Vasculopathy Related to Manic/Hypomanic Symptom Burden and First-Generation Antipsychotics in a Sub-Sample from the Collaborative Depression Study

Psychotherapy and Psychosomatics, 05/16/2012

The results provide evidence that chronicity of mood symptoms contribute to vasculopathy in a dose–dependent fashion. Patients with more manic/hypomanic symptoms had poorer endothelial function. First–generation antipsychotic exposure was associated with arterial stiffness, evidenced by higher augmentation pressure, perhaps secondary to elevated blood pressure. Vascular phenotyping methods may provide a promising means of elucidating the mechanisms linking mood disorders to vascular disease.


  • Participants with mood disorders were recruited for the National Institute of Mental Health Collaborative Depression Study (CDS) and followed prospectively.
  • A cross-sectional metabolic and vascular function evaluation was performed on a sub-sample near completion after a mean follow-up of 27 years.


  • A total of 35 participants from the University of Iowa (33) and Washington University (2) sites of the CDS consented to a metabolic and vascular function assessment at the Iowa site.
  • In multivariate linear regression, controlling for age, gender, and smoking, manic/hypomanic, but not depressive, symptom burden was associated with lower flow-mediated dilation.
  • Cumulative exposure to antipsychotics and mood stabilizers was associated with elevated augmentation pressure and mean aortic systolic blood pressure.
  • This appeared specifically related to first-generation antipsychotic exposure and mediated by increases in brachial systolic pressure.
  • Although second-generation antipsychotics were associated with dyslipidemia and insulin resistance, they were not associated with vasculopathy.

Author Commentary

In a prior analysis of 435 individuals with bipolar disorder from the Collaborative Depression Study (CDS), we found manic/hypomanic symptom burden (chronicity of clinically significant manic/hypomanic symptomatology) was significantly associated with cardiovascular mortality (Fiedorowicz et al. Psychosom Med 2009). This appeared to account for the greater risk of cardiovascular mortality in bipolar I, relative to bipolar II disorder as observed in the CDS sample and the only prior study to assess mortality differences by bipolar subtype (Angst F et al. J Affect Disord 1994). We were interested in replicating and extending the prior finding. To do so, we recruited a small subset of participants from the CDS, whose course of illness had been prospectively assessed for over a quarter century through participation, for a quantitative metabolic and vascular phenotyping assessment. We analogously found a dose-response relationship between manic/hypomanic symptom burden and endothelial dysfunction, based on a relationship with poorer flow-mediated but not nitroglycerin-mediated vasodilation. While difficult to study as reliable data is seldom available, the assessment of a dose-response between the long-term chronicity of illness and vascular outcomes circumvents some of the issues related to selection bias in case control studies (e.g. inpatient registry compared to national data) and provides additional evidence for a causal relationship between bipolar disorder and vascular disease. Such methods may assist in the identification of the most relevant mechanisms mediating the well-established relationship between bipolar disorder and vascular mortality (reviewed by Murray et al. Curr Psychiatry Rep 2009; Weiner M et al. Ann Clin Psychiatry 2011). References: Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord 2002;68:167-81. Fiedorowicz JG, Coryell WH, Rice JP, Warren LL, Haynes WG. Vasculopathy Related to Manic/Hypomanic Symptom Burden and First-Generation Antipsychotics in a Sub-Sample from the Collaborative Depression Study. Psychotherapy and Psychosomatics 2012;81:235-43. Fiedorowicz JG, Solomon DA, Endicott J, Leon AC, Li C, Rice JP, et al. Manic/hypomanic symptom burden and cardiovascular mortality in bipolar disorder. Psychosom Med 2009;71:598-606. Murray DP, Weiner M, Prabhakar M, Fiedorowicz JG. Mania and mortality: why the excess cardiovascular risk in bipolar disorder? Curr Psychiatry Rep 2009;11:475-80. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry 2011;23:40-7.

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