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 Patient’s view of medication Not necessarily the specific diagnosis .

Acute onset Severe depressive symptoms Positive previous response to medication Patient’s willingness to accept medication as an aid to successful treatment .Predictors of antidepressant response.

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 .

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cardiac patients May be useful for: Patients where prompt response is critical Determining compliance and metabolic availability .g. e.Indications for serum levels Unequivocally useful for: Patients who are not responding to usual doses Patients who are at increased risk for toxicity.

Therapeutic Blood Levels for antidepressants Known: imipramine desipramine nortriptyline Possibly known: amitriptyline Under assessment: All other antidepressants .

. There are two important observations that contribute to this rationale.How Antidepressants Work Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”.

. Drugs of abuse require repeated administration to produce tolerance and physical dependence.How Antidepressants Work Many drugs require long term administration to be effective.

not within the synapse. That is. .How Antidepressants Work Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons. activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity).

. Chronic: Down regulation of the post-synaptic receptors Alteration of second messenger systems Alteration of protein synthesis.“Synaptic Pharmacology” of antidepressants Acute: Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor.

After Dosing Antidepressants (days) Synaptic effects: hours to days Side effects: hours to days Therapeutic effect: 1 to 6 weeks 0 1 2 3 4 5 6 7 Series 1 .

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

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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 0 20 40 .5 3.Antidepressant half-lives (hrs) 3 3.

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 .

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and atypical antidepressants. are generally better choices. not efficacy The SSRIs. Why? .How to choose an antidepressant Rationale should be based on side effects. secondary amines.

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 0 10 20 30 40 50 60 70 80 .

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Dopaminergic uptake blockade Possible clinical consequences Psychomotor activation Antiparkinsonian effects Psychoses Increased attention/concentration .

4 0.8 1 1.2 Series 1 .2 0.6 0.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.

drowsiness Weight gain hypotension .Histamine H1 blockade Possible clinical consequences Sedation.

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 0 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 .

5 3 3.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 2 2.5 Series 1 (affinity) .5 1 1.5 4 4.

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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 .