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 Antidepressants
Atypical (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 exam Identify and r/o underlying medical problems Physical exam in the past year

Evaluation of the depressed patient

Optional exams:
Laboratory Neurological exam Dexamethasone suppression test TRH 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 symptoms Impairment of functioning Patients view of medication Not necessarily the specific diagnosis

Predictors of antidepressant response.

Acute onset Severe depressive symptoms Positive previous response to medication Patients willingness to accept medication as an aid to successful treatment

How to start antidepressants?

Start low to assess tolerance of side effects Increase dosage rapidly as tolerated Maintain typical dose for at least 4 to 8 weeks

Most common reasons antidepressants fail

Dosage too low Duration of trial to short Poor compliance Intolerable side effects

What is an adequate trial?

Adequate dose:
5 mg/kg/d Nortriptyline 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 doses Patients who are at increased risk for toxicity, e.g. cardiac patients

May be useful for:

Patients where prompt response is critical Determining compliance and metabolic availability

Therapeutic Blood Levels

for antidepressants

Known:
imipramine desipramine nortriptyline

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 receptors Alteration of second messenger systems Alteration of protein synthesis.

After Dosing Antidepressants

(days)
Synaptic effects: hours to days Side effects: hours to days Therapeutic effect: 1 to 6 weeks

Series 1

Pharmacokinetics of Antidepressants
Absorption is rapid Metabolism: extensive 1st pass Oxidation, hydroxylation, demethylation 5% = slow acetylators Protein bound: 90 95%

Antidepressant half-lives (hrs)

3 3.5 3.6 8 13 15 17 19 21 21 21 23

nefazodone trazodone venlafaxine amoxapine trimipramine bupropion doxepin fluvoxamine desipramine amitriptyline paroxetine

26 28

36

43

clomipram sertraline

78 60 80

87 100

imipramine nortriptyline maprotiline protriptyline fluoxetine

20

40

Cardiac Side-effects
of tricyclic antidepressants Cardiac conduction delay Anti-arrhythmic at therapeutic doses Arrhythmigenic at toxic doses Minimal effects on cardiac output

Cardiac Side-effects
of tricyclic antidepressants Monitoring EKG parameters: QTc = 450 msec PR = 210 msec QRS - >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)

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 20 40 60 80 100 120 potency

Serotonin reuptake blockade

Possible clinical consequences Gastrointestinal disturbances Anxiety (dose dependent) Sexual dysfunction

Serotonin uptake blockade

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazadone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 20 40 60 80 100 120 140 potency

(potency)

Blocking selectivity
5-HT vs. NE
amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine

potency

10

20

30

40

50

60

70

80

Dopaminergic uptake blockade

Possible clinical consequences Psychomotor activation

Antiparkinsonian effects
Psychoses Increased attention/concentration

Dopamine uptake blockade (potency)

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine amphetamine 0 0.2 0.4 0.6 0.8 1 1.2 Series 1

Histamine H1 blockade
Possible clinical consequences

Sedation, drowsiness Weight gain hypotension

Histamine H1 receptor blockade (affinity)

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine diphenhydramine

Series 1

50

100

150

200

250

300

350

400

450

Muscarinic receptor blockade

possible clinical consequences Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction

Muscarinic receptor blockade (affinity)

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 1 2 3 4 5 6 Series 1

alpha 1 receptor blockade

possible clinical consequences Postural hypotension

Reflex tachycardia
Dizziness

alpha-1 receptor blockade

amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Series 1

(affinity)

imipramine (Tofranil)
receptor affinities
25 20 15
Series 1

10 5 0
NE 5-HT DA alpha-1 HI ACH D2

fluoxetine (Prozac)
receptor affinities
30 25 20 15 10 5 0 Series 1

NE

5-HT

DA

alpha-1

HI

ACH

D2