Robert H. Howland and Michael E. Thase
Currently, a wide variety of therapies are available for the treatment of mood disorders. These therapies have been studied mainly in major depressive disorder and bipolar I disorder, although they also are commonly used in clinical practice for the treatment of such related mood disorders as dysthymia, minor depression, cyclothymia and bipolar II disorder (Howland, 1991; Howland and Thase, 1993). The diversity of the many antidepressant and antimanic therapies that are effective likely reflects the underlying pathophysiological heterogeneity that exists among the mood disorders (Howland and Thase, 1999b), although seemingly different therapies also may share common therapeutic mechanisms of action. For a significant proportion of mood disorder patients, the available standard antidepressant and antimanic therapies are not entirely effective, contributing to the development and clinical use of novel treatments. In this chapter we review standard antidepressant and antimanic therapies for mood disorders. We also review novel pharmacological and non-pharmacological therapies that are being studied and sometimes used for the treatment of major depressive and bipolar disorders.
During the 1950s, the clinical effects of tricyclic antidepressant (TCA) and monoamine oxidase inhibiting (MAOI) drugs were first discovered (Crane, 1957; Kuhn, 1958). Since the 1980s, numerous antidepressant drugs unrelated to the TCAs and MAOIs have been developed and studied for the treatment of depression (Kent, 2000; Sampson, 2001).
After their discovery, the TCAs were the cornerstone of pharmacotherapy for depression for nearly three decades (Nelson, 2000). The most commonly used TCAs, so called because of their cyclic chemical structure, include imipramine, desipramine, amitriptyline and nortriptyline. Doxepin, trimipramine and protriptyline are less commonly used. Clomipramine is approved for use in the United States only for the treatment of obsessive-compulsive disorder, but it is a highly effective antidepressant. The antidepressant effects of the TCAs are believed to be primarily due to their inhibition of the reuptake of the neurotransmitters norepinephrine and serotonin (Richelson, 2001), although they and other antidepressant drugs also directly or indirectly affect second-messenger systems (Popoli et al., 2000; Vaidya and Duman, 2001) that are implicated in the neurobiology of depression (Duman et al., 1997). Aside from clomipramine, the TCAs are more active on noradrenergic reuptake inhibition. They also potently block several important postsynaptic neurochemical receptors, which account for most of their typical side effects. Dry mouth, constipation, blurred vision, sinus tachycardia, urinary retention and memory dysfunction are due to cholinergic receptor blockade. Sedation and weight gain are primarily related to histaminic receptor blockade, although serotonergic and anticholinergic effects may also contribute to the weight gain associated with the TCAs and other types of antidepressant drugs (Fava et al., 2000). Dizziness, hypotension and reflex tachycardia are caused by their blockade of α–1 adrenergic receptors. The TCAs also have quinidine-like effects on cardiac conduction, which can cause serious cardiotoxic effects, including arrhythmias and conduction abnormalities, and can be fatal with an overdose as small as 7–10 times a daily therapeutic dose.
As a group, the TCAs do not differ significantly in their relative antidepressant efficacy (Thase, 1997). Two TCAs, nortriptyline and desipramine, are secondary amine metabolites of amitriptyline and imipramine, respectively, and they are often preferred because of less pronounced anticholinergic side effects. Placebo-controlled studies have found TCAs to be effective in adult and geriatric patients, but not in younger age groups (Brent et al., 1995). Interestingly, compared to men and to postmenopausal women, there is evidence that premenopausal women respond less well to TCAs than to other antidepressant drugs (Kornstein et al., 2000; Thase et al., 2000a). Higher TCA doses are often associated with greater therapeutic benefit, but this is limited by their greater side effect burden. Measuring plasma levels of imipramine, amitriptyline, desipramine and nortriptyline is clinically useful for achieving a therapeutic response (Bernstein, 1995). Because of their side effects and potential lethality, the use of TCAs has been gradually supplanted by newer generation antidepressants. The TCAs, however, can be quite effective in treating patients who do not respond to other drugs, and they remain especially effective treatments for more severe melancholic depressions (Thase and Rush, 1995).
The pharmacology and presumed mechanism of action of the MAOIs is distinctly different from all other antidepressants (Kennedy et al., 2000). The MAOIs phenelzine, tranylcypromine and isocarboxazid irreversibly and non-selectively inhibit the enzyme monoamine oxidase (MAO), which degrades norepinephrine, serotonin and dopamine, thereby increasing the availability of these neurotransmitters and likely contributing to their antidepressant effects (Richelson, 2001), although they may also directly or indirectly affect second-messenger systems (Popoli et al., 2000; Vaidya and Duman, 2001) that are implicated in the neurobiology of depression (Duman et al., 1997). Typical side