The neuroendocrine theory implicates hormonal abnormalities in depression due to hyperactivity of the hypothalamic–pituitary axis (HPA) meaning there is insufficient feedback suppression of corticotrophin-releasing factor (CRF) and glucocorticoids. Novel treatments have sought to normalize the HPA via CRF1, CRF2 and glucocorticoid antagonists, which reduce depressive symptoms. However, the majority of testing Inhibitors,research,lifescience,medical has been in mouse models and mixed results have been reported [Nemeroff and Owens, 2002]. This may be because

evidence regarding HPA abnormalities is correlational and only 50% of patients show HPA abnormalities. The plasticity hypothesis associates depression with reduced hippocampal neurogenesis and neurotrophin levels. A popular alternative explanation for delayed therapeutic onset derives from this hypothesis, in which the time lag is attributed to antidepressants causing altering intracellular enzymes (for example, adenylyl cyclase, cyclic adenosine monophosphate [cAMP] and Inhibitors,research,lifescience,medical protein kinase A) which activates expression of the neuroprotective BDNF [Malberg and Duman, 2003; Santarelli et al. 2003]. Thus, there has been interest in phosphodiesterases inhibitors (PDE4), which induces BDNF gene expression;

however, PDE4 have prodepressive actions in areas such as the nucleus accumbens [Berton and Nestler, 2006]. Inhibitors,research,lifescience,medical Conclusion Antidepressants offer substantial benefits in the short and long term to millions of people Inhibitors,research,lifescience,medical suffering from depression. To cast them as ineffective is inaccurate and, whilst Kirsch and colleagues opened our eyes to potential bias and inflation in the literature, the potential

for such studies to be sensationalized by the media is merely destructive to both drug companies and patients. A key issue disregarded by critics is the patient’s point of view, as if the patient is benefiting from antidepressant treatment does it matter whether this is being achieved via drug or placebo effects? However, it is evident that the ideal antidepressant has not been Inhibitors,research,lifescience,medical found as three key problems of intolerance, delayed therapeutic onset and limited efficacy persist. It is chemical structure imperative that future treatment of depression aims to improve this through focusing on novel targets and adopting Astemizole a more individualized approach. The reality of contemporary psychiatric practice is that these drugs are used, with effect, on a daily basis by millions: practicing clinicians are aware of the limitations, the side effects, and the need to holistically contemplate the psychosocial needs of the person in front of them. Guidelines are followed in most instances, but clinical judgement and individual pharmacological tailoring leads, with good outcomes for many. Footnotes Funding: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest statement: DKT has received honoraria from Lilly UK for educational talks.