Article

The pharmacogenetics of major depression: Past, present, and future

Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, Bethesda, MD 20892, USA.
Biological Psychiatry (Impact Factor: 9.47). 01/2008; 62(11):1205-7. DOI: 10.1016/j.biopsych.2007.09.016
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    ABSTRACT: Major depressive disorder (MDD) is estimated by the World Health Organization to be the fourth leading cause of loss of disability-adjusted life years. In the National Comorbidity Survey, MDD is the most common mental illness and is one of the most common and disabling of all illnesses (Kessler et al., 1994). The lifetime risk for MDD is 10–25% in women and 5–12% in men, and at any point its prevalence is 5–9% in women and 2–3% in men. Given the widespread and disabling nature of the illness, MDD is of great public health concern. The first useful antidepressants, imipramine and isoniazid, were serendipitously found to have antidepressant properties in the 1950s. These discoveries – coupled with the observation that reserpine, which depletes monoamines, induced depres-sion – led to the development of the monoamine hypothesis of depression. This led to the rational development of drugs which affect central nervous system monoamines, primarily norepinephrine (noradrenaline), serotonin (5-HT), and dopamine. The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) formed the foundation for several decades of pharmacologic treat-ments for depression, although their side-effects (including lethality in overdose in the case of TCAs, and strict dietary restriction to avoid hypertensive crises in the case of MAOIs) limited their utility and tolerability. Pharmaceutical research focused on the development of drugs with improved tolerability and safety. Next-generation drugs such as trazodone, a 5-HT 2 -receptor antagonist, were an incre-mental improvement, but not until the arrival to the market in 1988 of the first selective serotonin reuptake inhibitor (SSRI), fluoxetine (Prozac), did the use of antidepressants markedly change. Several other SSRIs followed, including parox-etine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro).

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