Antidepressant Part 2

Question 1

TCAs - MOA

Answer 1

TCAs block the reuptake transporter proteins

Increase synaptic NE and 5-HT (immediate)

Elevation of mood after 2-3 weeks

PK: 
Well absorbed orally
Highly lipophilic
Dosed at night (sedative)
Metabolized in liver
Long half-lives (18-70 hrs)

Question 2

TCAs - Therapeutics Uses

Answer 2

Depression, Bipolar disorder

Neuropathic pain
Chronic insomnia
Panic disorder
ADHD
OCD
Nocturnal enuresis

Question 3

TCAs - Adverse Effects

Answer 3

Postural Hypotension

Increased risk of successful suicide

Cardiac toxicity (low therapeutic index)

FLUSH

Question 4

TCAs - Drug Interactions

Answer 4

MAOIs - toxic synergism (irritability and convulsions) - SS

Direct-acting sympathomimetics

Indirect-acting sympathomimetics

Anticholinergic agents - additive effects; GI dysfunction

CNS depressants - increase sedative effect

Alcohol, opiates, benzodiazepines, antihistamines, antipsychotics, OTC cold medicines

Hepatic enzyme (CytP450) inhibitors (SSRI) - increase TCA - toxic

Hepatic enzyme inducers (barbituates) - decrease TCA effect due to increased metabolism

Question 5

SSRI - MOA

Answer 5

Binds to SERT → ↑ 5-HT levels in synapse

Effect appears after 2-3 weeks

No effect on NET

Increased cAMP → CREB phosphorylation → increased BDNF → increased neurogenesis

PK:
Well absorbed after oral administration
Dosed in morning (increase alertness)
Highly lipophilic
Half-lives vary: 15-24 hrs
Fluoxetine is longer acting (24-96 hrs)

Question 6

SSRIs - Therapeutic Uses

Answer 6

Depression

Generalized anxiety
Panic disorder
Social anxiety
Obsessive-compulsive disorder (OCD)
PTSD (sertraline and paroxetine)
Premenstrual dysphoric syndrome
Vasovagal symptoms (post-menopause)
Bulimia nervosa (Fluoxetine=Prozac)

Question 7

SSRIs - Adverse Effects

Answer 7

GI - Anorexia, nausea, vomiting (usually disappear in 1 wk); diarrhea

Sexual dysfunction, weight gain, insomnia, suicide risk

Discontinuation syndrome:
- Dizziness, nausea, vomiting, flulike symptoms, anxiety, irritability
- More apparent with short-acting SSRIs:
paroxetine>fluvoxamine>sertraline >citalopram»>fluoxetine

Question 8

SSRIs - Drug Interactions

Answer 8

Serotonin syndrome: patient presents with hyperthermia, agitation, hypertension, and convulsions (MAOIs, TCAs, opioids, triptans).

SSRI (mainly fluoxetine and paroxetine) are inhibitors of CYP450 system - increase effects of several drugs given concomitantly (TCAs).

Coumarin anticoagulants (warfarin) - may increase effect.

Question 9

SNRI MOA

Answer 9

Selectively block 5-HT & NE reuptake leading to accumulation of 5-HT & NE

Effect appears after 2-3 weeks

Lack potent antihistamine, alpha-adrenergic blocking, and anticholinergic effects of TCAs!

PK:
Well absorbed after oral administration
Dosed in morning (increase alertness)
Highly lipophilic
Metabolized in liver (Venlafaxine, Duloxetine)
Half-lives vary: 15-24 hrs

Question 10

SNRIs - Therapeutic Uses

Answer 10

Depression

Other uses:
Generalized anxiety disorder (Venlafaxine, Duloxetine)
Social anxiety disorder (Venlafaxine)
Diabetic neuropathy (Duloxetine)
Fibromyalgia (Milnacipran, Duloxetine)

Off-Label:
PTSD
Premenstrual dysphoric disorders
Hot flashes

Question 11

SNRIs - Adverse Effects

Answer 11

Venlafaxine and desvenlafaxine (Pristig): may raise blood pressure (diastolic hypertension).

Sexual dysfunction, Suicide risk

Discontinuation syndrome: (FLUSH)
-Dizziness, nausea, vomiting, flu-like symptoms, anxiety, irritability

Question 12

SNRIs - Drug Interactions

Answer 12

Serotonin syndrome: patient presents with hyperthermia, agitation, hypertension, and convulsions (MAOIs contraindicated).

Drugs that inhibit cytochrome P450 enzymes (IA2 or 2D6) - increase effects of duloxetine.

Warfarin: increases bleeding (SNRI &laquo_space;SSRI)

Alcohol - counteract SNRI; increase intoxicant effects

Question 13

Serotonin Receptor Antagonists

Answer 13

Highly sedating - commonly used for treating insomnia as an unlabeled hypnotic

5-HT2 receptor and alpha1-adrenergic receptor antagonist

Weak SERT inhibitor and antihistamine

Fewer side-effects than TCAs

Sexual side-effects - uncommon (&laquo_space;SSRIs)

Question 14

Mirtazapine

Answer 14

Use: Depression (w/ insominia)

MOA:

• Presynaptic alpha2-adrenergic receptor antagonist (Increases NE and 5-HT)
• 5-HT2 and 5-HT3 receptor antagonist
• Block histamine H1 receptors (sedative effects)

AE: increase appetite, weight gain (5-HT2C), Agranulocytosis (rare)

Question 15

Bupropion

Answer 15

Use: Depression (Wellbutrin), Smoking cessation (Zyban)
-Off-label: Neuropathic pain and weight loss

MOA:

• DAT and NET inhibitor (weak at SERT)
• Downregulates beta-adrenergic receptors?
• Noncompetitive antagonist at nicotinic acetylcholine receptors

AE: very little/no sedation, Contraindicated for patients with seizure disorders, Suicide risk

DOES NOT cause CV effects, weight gain, or sexual dysfunction

Question 16

Suicide Risk and Antidepressants

Answer 16

FDA requires that all antidepressants carry black box warnings, the strictest warnings for prescriptions.

Antidepressants are more likely to reduce suicide risk in the long run by improving mood. (Monitoring in 1st month is essential)

Question 17

Goal of MDD Treatment

Answer 17

Remission of all symptoms

Single-trial antidepressants: 30-40% success

Augmentation or switch: 70-80% success

Continuation therapy: 6-12 months

Question 18

Treatment-Resistant Depression

Answer 18

Inadequate drug dosage

Inadequate duration of therapy

Patient non-compliance

Question 19

Ketamine

Answer 19

Potent, high-affinity, noncompetitive Nmethyl-D-aspartate (NMDA) receptor antagonist

Use: Anesthetic/analgesic

Antidepressant effectiveness: ~1 week

Esketamine: nasal formulation

Question 20

Alternative Treatments

Answer 20

• ECT
• Deep brain stimulation (rTMS)
• Vagal stimulation
• St. John’s wort (herbal; hypericin)
• Exercise
• Helps reduce depression
• Increases adult hippocampal neurogenesis