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Letter to the Editor

The Importance of Negative Comorbidity

Rafael Tabarés-Seisdedos, MD, PhD; Manuel Gómez-Beneyto, MD, PhD; Josep-María Haro, MD, PhD; Ana González-Pinto, MD, PhD; and Eduard Vieta, MD, PhD

Published: August 15, 2009

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To the Editor: In their article “Comorbid Somatic Illnesses in Patients With Severe Mental Disorders: Clinical, Policy, and Research Challenges,” Fleischhacker et al1 describe a plan of action to increase collaboration between Psychiatry and Medicine based on the fact that there are many patients with severe mental illnesses such as schizophrenia, depression, and bipolar disorder who have poor physical health and, consequently, a short life expectancy. The publication of the article signals opportunities for discussion. In this respect, we would like to make 2 contributions.

First, although a number of clinical and social factors probably account for the excess of comorbid somatic illnesses in patients with severe mental disorders (eg, symptoms, medication, lifestyle, and limited access to health care services), associations may also be partly due to specific biologic overlaps at the genetic and molecular level between disorders that at first instance are considered to be distinct. For example, underlying genetic vulnerabilities may explain the comorbidities of asthma with mental disorders2 or migraine with other conditions such as endometriosis. 3,4

Table 1. Positive and Negative Medical Comorbidities in Several Complex Disordersa

Table 1

aData were identified by a systematic review using the MEDLINE database, supplemented with a manual search of reference lists. The diagnostic terms schizophrenia, bipolar disorder or manic-depression, depression, diabetes, and multiple sclerosis were combined with keywords indicating a population based register study.
Abbreviation: HIV = human immunodeficiency virus.

Click figure to enlarge

Second, in contrast with co-occurrence, few population-based studies have explored in detail the “negative” or “inverse” comorbidity in psychiatric and medical disorders (ie, a lower than expected probability of occurrence of diseases) (Table 1). It is intriguing that 2 rigorous population-based studies5,6 and the first meta-analysis of cancer incidence rates7 found a significantly lower risk of respiratory and prostate cancer in people with schizophrenia and their relatives compared with people without schizophrenia after adjusting for confounding variables. Moreover, schizophrenia is associated with tobacco smoking, the most studied risk factor for lung cancer. Lung and prostate cancers are associated with the highest numbers of deaths from cancer around the world, according to the World Health Organization.8 Although alternative explanations may be invoked (ie, biases arising from difficulties in adjusting for confounders or competing risks, cancer-protective effect of antipsychotic medications, obstetric complications, and lifestyle differences), we propose that the genetic predisposition toward schizophrenia might confer genetically reduced susceptibility to lung and prostate cancer.9 This is akin to the observation that individuals with young-adult-onset Hodgkin lymphoma are less likely to have a personal or family history of diabetes mellitus. Another finding is the reduced occurrence of rheumatoid arthritis in people with schizophrenia and in people with multiple sclerosis.

Comorbidity represents a significant opportunity to understand the biologic connections among disorders. Moreover, epidemiologic data suggest that negative comorbidity may be a valuable model for investigating common or related pathways or processes and testing new therapies. In fact, modulation of the dopaminergic system has been suggested as a new target for cancer therapy.10


1. Fleischhacker WW, Cetkovich-Bakmas M, De Hert M, et al. Comorbid somatic illnesses in patients with severe mental disorders: clinical, policy, and research challenges. J Clin Psychiatry. 2008;69(4):514-519. PubMed

2. Mrazek DA. Psychiatric symptoms in patients with asthma causality, comorbidity, or shared genetic etiology. Child Adolesc Psychiatr Clin N Am. 2003;12(3):459-471. PubMed doi:10.1016/S1056-4993(03)00028-2

3. Stam AH, van den Maagdenberg AM, Haan J, et al. Genetics of migraine: an update with special attention to genetic comorbidity. Curr Opin Neurol. 2008;21(3):288-293. PubMed doi:10.1097/WCO.0b013e3282fd171a

4. Nyholt DR, Gillespie NG, Merikangas KR, et al. Common genetic influences underlie comorbidity of migraine and endometriosis. Genet Epidemiol. 2009;33(2):105-113. PubMed doi:10.1002/gepi.20361

5. Lichtermann D, Ekelund J, Pukkala E, et al. Incidence of cancer among persons with schizophrenia and their relatives. Arch Gen Psychiatry. 2001;58(6):573-578. PubMed doi:10.1001/archpsyc.58.6.573

6. Levav I, Lipshitz I, Novikov I, et al. Cancer risk among parents and siblings of patients with schizophrenia. Br J Psychiatry. 2007;190:156-161. PubMed doi:10.1192/bjp.bp.106.024943

7. Catts VS, Catts SV, O’ Toole BI, et al. Cancer incidence in patients with schizophrenia and their first-degree relatives: a meta-analysis. Acta Psychiatr Scand. 2008;117(5):323-336. PubMed doi:10.1111/j.1600-0447.2008.01163.x

8. World Health Organization. Global Burden of Disease: 2004 Update. Accessibility verified May 20, 2009.

9. Tabares-Seisdedos R, Rubenstein JL. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry. 2009;14:563-589. PubMed doi:10.1038/mp.2009.2

10. Asada M, Ebihara S, Numachi Y, et al. Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter. Int J Cancer. 2008;123(3):511-518. PubMed doi:10.1002/ijc.23562

Rafael Tabarés-Seisdedos, MD, PhD

Manuel Gómez-Beneyto, MD, PhD

Josep-Marí­a Haro, MD, PhD

Ana González-Pinto, MD, PhD

Eduard Vieta, MD, PhD

Author affiliations: Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, CIBERSAM (Drs Tabarés-Seisdedos and Gómez-Beneyto); Sant Joan de Déu-SSM, Fundació Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Barcelona (Dr Haro); Department of Psychiatry, Santiago Apóstol Hospital, CIBERSAM, Vitoria (Dr González-Pinto); and the Bipolar Disorders Program, Clinical Institute of Neuroscience, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, CIBERSAM (Dr Vieta), Spain. Financial disclosure: None reported. Funding/support: None reported.


© Copyright 2009 Physicians Postgraduate Press, Inc.

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