Selective Serotonin Reuptake Inhibitors

The seven available agents in the selective serotonin reuptake inhibitor class are citalopram (Lund-beck’s Cipramil, Forest Laboratories’ Celexa, generics) and its single enan-tiomer, escitalopram (Lundbeck’s Cipralex, Forest’s Lexapro); paroxetine (GSK’s Paxil/Seroxat, Novartis’s Frosinor, generics); the controlled-release version of paroxetine (GSK’s Paxil CR); sertraline (Pfizer’s Zoloft); fluoxetine (Eli Lilly’s Prozac, generics); and fluvoxamine (Solvay/Fujisawa’s Luvox, Meiji Seika’s Depromel, generics). This section discusses in detail four of these drugs: escitalopram, paroxetine, sertraline, and fluoxetine. Selective serotonin reuptake inhibitors act by selectively inhibiting the presynaptic reuptake of serotonin (5-HT) while exerting little effect on norepinephrine or dopamine uptake.

Triple Reuptake Inhibitors

A novel mechanism for the treatment of depression that has attracted much attention is triple reuptake inhibition. Given their additional mechanism of action on dopamine, the triple reuptake inhibitors pose a potential threat to the clinical use and commercial fortunes of selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors. Agents of this type are being developed by Merck, whose DOV-216303 is in Phase II development and DOV-21947 in Phase Italy; by Sepracor, whose R-DDMS is set to enter Phase III trials pending resumption of development activity; and by GlaxoSmithKline (GSK) in collaboration with Neurosearch, whose NS-2359 is in Phase II development.

Serotonin-Norepinephrine Reuptake Inhibitors

Several antidepressants have dual action at both serotonergic and noradrenergic receptors. The most notable are the serotonin/norepinephrine reuptake inhibitors, particularly extended-release venlafaxine (Wyeth’s Effexor XR) and milnacipran (bioMerieux-Pierre Fabre’s Ixel/Dalcipran, Asahi Kasei/Janssen-Kyowa’s Toledomin; available only in France and Japan). The noradrenergic and specific serotonergic antidepressants (NaSSAs) mirtazapine (Organon’s Remeron/Remergil), nefazodone (Bristol-Myers Squibb’s Serzone/Dutonin/Nefadar/Reseril), and reboxetine (Pfizer’s Ves-tra/Edronax) also fall into this class, but nefazodone is associated with severe liver dysfunction and reboxetine, a noradrenergic agent only, is used only minimally.

Dopaminergic/Noradrenergic Agents

Bupropion (GSK’s Wellbutrin/Wellbutrin XR) acts on the noradren-ergic and dopaminergic system by inhibiting reuptake of norepinephrine and dopamine. Because bupropion does not affect the serotonergic system, this drug has become a common alternative or adjunct therapy for patients unable to bear the serotonergic side effects associated with serotonin reuptake inhibition (e.g., sedation, weight gain, fatigue, sexual dysfunction).

Tricyclic Antidepressants

Although tricyclic antidepressants are as effective as the selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors in treating most forms of depression, they have the potential for cardiotoxicity from overdose and are associated with a wide array of side effects that make them less tolerable than the newer antidepressants. They have been largely replaced by newer agents. Because of their side-effect profile, tricyclic antidepressants are no longer considered first-line treatment for major depression and are generally reserved for second-line treatment of patients whose disease is refractory to more than one drug from the other classes of antidepressants.

Minor Depression

Minor depression is only a proposed diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and there are no International Classification of Diseases codes to categorize it. The proposed diagnostic category for minor depression in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition describes a depressive disorder that requires the presence of two to four symptoms of depression, lasting for at least two weeks, that are identical to major depressive episodes in duration but involve fewer symptoms and less impairment.