L. Williams, J. Pasco, L. Kessing
May 27, 2016
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2
Influential Citations
20
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Quality indicators
Journal
Psychotherapy and Psychosomatics
Abstract
genotype of the A2350G polymorphism had significantly higher serum ACE activity [6] . Many of the pharmacological agents in use in psychiatry today were first tested experimentally for other indications [7] . ACE inhibitors are used worldwide as antihypertensive drugs, and are generally well tolerated with a good safety profile, making them an attractive option for the treatment of depression if proven effective [8] . Building on the theoretical framework and pre-clinical evidence that drugs that decrease angiotensin II might have desirable effects on MD, here we present the first clinical evidence that the use of ACE inhibitors indeed prevents the occurrence of MD using a large epidemiological cohort study. In a random population-based sample of men enrolled in the Geelong Osteoporosis Study [9] , 978 of the original group (n = 1,540) returned for a 5-year follow-up appointment between 2006 and 2011 (81.0% response from those alive and contactable). Methodological details are published elsewhere [9] . For the current analyses, participants for whom psychiatric data were not available (n = 17) were excluded, resulting in a sample of 961 men aged 24–98 years. A lifetime history of MD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, ed. 4, non-patient edition (SCID-I/NP) conducted at the Geelong Osteoporosis Study 5-year follow-up [10] . Self-reported medication use was documented by questionnaires administered at each visit. Participants were asked to bring in a list of medications or containers to assist with accurate recording of details. Anthropometry and lifestyle factors were measured and socio-economic status ascertained using Socio-Economic Index for Areas (SEIFA) index scores. SEIFA values were used to derive an Index of Relative Socio-economic Advantage and Disadvantage (IRSAD), which accounts for high and low income and type of occupation, and was categorized into quintiles according to cut-points for the study region. Two study designs were planned: 1 Nested case-control study: cases were participants diagnosed with an MD and controls were MD free. The use of ACE inhibitors was recognized if exposure preceded first-onset MD for cases and the 5-year assessment for controls. Logistic regression modelling was used to determine the association between ACE inhibitors and the likelihood for de novo MD. Adjustment was made for age alone and then for age, weight, height, alcohol, smoking, physical activity, socio-economic status and use of antidepressants, hormones, aspirin, diuretics, other hypertensive agents, non-steroidal anti-inflammatory agents and self-reported diabetes. 2 Retrospective cohort analysis: participants had no history of MD at baseline and were followed up until a first episode of MD or until the end of the 5-year follow-up period. To identify the risk for de novo MD associated with ACE inhibitors, Cox proportional-hazards regression was planned. In the case-control study, among 961 men, 165 were diagnosed with a MD (cases) and 796 had no history of a MD (controls). SevMood disorders (MD) are characterized by a low-grade inflammatory state [1] . The renin-angiotensin system, which plays a pivotal role in the regulation of blood pressure, is also one of the pathways known to modulate inflammation in the central nervous system. Renin cleaves angiotensinogen to generate angiotensin I, which in turn is metabolized to angiotensin II by the enzyme angiotensin-I-converting enzyme (ACE). The actions of angiotensin II in the central nervous system are mediated by angiotensin II, type 1 receptors (AT1R), which contribute to the activation of the hypothalamic-pituitary-adrenal axis and the consequent release of cortisol. This indicates that the renin-angiotensin system is involved in the regulation of the stress response. Based on this, a theoretical framework has been developed proposing that drugs capable of decreasing angiotensin II levels would be novel therapeutic targets for neuropsychiatric disorders related to inflammation, such as depression, and indeed a large body of pre-clinical evidence shows that AT1R blockers decrease neuroinflammation [2] . There are other supportive data. In silico genetic data suggest that angiotensin agents active at the AGTR1 site might have efficacy in MD [3] . Associations between ACE polymorphisms and late life depression are described, and altered methylation of the regulatory region of the ACE gene has been reported in depression [4, 5] . Carriers of the GG genotype of the ACE A2350G showed an association with depression, where higher serum ACE activity was seen. Furthermore, individuals with depression carrying the GC Received: August 16, 2015 Accepted after revision: February 9, 2016 Published online: May 27, 2016