Treatment of Mood Disorders - Therapeutic Modalities

Pharmacological Selection for Medically Ill Patients
Selective Serotonin Reuptake Inhibitors and the Cytochrome P450 System

In recent years the antidepressant class of choice in medically ill patients has been the selective serotonin reuptake inhibitors (SSRIs). SSRIs have been available for use in the treatment of depression since the 1970s. The best-known agents in this class are fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. SSRIs have become the most prescribed antidepressants worldwide. Generally, the SSRIs are far better tolerated than older antidepressants because of their milder side-effect profile and reduced potential for toxicity. Common side effects of SSRIs include nausea, diarrhea, mild anorexia, insomnia, sexual dysfunction, fatigue, agitation, and headache. Unlike their predecessors the tricyclic antidepressants (TCAs), the SSRIs possess low anticholinergic activity, low antihistaminergic activity, and low α1-adrenergic activity. As a result, they do not affect, or only minimally affect, blood pressure and cardiac rate and produce few, if any, cardiac side effects that resemble those produced by quinidine. Occasional bradycardia can occur with the use of SSRIs but is believed to be clinically insignificant. Overall, this class appears to be relatively free of the side effects, including the potential for lethal overdose, that had made the use of TCAs cumbersome.

The cytochrome P450 (CYP) microsomal enzymes are responsible for the metabolism of many medications, including the SSRIs. In humans, this system has been subdivided into enzymes involved with steroidogenesis and enzymes of the xenobiotic class. The xenobiotic CYP enzymes are involved in oxidative metabolism and are largely located in the endoplasmic reticulum of hepatocytes. To date, more than 30 isoenzymes have been identified; of these 30, only 5 (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A3/4) have been found to be of clinical significance in humans. Enzyme induction, enzyme inhibition, or genetic polymorphism can alter normal enzymatic function and activity (

Table 46-1). The most notable alteration of the CYP system is the inhibition of the CYP2D6 enzyme subgroup by multiple medications. CYP2D6 substrates include many of the SSRIs, antiarrhythmics, other antidepressants (TCAs), antipsychotics, codeine, oxycodone, and hydroxycodone. Fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram all inhibit certain CYP isoenzymes to various extents. Paroxetine is considered to be the most potent inhibitor of the CYP2D6 isoenzyme, and sertraline and citalopram are thought to be the least active.

In addition, it has been estimated that perhaps 5%-6% of the black and white population lacks the CYP2D6 isoenzyme, and thus toxic levels of some drugs may develop at fairly low dosages. In these individuals, drug interactions are more likely and lead to multiple adverse side effects and potentially to noncompliance. It is estimated that there are at least as many rapid-metabolizing individuals in the population as there are slow-metabolizing ones. These patients may be categorized as having a treatment-resistant condition because, at usual dosages of antidepressant, serum levels could be inadequate for successful treatment.

Treatment of Mood Disorders: Newer and Atypical Antidepressant Agents and the Cytochrome System » »


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Revision date: June 20, 2011
Last revised: by David A. Scott, M.D.