How Do Antidepressants Work? Minireview Prospects for Genetic Analysis of Drug Mechanisms

mood, one might predict that normal individuals treated with serotonin reuptake blockers would experience euFluoxetine and the Serotonin Model for Depression phoria, and that dietary serotonin depletion would inFluoxetine (a.k.a. Prozac) is well known for its ability to duce depression. In fact, these manipulations of serototreat clinical depression, one of the most prevalent of nin levels have little effect on mood except in individuals all psychiatric disorders. Yet the mechanism by which who are depressed or recently recovered from depresfluoxetine actually functions to relieve depression is not sion (McAllister-Williams and Young, 1998). Moreover, well understood. Fluoxetine is the best-known member even in depressed patients the effects of serotonin reupof a class of antidepressant drugs known as serotonintake blockers on mood do not correlate temporally with selective reuptake inhibitors (SSRIs). In popular actheir effects on serotonergic transmission; whereas counts, their antidepressant action is usually explained SSRIs and most tricyclics elevate synaptic serotonin in the context of a long-standing model of depression levels within hours, their effects on mood are not apparcalled the serotonin hypothesis. According to this ent for 2–6 weeks. Finally, although many drugs used model, levels of serotonergic neurotransmission in the to treat mood disorders block uptake or degradation of forebrain are a key determinant of mood: high activity serotonin, a number of effective antidepressants clearly results in euphoria, low activity results in dysphoria. do not, including selective norepinephrine reuptake inDepression is said to be caused by chronically low levels hibitors (SNRIs) such as desipramine and atypical antiof serotonergic transmission. SSRIs interfere with the depressants such as tianeptine, which enhances rather activity of the serotonin transporter (5-HTT), a reuptake than inhibits serotonin reuptake, MK869, which antagomolecule that removes serotonin from the synapse; nizes substance P receptors, and bupropion, whose tarthus, the putative low levels of synaptic serotonin in get is unknown (Baldessarini, 1996; Kramer et al., 1998). the depressed patient are elevated, and depression is Together, these observations indicate that any conrelieved. Consistent with this model, many other antidenection between serotonin and mood is likely to be more pressants, including tricyclics (e.g., clomipramine) and complicated and perhaps more indirect than a simplistic monoamine oxidase inhibitors, also potentiate serotoversion of the serotonin model would imply. Consenergic transmission by interfering with serotonin reupquently, most current versions of the serotonin model take or degradation. hypothesize that SSRIs are effective against depression Variations on this serotonin model represent the most not because of their acute effects on serotonergic transmission, but because of long-term adaptive changes in widely accepted explanation for antidepressant action