• SSRI's- Fluoxetine, Sertraline
• SNRI's- Venlafaxine
• TCA's
  • tertiary amines- amitriptyline
  • secondary amines- desipramine
• MAOI's- Tranylcypromine
• newer
  • serotonin receptor antagonists- Trazodone
  • dopamine reuptake inhibitors- Bupropion
  • autoreceptor antagonists- Mirtazapine

SIGECAPS

• sleep disturbance
• loss of interests
• guilt feelings
• decreased energy
• decreased concentration
• psychomotor retardation or agitation
• suicidal thoughts or impulses

• affects women more than men 3:2
• causes unkown (some genetic influence, and can be triggered by stress, hormones)
• comorbiditis are very common (drug and alcohol dependence)
• onset at any age

1. block SERT
2. inhibits reuptake of serotonin
3. acutely increase serotonin in synapse
4. over time neuronal pathways adapt and there is enhanced serotonergic transmission

• initial: adverse effects (hrs-days)
  • GI upset, CNS stimulation, restlessness
    • acute response to enhanced serotonin levels in brain, gut
  • typically improve with time
• delayed therapeutic response (2-6 wks)
  • gradual improvement of most depressive symptoms
  • positive results in great majority of patients (note: improvement of mood doesnt equal euphoria)

• anxiety disorders
  • panic
  • phobias
  • PTSD
  • OCD (esp. fluvoxamine)
• eating disorders (esp. bullemia)
• PMDD
• ADD/ADHD

selectivity allows it to be better tolerated, but it does have adverse effects

• CNS stimulation (insomnia, agitation)
• anxiety
• sexual dysfunction (unlike other adverse effects, this is a problem throughout course of treatment for most)
  • decreased libido
  • anorgasmia
• GI problems
• headache
• akathisia (motor restlessness)

• good absorption and bioavailability
• high protein bound
• oxidation via CYP3A4 and other P450 enzymes
• metabolism and excretion- phase two glucoronidation to metabolite excreted renally
• some SSRI's produce active metabolites: most importantly fluoxetine to norfluoxitine
  • both have very long half life
• most have very long half life
• kinetics important not for therapeutic response, but more so toxic response
  • discontinunation rxns aka withdrawal- increased likelihood with short half life
  • switch from one AD to another to minimize potential drug interactions

• block SERT, so increase serotonin in synaptic space
• block NET at medium to high doeses, leading to increase NE in synaptic space

• adverse effects
  • similar to SSRI's
  • unique: increase bp at high doses (increased NE)

• similar to SSRI's
• unique one: neuropathic pain

• shorter half life than SSRI's (but slow release prep for venlafaxine)
  • more frequent discontinuation syndrome aka withdrawal
• much lower protein binding than SSRI's
• metabolized to desvenlafaxine (active metabolite)

• no evidence of systematic differences in efficacy
  • drugs that block SERT or NET are equally effective, but does blocking both increase efficacy?
• individual differences not uncommon (polymorphisms in serotonin R genes or CYP enzymes)
  • so some who are unresponsive to SSRI's may respond to SNRI's
• consider drug interactions (esp. fluvoxamine which inhibits many P450 enzymes)
  • venlafaxine has low drug interactions
• shorter acting drugs increase risk for discontinuation syndrome aka withdrawal (ex: many SNRI's esp. venlafaxine)

• mechanism of action- antagonist at 5-HT₂ and alpha 1
• clinical effects
  • initial adverse effects- mixed
  • delayed therapeutic effects- 2-6 wks
    • sedative properties (w/no anticholinergic effect)

• sedation prominent
• orthostatic hypotension (alpha one block leads to decreased bp)
• few anticholinergic effects
• priapism (rare)

Overall, there is a lower response rate to this drug than typical more established ADD's

• mechanism of action
  • block DAT
  • weak SERT block
  • weak NET block
• indications- smoking cessation, other addictions potentially

• CNS stimulation- agitation, insomnia, anxiety
  • but can counter sedating side effects of other ADD's
• weight loss
• headache
• nausea
• potential for seizures (at high doses)

Somewhat lower overall response rate than other ADD's

• advantage- fewer sexual side effects
• disadvantage- may require multiple doses (but slow release preps are available)

• block presynaptic autoreceptors that would inhibit NE and serotonin release, so increased neuotransmission of NE, serotonin
  • alpha two
  • 5 HT_1a
• antagonists at
  • 5 HT₂ and 5 HT₃
  • muscarinic R
  • alpha one R
  • antihistamine (H1 blocker)

• initial adverse effects (hrs-day)
• delayed therapeutic effects (2-6 wks)
• sedative properties are useful (but comes with anticholinergic effects)

• sedation (although can be helpful)
  • due to antihistamine activity
• weight gain (due to antihistamine activity)
• dizziness
• some anticholinergic
  • dry mouth
  • constipation

• mirtazapine
• trazodone

• they are usually administered as adjuncts with other ADD's
• usually SSRI's

• block reuptake of both SERT and NET, leading to increase in concentration and duration of these amines in the synapse
  • tertiary amines (amitriptyline)- preferrentially block SERT
  • secondary amines (desipramine)- preferrentially block NET
• tertiary amines are metabolized to secondary amines, but still overall effect is to block reuptake of both amines
• block receptors for:
  • muscarinic R
  • alpha 1
  • H1 R

• MDD
• anxiety disorders
  • panic
  • phobias
  • OCD
• enuresis (bed wetting)
• neuropathic pain
• migraines

• initial adverse effects (largely due to receptor antagonist effects)- typically improve with time
  • drowsiness
  • autonomic symptoms- dry mouth, constipation
  • anxiety
  • dysphoria
  • difficulty concentrating
• delay therapeutic response (1-6 wks)
  • gradual improvement in most depressive symptoms
  • positive response in great majority of patients

low TI, so OD can cause death from arrhythmia

most side effects due to antagonist effects on muscarinic, alpha 1, H1 receptors

• heart
  • NE reuptake block
    • tachychardia
    • palpatation
  • anticholinergic- conduction block
  • non R mechanism- arrhythmias
• vascular- alpha 1 block leads to orthostatic hypotension
• autonomic- peripheral anticholinergic
  • dry mouth
  • constipation
  • urinary retention
  • blurred vision
• CNS- antichonlinergic
  • sedation
  • confusion
  • memory impairment
  • delirium
  • hallucination (at high doses)
• vegetative- due to antihistamine in CNS
  • increase appetite
  • weight gain
• sexual- impotence, delayed orgasm (alpha 1 block)

• well absorbed with high bioavailability (QD at night)
• high volume of distribution with high protein bound (difficult to dialyze)
• undergo extensive phase 1 and 2 met.
  • oxidation by CYP: glucoronidation allows for renal excretion
  • common polymorphism in CYP2D6 slow met., leading to increase blood levels
• metabolism produce active metabolites (tertiary amines yield secondary amines)
• most have long half life as do active metabolism
• kinetics important for toxic responses
  • when switch from one ADD to another, we must minimize potential drug interactions

• no evidence for systemic differences in efficacy, but individual differences not uncommon
• highest incidence of side effects and toxicity with tertiary amines (amitriptyline)
• best overall side effect profile: desipramine

• third line drug for MDD (lots of drug and food interactions)
• good efficacy in "atypical depression"

• irreversibly inhibit MAO
  • increases NE and serotonin in nerve terminals
  • most are unselective, so inhibit MAO-A and MAO-B
  • increases synaptic levels of biogenic amines
  • inhibition in periphery and brain

• acute
  • CNS stimulation- agitation, euphoria
  • appetite suppression
• delayed therapeutic (2-6 wks)
  • improvement of most depressive symptoms
  • somewhat less stimulation

at least two of the following

• significant weight gain and or increases in appetite
• hypersomnia
• leaden paralysis (heavy, leaden feelings in extremities)
• long standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment

• CNS stimulation (amphetamine like actions)
  • agitation
  • insomnia
  • hypomania
• postural hypotension (but no alpha one block)
• GI distress
• sexual dysfunction
• drug interactions

• kinetics largely irrelevant due to irreversible inhibition of enzyme MAO
• some MAOI's are inactivated by acetylation
  • large genetic differences in acetylation rate mean doses must be adjusted appropriately

• high TI, so fatalities rare
• serotonin syndrome
  • hyperthermia
  • muscle rigidity
  • myoclonus
  • akathesia
  • hyperreflexia
  • fluctating fital signs
  • mental status
• very high risk when combined with MAOI
• risk with trazadone, TCA's

• agitation
• delirium
• seizure

• low TI, so potential for fatal OD
• arrhythmias
• acidosis
• delirium
• hyperpyrexia
• seizures
• neuromuscular paralysis
• coma

tx- supportive, lavage (not dialysis), lidocaine for arrhythmias

• uncommon
• agitation
• delirium
• can leads to
  • hyperthermia
  • shock
  • coma
  • seizures

• known to have sign. risks, than avoid it
  • paroxetine- neonatal heart defects
  • phenelzine, tranylcypromine- HTN
• some associated wtih persistant pulm HTN of newborn (PPHN) if taken in the last half of pregnancy, but considered an option:
  • fluoxetine, sertraline
• increases in septal defects, but option is sertraline
• risk of limb malformation, but consider amitriptyline

But pregant women who stop AD during pregnancy were 5 times more likely to suffer relapse than those who did not stop

• no evidence of drug abuse with ADD
  • bupropion a theoretical risk, but no history
  • tranylcypromine metabolized to amphetamine
• tolerance
  • develop for most adverse effects
    • NOT for sexual dysfunction with SSRI, SNRI
    • NOT for cardiac toxicity with TCA
  • no evidence of tolerance for therapeutic effects
• dependence/withdrawal
  • some show discontinuation syndrome when abruptly stopped, esp. with short acting drugs (all SNRI's, many SSRI except fluoxetine, buproprion)
    • CNS stimulation- agitation, anxiety
    • other peripheral effects
  • avoidance- taper off when discontinuing

• inhibits CYP2D6 leads to affect on:
  • TCA's
  • clozapine
  • haloperidol
  • risperidone
  • beta blockers
  • codeine
  • oxycodone
  • antiarrhythmias

• some inhibit CYP's and increase blood levels of other drugs
  • fluvoxamine- increase TCA's, androgens/estrogen, BZ's, warfarin, clozapine
  • nefazodone- increase androgens/ estrogens, calcium channel blockers, citalopram, alprazolam, sidenafil

• barbituates
• carbamezepine
• rifampin
• st johns wart
• omeprazole

Affects sertraline, trazodone, mirtazapine

• erythromycin
• INH
• ketoconazole
• cimetidine
• ciprofloxacin
• quinidine
• haloperidol
• grapefruit juice

Affects SSRI's (except fluoxetine), venlafaxine, trazadone, mirtazapine, most TCA's

since many drugs partially detoxified by MAO, MAOI's have highest incidence of drug interactions

• sympathomimetics- cause headache, increase bp
• SSRI/SNRI/TCA/trazodone/nefazadone- serotonin syndrome
• tyramine in foods can cause HTN crisis (cheese effect)- must regulate diet
• meperidine, dextromethorphan- reports of fatalities, severe toxicity

• allow long time (2-5 wks) after MAOI before starting a new drugs
• allow at least two weeks (longer with fluoxetine) before starting MAOI

• past history of drug response with patient and family is important
• individual differences to responses are common
• tolerance to adverse effects is key
• all require 2-6 wks for complete clinical effect (build up dose over several weeks to minimize adverse effects)

• psychotic depression (add D2 blocker)
• atypical depression (TCA's poor)
• bipolar disorder (lithium, anticonvulsants, antipsychotics)
• anxious depression (add BZ's)

Five D's

• adequate dose
• adequate duration
• proper dx
• additional drugs (adjucnts may increase response or ADD combinations from different classes)
• different (additional) dx

• kindling model
  • repeated episodes of depression may lower threshold
  • this leads to increase chance of subsequant episodes
  • if so prevent progression with maintenance ADD therapy
• 50% reduction in relapse over 9-36 months of ADD tx

• it has shown an increase in risk of suicide over the first 2 weeks of tx
• however, it appears that the benefits are greater than the risks of suicidal ideation/ attempt