Antidepressant Part 2 Flashcards
TCAs - MOA
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)
TCAs - Therapeutics Uses
Depression, Bipolar disorder
Neuropathic pain Chronic insomnia Panic disorder ADHD OCD Nocturnal enuresis
TCAs - Adverse Effects
Postural Hypotension
Increased risk of successful suicide
Cardiac toxicity (low therapeutic index)
FLUSH
TCAs - Drug Interactions
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
SSRI - MOA
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)
SSRIs - Therapeutic Uses
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)
SSRIs - Adverse Effects
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
SSRIs - Drug Interactions
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.
SNRI MOA
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
SNRIs - Therapeutic Uses
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
SNRIs - Adverse Effects
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
SNRIs - Drug Interactions
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 «_space;SSRI)
Alcohol - counteract SNRI; increase intoxicant effects
Serotonin Receptor Antagonists
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 («_space;SSRIs)
Mirtazapine
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)
Bupropion
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
Suicide Risk and Antidepressants
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)
Goal of MDD Treatment
Remission of all symptoms
Single-trial antidepressants: 30-40% success
Augmentation or switch: 70-80% success
Continuation therapy: 6-12 months
Treatment-Resistant Depression
Inadequate drug dosage
Inadequate duration of therapy
Patient non-compliance
Ketamine
Potent, high-affinity, noncompetitive Nmethyl-D-aspartate (NMDA) receptor antagonist
Use: Anesthetic/analgesic
Antidepressant effectiveness: ~1 week
Esketamine: nasal formulation
Alternative Treatments
- ECT
- Deep brain stimulation (rTMS)
- Vagal stimulation
- St. John’s wort (herbal; hypericin)
- Exercise
- Helps reduce depression
- Increases adult hippocampal neurogenesis
