The usual dosages and dose ranges of antidepressant medications are listed in Table 17-1, along with the severity of common side effects. Although they usually are used initially in divided doses, transition to a single daily dose usually is possible due to the relatively long half-lives and wide range of tolerated concentrations of most antidepressants. With the tricyclic antidepressants, dosing is most safely done with single doses up to the equivalent of 150 mg of imipramine.
Tricyclic and Selective Serotonin Reuptake Inhibitors
SSRIs and other atypical modern agents now are broadly accepted as drugs of first choice, particularly for medically ill or potentially suicidal patients and in the elderly and young. MAO inhibitors commonly are reserved for patients who fail to respond to vigorous trials of at least one of the newer agents and a standard tricyclic antidepressant, administered alone or with lithium to enhance overall therapeutic effectiveness. The somewhat less anticholinergic secondary-amine tricyclics, particularly nortriptyline and desipramine, are alternatives or a second choices for elderly or medically ill patients, particularly if administered in moderate, divided doses (Table 17-1). Patients with severe, prolonged, disabling, psychotic, suicidal, or bipolar depression require vigorous and prompt medical intervention.
Indications for the MAO inhibitors are limited and must be weighed against their potential toxicity and their complex interactions with other drugs. Thus, the MAO inhibitors generally are considered drugs of late choice for the treatment of severe depression. Nevertheless, MAO inhibitors sometimes are used when vigorous trials of several standard antidepressants have been unsatisfactory and when ECT is refused. In addition, MAO inhibitors may have selective benefits for conditions other than typical major depression, including illnesses marked by phobias and anxiety or panic as well as dysphoria, and possibly in chronic dysthymic conditions. Similar benefits, however, may be found with imipramine-like agents or SSRIs.
The safe and effective treatment of bipolar depression is a difficult clinical challenge. This condition sometimes is misdiagnosed in patients with bipolar disorder who present with mixed dys-phoric-agitated moods, who then are inappropriately treated with an antidepressant without a mood stabilizing agent to protect against worsening agitation or mania. For this reason, the management of manic, mixed, and depressive mood states in bipolar disorder best relies on lithium or other mood-stabilizing agents, notably the anticonvulsant lamotrigine, as the primary treatment (see Chapter 18). An antidepressant can be added cautiously and temporarily to treat bipolar depression, but the additional benefit and safety of sustained combinations of an antidepressant with a mood stabilizer are unproven. The combination SSRI/atypical antipsychotic (fluoxetine/olanzapine; symbyax) is FDA-approved for treatment of depressive episodes associated with bipolar disorder.
The natural history of major depression (either as unipolar depression or depressive phases of bipolar disorder) is that individual episodes tend to remit spontaneously over 6-12 months; however, there is a high risk of relapse of depression for at least several months after discontinuation of antidepressant treatment. This risk is estimated at 50% within 6 months and 65-70% at 1 year, rising to 85% by 3 years. To minimize this risk, it is best to continue antidepressant medication for at least 6 months following apparent clinical recovery. Continued use of initially therapeutic doses is recommended, although tolerability and acceptance by patients may require flexibility.
Many depressed patients follow a recurring course of episodic illness, often with lesser levels of symptoms and disability between major episodes, and therefore merit consideration of long-term maintenance medication to reduce the risk of recurrence. Such treatment has been tested for as long as 5 years, using relatively high doses of imipramine, with evidence that early dose reduction led to a higher risk of relapse. Long-term supplementation of an antidepressant with lithium may enhance the result. Prolonged maintenance treatment of patients with recurring major depression for more than a year has rarely been evaluated with modern antidepressants, and long-term dose-response data with any antidepressant are very limited. The use of indefinitely prolonged maintenance treatment with an antidepressant is guided by the history of multiple, and especially severe or life-threatening, recurrences and the impression that recurrence risk is greater in older patients. Because rapid discontinuation or sharp reduction in doses of antide-pressants and lithium may contribute to excess early recurrence of illness, gradual reduction and close clinical follow-up over at least several weeks are recommended when maintenance treatment is to be discontinued and when stopping continuation therapy within the months following recovery from an acute episode of depression.
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