• Dysregulation of NT receptors resulting in pre- and post-synaptic receptors
• This helps explain the delay in AD effect
• 5-HT system targeted in this theory
• Changes in pre- and post-synaptic receptor density (sensitivities) is described as being "down-regulated"

• Thyroid and hypothalamic pituitary axis dysregulated
• If levothyroxine doesn't work, they need to be on Antidepressant therapy

5-HT

depressed mood, anxiety, panic, phobia, obsessions/compulsions, food craving

DA

anhedonia, decreased energy, poor memory/cognition, impaired attention

NE

impaired attention, problems concentrating, deficiencies in working memory, slowness of information processing, depressed mood, psychomotor retardation, fatigue

- A period of at least 2 wks in which pt exhibits depressed mood and/or anhedonia

> 5 out of 9 symptoms:

• changes in weight
• sleep
• psychomotor agitation or retardation
• loss of energy (small tasks)
• feeling of worthless/guilt
• difficulty concentrating and making decisions
• SI (life is not worth living, ppl would be better off if I were gone)

-Symptoms do not meet criteria for mixed episode

-Must impair social or occupational areas of functioning

-Not due to substance abuse or general medical conditions

-Not due to bereavement -- loss of loved one in the past two months

-MDD = > Major Depressive Episode

-The episode has ended when the full criteria for the major depressive episode have not been met for at least 2 conescutive months

-R/o mania or hypomania

3 Cardinal Signs of Atypical Depression

1. Overeating
2. Hypersomnia
3. Leaden paralysis

• Mild, moderate, severe
• Psychotic features
• Catatonic features
• Melancholic features
• Atypical features
• Postpartum features

Less severe symptoms --> more chronic and persistent

• Depressed mood is present for > 2 years
• During period of depressive mood, must exhibit > 2 of the following: change appetite, sleep, low energy, low self-esteem, poor concentration, hopelessness
• Cannot be w/o symptoms for > 2 mo period
• The disturbance is not better accounted for by chronic MDD or MDD in partial remission and there has never been a manic episode

Cardiovascular Agents

methyldopa, reserpine, clonidine, beta-blockers

Sedatives Hypnotics

EtOH, benzodiazepines, barbiturates, chloral hydrate

Analgesics

Opioids

Hormones

corticosteroids, progesterone, estrogen withdrawal, anabolic steroids

Others

interferon, accutane, withdrawal from stimulants

Biological:

• stroke
• hypothyroidism
• anemia
• Parkinsons disease
• premenstrual dysphoria
• syphilis
• lupus

Psychological reaction:

• chronic pain
• HIV/AIDS
• cancer
• diabetes
• CHF

Indications

Major depression, tx-resistant depression, depression w/ psychosis, depression in pregnancy

6-12 tx usually required, admin 2-3 wk

Response in 1st 1-2 wks, follow-up w/ pharmacotherapy

ADRs

HA, cognitive, impairment, confusion, memory impairment (anterograde, retrograde amnesia), muscle soreness

• Glycopyrrolate -- to reduce airway secretions
• Short-acting barbiturate -- anesthesia
• Succinylcholine -- muscle relaxant
• Nifedipine or esmolol -- antihypertensive -- control for increase in pulse and BP

MOA

Affinitiy for:

GABA-a and GABA-b

5-HT1, 5-HT3, and 5-HT4 antagonism

5-HT reuptake inhibition

Drug Interactions

CYP2C9/3A4 inducer; 1A2 inducer (mild)

Reports of decreased serum concentrations of OC, theophylline, warfarin, protease inhibitors

Serotonin Syndrome

Indications

refractory and atypical depression

ADRs

Orthostatic hypotension, bradycardia, insomnia, weight gain, sexual dysfunction, dry mouth, constipation

MAOI Drug Interactions

• Meperidine -- circulatory collapse
• Sympathomimetics -- HTN crisis (amphetamines, pseudoephedrine, methylphenidate)
• Serotonergic agents: Serotonin syndrome -- Dextromethorphan, Buspirone, SSRIs/SNRIs, TCAs

• Pheochromocytoma
• Hepatic or renal dysfunction
• Cardiovascular disease or defect
• Excessive caffeine use
• Elective surgery
• Sympathomimetic therapy
• SSRIs (2 week wash-out, 5 weeks for fluoxetine)

• Major depression
• Neuropathic pain
• Anxiety disorders (OCD, panic disorder)
• Enuresis

• Desipramine
• Nortriptyline
• Protriptyline

TCAs: Secondary Amines

MOA

NE and 5-HT Reuptake Inhibitors

• H1, ACh, and Alpha1 blockade
• Primary effects on NE
• Better tolerated than tertiary amines

• Amitriptyline
• Imipramine
• Clomipramine
• Doxepin
• Trimipramine

TCAs: Tertiary Amines

MOA

NE and 5-HT Reuptake Inhibitors

• H1, ACh, and Alpha1 blockade
• Primary effects on 5-HT

TCAs: Secondary Amines

Plasma Levels

50-150 ng/mL

Toxic > 500 ng/mL

TCAs: Tertiary Amines

Plasma Levels

250 ng/mL

Toxic > 500 ng/mL

• Anti-ACh Side Effects
• Sedation, weight gain, sexual dysfunction
• Decrease in seizure threshold
• Cardiovascular: orthostasis, tachycardia, ST depression, T-wave flattening, QRS prolongation, QTc prolongation, ventricular fibrillation, lethal overdose
• Avoid in: elderly, prostatic hypertrophy, narrow angle glaucoma, erectile dysfunction, memory impairment

• Fluoxetine
• Sertraline
• Paroxetine
• Fluvoxamine
• Citalopram
• Escitalopram

• Nausea
• Insomnia
• Headache
• Sexual dysfunction

• Nausea
• Diarrhea
• Insomnia or sedation
• Sexual dysfunction
• More GI upsets than other SSRIs

• Constipation
• Dry mouth
• Weight gain
• Nausea
• Headache
• Sexual dysfunction

• Sedation
• Nausea
• Headache
• Sexual dysfunction
• Drug interactions more common

• Nausea
• Headache
• Sedation or Insomnia
• Sexual dysfunction

• Anxiety
• Agitation
• Irritability
• Sleep disturbances
• Dizziness
• Nausea
• Paresthesias (usually occurs 1-3 days after d/c SSRI; lasts up to 2 wks)
• Worst with paroxetine, fluvoxamine, venlafaxine (shortest t1/2)
• Taper ALL SSRIs slowly at 5-7 day intervals (except fluoxetine)

Medications:

• SSRIs
• MAOIs
• Clomipramine
• DXT
• Meperidine
• TCAs
• Lithium
• SAM-e
• St. John's Wort
• Trazadone
• Buspirone
• Triptans
• Linezolid
• Tramadol

Symptoms:

• confusion/delirium (mental status changes)
• agitation
• GI (abdominal pain, NVD)
• Tremor
• Restlessness
• Hyperreflexia
• HTN
• Tachycardia
• Fever
• Diaphoresis
• Myoclonus
• Rigidity

Tx:

• Avoid combos if possible
• Allow appropriate wash-out periods (2 wks)
• D/c offending agents if observed

Sedation

Fluvoxamine > paroxetine > sertaline > es/citalopram > fluoxetine

• NVD -- esp. sertraline
• HA, anxiety, insomnia
• Hyponatremia
• Prolonged bleeding (decreased platelet aggregation)
• Sexual dysfunction (anorgasmia, delayed ejaculation, decreased libido, impaired erection)

MOA

• Blocks 5-HT reuptake
• Postsynaptic 5-HT2a antagonist
• H1 antagonist

ADRs

• Sedation
• Orthostasis
• Priapism!

MOA

• Blocks 5-HT reuptake
• postsynaptic 5-HT2a antagonist
• Better tolerated than trazadone

ADRs

Liver failure -- unpredictable

3A4 inhibitor -- lots of drug rxs

MOA

Inhibits DA and NE (minimal) reuptake

ADRs

HA, insomnia, nausea, agitation, seizure, weight loss

NO SEXUAL DYSFUNCTION!

CI

Epileptics, Active Eating Disorders, Chronic Alcoholism

Choose QD -- Wellbutrin XL

It's a stimulating drug -- give in AM and no later than 4 pm

• Nausea
• HA
• Insomnia
• Sweating
• Sexual dysfunction
• Increased diastolic BP (dose-related > 225 mg/day)

• Venlafaxine
• Desvenlafaxine
• Duloxetine
• Milnacipran

• Nausea
• Insomnia
• HA
• Dry mouth
• Constipation
• Sweating
• Sexual dysfunction
• Hepatotoxicity

• Depression
• Diabetic neuropathy
• Fibromyalgia

• Depression
• Fibromyalgias

MOA

• Increases 5-HT and NE release
• Blocks post-synaptic 5-HT2/3
• Inhibits presynaptic alpha2  and H1 receptors

ADRs

• Sedation
• Increases appetite
• Weight gain
• Dizziness
• Less sexual dysfunction
• May increase triglycerides, cholesterol

MAOIs

Mirtazapine

TCAs

Trazadone (safest)

SSRIs

Mirtazapine

Bupropion

Nefazadone

• Continue at therapeutic dose 4-6 wks
• Try dual mechanism antidepressant (mirtazapine, venlafaxine, MAOIs)

Augmentation Strategies:

• Thyroid Hormone
• Lithium
• Aripiprazole
• ECT -- esp for pregnant pts, suicidal pts

• Fluoxetine is most well-studied
• SSRIs are Pregnancy Category C -- paroxetine recently moved to Cat. D -- may increase risk of fetal heart defects
• Infant Exposure to SSRIs: Increased risk to develop restlessness, tremors, and irritability, pulmonary HTN (rare)
• Untreated depression in pregnancy: suicide risk, poor prenatal care, postpartum depression