2007]. It is undisputed that the largest suicide risk is untreated depression, as suicidal behaviour is high in depressed adolescents before treatment and each depressive episode is associated with an additional 10% risk of chronicity [Keller et al. 1992]. Thus, the substantial advantages of AG-014699 chemical structure antidepressants over untreated depression and chance of successful recovery appear to outweigh the increased risk of nonfatal self-harm, is compelling evidence for the effectiveness of antidepressants in

depression management. Antidepressant treatment in the long term Substantial Inhibitors,research,lifescience,medical benefits are also apparent with long-term antidepressant treatment. Geddes and colleagues report a 70% reduction in risk of relapse compared with placebo, which persisted up to 36 months after recovery [Geddes et al. 2003]. Kupfer and colleagues conducted a 5-year maintenance trial with patients receiving continued imipramine or placebo treatment, or imipramine treatment for 3 years Inhibitors,research,lifescience,medical followed by placebo for 2 years [Kupfer et al. 1992]. Continued imipramine treatment was highly effective in preventing recurrence, with an 11 times greater risk of recurrence for

those not receiving imipramine. However, high rates of relapse after discontinuing antidepressants Inhibitors,research,lifescience,medical does not necessarily imply antidepressants are effective, as depressive-like discontinuation symptoms may be misdiagnosed as relapsing [Moncrieff and Kirsch, 2005]. These symptoms may unblind patients making them more vulnerable to relapse through the so-called ‘nocebo’ effect, in which Inhibitors,research,lifescience,medical negative

expectations associated with being taken off medication, can induce physical illness. Critics argue that, as patients still relapse when continuing to take medication, antidepressants do not offer a cure to depression, but instead only modify the risk of depressive relapse. Nonetheless, as currently Inhibitors,research,lifescience,medical a curative treatment for depression is not available, antidepressants offer substantial benefits compared with untreated depression. Why is antidepressant efficacy limited? Whilst it is clear that antidepressants provide substantial benefits first for many in the short and long term, it is also evident that problems persist, such as intolerance, delayed therapeutic onset, limited effectiveness and relapse issues. Why is this? A potential problem as to why antidepressants have limited efficacy is that they act by increasing monoamine levels, although individuals with depression do not suffer lower levels of these neurotransmitters. There is immediate increase in monoamine levels following antidepressant ingestion; yet a therapeutic delay is common. Therapeutic effects would appear to be modulated by subsequent neurophysiological changes such as differential expression of monoaminergic receptor levels and downstream intracellular effects on metabotropic enzyme cascades and subsequent alterations to nuclear transcription of proteins such as brain-derived neurotrophic factor (BDNF).