The Use of Statins After a Cardiac Intervention Is Associated With Reduced Risk of Subsequent Depression: Proof of Concept for the Inflammatory and Oxidative Hypotheses of Depression?
Objective: Depression is associated with immune activation as well as oxidative stress. Statins have in vitro and in vivo antiinflammatory and antioxidative properties. We prospectively investigated whether the use of statins was associated with a reduced risk of development of depression in individuals who have had a cardiac event or intervention.
Method: Participants were recruited between May 2005 and March 2006 from the Geelong Hospital, Geelong, Australia, a tertiary hospital in regional Australia that serves a catchment area shown to be representative of the broader Australian community. Patients who were hospitalized for angioplasty, myocardial infarction, or coronary artery bypass graft surgery (N = 193) were followed up prospectively for 9 months to assess development of depression. Depression data were collected 3 months postdischarge (T1) by structured clinical interview (using the Mini International Neuropsychiatric Interview, version 5) and 9 months postdischarge (T2) by self-report (using the Hospital Anxiety and Depression Scale). Major depressive disorder, minor depression, and dysthymia were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Data on statins were collected from medical records. The association between statin therapy and depression was tested using both linear and logistic regression models controlling for clinical, psychological, and demographic confounders.
Results: At discharge, 157 participants (81.3%) were receiving statin therapy. Adjusting for possible confounders, taking statins at discharge had a protective effect on depression at T1, reducing the likelihood of dysthymia, minor depression, or major depression by 69% (95% CI, 0.097-0.972; P = .045). At the T2 end point, statin therapy again had a protective effect and was associated with a 79% reduction in the likelihood of depression (95% CI, 0.052-0.876; P = .032). The linear regression model to predict depression at T2 was significantly different from zero (F11,180 = 8.686, P < .001) and explained 36.3% of the variance in depression.
Conclusions: The use of statins was associated with significant reduction in the risk of depression in individuals who have had a cardiac event. This supports the role of oxidative and inflammatory processes in depression and opens the door to rational and novel pathophysiologically based therapies distinct from conventional antidepressants.
J Clin Psychiatry 2011;72(9):1229-1235
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: November 9, 2009; accepted March 15, 2010.
Online ahead of print: December 14, 2010 (doi:10.4088/JCP.09m05825blu).
Corresponding author: Michael Berk, MD, PhD, Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, PO Box 281, Geelong VIC 3220, Australia ([email protected]).
Depression is associated with both increased immune activation and impaired immune function.1 Evidence of immune dysfunction in depression includes an impaired lymphocyte proliferative response to mitogens, increased monocyte phagocytosis, and increased concentrations of proinflammatory cytokines and positive acute phase proteins.2-4 In healthy volunteers, administration of exogenous cytokines induced many of the core phenotypes of a depressive illness, including behavioral and cognitive alterations, a depressed mood state, increased stress reactions, cognitive impairment, and difficulties with motivation.3 These studies are perhaps the best human experimental models of depression. Treatment with established antidepressants reduced inflammatory marker levels in patients with major depressive disorder,5,6 and treatment nonresponse was associated with elevated inflammatory marker levels.7 In a 10-year follow-up study, elevated levels of C-reactive protein (CRP) predicted the subsequent risk for de novo depression, suggesting that immune dysregulation is not simply an epiphenomenon of depression but that it contributes to the genesis of the disorder.8
Statins have known effects on inflammatory cytokines, and they also reduce markers of oxidative stress. It is possible that this effect is greater in lipophilic than in hydrophilic statins.9 Statins have reduced markers of oxidative stress and inflammatory markers in spontaneously hypertensive rats.10 They have been shown to reduce inflammation and oxidative stress in patients with hypertension and dyslipidemia.11 In patients who have had an acute cardiac event, statins induced a rapid reduction of tumor necrosis factor-alpha and interferon-gamma production in stimulated T-lymphocytes and inhibited the Th-1-immune response.12 In human hepatocytes, statins reduced interleukin-6-induced expression of CRP,13 suggesting a hepatic source of its anti-inflammatory effects.
There are also extensive data on the relationship between oxidative stress and depression. Compared with healthy controls, patients with depression have significantly elevated markers of oxidative damage, which includes lipid peroxidation products,14-17 the oxidized DNA marker 8-hydroxy-2′ ²-deoxyguanosine,18 and depleted omega-3 fatty acids that indicate oxidative damage of erythrocytic membranes.19 Altered antioxidant levels have also been found in those persons with depression, including diminished levels of serum vitamins C15 and E,20,21 albumin,22 and alterations in the antioxidative enzymes superoxide dismutase,14-16,23 glutathione peroxidase, and glutathione reductase.14 There is a significantly higher oxidative stress index, as determined by the ratio of total plasma peroxide to total plasma antioxidant potential, in medication-free patients with depression,24 and there are studies showing correlations between depressive severity and the magnitude of disturbances in their respective oxidative indices.14,16,18,21 Concordant with these findings, there is preclinical evidence that established antidepressant agents, including venlafaxine, moclobemide, and phenelzine, reduce markers of oxidative stress.25-29 Lastly, markers of oxidative stress normalize with the resolution of depression.14,15 In aggregate, these studies provide substantial evidence for the role of oxidative systems in the pathophysiology of depression.
There are now clear data to show that statins additionally reduce oxidative stress. Statins have in vitro antioxidant and DNA protective effects.30 In spontaneously hypertensive rats, statins reduced reactive oxygen species production in circulating monocytes.10 Given the data suggesting a dysregulation in glutathione in depression, the fact that statins may reverse oxidative stress by up-regulation of glutathione synthesis is of considerable interest.31 Statins decrease lipid peroxidation, reducing oxidized low-density lipoprotein accumulation by increasing the expression of the free radical scavenging enzyme SOD1.32 These data suggest that in vivo statin treatment reduces oxidative stress and that this mechanism may be additive in its potential efficacy profile. Principally exploring the finding that there may be a relationship between cholesterol and mood, a couple of earlier studies examined the relationship between statin use and depression and found a protective effect.33,34 In a 10-year, community-based prospective study, the hazard ratio for the emergence of de novo major depression was 0.20 (95% Cl, 0.04-0.85, P = .03) among women taking statins.35
The aims of this study were therefore to examine the effects of statin treatment on the development of depression in patients who were hospitalized for myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft surgery (CABG). Given the nexus between inflammatory and oxidative stress in depression and the effects of statins on those parameters, we hypothesized that those individuals taking statins would have a lower risk of developing depression. We hypothesized that there would be a significant association between statin therapy and depression, even when potentially confounding clinical (ie, disease severity,36 functional cardiac status,37,38 smoking,39,40 diabetes,41 body mass index [BMI]42), psychological (ie, history of depression,40,43 neuroticism44,45), and demographic (ie, sex,46 age47) factors were statistically controlled a priori.
METHOD
Sample
Participants were recruited between May 2005 and March 2006 from the Geelong Hospital, Geelong, Australia, a tertiary hospital in regional Australia that serves a catchment area shown to be representative of the broader Australian community.48 All English-speaking, consenting patients who were hospitalized for PTCA, MI, or CABG during this time were eligible for participation. According to discharge diagnoses, 528 patients were treated for these presentations during the study period. Patients with different coronary artery disease (CAD) presentations were regarded as a homogenous group on the basis of evidence that the association between depression and CAD is found across all subgroups of CAD patients, with similar prognostic effects for cardiac49,50 and quality of life51,52 outcomes. Participants were recruited by postal invitation and follow-up phone calls 6 weeks postdischarge. Reasons for nonparticipation were death (n = 13), lack of facility in English (n = 16), inability to consent (n = 9), medical illness (n = 9), depression (n = 3), and no given reason (n = 249). Agreement to participate was obtained from 229 patients. The study received ethics approval from the Barwon Health and University of Melbourne institutional review committees. After complete description of the study to participants, written informed consent was obtained.
Procedures
Self-report data were collected at 3 months (T1) and 9 months (T2) after hospital discharge. Baseline assessment was undertaken 3 months postdischarge, rather than during admission, to avoid potential confounding of the effects of acute illness and stress associated with hospitalization with the assessment of predictor variables and to minimize the burden on participants. Other studies39,40,53 have highlighted difficulties in reliably identifying patients in whom depression will emerge, persist, or worsen solely on the basis of level of depressive symptomatology present during hospitalization. Structured clinical interviews were administered by telephone at T1. Telephonic administration of structured clinical interviews has been found to be valid and reliable.54,55 For analyses, participants were assigned to the diagnostic group major depressive disorder (MDD) or to a broader group any depressive disorder (ADD). The latter comprised, in addition to participants with MDD, participants with minor depression and dysthymia.
Participants were mailed self-report questionnaires at T1 and T2. T1 questionnaires assessed neuroticism and functional disability. The depression self-report measure was administered at T2. Relevant clinical and sociodemographic data were collected by T1 self-report and from medical records at T1. Additional details regarding the study methodology have been published elsewhere.56
Measures
Clinical data such as disease severity, presence of diabetes, and discharge medications such as aspirin and statins were obtained from medical records. Disease severity was measured with left ventricular ejection fraction (LVEF). An LVEF ≤ 30% was considered poor. Body mass index was computed based on self-reported height and weight (kg/m2) at the time of the index event. Sociodemographic data, prior history of depression, and tobacco use at the index event were gathered by self-report.
Clinical depression was assessed at T1 using the Mini International Neuropsychiatric Interview version 5 (MINI),57,58 a diagnostic structured interview compatible with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and similar to the Structured Clinical Interview for DSM-IV Disorders (SCID)59 in operation and principle. The MINI has excellent psychometric properties and has been validated against the SCID-Patient Version60 and the Composite International Diagnostic Interview (CIDI).57,58,61,62 The MINI modules for depression and dysthymia were administered. Major depressive disorder was diagnosed if participants fulfilled at least 1 DSM-IV core criterion (depressed mood or anhedonia) and at least 4 additional DSM-IV criteria within a 2-week duration. With the use of the MINI depression module, minor depression was diagnosed if participants fulfilled at least 1 DSM-IV core criterion and 1 to 3 additional DSM-IV criteria within a 2-week period.
Depressive symptomatology was measured at T2 with the 7-item depression subscale of the Hospital Anxiety and Depression Scale (HADS).63 The HADS has well-established psychometric properties64,65 and is widely used in studies with cardiac patients.66-68 Possible scores range from 0 to 21. Higher scores denote greater depressive symptomatology. Cronbach α at T2 was 0.84. In accordance with previous data,65,69-71 a score ≥ 8 was considered to indicate depression.
Neuroticism was measured with a 10-item scale from the self-report version of the Revised NEO Personality Inventory (NEO PI-R),72 the International Personality Item Pool Representation of the NEO PI-R (IPIP-NEO).73 Scores range from 10 to 50, with higher scores indicating greater neuroticism. The IPIP-NEO has been shown to be reliable74 and valid72,75 and its factor structure has been confirmed76,77 (Cronbach α = 0.88).
Functional status (effort tolerance) was measured using the 10 items from the Short Form-36 (SF-36)78 that assess physical functioning. Items include activities such as walking 1 block and climbing a flight of stairs. In the original context, these items assess limitations on physical activities. Here, the response format was altered to assess the severity of symptoms experienced when performing these physical tasks. The items are similar to measures like the Canadian Cardiovascular Society grading scale for angina severity79 and the New York Heart Association classification criteria for the prescription of physical activity for cardiac patients.80 Responses include I do not experience symptoms, I experience mild symptoms, I experience severe symptoms, and I am not able to perform this activity. Scores range from 0 to 30, with lower scores indicating greater functional disability.
Analysis
Data were analyzed using SPSS version 16.0 (SPSS Inc, Chicago, Illinois). All tests were 2-tailed, and α was set at .05. Multivariate analyses to predict the association between statins and depression at T1 comprised predicting MDD and ADD, as defined above. At T2, multivariate analyses comprised both linear (HADS as a continuous variable) and logistic regression (HADS with a cutoff ≥ 8). All predictor variables were entered in 1 block. Multivariate analyses were adjusted for age, sex, functional status (effort tolerance), neuroticism, history of depression, smoking, diabetes, BMI, disease severity, and aspirin therapy. Scores for effort tolerance at T1 were transformed by cubing the original scores. T2 HADS scores were transformed using the square root of the original scores.
RESULTS
Characteristics of the Sample
T1 questionnaires were completed by 193 of the 229 recruited patients (84%; or 37% of all patients treated during the study period, including those deceased and ineligible). Compared to nonparticipants, participants were significantly more likely to be male (χ21 = 5.93, N = 528, P = .02) and were, on average, younger (t526 = 3.12, P < .01). The mean (SD) age for participants versus nonparticipants was 64.14 (10.37) versus 67.31 (11.70) years, respectively. Twenty-eight participants did not return their questionnaires for an unspecified reason, 3 withdrew due to physical illness, and 4 withdrew due to depression. There were no significant sex differences between those who completed T1 questionnaires and those who did not (χ21 = 0.64, N = 229, P = .42), but nonrespondents were, on average, significantly younger than respondents (t227 = −2.13, P < .03). The mean (SD) age of nonresponders was 59.94 (13.22) years. At T2, 184 of the 193 T1 participants remained (95%; or 35% of the original patient group [184 of 528]). One participant had formally withdrawn due to depressive illness, and 8 participants did not return their questionnaires for unspecified reasons. Complete data were available for 180 participants. There were no sex or age differences between participants who completed T2 questionnaires and those who did not. Baseline clinical, sociodemographic, and psychological data for the sample are described in Table 1.
Click figure to enlarge
Association Between Statin Therapy and Depression
The statins used were pravastatin (n = 14), simvastatin (n = 29), and atorvastatin (n = 114). A total of 157 patients were taking statins. There was insufficient power to test the effect of individual agents. The logistic regression model to test the association between statin therapy prescribed at time of hospital discharge and ADD 3 months later (T1) was significant (χ211 = 78.08, N = 189, P < .001). Inspection of the odds ratios (Table 2) showed that taking statins at discharge had a protective effect, reducing the likelihood of dysthymia, minor depression, or major depression at T1 by 69% (95% CI, 0.097-0.972; P = .045). The model to predict MDD was significant (χ211 = 64.41, N = 180, P < .001), but statin therapy was not a reliable predictor of MDD (P = .486; analyses not shown).
Click figure to enlarge
At T2, 29 (16.1%) participants scored ≥ 8 on the HADS, and they were classified as depressed. The mean (SD) score on the HADS was 3.70 (3.60). Multivariate analyses to predict depression 9 months after hospital discharge are shown in Table 3 (logistic regression) and Table 4 (linear regression). The logistic regression model was significant (χ211 = 53.08, N = 180, P < .001). Inspection of the odds ratios in Table 3 showed that statin therapy at discharge had a protective effect, reducing the likelihood of depression at T2 by 79% (95% CI, 0.052-0.876; P = .032). The linear regression model to predict depression was significantly different from zero (F11,180 = 8.686, P < .001), and it explained 36.3% of the variance in depression at T2. The results of the linear regression analysis confirm the negative association between statin therapy and depression (β = -0.340; P = .049). Inspection of the partial and semipartial correlations showed that statin therapy contributed 2.28% of the unique variance and 1.5% of the total variance in depression.
Click figure to enlarge
Click figure to enlarge
The 2 measures of depression were significantly correlated. The correlations between the HADS and the variables MDD and ADD were 0.41 (P < .001) and 0.54 (P < .001), respectively. Other data based on this patient group81 have shown that, relative to the structured clinical interview as the referent standard, the operating characteristics of the HADS are acceptable for detecting depression.
DISCUSSION
The results of this study suggest that statin therapy at time of discharge following cardiac event is associated with a 79% reduction in the likelihood of developing depression 9 months later. This is an unexpectedly large clinical effect; however, it is concordant with the ability of statins to reduce inflammatory cytokines, which appear to play an etiological role in the genesis of depression. In addition, the antioxidant properties of statins are concordant with the data showing increased oxidative stress in depression. Conventional antidepressants have been shown to reduce both oxidative stress and cytokines.
A number of the methodological characteristics of this study merit discussion. Strengths of the study include its prospective nature and the low attrition rate. We were able to include a diverse array of cardiac, lifestyle, and psychological factors that have been shown to predict depression, and we were able to adjust for these in the multivariate models; however, confounding by additional variables remains possible. The results of the study may have been influenced by variables present before the onset of the study assessments. We acknowledge limitations in the generalizability of the study. The compliance rate was low, and it is possible that patients with depression were less likely to participate, possibly resulting in an underestimation of the effects of statins. Statins were not randomly assigned, and individual statins were not examined. There is evidence that statins differ in efficacy.82 The percentage of patients remaining on statin therapy at T2 is not known. Respondents were more likely to be male and were on average older than nonrespondents. The study was restricted to individuals who have had a cardiac event, and while this group is at higher risk of developing depression,83 it is unclear if all the risk factors for this group, and hence the results of this study in their entirety, can be extended to the general population. As the age range of the sample was relatively old, it is also unclear if these findings would apply to younger patients. While we had data for a range of cardiac medications, including aspirin, we did not have data on other agents, such as nonsteroidal anti-inflammatory drugs, that may impact inflammatory processes and impact the model. It would have been of value to have blood levels of such inflammatory markers. Future studies of statins and depression may wish to examine whether changes in symptoms are indeed correlated with altered inflammatory markers.
One possible confounding explanation for the effect of statins is via cholesterol. Low serum cholesterol was associated with increased depressive symptoms in cross-sectional population studies.84,85 There are prospective reports of an association between low serum cholesterol and the risk of depression.86-90 There are 2 intervention studies that show conflicting results in terms of the relationship between cholesterol-reducing diets and mood and hostility,91,92 which do not allow definitive conclusions to be made.
Nevertheless, these data suggest that the use of statins is associated with a substantially reduced risk of depression in individuals who have had a cardiac event. The known effects of statins on oxidative and inflammatory processes support the role of oxidative and inflammatory processes in depression. Although there are limitations on the generalizability of these findings, these preliminary data open the door to rational and novel pathophysiologically based therapies distinct from conventional antidepressants, which have a limited range of efficacy in the treatment and prevention of depression.
Drug names: atorvastatin (Lipitor), phenelzine (Nardil), pravastatin (Pravachol and others), simvastatin (Zocor and others), venlafaxine (Effexor and others)
Author affiliations: Centre for Women’s Mental Health, Royal Women’s Hospital, Parkville (Dr Stafford); Departments of Psychology and Psychiatry (Dr Stafford) and Clinical and Biomedical Sciences, Barwon Health (Dr Berk), University of Melbourne; Australia Orygen Research Centre, Parkville (Dr Berk); and the Mental Health Research Institute, Parkville (Dr Berk), Victoria, Australia.
Potential conflicts of interest: Dr Stafford has received grant/research support from the University of Melbourne. Dr Berk has received grant/research support from the Stanley Medical Research Foundation, the Medical Benefits Fund, the National Health and Medical Research Council, Beyond Blue, the Geelong Medical Research Foundation, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier; is a member of the speakers/advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Pfizer, sanofi synthelabo, Servier, Solvay, and Wyeth; and is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Servier.
Funding/support: None reported.
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