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 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

Predictors of antidepressant response. Acute onset Severe depressive symptoms Positive previous response to medication Patient’s 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) Series 1 Synaptic effects: hours to days Side effects: hours to days Therapeutic effect: 1 to 6 weeks

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

Antidepressant half-lives (hrs)

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)

Serotonin reuptake blockade Possible clinical consequences Gastrointestinal disturbances Anxiety (dose – dependent) Sexual dysfunction

Serotonin uptake blockade (potency)

Blocking selectivity 5-HT vs. NE

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

Dopamine uptake blockade (potency)

Histamine H 1 blockade Possible clinical consequences Sedation, drowsiness Weight gain hypotension

Histamine H 1 receptor blockade (affinity)

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

Muscarinic receptor blockade (affinity)

alpha – 1 receptor blockade possible clinical consequences Postural hypotension Reflex tachycardia Dizziness

alpha-1 receptor blockade (affinity)

imipramine (Tofranil) receptor affinities

fluoxetine (Prozac) receptor affinities