Looking back over relevant research papers that caught my attention last month, some stand out for me more than the others.  Here are three on depression that stood out and got me thinking.  The Fergusson et al paper looks at links between alcohol abuse and major depression.  There has been debate for years on whether alcohol dependence leads to depression or depression leads to alcohol dependence.  In this kind of debate, it's usually a good bet that both pathways contain some truth.  What this study adds is that often it is the alcohol dependence that is primary.  As the authors state " ... the associations between AAD (alcohol abuse or dependence) and MD (major depression) were best explained by a causal model in which problems with alcohol led to increased risk of MD as opposed to a self-medication model in which MD led to increased risk of AAD." 

The Gimeno et al study also looks at precursors to depression.  This time it's the well known association between depression and low-grade inflammatory processes.  They found that baseline markers of low-grade inflammation predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up.  This a huge and complex subject with relevance to a wealth of health outcomes.  Chronic low-grade inflammation also, for example, increases the risk of coronary heart disease, while health practices like eating whole rather than processed grain or losing weight decrease chronic inflammatory markers.  Maybe we should be thinking a lot more about improving lifestyle as a very important way of reducing both the risk of depression and also, of course, helping health more generally.  To make life more interesting, the reverse pathway is also relevant with psychological trauma sometimes linked with subsequent increases in inflammatory processes, and there are also common genetic processes as well.  I have a bit of a worry that this kind of complex mind-body territory isn't paid attention to by most mental health clinicians - whether psychotherapists or psychiatrists. 

The third depression study by Whang et al is also thought provoking.  Unsurprisingly, they found links between depression and increased risk of subsequent cardiac problems.  What was more surprising was the strong link between antidepressant use and cardiac problems.  This flies in the face of other research findings - for example that SSRI antidepressants actually reduce inflammatory processes over and above their antidepressant action and that antidepressant use does not affect mortality for depressed patients who have suffered a heart attack.  The authors note that in fact antidepressant use might be a marker of worse depression and so, in themselves, antidepressants may not contribute to any increased cardiac risk.  There is however a need to clarify this issue further.

Fergusson, D. M., J. M. Boden, et al. (2009). "Tests of Causal Links Between Alcohol Abuse or Dependence and Major Depression." Arch Gen Psychiatry 66(3): 260-266.  [Abstract/Full Text]
Context There has been a great deal of research on the comorbidity between alcohol abuse or dependence (AAD) and major depression (MD). However, it is unclear whether AAD increases the risk of MD or vice versa. Objective To examine the associations between AAD and MD using fixed-effects modeling to control for confounding and using structural equation models to ascertain the direction of causality. Design Data were gathered during the course of the Christchurch Health and Development Study, a 25-year longitudinal study of a birth cohort of children from New Zealand (635 boys, 630 girls). Setting General community sample. Participants The analysis was based on a sample of 1055 participants with available data on AAD and MD at ages 17 to 18, 20 to 21, and 24 to 25 years. Main Outcome Measures Symptom criteria for AAD and MD from the DSM-IV at ages 17 to 18, 20 to 21, and 24 to 25 years as well as measures of life stress, cannabis use, other illicit drug use, affiliation with deviant peers, unemployment, partner substance use, and partner criminality at ages 17 to 18, 20 to 21, and 24 to 25 years. Results There were significant (P < .001) pooled associations between AAD and MD. Controlling for confounding factors using conditional fixed-effects models and time-dynamic covariate factors reduced the magnitude of these associations, but they remained statistically significant. Structural equation modeling suggested that the best-fitting causal model was one in which AAD led to increased risk of MD. Conclusions The findings suggest that the associations between AAD and MD were best explained by a causal model in which problems with alcohol led to increased risk of MD as opposed to a self-medication model in which MD led to increased risk of AAD.

Gimeno, D., M. Kivimaki, et al. (2009). "Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study." Psychological Medicine 39(03): 413-423.  [Abstract/Full Text]
Background: A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers.  Method:  In a prospective occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 1991-1993 and at follow-up in 2002-2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis.  Results:  Baseline C-reactive protein (β=0.046, p=0.004) and interleukin-6 (β=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (β=0.038, p=0.036) and interleukin-6 (β=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up.  Conclusions:  These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.

Whang, W., L. D. Kubzansky, et al. (2009). "Depression and Risk of Sudden Cardiac Death and Coronary Heart Disease in Women: Results From the Nurses' Health Study." J Am Coll Cardiol 53(11): 950-958. [Abstract/Full Text]
Objectives: We assessed the association between depression and sudden cardiac death (SCD) and cardiac events among individuals without baseline coronary heart disease (CHD). Background: Depression is a risk factor for cardiac events and mortality among those with CHD, possibly from arrhythmia. Methods: We studied depressive symptoms and a proxy variable for clinical depression consisting of severe symptoms and/or antidepressant medication use and their relationship to cardiac events in the Nurses' Health Study. Questionnaires in 1992, 1996, and 2000 assessed symptoms with the Mental Health Index (MHI-5), and antidepressant use was assessed in 1996 and 2000. Primary end points included SCD, fatal CHD, and nonfatal myocardial infarction. Results: Among 63,469 women without prior CHD/stroke in 1992, 7.9% had MHI-5 scores <53, previously found to predict clinical depression. Depressive symptoms were associated with CHD events, and the relationship was strongest for fatal CHD, where the association remained significant even after controlling for CHD risk factors (hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.11 to 2.00 for MHI-5 score <53). In models from 1996 onward, our proxy variable for clinical depression was most associated with SCD in multivariable models (HR: 2.33, 95% CI: 1.47 to 3.70), and this risk was primarily due to a specific relationship between antidepressant use and SCD (HR: 3.34, 95% CI: 2.03 to 5.50). Conclusions: In this cohort of women without baseline CHD, depressive symptoms were associated with fatal CHD, and a measure of clinical depression including antidepressant use was specifically associated with SCD. Although antidepressant use might be a marker of worse depression, its specific association with SCD merits further study.