Antidepressants
PRITE Review
Samir Sabbag
PGY-3 Psychiatry
August 24, 2009
Overview

Goal in Depresion


Achieve complete remission
With Treatment
News – if remission: lower relapse rate
 Bad News – remitters have frequent relapses
 Good
Suicide rates higher at ages 18-24
 All effective Antidepressants boost

 DA,
5HT and NE
Monoamine(MA) Hypothesis of
Depression
MA Boost  Therapeutic Action








5HT
NE
DA
5HT
NE
DA
NE
DA





5HT
NE
DA
NE
DA

5HT

5HT
NE
DA

5HT


Selective Serotonin
Reuptake Inhibitors
(SSRIs)
Available SSRIs
Fluoxetine (Prozac)
 Paroxetine (Paxil)
 Sertraline (Zoloft)
 Citalopram (Celexa)
 Escitalopram (Lexapro)
 Fluvoxamine ( Luvox)

Mechanism of action

All SSRIs inhibit
reuptake of 5HT
by presynaptic
neurons
SSRI Therapeutic Indications








Depression
OCD (give higher doses)
Panic Disorder
PTSD (help with intrusive and avoidant sx)
GAD
Premenstrual Dysphoric disorder
Social Anxiety disorder
Eating disorders (Fluoxetine)
SSRI ½ lives and metabolites

Fluoxetine



Active Metabolite: 7-9 days
Sertraline

: longest ½ life
4-6 days!
: 26h
Active Metabolite: 3-5 days
No active metabolites
 Citalopram
: 35h
 Escitalopram : 27-32h
 Paroxetine
: 21h (most likely to cause withdrawal reaction)
 Fluvoxamine : 15h
SSRIs

Plasma Protein binding
 Highly bound
 Fluoxetine, Sertraline and Paroxetine
 Least bound
 Escitalopram

CYP 450
 Fluvoxamine: marked
 1A2, 2C and 3A
 Fluoxetine
 2D6
effect on CYP
and Paroxetine
 Least likely to cause problems
 Citalopram, Sertraline and Escitalopram
SSRIs - General Side Effects





Restlessness, psychomotor retardation, mild
parkinsonism and dystonic movements (5HT-2A in
basal ganglia)
Myoclonus, sleep disturbance and nocturnal
awakening (2A in brainstem)
Sexual dysfunction, apathy and decreased libido (2A
and 2C in spinal cord)
N/V (5HT-3 in hypothalamus and brainstem)
Increased bowel motility, GI cramps and diarrhea
(5HT3 and 4 in GI tract)
GI Sx  Most common SE leading to discontinuation
SSRIs - General Side Effects

Suicide
 increased
thoughts/actions in children, adolescents
and young adults <25
 Closely monitor first few weeks when starting SSRI

Pregnancy


Hematologic


Small increase in anencephaly, craniosynostosis and
omphalocele (as per population registries)
Prolonged bleeding time - functional impairment of platelet
aggregation
Endocrine

Can decrease glucose concentrations acutely
SSRIs - General Side Effects

Most common SE associated with long term
treatment:
Dysfunction – continues as long as the
drug is taken
 Sexual

Sleep disturbances
 Extremely
vivid dreams or nightmares
 Bruxism, restless legs, nocturnal myoclonus

Yawning
associated with fatigue – effect of SSRI on
hypthalamus
 Not
Citalopram and Escitalopram


Most selective inhibitors of serotonin reuptake
Citalopram may have some sedative effects (H1)
Citalopram
Escitalopram
Fluoxetine

5HT2C receptor block
 NE


and DA release
Increased energy
Activation/anxiety
 Antibulimic/anorexic
effects
 Boosts antidepressant
action of Olanzapine in
Bipolar Depression

NE reuptake blockade
Fluoxetine
Of the SSRIs, most likely to cause
headaches
 Can cause anxiety, specially during 1st
weeks of use  on the long run decrease
anxiety
 SSRI most likely to cause insomnia

Sertraline
Atypical Depression
Overeating and oversleeping
Extreme sensitivity with
interpersonal loss or rejection
Severe psychomotor retardation
Mood reactivity


Sigma 1 action  anxiolytic
weak DA and NE reuptake inhibition
 Improves
energy, motivation and concentration
 Helps with atypical depression

Fist line in Panic d/o (also Paroxetine)
Paroxetine

Anticholinergic (M1)
 calming/sedating
 Good

for anxiety sx
weak NE reuptake inhibition
 antidepressant

effects
Nitric Oxide Synthetase (NOS)
and 2D6
 Sexual
dysfunction
Paroxetine

Withdrawal reaction with sudden d/c
 Anticholinergic
rebound
 Substrate and inhibitor for 2D6

Rapid decline in plasma when d/c
First line in Panic disorder (also Zoloft)
 Anticholinergic activity


Dry mouth, constipation, sedation
Paroxetine

Fetal abnormalities
 Cardiac
malformation (R Ventricular outflow
obstruction)
 Pulmonary hypertension
 Seen with doses >25mg in 1st trimester

More frequent and pronounced weight
gain than other SSRIs
Fluvoxamine
Not normally used as antidepressant
 Used for OCD, Panic d/o, PDD,
Aggression in autism
 SSRI with the most DDI of all

Serotonin Syndrome

Constellation of sx composed, in order of
appearance, by
1.
2.
3.
4.
5.
6.
Diarrhea
Restlessness
Extreme agitation, hyperreflexia, autonomic
instability with fluctuation of vital signs
Myoclonus, seizure, hyperthermia, rigidity, shivering
Delirium, coma, status epilepticus,
cardiovascular collapse
Death
Serotonin Syndrome

SSRI + MAOI, MAOB Inhibitors, L-Tryptophan,
Lithium, SSRIs, SNRIs, TCAs, Buspirone,
Meperidine, Nefazodone, Trazodone, Linezolid
 may

raise SSRI to toxic levels
Treatment
 Remove
offending agent
 Supportive care

nitroglycerine, methysergide, cooling
blankets, chlorpromazide, dantrolene,
benzodiazepines, anticonvulsants,
mechanical ventilation, paralyzing agents
Serotonin Syndrome

May resemble NMS
 Serotonin
Syndrome more likely to have
Myoclonus
 Hyperreflexia
 GI symptoms

 NMS

more likely to have
Muscular rigidity
SSRI Discontinuation Syndrome

Abrupt discontinuation of SSRI
 Especially

Shorter ½ lives
 Least


Fluvoxamine and Paroxetine
likely: Fluoxetine
Longer ½ life
Symptoms
 Dizziness,
weakness, nausea, h/a, anxiety,
rebound depression, poor concentration,
upper respiratory sx, paresthesias.
Tricyclic and Tetracyclic
Antidepressants
(TCAs)
Tricyclics
Which of the following is a
secondary TCA?
 Protriptyline
 Clomipramine
 Maprotiline
 Amitriptyline
 Doxepine
Available TCAs

Tertiary Amines

Secondary Amines
 Clomipramine
 Desipramine
 Imipramine
 Protriptyline
 Trimipramine
 Nortriptyline
 Amitriptyline
 Doxepin

Tetracyclics
 Maprotyline
 Amoxapine
Pharmacologic Actions
Significant metabolism - 1st pass effect
 CYP450

 2D6

(many meds may rise levels to toxic)
Half-lives from 10-70 hours
 Longer

Nortriptyline, Maprotiline and Protriptyline
Pharmacologic Actions

TCA’s block reuptake pumps

NE and/or 5HT

Most 5HT selective  Clomipramine

Most NE selective  Desipramine
TCA Receptor Structure
Serotonin reuptake block
NE reuptake block
SIDE EFFECTS
SIDE EFFECTS
Histamine 1 receptor block
Weight gain
Doxepin
most antihistaminergic of the TCAs
SIDE EFFECTS
Muscarinic (M1) receptor block
Bethanecol
Tx
urinary retention
(M1) Anticholinergic SE

Can aggravate Narrow Angle Glaucoma
 Avoid

TCAs in this condition – Amitriptyline
Can cause Anticholinergic Delirium
 Especially
if TCA used with dopamine
receptor antagonist or anticholinergics
 Treatment: IM or IV physostigmine
Least Anticholinergic
Amoxapine, Nortriptyline
Desipramine, Maprotiline
SIDE EFFECTS
Alpha-1 adrenergic receptor block
Most common cause of TCA d/c
Orthostatic Hypotension
Overdose with TCAs

TCAs – block voltage-sensitive Na
channels
– coma, seizures
 Heart – arrhythmia, death
 Brain
OD –monitored with EKG
 Most frequent cause of death: arrhythmia
 EKG changes: PR, QRS, QTc prolongation
 Very common cause for discontinuation:
Tachycardia

Uses in Depression
Melancholic Features
Depressed mood
Severe anhedonia
Early morning awakening
Weight loss
Profound guilt
Very effective
 More likely to induce mania than
bupropion or SSRIs
 Better response

 Melancholic
features, prior major depressive
episodes, family hx

In the US
 Clomipramine
only approved for OCD
Other Uses

Panic disorder
 Imipramine

– FDA approved
OCD
 Only

– most studied drug
GAD
 Doxepin

Clomipramine – use first SSRIs
Pain and Migraine prophylaxis
 Amitriptyline

TCAs have
caused SUDDEN
DEATH in children
and adolescents!
– used most often
Childhood enuresis
 Imipramine
Special Considerations

Amoxapine



May cause Parkinsonian sx
Avoid in Parkinson’s Disease
Blood levels of 4 TCAs can be monitored



Nortriptyline, Desipramine, Clomipramine and Imipramine
Nortriptyline: THERAPEUTIC WINDOW
TCAs have low risk for inducing seizures

Except for Maprotiline


May cause seizures when dose increased
too fast or kept at hight doses
Clomipramine and Amoxapine

May lower seizure threshold
DO NOT give
TCAs during
ECT!  serious
cardiac effects
Special Considerations

Nortriptyline
 least

Desipramine and Protriptyline
 most

likely to cause orthostatic hypotention
activating of the TCAs
Relative contraindication for TCA use
 Bundle

branch block
Cardiac disease or age >40
 Do
EKG prior to TCA use
Drug Interactions

CYP 1A2, 2D6 and 3A4  dirty drugs

Birth control pills and nicotine decrease TCA levels

Fluoxetine, Fluvoxamine and Paroxetine increase TCA
levels x4!! (CYP 2D6)


If used together  use lower dose of TCA
Antipsychotics and Methylphenidate increase TCA levels
Monoamine Oxidase
Inhibitors (MAOIs)
Therapeutic Indications

Depression
 Atypical
Depression

Panic Disorder

Bulimia
PTSD
Migraine
ADD



Available MAOIs

Irreversible

 Phenelzine
 Tranylcypromine
Reversible/Selective
MAO-A (RIMA)
 Moclobemide
 Isocarboxazid
(not in the US)

Selective MAO-B
 Selegiline
(transdermal patch)
Pharmacokinetics

MAOIs inhibit MAO A and B
 Stops MAO from destroying
 NE, 5HT and DA
 Increasing these neurotransmitters

Irreversible
 MAO
enzyme synthesized again in 2 weeks
 Need for dietary restrictions
 Washout period needed when starting a new antidep.

Reversible
 MAO
enz synthesized again in 24-48h
 Flexible dietary restrictions
Irreversible MAOIs
MAOI
MAOI
Two things to know about MAOIs:

Serotonin Syndrome
 fentanyl
 SSRIs
 SNRIs
 clomipramine
 meperidine

(Demerol)
Hypertensive Crisis
 Mainly
NE
 Tyramine
(Sublimaze)
 Lithium/Carbamazepine
 Tryptophan
 Other opioids
(methadone, tramadol)
Hypertensive Crisis

Tyramine in diet + MAO-A inhibition in gut
NORMALY,
in someone
not taking
MAOIs…
NE
NE
MAO-A destroys
NE
Alpha-1
receptors
Hypertensive Crisis

Tyramine containing
products


Aged Cheese
Tap beers
 Smoked fish
 Fava beans
NE
MAO-A
NE
Alpha-1
receptors
MAO-A
Hypertensive Crisis
Irreversible
MAOI
+
NE
NE
Alpha-1
receptors
Interesting facts

Selegiline
 Inhibits
MAO-B
no destruction of MAO-A in the gut
 not involved with intestinal tyramine reaction
 no dietary restrictions


HTN crisis
 Can

also be caused by DDI
pseudoephedrine
Side Effects

Most frequent side effect
 Orthostatic

Hypotension
Other SE
 Insomnia
 Dizziness
 Weight
 Paresthesias
gain
 Edema
 Sexual

 Switch
to mania
dysfunction
Contraindicated in pregnancy and nursing
Bupropion
(Wellbutrin)
Pharmacokinetics


NE and DA reuptake inhibitor
3 formulations available
DRI
 immediate
release (TID)
 sustained release (BID)
 extended release (QD)

Bupropion
3 active metabolites
 hydroxybupropion
 threohydroxybupropion
 erythrohydroxybupropion
NRI
Therapeutic Indications

Depression


Seasonal Affective Disorder (SAD)



DA reward pathways
ADHD



the only FDA approved antidepressant
fist line treatment: phototherapy
Smoking cessation


comparable efficacy to SSRIs
second line agent
appropiate for comorbid ADHD and depression
Hypoactive sexual desire

self or additive to other antidepressants (SSRIs)
The Good, the Bad and the Ugly

The GOOD
 No
sexual dysfunction
 Safe in pregnancy (class B)
 No anticholinergic effects
 No weight gain
 No drowsiness
 No orthostatic hypotension/cardiovascular
Side Effects

The BAD
 Insomnia
 but increases REM sleep
 Anxiety
 Not good for panic d/o or anxiety
 GI
distress (especially nausea)
 Restlessness/Agitation
 Hypertension
 Psychotic symptoms
Side Effects

The UGLY
 Seizures
Incidence is 0.05% with 300mg or less
 Risk increases with doses >400mg per day


 May
0.1%!!
cause death with OD
Uncontrollable seizures
 Sinus bradycardia
 Cardiac arrest

Selective SerotoninNorepinephrine Reuptake
Inhibitors
(SNRIs)
SNRIs

Venlafaxine (Effexor)
 Depression
 GAD
 Social
anxiety disorder
Desvenlafaxine Succinate (DVS)(Pristiq)
 Duloxetine (Cymbalta)

 Depression
 GAD
 Diabetic
Neuropathic Pain
Pharmacokinetics

Selective NE and 5HT reuptake inhibitors
 TCAs
do too, but not selective (SE!)
 Potent inhibitor of NE and 5HT
 Weak inhibitor of DA reuptake
 At lower doses – act like SSRIs
 At higher doses – inhibit NE and 5HT

No activity in
 Cholinergic
(M1)
 Histaminergic (H1)
 Adrenergic (alpha1)
Pharmacokinetics

Half lives
– 3.5 hours
 ODV – 9 hours
 Duloxetine – 12 hours
 Venlafaxine

Discontinuation
Syndrome!
P450
 Venlafaxine – 2D6
 Active metabolite O-desmethylvenlafaxine (ODV)
 Duloxetine
– 2D6 and 1A2
Side Effects

Venlafaxine
 Most
common: nausea, sedation, dry mouth,
dizziness, anxiety, nervousness, insomnia, weigh
loss, constipation
 Sexual dysfunction
 HTN at higher doses
 Midryasis – monitor patients with acute narrow-angle
glaucoma
 Platelet aggregation (serotonin-related impairment)
 In pts with liver disease – decreased clearance
Side Effects

Duloxetine
 Most common
 Nausea


SE leading to discontinuation
Liver toxicity
Avoid in
 Hepatic
insufficiency
 ESRD
 Uncontrolled

No HTN
narrow-angle glaucoma
Mirtazapine
(Remeron)
Pharmacokinetics

Does NOT work by inhibiting
reuptake of NE and 5HT!

Mechanism of Action
 Antagonist
Mirtazapine
of central presynaptic alpha-2 adrenergic
receptors

Increased release of NE and 5HT from neurons
 Blocks postsynaptic 5HT-2 and 3 receptors
 Decreases anxiety, stimulates appetite, relieves insomnia,
decreased nausea and diarrhea
 Strong antagonist of histamine H1 receptors
 sedation at low dose – weaker at higher doses
Therapeutic Indications

Depression
 melancholic
features
 elderly
 Augmentation with SSRIs or Venlafaxine
 counteract nausea, agitation and insomnia
 NO CYP 450 effects!

Cancer patients
 GI
side effects of chemotherapy
 sedation and stimulation of appetite
Side Effects


Weight gain and stimulation of appetite
Somnolence
 in more than 50% of persons
 avoid alcohol and sedating OTC
 potentiates sedative effects





medications
↑ cholesterol, triglycerides and ALT
Dizziness
In some orthostatic hypotension
Agranulocytosis
Low incidence of sexual SE
Nefazodone and Trazodone
Nefazodone

Shortest ½ life of all antidepressants
 2-3

hours!
Active metabolites
 hydroxynefazodone
(principal)
 mCPP (meta-chlorophenylpiperazine)

5HT effects – migraine, anxiety and weight loss
Nefazodone
Orthostatic hypotension,
dry mouth, sedation




No sexual
dysfunction
No anticholinergic SE
Increases REM
sleep
Cytochrome
P450 3A4

elevation of

Antianxiety,
antidepressant and
somnolence



Alprazolam
Triazolam
Haldol
Digoxin
Therapeutic Indications
Depression
 Panic disorder
 Premenstrual dysphoric disorder
 GAD
 Chronic pain
 PTSD
 Chronic fatigue syndrome

Nefazodone

When switching from SSRI to Nefazodone
 Won’t

protect from withdrawal symptoms
High risk for hepatotoxicity
Trazodone

Active metabolite
 mCPP
(metachlorophenylpiperazine)


Migraine, anxiety, weight loss
Strong anti H1 effect
 Use
in insomnia
 ↓ REM sleep
 ↑ total sleep time
 ↓ number and duration of nighttime
awakenings
Trazodone
More risk of orthostatic hypotension than
Nefazodone (alpha 1)
 ½ life

 5-9

hours
Can cause priapism