Andrade: Anti-depressants

Question 1

Antidepressant Classes: (3 Main Ones)

Answer 1

Tricyclic Antidepressants (TCAs)

Selective Serotonin (+/- NE) Reuptake Inhibitors (SSRIs and SNRIs)

Monoamine Oxidase Inhibitors (MAOIs)

Other

Question 2

Tricyclic Antidepressants (TCAs): (3)

Answer 2

Imipramine

Desipramine

Chlorimipramine

Question 3

Selective Serotonin (+/- NE) Reuptake Inhibitors (SSRIs and SNRIs): (4)

Answer 3

Fluoxetine (SSRI)

Sertraline (SSRI)

Paroxetine (SSRI)

Venlafaxine (SNRI)

Question 4

Monoamine Oxidase Inhibitors (MAOIs):

Answer 4

Phenelzine

Question 5

Antidepressant

Other: (4)

Answer 5

• Buproprion
• Nefazodone
• Trazodone
• Mirtazapine

Question 6

Non-Pharmacological Interventions:

Answer 6

Electroconvulsive therapy

Cognitive therapy and other forms of psychotherapy (appears to be more effective than drugs alone)
- Graph showing patients who remained well after acute treatment (highest percentage= those with prior cognitive therapy)

Question 7

TCAs/SSRIs/SNRIs/MAOIs

Elicit therapeutic effects on depression by:
MOAs:

Answer 7

TCAs/SSRIs/SNRIs/MAOIs: elicit therapeutic effects on depression by modulating the function of the monoamine systems in the brain

MOA of these Drugs: regulate serotonergic and noradrenergic neurotransmission by inhibiting the reuptake of these monoamines

Question 8

Function of Monoamine NTs:

Answer 8

Function of Monoamine NTs: neuromodulators that do not transmit fast excitatory or inhibitory signals, but rather regulate how neurons function (ie. how neurons integrate excitatory and inhibitory synaptic transmission)

Can therefore orchestrate the functional state of the brain (ie. appear to help “code” the behavioral state of the organism)

Question 9

Monoamine NTs

Serotonin:

Answer 9

Serotonin: neurons located mostly in the dorsal raphe nucleus of the brain
- Very active during awake/alert states

Question 10

Monoamine NTs

NE:

Answer 10

NE: neurons located in the locus ceruleus

• Unlike 5HT, not very much correlation with arousal level
• However, when something happens in the environment that excites the animal (ie. reward or anticipation of reward), activation of these neurons occurs
• Therefore, activity of neurons in this area marks saliency

Question 11

Imipramine:

Answer 11

Imipramine: inhibits NE and 5HT uptake with comparable potencies

Question 12

Chlorimipramine:

Answer 12

Chlorimipramine: preferentially inhibits 5HT uptake

Question 13

Desipramine:

Answer 13

Desipramine: preferentially inhibits NE reuptake

Question 14

TCAs

Delayed therapeutic onset:

Answer 14

Delayed therapeutic onset: generally takes 2-4 weeks to see effects (although effect of increasing monoamine availability is instantaneous)

Therapeutic delay also reflects the persistence of memory (time for brain to be “rewired”)

Question 15

TCAs
Delayed therapeutic onset

Suggests the need for:
Examples:

Answer 15

Suggests the need for the development of secondary adaptive responses to treatment

Examples:

• Changes in the beta-adrenergic receptor function
• Changes in the activity of the serotonergic neurons

Question 16

TCAs

Response varies:

Answer 16

Response varies: not all patients will respond to any given TCA

Question 17

TCAs

Absorption:

Answer 17

Absorption: generally well absorbed after oral administration
- Lipophilic: bind to plasma proteins (potential for DDIs) and accumulate in tissues

Question 18

TCAs

Metabolism:

Answer 18

Metabolism: in the liver by CYPs (potential for DDIs) with some production of active metabolites
- Inactivation and elimination of TCAs occurs over days

Question 19

TCAs
SEs

Anti-muscarinic:
Anti-alpha1 adrenergic:

Answer 19

Anti-muscarinic: dry mouth, constipation, blurred vision etc.

Anti-alpha1 adrenergic: postural hypotension

Question 20

TCAs
SEs

Other:
Low safety factor:

Answer 20

Other:
o Weight gain, sedation and sexual dysfunction
o Can induce mania in patients with undiagnosed BPD

Low safety factor: ODs potentially life-threatening due to cardiac toxicity (conduction delays and arrhythmias)

Question 21

Most widely used antidepressants

Answer 21

SSRIs AND SNRIs

Question 22

SSRIs: (5)

Answer 22

o	Fluoxetine*
o	Citalopram
o	Paroxetine*
o	Sertraline*
o	Fluvoxamine
.

Question 23

SNRIs: (3)

Answer 23

o Venlafaxin*
o Duloxetine
o Milnacipran
.

Question 24

SSRIs AND SNRIs

Delayed therapeutic onset:
Response varies:

Answer 24

Delayed therapeutic onset: generally at least 2-4 weeks (same as TCAs)

Response varies: not all patients respond to any given SSRI/SNRI (same as TCAs)

Question 25

SSRIs AND SNRIs

Augment therapeutic effect with 2nd generation APD:

Examples:

Answer 25

Augment therapeutic effect with 2nd generation APD: may be modestly augmented, but also increases adverse effects (ie. weight gain and akathisia)
- Examples: apripazole or olanzapine

Question 26

SSRIs AND SNRIs

Absorption:
Plasma protein binding:
Half Life:

Answer 26

Absorption: generally well absorbed after oral administration
o Plasma protein binding: variable
o Half Life: variable (less than a day to multiple days)

Question 27

SSRIs AND SNRIs

Metabolism:

Answer 27

Metabolism: by multiple hepatic enzymes

o In some cases, metabolites are active (ie. norfluoxetine is the active metabolite of fluoxetine)

Question 28

SSRIs AND SNRIs

Side Effects:

Answer 28

General: MUCH LESS prominent than with TCAs

Some side effects include:
o	Jitteriness
o	Insomnia
o	N/V/D
o	Headache
o	Dizziness
o	Fatigue
o	Sexual dysfunction

Question 29

MAOIs

Function of MAO:
Inhibition leads to:

Answer 29

Function of MAO: catalyzes the oxidation of serotonin and NE inside the synaptic terminal

Inhibition leads to increase in intraterminal concentrations of these NTs, thus increasing the concentration packaged into vesicles and a subsequent increase in the release of 5HT and NE

Question 30

MAOIs

Drugs in the Class: (4)

Answer 30

• Phenelzine*
• Selegiline
• Tranylcypromine
• Moclobemide

Question 31

MAOIs

MAO Isoforms:

Answer 31

Two Isoforms: show differential expression on 5HT and NE neurons

• MAO-A: found in dorsal raphe (5HT), locus ceruleus (NE) and substantia nigra (DA)
• MAO-B: only found in the dorsal raphe (5HT)

Question 32

Classic MAOIs (Phenelzine and Tranylcypromine):

Answer 32

Classic MAOIs (Phenelzine and Tranylcypromine): IRREVERSIBLY inhibit MAO-A and MAO-B

Question 33

Classic MAOIs (Phenelzine and Tranylcypromine)
Results:

Answer 33

Loss of ability to metabolize tyramine (indirect acting sympathomimetic) resulting in hypertensive crisis if tyramine levels get too high (“cheese effect”)

Potential DDIs with uptake inhibitors

Question 34

MAOIs

Moclobemide:

Answer 34

Moclobemide: REVERSIBLE inhibitor of MAO-A only (less likely to trigger cheese effect because if NE begins to rise, will outcompete drug for MAO-A and be broken down–> therefore, never gets too high)
o Not available in US

Question 35

MAOI

Selegiline:

Answer 35

Selegiline: REVERSIBLE inhibitor of MAO-B only (no cheese effect)

Question 36

Other Antidepressants: (4)

What can help with insomnia?

Answer 36

General: precise MOAs still unknown; use based upon relief of specific side effects
o Bupropion
o Mirtazapine
o Nefazadone
o Trazodone: sedative properties of trazodone help with insomnia