DEAR EDITOR:
In the January 2009 issue of Psychiatry (Edgemont), Khawaja et al[1] provided a masterful and exhaustive elucidation of the bidirectional association between depression and coronary artery disease. The pathways from depression to coronary artery disease are complex and circuitous. They include autonomic dysfunction, hypothalamic-pituitary adrenal axis hyperactivity, platelet activation, and release of proinflammatory cytokines. An emerging body of literature implicates coronary risk factors, such as hypertension, diabetes, dyslipidemia, cigarette smoking, and obesity, in the pathogenesis of “vascular” depression.2 The vascular depression hypothesis initially emerged with the discovery that depression with an onset in late life is commonly associated with subcortical and periventricular brain white matter hyperintensity (WMH) microvascular lesions, visualized on magnetic resonance imaging.[2] A recent longitudinal study of 639 older patients conducted in 11 European centers revealed a correlation between the intensity of WMH lesions and the subsequent development of depression.[3] These subcortical brain lesions appear to interrupt the integrity of vital frontostriatal limbic circuits providing a biological substrate for vascular depression. This is a condition distinguished by apathy, executive function deficits, and resistance to antidepressant treatment.[4] At least one promising study has suggested that lowering blood pressure reduces the progression of WMH lesions.[4] Managing hypertension is known to reduce the risk of stroke. Similarly, lowering blood pressure may prevent late-life vascular depression.
Whereas the vascular depression hypothesis has focused exclusively on depression with an onset in late life, vascular risk factors may be equally relevant in the pathogenesis and course of depression in younger individuals.[5] We recently examined the influence of comorbid vascular factors on treatment outcome. Patients, ranging in age from 18 to 75 years, who were hospitalized with depression on the adult psychiatry unit of a general hospital in mid-Michigan completed a brief cardiovascular risk questionnaire. The cohort of patients referred for electroconvulsive therapy (ECT) following failure to respond to drug treatment was compared to that which responded to antidepressant medications. Forty-three (23%) of the 187 study patients who failed to respond to antidepressants were subsequently referred for ECT. These patients had a disproportionately high prevalence of cardiovascular risk factors. The relative risk of hypertension in drug nonresponders was 1.6, diabetes mellitus 2.4, dyslipidemia 1.8, and obesity 1.6. The presence of any cardiovascular risk factor was associated with a later onset of depression (Pearson correlation coefficient r=0.275, p=0.01). The SADHART and ENRICHD study, cited by Khawaja et al,[1] affirmed that in depression following myocardial infarction (MI), the use of selective serotonin reuptake inhibitor (SSRI) antidepressants is associated with a lower risk of subsequent MI recurrence and death. Is it possible that preventing hypertension, diabetes, and dyslipidemia will prevent depression in some susceptible individuals and improve the outcome of depression treatment in others?
References
1. Khawaja IS, Westermeyer JJ, Gajwani P, Feinstein RE. Depression and coronary artery disease: the association, mechanisms, and therapeutic implications. Psychiatry (Edgemont). 2009;6(1):38–51.
2. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, et al. Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry. 2008;165:238–244.
3. Teodorczuk A, O’Brien JT, Firbank MJ, Pet al. White matter changes and late-life depressive symptoms: Longitudinal study. Br J Psychiatry. 2007;191:212–217.
4. Schiffrin E. Blood pressure lowering in PROGRESS (Perindopril Protection Against Recurrent Stroke Study) and white matter hyperintensities: should this progress matter to patients? Circulation. 2005;112:1525–1526.
5. Iosifescu DV, Renshaw PF, Lyoo IK, et al. Brain white-matter hyperintensities and treatment outcome in major depressive disorder. Br J Psychiatry. 2006;188:180–185.
With regards,
Dale A. D’Mello, MD
Associate Professor, Department of Psychiatry, Michigan State University, East Lansing, Michigan
Alric Hawkins, MD
Resident, Department of Psychiatry, Vanderbilt University, Nashville, Tennessee
AUTHOR RESPONSE
We appreciate the comments by D’Mello and Hawkins on our review article published in the January 2009 issue of Psychiatry (Edgemont).[1] They discuss an important issue of the effect of metabolic disorders on depression. One of the reasons why DSM IV removed the category of “organic depression” is that all psychiatric disorders have some “organic” basis to them.
D’Mello and Hawkins discuss the “vascular depression” hypothesis, referencing some studies that point to the relationship of subcortical and periventricular brain white matter hyperintensity (WMH) microvascular lesions as a cause of subsequent depression. The correlation of WMH and development of depression is an important and interesting finding. It is possible that microvascular disease causing these lesions could interrupt the integrity of the frontostriatal limbic circuits, thus making a person more susceptible to depression with distinguished clinical features, such as apathy, executive dysfunction, and treatment resistance to medications. We appreciate the authors sharing their study results, suggesting that the treatment-resistant group had more cardiovascular and metabolic comorbidities than those who are responders to medications. Does this damage cause cell death in certain areas of the brain? Increased neurogenesis in hippocampus has been hypothesized as a mechanism of electroconvulsive therapy (ECT),[2] and it would be interesting to see if the treatment-resistant group shows improvement in their depression with ECT.
We would like to add further to the discussion of metabolic disorder’s effect on vascular health by pointing to the association of sleep disorders with cardiovascular health. In an 18-year follow up of the Wisconsin cohort study,[3] the adjusted hazard risk of cardiovascular mortality of patients with untreated obstructive sleep apnea was 5.2 (1.4–19.2). Intermittent hypoxemia associated with sleep apnea has been linked to endothelial dysfunction causing direct damage to the vascular system.[4] In addition to this, in one study,[5] longer sleep duration was associated with reduced calcification incidence over five years. Pepperell et al6 found a small but significant reduction in daytime blood pressure in a normotensive cohort after four weeks of continuous positive airway pressure (CPAP) therapy, especially for those who had frequent desaturation episodes. We wonder how many of D’Mello’s treatment-resistant patients had sleep apnea.
We agree with the authors that it is plausible that preventing metabolic disorders or treating them effectively could prevent vascular depression. A large, prospective study should be conducted with the population at risk being treated aggressively for metabolic problems and compared to the controls of patients whose metabolic disorders are either uncontrolled or not treated. We encourage such a study to be conducted as it surely would further our understanding of the relationship between coronary artery disease, metabolic disorders, and depression.
References
1. Khawaja IS, Westermeyer JJ, Gajwani P, Feinstein RE. Depression and coronary artery disease: the association, mechanisms, and therapeutic implications. Psychiatry (Edgemont). 2009;6(1):38–51.
2. Madsen TM, Treschow A, Bengzon J, et al. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry. 2000;47:1043–1049.
3. Young T, Finn L, Peppard P, et al. Sleep disordered breathing and mortality: eighteen year follow-up of the Wisconsin sleep cohort. Sleep. 2008;31(8):1071–1078
4. Caples SM, Garcia-Touchard A, Somers VK. Sleep disordered breathing and cardiovascular risk. Sleep. 2007;30(3):291–303
5. King CR, Knutson KL, Tathouz PJ, et al. Short sleep duration and incident coronary artery calcification. JAMA. 2008;300(24):2859–2866.
6. Pepperell JC, Ramdassight-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomized parallel trial. Lancet. 2002;359:204–210.
With regards,
Imran S. Khawaja, MBBS
Psychiatrist, Sleep Medicine Physician, VA Medical Center Minneapolis, Minnesota; Assistant Professor, Department of Psychiatry, University of Minnesota; Fellow, Sleep Medicine, Mayo Clinic, Rochester, Minnesota
Joseph W. Westermeyer, MD, PhD
Professor of Psychiatry, Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis, Minnesota; VA Medical Center, Minneapolis, Minnesota
Prashant Gajwani, MD
Hoffman-La Roche, Inc., Nutley, New Jersey
Robert E. Feinstein, MD
Professor of Psychiatry, Department of Psychiatry, University of Colorado, Denver, Colorado
