Pharmacotherapy

Once the diagnosis of major depression has been established and other potential causes of symptoms have been ruled out, antidepressant medication may be instituted.

Clinicians can view the drug treatment plan as comprising three distinct phases:

1) An acute phase lasting six to 12 weeks whose goal is the removal of signs and symptoms of depression and return to the premorbid level of functioning. Patients should be seen frequently during this period to determine drug response, monitor for side effects, adjust dosage, and provide support. All patients should be seen within two to four weeks of initiating pharmacotherapy. Clinicians can anticipate that as many as 70% of patients will respond to the initial antidepressant. If by 12 weeks the patient still has not responded satisfactorily, the medication should be changed or a referral made to confirm the diagnosis of depression and recommend alternative treatment.

2) A continuation phase lasting four to nine months whose main goal is prevention of relapse. Medication should be continued at full dosage for at least this length of time after symptoms have resolved, since premature discontinuation increases the risk of relapse by 20% to 40%.

3) A maintenance phase lasting from one year to a lifetime that is aimed at preventing further recurrences of depression in high-risk patients. Maintenance therapy should be considered for those who have had three or more episodes of major depression, or two or more episodes plus a family history of recurrent major depression or bipolar disorder, onset of depressive symptoms before age 20, or in any patient deemed to have severe, life-threatening depression. A psychiatric consultation should be obtained before assigning a patient to maintenance therapy. When placing a patient on antidepressant drug therapy for the first time, it should be stressed that the benefit may not be apparent for two to four weeks in fact, there may be unpleasant side effects, such as jitteriness or insomnia, before any improvement is noted. The patient should be encouraged to remain in close touch with the office during this period. Studies show that compliance with psychoactive drug therapy is poor, not because the agents do not work but because they are not given a chance to work. A high percentage of prescriptions are never filled or, if they are filled, patients stop taking the drug after only a few weeks. More attention to communication at this stage, handing patients your visiting card and asking them to call can improve adherence and have a significant impact on treatment outcome.

Selective serotonin reuptake inhibitors have become the first-line treatment of depression in the primary care setting. Safe and convenient to use, they can be taken once a day—generally in the morning to avoid sleep disturbance. Acute side effects that may lead to early discontinuation include insomnia, nervousness, gastrointestinal disturbance, and headache. Chronic side effects include sexual dysfunction, weight fluctuation, and restricted affect.

While all SSRIs are roughly equal in efficacy, individual patients may respond better to one than to another, so a switching within the class can be an effective strategy for dealing with inadequate response. Dose-response also varies, with some patients responding to half the recommended starting dose and others requiring upward adjustment. The fact that certain SSRIs (fluoxetine, sertraline) tend to be more activating than others (citalopram, paroxetine) can be exploited for clinical benefit. For example, fluoxetine may be a good initial choice for a depressed, hypersomnolent patient, while paroxetine or citalopram would generally be preferable for a patient with mixed depression and anxiety. Treatment with fluoxetine is initiated at 10 to 20 mg a day. (Elderly patients and those with hepatic or renal impairment should be started at no more than 10 mg a day.) The drug is metabolized in the liver to norfluoxetine, which has a half-life of up to two weeks. This virtually eliminates the risk of discontinuation syndrome but can result in drug interactions if a new medication is started soon after fluoxetine treatment is suspended.

Sertraline tends to be somewhat less activating than fluoxetine. The starting dosage of 25 to 50 mg a day should be increased in 25-to 50-mg increments to between 100 and 200 mg a day.

Paroxetine is generally started at 10 mg a day and gradually titrated to 20 to 30 mg a day. The maximum dosage for depression is 50 mg a day. For patients who find paroxetine sedating, dosing can be shifted to bedtime.

Citalopram is the most selective SSRI and the one most recently approved for treatment of major depression in the United States. Treatment is initiated at 20 mg a day, with titration to 40 to 60 mg a day over a period of four weeks. As with other SSRIs, dosage reduction of up to 50% is generally recommended for elderly patients and those with hepatic or renal impairment. Common side effects of citalopram include nausea, dry mouth, somnolence, insomnia, and increased sweating. Sexual side effects can occur but appear to be less prominent than with other SSRIs.

Bupropion is chemically unrelated to other classes of antidepressants but offers equivalent efficacy. Because it tends to promote activation, it is useful for patients with excessive fatigue and somnolence. Patients who have discontinued SSRIs due to sexual dysfunction may find bupropion (which does not share this problem) to be a good choice. The drug is sometimes used adjunctively with an SSRI, since the two target different receptors.

Because bupropion was associated with a 0.4% incidence of seizures in one study, the drug is contraindicated in patients with a history of seizure disorders as well as in those with eating disorders or other conditions likely to result in electrolyte imbalance. Starting dosage is 100 to 150 mg a day, with 300 mg a day being the usual efficacious dosage. Bupropion dosage should not exceed 450 mg a day.

Tricyclic antidepressants are now rarely used in outpatient treatment of depression despite their low cost and long track record of safety and efficacy. Their primary disadvantage is a relatively higher incidence of systemic side effects, which can provoke problems in elderly patients and those with concurrent medical disease and may cause even young, healthy patients to terminate therapy prematurely. Occasionally, the side effects of tricyclics may be exploited for clinical benefit. For example, a patient with wasting syndrome or peripheral neuropathy related to HIV infection may profit from the weight gain and decreased neuropathic symptoms associated with this class. Or a patient with migraine headache in addition to depression might find both conditions ameliorated by a tricyclic antidepressant.

In general, secondary amines such as desipramine and nortriptyline have fewer side effects than parent tertiary amines such as amitriptyline. Because of their lethal potential, tricyclics should never be prescribed for patients believed to be at risk of suicide.
Monoamine oxidase inhibitors should not be used in the primary care setting without psychiatric consultation. While effective, these agents have potentially serious side effects and drug interactions that necessitate close monitoring and thorough patient education.