HT-2 recceptors in cerebral cortex

Question 21

What should we monitor for initially when administering drugs for treatment of depression? (5)

Answer 21

1. Routine Physical Exam
2. Complete Blood Count
3. Serum Electrolytes
4. Liver Function Studies
5. Thyroid Function Studies

Question 22

Pt presents with flu-like symptomes, imbalance. Also reports electrical feelings in extremities, sensory distrubances. Pt mentions her is hyperaroused with insomnia, and is experience anxiety, with intesinfiying depressive symptoms. This occurred suddenly. What is the cause (in assoc with this lecture)

Answer 22

**Serotonin discontinuation** these are the symptoms you see if you abruptly stop taking the drug

Question 23

what is seen in neuroimaging studies in depression? (3)

Answer 23

1. altered structure- reduced hippocampal region 2. receptor changes - reduced 5-HT-2 receptor concentration in cortical regions 3. changes in brain activity, hypofrontaility, increased activity in prefrontal and limbic regions

Question 24

What should you monitor with ongoing care with mirtazapine?

Answer 24

CBC

Question 26

Administration guidelines for treatment

Answer 26

* Start at low dose and titrate dose up gradually as tolerated. * Use enough dose to work * allow enough time to work typically atleast 6 weeks * avoid abrupt discontinuation to avoid problems with withdrawal reactions

Question 27

what is the correlation between hippocampal volume and duration of untreated depression?

Answer 27

length of depressed time without tx and deplation of hippocampus volume had a strong correlation

Question 28

What should you monitor in ongoing care with TCA treatment?

Answer 28

EKG

Question 30

What should you monitor with ongoing care with MAOIs?

Answer 30

Liver function studies and BP

Question 31

4 main MOA inhibitors

Answer 31

PHENELZINE (NARDIL) TRANYLCYPROMINE (PARNATE) ISOCARBOXAZID (MARPLAN) *\*first 3 are non selective * SELEGILINE (TRANSDERMAL PATCH) *\* Selective for MAOB at lower doses*

Question 32

Side effects associated with TCAs: blockage of alpha 1 adrenergic receptors

Answer 32

orthostatic **hypo**tension, erectile dysfunction

Question 34

what types of side effects do you get with SSRIs? Why do they occur?

Answer 34

SSRIS block reuptake of serotonin, thus yu have more serotonin around to interact with serotonin receptors. There are lots of receptors with different functions, and SSRIs are not selective. * 5HT1: antidepressant and anxiolytic actions * 5HT2: agtation, enrvousness, insomnia, sexual dysfunction * 5HT3: nausea, vomiting, HA

Question 35

Major depressive episode: conditions and definition

Answer 35

depressed mood or anhedonia (loss of the capacity to experience pleasure) for atleast 2 weeks

Question 36

What regulated synaptic plasticity in termes of depression??

Answer 36

Modification in synaptic AMPA and NMDA receptor (by insertion, internalization, and trafficking)

Question 37

Side effects associated with TCAs: blockage of muscarinic acetylcholine receptors

Answer 37

atropine like effects: blurred vision, dry mouth, constipation, urinary retention, mental confusion

Question 38

With major depressive disorder, what are following conditions you need atleast 5 of for greater than 2 weeks?

Answer 38

SIGECAPS **Sleep** Disturbance **Interest** decreased **Guilt** **Energy** decreased **Concentration** decreased **Appetite** disturbed **Psychomotor** agitation or retardation **Suicidal** Ideation

Question 39

what is the significance of tyramine with MAO inhibitors?

Answer 39

- tyramine is an aa rich in certain foods - tyramine is metabolized by both types of MAOs, gets broken down in the gut so doesn't get to CNS - if on an MAO inhibitor, tyramine isn't broken down, gets into CNS, similar to NE structure, displaces NE, - NE sudden release causes hypertensive state and huge spike in BP/hypertensive crises

Question 40

Mechanism of action of TCAs

Answer 40

they inhibit the reuptake pumps responsible for recapturing NE and 5HT (serotonin)

Question 41

imipramine is now used as a tricyclic antidepressant. what was it originally used to treat?

Answer 41

It was developed as an antihistamine, hence why a side effect now is SEDATION.

Question 42

What is the MOA of mirtazapine and the effect?

Answer 42

mirtazapine works not by inhibiting serotonin reuptake pumps but instead inhibits presynaptic alpha 2 receptors. Recall that those receptors are involved in negative feedback loop where NE inhibits further release. Inhibting these receptors leads to an increase release of NE.