Antidepressants are used commonly in medical and psychiatric practice. As a class, antidepressants have in common their ability to treat major depressive illness. Most antidepressants are also effective in the treatment of panic disorder and other anxiety disorders. Some antidepressants effectively treat obsessive-compulsive disorder (OCD) and a variety of other conditions (see indications below).

The most commonly prescribed antidepressants are listed in Table 12-1. Antidepressants are subdivided into groups based on structure or prominent functional activity: selective serotonin reuptake inhibitors (SSRls), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOls), and other antidepressant compounds with a variety of mechanisms of action. Antidepressants are typically thought to act on either the serotonin or norepinephrine systems, or both. Choice of medications typically depends on diagnosis, history of response (in patient or relative), and the side-effect profile of the medication. Antidepressant effects are typically not seen until 2 to 4 weeks into treatment. Side effects must be carefully monitored, especially for TCAs and MAOls.

Indications

Table 12-2 lists the indications for antidepressants.
The main indication for antidepressant medications is major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Antidepressants are used in the treatment of all subtypes of depression, including depressed phase of bipolar disorder, psychotic depression (in combination with an antipsychotic medication), atypical depression, and seasonal depression. Antidepressants also are indicated for the prevention of recurrent depressive episodes.

Antidepressant medications may be effective in the treatment of patients with dysthymic disorder, especially when there are clear neurovegetative signs or a history of response to antidepressants.

Panic disorder with or without agoraphobia has been shown to respond to SSRls, MAOls, TCAs, and high-potency benzodiazepines (alprazolam and clonazepam).

OCD has been shown to respond to the serotonin-selective tricyclic clomipramine (Anafranil) and to SSRIs at high doses (e.g., fluoxetine at 60-80mg/ day). Obsessions tend to be more responsive to pharmacotherapy than compulsions. Symptoms of OCD respond more slowly than symptoms of major depression. Trials of 12 weeks or more are needed before a medication can be ruled a failure for an OCD patient.

The binging and purging behavior of bulimia has been shown to respond to SSRls, TCAs, and MAOls in several open and controlled trials. Because SSRIs have the most benign side-effect profile of these medications, they are often the first-line psychopharmacologic treatment.

Mechanisms of Action

Antidepressants are thought to exert their effects at particular subsets of neuronal synapses throughout the brain. Their major interaction is with the monoamine neurotransmitter systems (dopamine, norepinephrine, and serotonin). Dopamine, norepinephrine, and serotonin are released throughout the brain by neurons that originate in the ventral brainstem, locus ceruleus and the raphe nuclei, respectively. These neurotransmitters interact with numerous receptor subtypes in the brain that are associated with the regulation of global state functions including appetite, mood states, arousal, vigilance, attention, and sensory processing.

SSRls act by binding to presynaptic serotonin reuptake proteins, thereby inhibiting reuptake and increasing the levels of serotonin in the synaptic cleft.

TCAs act by blocking presynaptic reuptake of both serotonin and norepinephrine. MAOls act by inhibiting the presynaptic enzyme (monoamine oxidase) that catabolizes norepinephrine, dopamine, and serotonin, thereby increasing the levels of these neurotransmitters presynaptically.

These immediate mechanisms of action are not sufficient to explain the delayed antidepressant effects (typically 2 to 4 weeks). Other unknown mechanisms must play a role in the successful psychopharmacologic treatment of depression.

Choice of medication

Many textbooks and articles assert that all antidepressants have roughly the same efficacy in treating depression. More recent data looking at rates of remission of depression indicate that venlafaxine and tricyclic antidepressants may be more effective than the SSRls at achieving depression remission. The higher rates of remission are believed to be related to the combined actions of venlafaxine and TCAs on serotonin and noradrenergic systems. These effects may be achieved also by combinations of antidepressants such as bupropion and SSRls. This complicates medication choice, as before medication choice was based mainly on symptom profile and diagnosis, prior patient response, side-effect profile, and patient tolerance. Another factor to consider when treating depression is remission rates with a particular drug. More research must be done in this area to determine the relative rates of depression remission, particularly in subtypes of patients with depression. SSRls, bupropion, venlafaxine, mirtazapine, and nefazadone are the most well tolerated antidepressants and are generally thought of as first-line agents for major depression. Compared with TCAs and MAO Is, these medications have very low sedative, anticholinergic, and orthostatic hypotensive effects. These agents should be considered for use especially in patients with cardiac conduction disease, constipation, glaucoma, or prostatic hypertrophy.

Among the tricyclic antidepressants, nortriptyline and desipramine have the least sedative, anticholinergic, and orthostatic hypotensive effects. They can be used as first-line agents in younger, healthier people, especially if cost is a consideration (tricyclics are much less expensive than SSRls, bupropion, or venlafaxine).
Because of the necessary diet restrictions and the risk of postural hypotension, the MAOls (phenelzine and tranylcypromine) should be used most selectively. They can be quite effective, however, and are used in patients for whom SSRls and tricyclics have failed, in patients with a concomitant seizure disorder (MAOls and SSRls do not lower the seizure threshold), or in those with atypical depressions or social phobia (MAOls or SSRls are most effective).

High-dose SSRls and clomipramine (despite its high sedative, anticholinergic, and orthostatic hypotensive effects) are the treatments of choice for OCD.

Therapeutic monitoring

Approximately 50% of patients who meet DSM-IV criteria for major depression will recover with a single adequate trial (at least 6 weeks at a therapeutic dosage) of an antidepressant. The most common reasons for failed trials are inadequate dose and inadequate trial length. However, dosage and length of trial are often limited by side effects (or noncompliance).

Patients on antidepressants should be monitored carefully for side effects or adverse drug reactions (listed below). Generally, antidepressant therapy of a first episode of unipolar depression should continue for 6 months. Patients with recurrent or chronic depression require longer or perhaps life-long maintenance treatment. Increasing the dose, augmentation with lithium or T3 (Cytomel), or a psychostimulant (e.g., methylphenidate), switching antidepressants, or addition of a second antidepressant is helpful in treating refractory depression.

Patients on most TCAs require serum level measurements to determine appropriate dosing.

Side Effects and Adverse Drug Reactions

SSRls
Although specific SSRls have slightly different side- effect profiles, as a group their main side effects are nausea, headache, neuromuscular restlessness (resembling akathisia), insomnia or sedation, and delayed ejaculation/anorgasmia. SSRls combined with MAOls are dangerous: a fatal serotonin syndrome may result.

TCAs
TCAs in many patients are quite well tolerated but overall are less tolerated by patients for their side effects than the SSRls, bupropion, or venlafaxine.
The major side effects associated with TCAs are orthostatic hypotension, anticholinergic effects, cardiac toxicity, and sexual dysfunction. Specific TCAs have relative degrees of each of these effects.

Orthostatic hypotension is the most common serious side effect of the TCAs. This is particularly worrisome in elderly patients, who may be more prone to falls. Anticholinergic toxicity can be mild, including dry mouth, constipation, blurred near vision, and urinary hesitancy, or more severe, with agitation, motor restlessness, hallucinations, delirium, and seizures.

Cardiac toxicity may limit the use ofT CAs in some patients. TCAs have quinidine-like effects on the heart, potentially causing sinus tachycardia; supraventricular tachyarrhythmias; ventricular tachycardia; ventricular fibrillation; prolongation of PR, QRS, and QT intervals; bundle branch block; first-, second-, and third-degree heart block; or ST and T-wave changes.
Major complications from TCAs are rare in patients with normal hearts. TCAs should be avoided in patients with conduction system disease.

Sexual dysfunction includes impotence in men and decreased sexual arousal in women.

MAOIs
Patients who take MAOls are at risk for hyperadrenergic crises from the ingestion of sympathomimetic amines (such as tyramine) that fail to be detoxified because of inhibition of the gastrointestinal monoamine oxidase system. Improper diet can lead to severe hypertensive crises (tyramine crisis) with potential myocardial infarction or stroke. Foods that must be avoided include cured meats or fish, beer, red wine, all cheese except cottage and cream cheeses, and overripe fruits. Many over-the-counter cold and pain remedies must also be avoided. Treatment of hypertensive crisis, if severe, may require emergency medical attention, including IV phentolamine (an alpha blocker) or continuous IV nitroprusside infusion.

MAOls cause a dose-related orthostatic hypotension: tranylcypromine can cause insomnia and agitation; phenelzine can cause daytime somnolence.

Other Antidepressants
Venlafaxine (Effexor, Effexor XR) is a serotonin and noradrenergic reuptake inhibitor with a better side effect profile than TCAs or MAOls. A May 2002 meta-analysis of prior antidepressant trials suggested that venlafaxine and TCAs may have a greater remission rate than SSRls. Further study is needed including more head-to-head comparison trials.

Nefazodone (Serzone) and trazodone (Desyrel) are serotonin-modulating antidepressants. Trazodone is prescribed rarely as a sole antidepressant but is often prescribed as an adjunct to an SSRI for sleep because it has strong sedative properties (at higher doses it serves as an antidepressant). In addition to sedation, trazodone can on rare occasions induce priapism (prolonged, painful penile erection) that can cause permanent damage. Patients must be instructed to seek emergency treatment should such an erection occur. Nefazodone is similar to trazodone but is less sedating at therapeutic doses. It appears to have a low rate of sexual dysfunction.

Bupropion (Wellbutrin, Wellbutrin SR, Zyban) appears to work by inhibiting the uptake of dopamine and norepinephrine. Bupropion has a low incidence of sexual side effects. In addition to its efficacy in treating major depression, bupropion has been shown to be effective in smoking cessation (marketed as Zyban) and attention deficit disorder.

Bupropion has a higher than average risk of seizures compared with other antidepressants. The risk of seizures is greatest above a daily dose of 450mg or after a single dose of greater than 150 mg of immediate-release bupropion.

Mirtazapine (Remeron) is classified as a modulator of norepinephrine and serotonin. It is quite sedating in some individuals, and has a low incidence of sexual dysfunction.

Phototherapy
Phototherapy consists of the controlled administration of bright light to treat specific psychiatric illnesses. Phototherapy is administered using specially designed bright light boxes and has been shown effective in the treatment of the seasonal subtype of major depression (also known as seasonal affective disorder). Phototherapy is also used in the treatment of the delayed sleep phase syndrome and jet lag. In the treatment of seasonal affective disorder, early morning bright light therapy is superior to evening light in most individuals. Light intensity of 2,500 to 10 000 lux is most effective. Light therapy can induce mania in susceptible individuals.

Electroconvulsive Therapy (ECT)
ECT (formerly known as electric shock therapy) is one of the oldest and most effective treatments for major depression. ECT also has some efficacy in refractory mania and in psychoses with prominent mood components or catatonia. ECT appears to work via the induction of generalized seizure activity in the brain. The peripheral manifestations of seizure activity are blocked by the use of paralytics, and memory for the event is blocked by the use of anesthetics and by seizure activity. Modern ECT produces short-term memory loss and confusion.
Bilateral ECT is more effective than unilateral ECT but produces more cognitive side effects.

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TABLE 12-1 - Commonly Prescribed Antidepressants

Drug (Brand Name)	Suggested Starting Dosage *	Suggested Maximum Dosage *
SSRls
Fluoxetine (Prozac)	5-20 mg/day	80 mg/day
Sertraline (Zoloft)	25-50 mg/day	200 mg/day
Paroxetine (Paxil)	10-20 mg/day	50 mg/day
Fluvoxamine (Luvox)	25-50 mg qhs	300 mg qhs
Citalopram (Celexa)	20 mg/day	60 mg/day
Escitalopram (Lexapro)	10 mg/day	40 mg/day
TCAs
Nortriptyline (pamelor)	10-25 mg/day	150 mg/day
Imipramine (Tofranil)	10-50 mg/day	300 mg/day
Desipramine (Norpramin)	10-25 mg/day	300 mg/day
Clomipramine (Anafranil)	25-50 mg/day	250 mg/day
MAOls
Tranylcypromine (Parnate)	10-20 mg/day	60 mg/day
Phenelzine (Nardil)	15-30 mg/day	90 mg/day
Other antidepressants
Bupropion (Wellbutrin)	75-100 mg/day	150mg tid
Bupropion SR (Wellbutrin SR. Zyban)	150 mg/day	200 mg bid
Nefazodone (Serzone)	50-100 mg bid	600 mg/day
Venlafaxine (Effexor)	25 mg tid	125 mg tid
Mirtazapine (Remeron)	15mg qhs	45 mg qhs
Trazodone (Desyrel)	50 mg qhs	400 mg qhs

_* Geriatric patients generally require lower doses.
Modified from Stoll A, Psychopharmacology reference card 1.1996. Marcello Lanares, MD, PhD, Clinical and Experimental Medicine, Columbus