Pharmacology of Antidepressants

Douglas L. Geenens, D.O.The University of Health Sciences

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