1.Tricyclics The first-generation antidepressants demonstrate varying degrees of selectivity for the reuptake pumps for norepinephrine and serotonin(Table 30-2)but selectivity is much lower than for the SSRIs.They also have numerous autonomic actions,as described below under Adverse Effects. 2.Second-generation agents Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism (see Chapter 29).A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients.However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome,and perhaps tardive dyskinesia. Maprotiline (a tetracyclic drug)is most like desipramine in terms of its potent norepinephrine uptake inhibition.Like desipramine,it has fewer sedative and antimuscarinic actions than the older tricyclics. Clinical experience with trazodone has indicated unpredictable efficacy for depression, although it has proved very useful as a hypnotic,sometimes being combined with MAOIs,which disturb sleep. 3.Subsequent non-SSRI agents%Four antidepressants%nefazodone,venlafaxine, duloxetine,and mirtazapine%are all related to earlier agents in either structure or mechanism of action.Nefazodone is closely related to trazodone but is less sedating. It produces fewer adverse sexual effects than the SSRIs (see below)but is a potent inhibitor of CYP3A4.(Fluvoxamine causes the same inhibition of CYP3A4.) Venlafaxine is a potent inhibitor of serotonin transport and a weaker inhibitor of norepinephrine transport.At lower therapeutic doses,venlafaxine behaves like an SSRI.At high doses (more than 225 mg/d),it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine transporter inhibition. Doses in the range of 225 mg/d or more may confer broader therapeutic effects than SSRIs,but titration up to these doses is needed to control adverse effects. Mirtazapine is a potent antihistaminic with greater sedating effects than the other second-and third-generation antidepressants.Its use is also more likely to be associated with weight gain.The hypothesized mechanism of action of mirtazapine combines 5-HT2 receptor and a-adrenoceptor antagonism and,if established in humans,would be unique among available drugs.Thus,mirtazapine may prove beneficial in patients who can tolerate its sedative effects and do not respond well to SSRIs or cannot tolerate their sexual adverse effects. 4.Selective serotonin reuptake inhibitors%These drugs achieve high ratios of SERT versus NET inhibition of 300 to 7000 (Table 30-2).Fluoxetine was the first SSRI to reach general clinical use.Paroxetine and sertraline differ mainly in having1. Tricyclics The first-generation antidepressants demonstrate varying degrees of selectivity for the reuptake pumps for norepinephrine and serotonin (Table 30-2) but selectivity is much lower than for the SSRIs. They also have numerous autonomic actions, as described below under Adverse Effects. 2. Second-generation agents Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism (see Chapter 29). A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients. However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome, and perhaps tardive dyskinesia. Maprotiline (a tetracyclic drug) is most like desipramine in terms of its potent norepinephrine uptake inhibition. Like desipramine, it has fewer sedative and antimuscarinic actions than the older tricyclics. Clinical experience with trazodone has indicated unpredictable efficacy for depression, although it has proved very useful as a hypnotic, sometimes being combined with MAOIs, which disturb sleep. 3. Subsequent non-SSRI agents¾ Four antidepressants¾nefazodone, venlafaxine, duloxetine, and mirtazapine¾are all related to earlier agents in either structure or mechanism of action. Nefazodone is closely related to trazodone but is less sedating. It produces fewer adverse sexual effects than the SSRIs (see below) but is a potent inhibitor of CYP3A4. (Fluvoxamine causes the same inhibition of CYP3A4.) Venlafaxine is a potent inhibitor of serotonin transport and a weaker inhibitor of norepinephrine transport. At lower therapeutic doses, venlafaxine behaves like an SSRI. At high doses (more than 225 mg/d), it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine transporter inhibition. Doses in the range of 225 mg/d or more may confer broader therapeutic effects than SSRIs, but titration up to these doses is needed to control adverse effects. Mirtazapine is a potent antihistaminic with greater sedating effects than the other second- and third-generation antidepressants. Its use is also more likely to be associated with weight gain. The hypothesized mechanism of action of mirtazapine combines 5-HT2 receptor and a-adrenoceptor antagonism and, if established in humans, would be unique among available drugs. Thus, mirtazapine may prove beneficial in patients who can tolerate its sedative effects and do not respond well to SSRIs or cannot tolerate their sexual adverse effects. 4. Selective serotonin reuptake inhibitors¾ These drugs achieve high ratios of SERT versus NET inhibition of 300 to 7000 (Table 30-2). Fluoxetine was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having