Post on 22-Dec-2015
Pharmacology of Antidepressants
Dr Andrew P Mallon
Classes of Antidepressants
Tricyclic-tertiary amines
amitriptyline (Elavil)imipramine (Tofranil)doxepin (Sinequan)
clomipramine (Anafranil)trimipramine (Surmontil)
Classes of Antidepressants
Tricyclic-secondary amines
desipramine (Norpramin)nortriptyline (Pamelor)protriptyline (Vivactyl)amoxapine (Ascendin)
Classes of AntidepressantsAtypical (non-tricyclic)
maprotiline (Ludiomil)trazodone (Desyrel)
bupropion (Wellbutrin)venlafaxine (Effexor)nefazodone (Serzone)
mirtazapine (Remeron)
Classes of Antidepressants
Specific serotonin reuptake inhibitors (SSRIs)
fluoxetine (Prozac)sertraline (Zoloft)paroxetine (Paxil)
fluvoxamine (Luvox)citalopram (Celexa)
Classes of Antidepressants
Monoamine oxidase inhibitors (MAOIs)
phenelzine (Nardil)isocarboxazid (Marplan)
tranylcypromine (Parnate)selegiline (Deprenyl)
Classes of Antidepressants
Psychostimulants
methylphenidate (Ritalin)dextro-amphetamine (Dexedrine)
magnesium pemoline (Cylert)dex + amphetamine (Adderall)methamphetamine (Desoxyn)
modafinil (Provigil)
Evaluation of the depressed patient
Goals of the evaluation
Establish a diagnosis
Identify specific target symptoms
Consider comorbidity
Quantify depression and/or specific symptoms
Evaluation of the depressed patient
Obtain psychiatric history and perform mental status examIdentify and r/o underlying medical problemsPhysical exam in the past year
Evaluation of the depressed patient
Optional exams:LaboratoryNeurological examDexamethasone suppression testTRH test
Is an antidepressant indicated?
The decision to treat a patient with antidepressants should be based on the following:
Severity of symptoms and ability to identify target symptomsImpairment of functioningPatient’s view of medicationNot necessarily the specific diagnosis
Predictors of antidepressant
response.
Acute onsetSevere depressive symptomsPositive previous response to medicationPatient’s willingness to accept medication as an aid to successful treatment
How to start antidepressants?
Start low to assess tolerance of side effectsIncrease dosage rapidly as toleratedMaintain typical dose for at least 4 to 8 weeks
Most common reasons antidepressants fail
Dosage too lowDuration of trial to shortPoor complianceIntolerable side effects
What is an adequate trial?
Adequate dose:5 mg/kg/dNortriptyline 100 to 150/d (therapeutic window)Fluoxetine 20 mg/d
Adequate duration:4 – 8 weeks
Indications for serum levels
Unequivocally useful for:Patients who are not responding to usual dosesPatients who are at increased risk for toxicity, e.g. cardiac patients
May be useful for:Patients where prompt response is criticalDetermining compliance and metabolic availability
Therapeutic Blood Levels
for antidepressantsKnown:
imipraminedesipraminenortriptyline
Possibly known:amitriptyline
Under assessment:All other antidepressants
How Antidepressants Work
Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”. There are two important observations that contribute to this rationale.
How Antidepressants Work
Many drugs require long term administration to be effective.Drugs of abuse require repeated administration to produce tolerance and physical dependence.
How Antidepressants Work
Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse. That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity).
“Synaptic Pharmacology”of antidepressants
Acute:Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor.
Chronic:Down regulation of the post-synaptic receptorsAlteration of second messenger systemsAlteration of protein synthesis.
After Dosing Antidepressants
(days)
Series 1
Synaptic effects: hours to days
Side effects: hours to days
Therapeutic effect: 1 to 6 weeks
Pharmacokinetics of Antidepressants
Absorption is rapidMetabolism: extensive 1st passOxidation, hydroxylation, demethylation5% = “slow acetylators”Protein bound: 90 – 95%
Antidepressant half-lives (hrs)
Cardiac Side-effectsof tricyclic antidepressants
Cardiac conduction delayAnti-arrhythmic at therapeutic dosesArrhythmigenic at toxic dosesMinimal effects on cardiac output
Cardiac Side-effectsof tricyclic antidepressants
Monitoring EKG parameters:QTc = 450 msecPR = 210 msecQRS - >30% above baseline
How to choose an antidepressant
Rationale should be based on side effects, not efficacy
The SSRIs, secondary amines, and atypical antidepressants, are generally better choices.
Why?
Norepinephrine uptake blockade
Possible clinical consequences
Tremors
Tachycardia
Norepinephrine uptake blockade (potency)
0 20 40 60 80 100 120
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazodone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
potency
Serotonin reuptake blockade
Possible clinical consequences
Gastrointestinal disturbancesAnxiety (dose – dependent)Sexual dysfunction
Serotonin uptake blockade(potency)
0 20 40 60 80 100 120 140
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazadone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
potency
Blocking selectivity5-HT vs. NE
0 10 20 30 40 50 60 70 80
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazodone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
potency
Dopaminergic uptake blockade
Possible clinical consequences
Psychomotor activation
Antiparkinsonian effects
Psychoses
Increased attention/concentration
Dopamine uptake blockade (potency)
0 0.2 0.4 0.6 0.8 1 1.2
amphetamine
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazodone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
Series 1
Histamine H1 blockadePossible clinical consequences
Sedation, drowsiness
Weight gain
hypotension
Histamine H1 receptor blockade (affinity)
0 50 100 150 200 250 300 350 400 450
diphenhydramine
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazodone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
Series 1
Muscarinic receptor blockade
possible clinical consequences
Blurred visionDry mouth
Sinus tachycardiaConstipation
Urinary retentionMemory dysfunction
Muscarinic receptor blockade (affinity)
0 1 2 3 4 5 6
fluvoxamine
paroxetine
sertraline
fluoxetine
nefazodone
venlafaxine
buproprion
trazodone
maprotiline
amoxapine
protriptyline
nortriptyline
desipramine
trimipramine
clomipramine
doxepin
imipramine
amitriptyline
Series 1
alpha – 1 receptor blockade
possible clinical consequences
Postural hypotension
Reflex tachycardia
Dizziness
alpha-1 receptor blockade (affinity)
imipramine (Tofranil)receptor affinities
0
5
10
15
20
25
NE 5-HT DA alpha-1 HI ACH D2
Series 1
fluoxetine (Prozac)receptor affinities
0
5
10
15
20
25
30
NE 5-HT DA alpha-1 HI ACH D2
Series 1