SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
The use of an SSRI is appropriate for patients who are at risk from side effects commonly seen with TCAs. The SSRIs are all equally effective but differ in their half-lives and onset and duration of action. Controlled studies have shown that SSRIs do not exacerbate suicidal ideas in patients. However, sexual dysfunction, nausea, nervousness, and agitation may limit their use. Hyponatremia has been reported in patients also taking diuretics. Administration of SSRI with an MAO inhibitor is not recommended. In fact, a washout period should be used when transferring patients from one treatment to another to avoid the serotonergic syndrome. All SSRIs are highly protein bound and may displace or be displaced by other drugs. These drugs also inhibit Cytochrome P450 enzymes and should be used with caution with other drugs that are hepatically metabolized such as warfarin. All SSRI products have active metabolites. New SSRIs soon to be marketed include Venlafaxine (Effexor) and Flouoxamine (Luvox).
Fluoxetine is started at 20 mg once daily in the morning, and doses can be increased up to 80 mg daily. Doses higher than 20 mg should be given in the morning and at noon. A liquid preparation is also available for those who cannot use the tablets or want to titrate the dose lower than 20 mg. If the patient misses a dose or is not compliant, they will not experience any ill effects due to the drug's long elimination half-life of two to three days. Fluoxetine is metabolized in the liver to an active compound.
Paroxetine is started at 20 mg once daily in the morning. Patients not responding to treatment after three to four weeks may benefit from incremental increases of 10 mg per day up to a maximum of 50 mg daily. Doses should be increased at one-week intervals. The elimination half-life is 21 hours. In the elderly patient or those with severe renal (Creatine clearance < 30 ml/min) or hepatic impairment plasma concentrations may be increased. The dose in these patients should be started at 10 mg per day and increased to a maximum of 40 mg per day. Paroxetine is metabolized by the liver to a less active compound.
Sertraline is started at 50 mg once daily, and doses can be increased up to 200mg daily. One week should elapse between adjustment of doses because of the half-life of 26 hours. According to product information, a lower dose or less frequent dosing interval should be used in patients with hepatic impairment, and care should be used in patients with renal impairment. Steady state is achieved in elderly patients in two to three weeks. In one study, clearance of sertraline was reduced by 40 percent in elderly patients, Zoloft undergoes a first-pass effect and is metabolized to a less active compound.
Bupropion (Wellbutrin) and Trazodone (Desyrel) and chemically unrelated to the TCA, SSRI, or MAO inhibitors. They are weak inhibitors of Serotonin and can be considered first-line therapies for depression.
Buproprion (Wellbutin) is started at 100 mg twice daily and can be increased up to 150 mg three times daily. Bupropion should be avoided in patients with eating disorders and is contra-indicated in patients with seizure disorders. Wellbutrin can cause activation or the feeling of agitation but causes fewer changes in cardiac conduction and orthostasis compared to the TCA. Wellbutrin has been shown to have a minimal risk for causing sexual dysfunction. Patients who are on MAO inhibitors should not receive Wellbutrin. In fact, a 14-day washout period should be used when transferring patients from one treatment to another. Seizures partially related to blood levels have been reported with the use of Wellbutrin. To avoid this, the maximum daily dose of 450 mg (150 mg three times daily) should not be exceeded, and patients should not try to make up a dose when they have missed one. All doses should be given six hour apart, and no more than 150 mg should be given at one time.
One advantage of Trazodone in the treatment of elderly patients is that no dosage alternation is required. Although just as effective as other antidepressant,s Trazodone has a short half-life (three to nine hours), which requires multiple daily dosing to achieve effective plasma levels. In addition, its major metabolite also blocks alpha receptors and may account for the adverse reactions of dryness of the mouth and orthostatic hypotension. Trazodone has strong sedative properties but little anticholinergic effect. However, it may cause arrhythmias in patietns with prexisting cardaic disease. Trazodone has also been reported to cause priapism (incidence 1:6000).
The MAO inhibitors (Isocarboxazid, Phenelzine, and Tranylcypromine are reserved for patients who have not responded to a trial of TCA, SSRI, or heterocyclics. These agents are considered second-line treatments because they require significant dietary restriction (cheese, red wine, beer, chocolate) and interact with many other medications. However, patients who have major depressive disorder with atypical features or those with a family history of a response to MAO inhibitors may benefit from these agents.
ANTIDEPRESSANT TREATMENT GUIDELINES (US Department of Health,1993)
*Titrate up to the maximum dose during a 4-6 week period.
*Partial responders after treatment for 4-6 weeks should be on maximum doses without intolerable side effects before switching to another agent. Medication underdosing is the most common problem in the partially responsive patient.
*Non-responders on adequate doses for 6 weeks should be tried on a different class of antidepressants.
*Blood levels of TCA may be helpful in partial responders.
*Patients should be asked about their medication compliance. Non-compliant patients receiving multiple doses per day can benefit by switching to a drug with once-daily dosing.
*Drug interactions should be monitored.
*Re-evaluate therapy at 12 weeks. Psychotherapy can be added if only a partial response is reported.
*Re-evaluate therapy 4-6 months after beginning treatment. If a patient is feeling better, discontinuing medication at 6 months instead of 9 months can save health care dollars, especially for those antidepressants such as SSRIs or Welbutrin, which are not avaiable as generics.
*Patients with a single episode of major depressive disorder are advised to discontinue treatment after 4-6 months of treatment.
1. Value Rx: Formulary Update. Fall, 1993, pp. 1-6.