Antidepressants

Introduction: Major (unipolar) depression has five or more symptoms for 2 weeks or more (10-25% females, 5-15% males). Dysthymia is a depressed mood of 2 years or longer in duration. Bipolar disease has a strong hereditary component and patients are likely to have a comorbid substance abuse disorder. Therapeutic effects of antidepressants are no observed for 3-4 weeks. In general, antidepressants that are effective in treating unipolar depression are effective in treating dysthymia. Bipolar disorder is treated with lithium, valproate, or carbamazepine, with haloperidol used to treat acute mania.

MAO inhibitors: Phenelzine and tranylcypromine non-selectively inhibit both types of MAO. Inhibition is irreversible. MAO inhibitors have serious toxicities and inhibit the metabolism of other drugs. Interaction with other agents can precipitate a hypertensive crisis.

Tricyclic antidepressants: Demethylation on the nitrogen of the side chain reduces sedative activity (desipramine & nortriptyline less sedating, norepi-specific).

Tertiary amine inhibit serotonin and norepinephrine uptake, while secondary amines are norepi-specific. Tricyclics inhibit microsomal enzymes.

• Pharmacological actions: Antidepressant action (requires presence of depression), inhibition of amine uptake pumps (develops rapidly), down-regulation of biogenic amine receptors, sedation (antagonism of H1 receptors), anticholinergic effects, quinidine-like effects on the heart (conduction defects and arrhythmias); orthostatic hypotension.

• Adverse effects: Orthostatic hypotension (1 blockade), ECG changes, tachycardia, conduction block, CHF, ventricular fibrillation, lowered seizure threshold, sedation, inhibition of microsomal enzymes.

• Drug interactions: Reduced antihypertensive action of guanethidine and methyldopa. Synergists anticholinergic effects with atropine. Lowered seizure threshold requires increase in medication. Enhancement of sympathomimetics (l-dopa in Parkinson’s patients). Reduced antihypertensive action of clonidine (antagonism of 2). Additive sedative effects with alcohol.

• Toxicity and treatment: Narrow therapeutic window. Cardiac arryhythmias, hypotension, convulsions, and coma. Treatment includes respiratory support, gastric aspiration, and lavage, activated charcoal, cooling for hyperthermia (anticholinergic effect), fluid expansion.

Third-generation drugs

Amoxapine – Non-selective reuptake inhibitor.

Maprotiline – NE reuptake inhibitor; useful in patients with low energy and persistent lethargy.

Trazodone – Atypical antidepressant relatively selective for 5-HT with no anticholinergic actions; extremely sedating and causes priapism in men.

Fluoxetine (Prozac) – SSRI that eventually causes down-regulation of presynaptic 5-HT receptors; extensively converted to metabolite with very long half-life; also useful for obsessive-compulsive disorder, panis disorder, PMS, and bulimia; side effects are headache, tremor, sexual dysfunction, and restlessness; all are transient except for headache, which may actually increase; wait 2 weeks after cessation of MAO therapy before beginning fluoxetine; fluoxetine worsens EPS when taken with antipsychotics.

Sertaline (Zoloft) & Paroxetene (Paxil) – SSRIs; sertaline does not influence metabolism of other drugs while paroxetene does; fewer side effects than fluoxetine; paroxetene only antidepressant approved for social phobia.

Bupropion – Dopamine reuptake inhibitor; can be used to wean smokers away from nicotine; high seizure incidence; used in ADHD; high seizure incidence in patients with bulimia.

Differences between tricyclics and 3rd generation drugs: 3rd generation drugs have little or no anticholinergic activity (amoxapine and maprotiline have low incidence); incidence of hypotension is low; adverse cardiac effect are low.

Category: Pharmacology Notes