Compared with men, women are at increased risk of depression, especially at several reproductive-related lifecycle points. This may be partially due to changing levels of estrogen, a hormone that can affect levels of neurotransmitters and neural proteins. As estrogen levels vary throughout the lifespan, risk of depression in women also varies, and not all treatments are appropriate or effective at all times. In adolescence, onset of depression may be associated with onset of puberty, but treating underage girls with antidepressants can risk suicidality. In females of childbearing age, mood disturbances associated with menstrual cycles signal a risk for later full-blown major depressive disorder. In depressed pregnant and postpartum women, risks of treatment versus risks of nontreatment are intricate and require case-by-case evaluation. In perimenopause, vasomotor symptoms may be harbingers of oncoming depression and also may signal the presence of dysregulated hormones and neurotransmitters. Relieving vasomotor symptoms may be a necessary dimension of treating depression. In postmenopause, response to selected antidepressants may depend on whether the patient is also taking hormone-replacement therapy. To attain optimal outcomes, modern psychopharmacologists must tailor treatment of depression to a woman's reproductive stage of life. TRIMONOAMINE MODULATORS AND DEPRESSION Clinicians often target the three neurotransmitters most implicated in depression-serotonin (5-HT), norepinephrine (NE), and dopamine (DA)-by using antidepressants to block reuptake at the respective neurotransmitter reuptake transporters. 1 However, other agents can modulate all three neurotransmitters without

-(glutathion-S-yl)-N-methyl-␣-methyldopamine (5-GS-N-Me-␣-MeDA), the caffeic acid metabolite 2-(glutathion-S-yl)-caffeic acid (2-GS-CA), and four GSH conjugates of 2-hydroxy (OH) and 4-OH estrogens (GS estrogens). MRP1-mediated E

The hypothalamic-pituitary-adrenal axis is a key mediator of the stress response in humans. The corticotropin-releasing factor (CRF) type 1 receptor (CRFR-1) in the pituitary gland is a gatekeeper for that response, and the CRFR-1 receptor is also present in many other mood- and cognition-related neural structures. Behaviorally, a number of relationships between stress and psychiatric disorders can be observed: chronic or repeated stress is associated with onset of depression; stressors can cause a recovering alcoholic to relapse; overactive stress responses mark many anxiety disorders; and insomnia can arise from an overactive stress response. Thus, a CRFR-1 antagonist could be useful for treating or preventing the consequences of CRF-mediated stress in depression, anxiety, insomnia, and substance abuse.