ANTIDEPRESSANTS

Antidepressant Pharmacokinetics Major Depressive Disorder

Orally administered Symptoms: Sadness, fatigue, ↓concentration,
90-95% bound to plasma proteins → don’t use w/Warfarin anhedonia, ∆appetite, ∆sleep, suicidal ideations
Metabolized by liver → Excreted by kidneys Rx: Takes 2-4 weeks, 85% remission
Long half-lives → several wks for therapeutic levels Prevalence: 15% of all adults during any year of life
Small therapeutic index → electrophysiologic CNS effects for months/years (vs. episodes that last wks-month)
Cause: NE + 5HT ± DA imbalance
I. 5 general classes of antidepressants
a. Tricyclics
b. SSRIs
c. SNRIs
d. Atypical or miscellaneous
e. MAOIs
II. Anti-Depressant Side Effects
a. Sedation – largest initial problem (↑5HT)
b. Cardiovascular – most serious side effects
i. ↑NE → Orthostatic HTN → ↑HR
ii. Anti-muscarinic effects → ↓SA node effects → unmask SNS influences
c. Seizures – lower seizure threshold (↑NTs in brain)
d. Sexual dysfunction – very troubles, leads to noncompliance (↑5HT)
e. Blood abnormalities - Bone marrow depression, thrombocytopenia, eosinophilia
i. ↑Bleeding - esp. w/Warfarin, Aspirin, NSAIDs
ii. Hyponatremia (elderly) – headache, weakness, unsteady, confusion, ↓concentration/memory

f. Serotonin Syndrome - excess 5HT → autonomic effects (~malignant hyperthermia)

i. CNS: agitation, hallucinations, coma, ∆ mental status, ↓coordination
ii. Muscle: twitching, stiffness/tightness
iii. Cardiac: tachycardia, ↑ or ↓BP
iv. Other: sweating/fever, nausea/vomiting, diarrhea
g. Manic episodes
i. ↑energy, insomnia, racing thoughts/speech, recklessness, grand ideas, excessive
happiness/irritability
h. Suicidality – in children/teens/young adults (suicidality is separate from mood disorder)
III. Anti-Depressants Drug Interactions
a. CNS depressants (alcohol)
b. anti-muscarinic
c. MAOIs
d. sympathomimetics
IV. Tricyclic Antidepressants (TCAs) – “-tryptyline” & “-ipramine”
a. MOA – Blocks the “amine” presynaptic reuptake pump → inhibits reuptake of 5HT & NE
i. ↑NE = ↑BP, ↓Appetite, Alertness & Anti-SLUDE effects
1. Dry mouth, urinary retention, constipation, ↓secretions
ii. ↑5HT= ↑Mood, ↓Appetite, Sedation & ↓Libido/Sexual function
b. Uses
i. Depression, Panic disorders, Generalized Anxiety Disorder “Tri-C” Toxicity:
ii. Neuropathic pain, Fibromyalgia – blocks Na+ channels also Anti-Cholinergic Toxidrome
c. Side Effects – promiscuous TCAs also block Convulsions (Seizures)
i. mAChR, Histamine & α1 receptors Coma
1. Anti-cholinergic = Anti-SLUDE effects & Delirium Cardiotoxic (Arrhythmia)
a. Confusion/Hallucinations in Elderly – used Rx = NaHCO3
Nortriptyline Respiratory depression
2. Anti-histamine = Drowsiness/Sedation, Weight gain Hyperpyrexia
3. α1 receptors antagonism = Orthostatic hypotension
 Tricyclics
(-triptyline or -ipramine)
Blocks the “amine” presynaptic reuptake pump → inhibits reuptake of 5HT & NE
 5HT & NE
Tertiary Amine TCAs - “DA Cl-IT” Secondary Amine TCAs - “DAMPN”
MORE anti-cholinergic side effects
LESS anti-cholinergic side effects
Blocks 5HT & NE reuptake
Higher affinity for blocking just NE reuptake
Long acting w/active metabolites
Drug Comments Drug Comments
Can be given I.M.
Cardioprotective indicated for elderly (metabolite of
Amitryptyline Nortriptyline
most common TCA used for neurogenic amitriptyline)
pain
used for OCD
Clomipramine Protriptyline no sedation (for sleepy depressives)
non-selective, can cause seizures
long-acting “pamoate” formulation
available
Imipramine Desipramine metabolite of imipramine
Can be given i.m.
Can use for Panic disorder
↑ sedation (very sedating) Very new with ↑ seizure potential (stronger
Trimipramine Maprotiline
moderate anti-cholinergic effects on NE)
Dibenzodiazepine that is a metabolite of
↑ sedation (used as hypnotic in insomnia) Loxapine (antiphyschotic)
Doxepin Amoxapine
absent cardiovascular side effects Therefore it has dopaminergic &
adrenergic mechanisms

SSRIs
Selective 5HT reuptake inhibitors → ↑ 5HT
Monopolar depression (1st choice)
Premenstrual dysphoric disorder (1st choice)
Uses Panic disorders
Social anxiety
GAD
More mood related
Don’t have as many NE or autonomic side effect
Side Effects
Can have sexual side effects (dose related, stimulation of 5HT2A causes inhibited orgasm)
More tolerable than TCAs
* = CYP2D6 inhibitors
Tamoxifen
NOTE  Estrogen receptor antagonist– chemo prodrug activated by CYP2D6
 So with inhibited CYP2D6 less active tamoxifen is available
 ↓ efficacy if taken w/* drugs → ↑ breast cancer recurrence, can use “-pram” SSRI’s
SSRIs Comments Interactions Other uses
Bulimia
Fluoxetine* T½ = 72 hr CYP2D6 inhibitors OCD
(Prozac)
(obsessive thoughts)
CYP2D6 inhibitors
Highly anticholinergic side effect (can cause delirium)
Paroxetine* Can cause Erectile dysfunction (reduced NO) PTSD
(Paxil) Viagra not effective
Slows orgasm ( stimulation of 5HT2A)
if taking paroxetine
Sertraline* T½ = 36 hr CYP2D6 inhibitors PTSD
(Zoloft)
Citalopram Safe with Tamoxifen
(Celexa)
Escitalopram adolescent approved Safe with Tamoxifen
(Lexapro)
Fluvoxamine
(Luvox)
 SNRIs
“Mi DVD”
Selective 5HT & NE reuptake inhibitors → ↑ 5HT & ↑ NE
(Have better affinity for just 5HT & NE whereas tricyclics have affinity for a lot of transporters)
“Sleepy” Depressives
Neuropathic pain
Uses
Fibromyalgia (Milnacipran & Duloxetine)
GAD
Less anti-cholinergic & anti-histaminic effects than TCAs
Side Effects
(Insomnia, nausea, dizziness, somnolence, fatigue, dry mouth, constipation, headache)
Within this class, the affinity for NE vs. 5-HT can vary – allows for some more fine tuned control
NOTE
Many people still need noradrenergic boost to help with their depression
SNRIs Comments Affinity 5HT:NE Other uses
Milnacipran T½ = 6-8 hrs 1:1 fibromyalgia approved
(Ixel)
Duloxetine fibromyalgia approved
T½ = 10 hrs, 1:10
(Cymbalta) (neuropathic pain)
T½ = 7-8 hrs
Venlafaxine Phenethylamine that shows withdrawal & rebound 1:30 PTSD
(Effexor)
effects w/chronic use
Desvenlafaxine T½ = 11 hrs
1:30
(Pristiq) Isomer of Venlafaxine

Atypical or Miscellaneous
Antidepressants
Drug MOA Uses Side Effects
Low dose (Zyban)
smoking cessation No sexual side effects
Bupropion NE & DA reuptake inhibitor -No 5HT effects
(Wellbutrin) High dose (Wellbutrin)
(Zyban)
(Like cocaine) 3x ↑ Seizures
Antidepressant
Avoid with eating disorders
ADHD
Central α2 auto receptor antagonist:
↑ NE & ↑ 5HT
Anti-depressant Blocks H1 receptors:
Also blocks
Mirtazapine PTSD Sedation (most prominent)
α1
Premature ejaculation (in. 5HT2A) Weight gain
5HT2A
H1
No cardiac or anticholinergic
effects
Sedative-Hypnotic (insomnia) esp. Monitor for
Trazodone 5HT reuptake inhibitor
in the hospital for depressive patients Priapism
Orthostatic hypotension
arrythimias
5HT reuptake inhibitor
Dual Action: Low incidence of sexual side
Vilazodone &
- Anti-depressant & Anxiolytic effects
Partial 5HT1A agonist
 MAOIs
Irreversibly inhibits monoamine oxidase → ↑ 5HT, ↑ NE & ↑ DA
Monoamine oxidase normally metabolizes monoamines
Treatment-resistant depression (refractory deperession)
Uses
Social anxiety
Side Effects
**TYRAMINE** - found in aged foods (cheese) & fermented beverages (wine)
 MAO metabolizes Tyramine & NTs
Drug interaction
 Tyramine is a catecholamine (NE/DA) releaser
 Block MAO → Tyramine builds up → ↑ Catecholamine release → HTN crises
MAOIs Other uses
Tranylcypromine
Isocarboxazid
Phenelzine Social anxiety (gold standard)

Delirium causing medications

Highly anticholinergic agents Anti-inflammatory agents Cardiovascular Antihistamines Opioid analgesics
Tricyclic antidepressants

Paroxetine
Digoxin Cimetidine
Prednisone meperidine
Methyldopa Ranitidine
Low potency, first-gen antipsychotics
Chlorpromazine
Thioridazine

MOOD STABILIZERS
I. Bipolar Disorder
a. Depression + Mania (extreme ups and downs)
b. Rx with mood stabilizer (levels them out) + antipsychotic (treats psychosis-induce mania & ↑mood)
Most prescribed for bipolar
Mood
MOA Uses Side Effects Other
Stabilizer
GI– nausea/diarrhea Oral, Enters CNS slowly
-↑ion in lumen Long-acting (T ½=24 hr)
Not well understood: Cardiac - arrhythmia Excreted 95% unchanged in
↓Nerve metabolism CNS – drowsiness, weight gain, insomnia urine
Renal – polyuria, thirst/dry mouth, nephrogenic Not plasma prot. bound
Blocks Na+ actions DI Excreted in milk
Bipolar -ADH inhibitor, -no breast feeding
↓ NT release Disorder -↓Na reabsorption in PCT Ineffective in 30%
Lithium ∆ Reuptake 5HT/NE/DA Thyroid – diffuse enlargement, hypothyroidism
(rare) Diuretics
↓Protein kinases (PKC) in Blood - ↑PMNs w/chronic Rx ↓Li levels
CNS & inhibits inositol Acute Li Toxicity- altered mental status, coarse -osmotic, acetazolamide
monophosphatase tremor ataxia, coma, convulsions, vomiting, ↑Li levels
profuse diarrhea -thiazides, loops
~ NMS & Serotonin Synd but,
NO hyperthermia or fever NSAIDs - ↑Li levels

Other Mood stabilizers

Mood Stabilizer MOA Uses Side Effects Other
Anticonvulsant
Na+ Channel Blocker Bipolar Depression Minimal risk of inducing
Lamotrigine ↓GLUT release no effect on mania mania

Anticonvulsant
Bipolar Disorder = DOC
Valproic Acid Na+ Channel Blocker
Mania
Ca2+ & GABA effects
Anticonvulsant Off-label use
Carbamazepine Na+ Channel Blocker
Tx-resistant, mild Bipolar Disorder
Under investigation
 Antipsychotics
For maintenance therapy
Olanzapine Used with mood stabilizers to boost mood & ↓
Given with Li &
Aripiprazole ↓ DA psychosis induced mania
Lamotrigine
Risperidone Used for maintenance therapy
Quetiapine Used with mood stabilizers to boost mood & ↓
Ziprasidone ↓ DA psychosis induced mania Given with Li & Valproate
Lurasidone Used for maintenance therapy