been reported for a2,b,and 5-HTIA systems(color).VAT denotes a vesicle-associated transporter II.CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS Clinical Indications The major indication for antidepressant drugs is to treat depression,but a number of other uses have been established by clinical experience and controlled trials. A.DEPRESSION This indication has been kept broad deliberately,even though evidence from clinical studies strongly suggests that the drugs are specifically useful only in major depressive episodes.Major depressive episodes are diagnosed primarily on the basis of the persistent degree and quality of depressed mood or loss of interest and pleasure in most activities,usually accompanied by disturbances of sleep,appetite,sexual drive,activity,or ability to concentrate.The diagnosis of major depression may be uncertain in individual patients,so that on balance this condition is underdiagnosed and undertreated.The depressed phase of bipolar illness definitely requires pharmacologic treatment given the high rate of suicide in persons with this disorder. Standard antidepressants are usually added to lithium or another antimanic agent; SSRIs are less likely to induce mania than the older tricyclic agents.There are, however,few controlled studies on their relative efficacy or proper duration of use. Finally,recent controlled studies support the additional labeling of the anticonvulsant lamotrigine for maintenance and prophylaxis of the depressed phase of bipolar illness. B.ANXIETY DISORDERS:PANIC,GENERALIZED ANXIETY,AND SOCIAL PHOBIA Imipramine was first shown in 1962 to have a beneficial effect in the acute episodes of anxiety that have come to be known as panic attacks.It has also been demonstrated that SSRIs,venlafaxine,and duloxetine are effective in panic,generalized anxiety disorder (GAD),and social phobia,but they require 6-8 weeks of treatment.Since there is considerable comorbidity between depression and anxiety disorders,it is advantageous for many patients to use a treatment that is helpful for both conditions. In some instances,because they are well tolerated and their clinical effects become evident promptly,benzodiazepines remain the preferred drugs for anxiety disorders despite the physiologic dependence associated with long-term use. C.OBSESSIVE-COMPULSIVE DISORDERS Potent SSRIs are uniquely effective for treating these disorders.Recent studies have focused on fluoxetine and other SSRIs,although clomipramine,the most potent mixed serotonin and norepinephrine transporter inhibitor,may be especially effective. Fluvoxamine is marketed exclusively for this disorder in the United States.been reported for a2, b, and 5-HT1A systems (color). VAT denotes a vesicle-associated transporter. II. CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS Clinical Indications The major indication for antidepressant drugs is to treat depression, but a number of other uses have been established by clinical experience and controlled trials. A. DEPRESSION This indication has been kept broad deliberately, even though evidence from clinical studies strongly suggests that the drugs are specifically useful only in major depressive episodes. Major depressive episodes are diagnosed primarily on the basis of the persistent degree and quality of depressed mood or loss of interest and pleasure in most activities, usually accompanied by disturbances of sleep, appetite, sexual drive, activity, or ability to concentrate. The diagnosis of major depression may be uncertain in individual patients, so that on balance this condition is underdiagnosed and undertreated. The depressed phase of bipolar illness definitely requires pharmacologic treatment given the high rate of suicide in persons with this disorder. Standard antidepressants are usually added to lithium or another antimanic agent; SSRIs are less likely to induce mania than the older tricyclic agents. There are, however, few controlled studies on their relative efficacy or proper duration of use. Finally, recent controlled studies support the additional labeling of the anticonvulsant lamotrigine for maintenance and prophylaxis of the depressed phase of bipolar illness. B. ANXIETY DISORDERS: PANIC, GENERALIZED ANXIETY, AND SOCIAL PHOBIA Imipramine was first shown in 1962 to have a beneficial effect in the acute episodes of anxiety that have come to be known as panic attacks. It has also been demonstrated that SSRIs, venlafaxine, and duloxetine are effective in panic, generalized anxiety disorder (GAD), and social phobia, but they require 6-8 weeks of treatment. Since there is considerable comorbidity between depression and anxiety disorders, it is advantageous for many patients to use a treatment that is helpful for both conditions. In some instances, because they are well tolerated and their clinical effects become evident promptly, benzodiazepines remain the preferred drugs for anxiety disorders despite the physiologic dependence associated with long-term use. C. OBSESSIVE-COMPULSIVE DISORDERS Potent SSRIs are uniquely effective for treating these disorders. Recent studies have focused on fluoxetine and other SSRIs, although clomipramine, the most potent mixed serotonin and norepinephrine transporter inhibitor, may be especially effective. Fluvoxamine is marketed exclusively for this disorder in the United States