Systematic Review on Excess Rates of Physical Illness in Schizophrenia

1. Systematic Review on Excess Rates of Physical Illness in Schizophrenia Stefan Leucht, MD Department of Psychiatry and Psychotherapy, TU-Munich, Germany Programme on the physical health of people with mental disorders Published in: Leucht S, Burkard T, Henderson J, Maj M, Sartorius N. Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand. 2007 Nov;116(5):317-33

2. 50% increased risk of death from medical causes in schizophrenia, and 20% shorter lifespan(Harris et al. Br J Psychiatry 1998;173:11) Increased Mortality Rates for Medical Disorders in schizophrenia

3. Method • MEDLINE search (1966 – 2006) combining the MESH term of schizophrenia with the general MESH terms of physical illnesses: • Bacterial Infections and Mycoses [C01] + • Virus Diseases [C02] + • Parasitic Diseases [C03] + • Neoplasms [C04] + • Musculoskeletal Diseases [C05] + • Digestive System Diseases [C06] + • Stomatognathic Diseases [C07] + • Otorhinolaryngologic Diseases [C09] + • Nervous System Diseases [C10] • Eye Diseases [C11] • Urologic and Male Genital Diseases [C12] • Female Genital Diseases and Pregnancy Complications [C13]

4. Cardiovascular Diseases [C14] Hemic and Lymphatic Diseases [C15] Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] Skin and Connective Tissue Diseases [C17] Nutritional and Metabolic Diseases [C18] Endocrine System Diseases [C19] Immune System Diseases [C20] Disorders of Environmental Origin [C21] Animal Diseases [C22] Pathological Conditions, Signs and Symptoms [C23] + 44202 hits! Method

5. Bacterial Infections and Mycoses, Viral Diseases, Parasitic Diseases Bacterial infections and mycoses Surprisingly little (a few studies on tuberculosis) Viral diseases 1. HIV (~20 studies), Hepatitis B and C Mostly USA east coast cities, very high prevalence rates, but broad range (1.3-22.9%),no population-based studies Paradox—reduced sexual interest—high rates of HIV Epidemiological studies of better methodology still warranted 2. Bornavirus, influenza virus (etiological studies) Parasitic diseases Toxoplasma gondii, 21 reports Mainly increased T gondii antibody titers in schizophrenia

6. Neoplasms Probably the best studied area with a number of population based studies available (n=13), many more studies of less good quality (first one 1909) Most of the studies show decreased rates of cancer in people with schizophrenia Only the largest one, a Finnish population based studies showed increased rates, reasons are unclear, therefore despite the enormous amount of studies the puzzle has not been put together yet. Specific kinds of cancer different results, e.g. lung cancer in large Danish studies decreased, but in Finnish or recent Israeli study increased Hypotheses explaining decreased risk: medication, early Danish studies say that smoking was not allowed in psychiatric hospitals, discussion on genetic factors that are associated with the development of schizophrenia on the one hand and protection against cancer on the other hand.

7. Musculoskeletal Diseases Rheumatoid Arthritis: 19 studies, almost all show reduced rates of RA in schizophrenia Hypotheses: institutionalization, immobility, less active life, antinflammatory effects of antipsychotic drugs, immunsystem related factors • methodological artefact: Mors et al. 1999 population based not only decreased rates of osteoarthritis, but also of arthrosis and unspecific back pain. Artefact of underreporting by people with schizophrenia (e.g. because of decreased pain sensitivity). • Osteoporosis: 13 studies. Quality of most of the studies is limited, especially large population based studies are not available. However, almost all show reduced bone mineral densitiy in people with schizophrenia.

8. Digestive System Diseases, Nutritional and Metabolic Diseases Endocrine System Diseases Weight gain, diabetes, metabolic syndrome: Many studies on the effects of the new generation antipsychotics Given that this question is a hot topic, relatively few high quality studies on pure epidemiology were found. Epidemiology is not clear, most studies show increased BMI and higher rates of diabetes of people with schizophrenia compared to normal controls. More studies are needed, especially studies outside the US. Increased rates of overweight were already found in the preatypical area. Hypotheses: medication, some small not very convincing studies that increased rates even in antipsychotic naïve patients, life-style (little exercise, poor quality of food – little evidence available)

9. Prevalence of overweight in US adults 1. Behvioral Risk Factor Surveillance System (BRFSS, * BMI >30)

10. Only in America... 

11. 0.04 Ziprasidone Fluphenazine 0.374 0.8 Aripiprazol 0,6kg within 4 weeks Amisulpride 1.08 Haloperidol 2.1 Risperidone 2.58 Chlorpromazine 2.92 Sertindole 3.19 Thioridazine 4.15 Olanzapine 4.45 Clozapine 0 1 2 3 4 5 Weight gain in kg Meta-analysis of weight gain liabilities 4 – 10 week studies, N=72 Allison et al., J Clin Psychiatry 2001; 62 (suppl 7):22-31

12. Digestive System Diseases, Nutritional and Metabolic Diseases Endocrine System Diseases Weight gain, diabetes, metabolic syndrome: Many studies on the effects of the new generation antipsychotics Given that this question is a hot topic, relatively few studies on pure epidemiology were found and even fewer studies with high quality. Epidemiology is not clear, most studies show increased BMI and higher rates of diabetes of people with schizophrenia compared to normal controls. More studies are needed, especially studies outside the US. Increased rates of overweight were already found in the preatypical area. Hypotheses: medication, some small not very convincing studies that increased rates even in antipsychotic naïve patients, life-style (little exercise, poor quality of food – little evidence available)

13. No schizophrenia Schizophrenia BMI Distributions for General Population and Those With Schizophrenia (1989) 30 Under-weight Acceptable Overweight Obese 20 Percent 10 0 < 18.5 18.5-20 20-22 22-24 24-26 26-28 28-30 30-32 32-34 > 34 BMI Range Allison DB et al. J Clin Psychiatry. 1999;60:215-220.

14. Schizophrenia: Natural Causes of Death • Higher standardized mortality rates (SMR) for men than the general population from1: • Diabetes 2.7 × general population • Cardiovascular disease (CVD) 2.3 × general population • Respiratory disease 3.2 × general population • Infectious diseases 3.4 × general population • The largest single cause of death in schizophrenic patients is CVD, despite it not having the largest mortality ratio compared with the general population1 • That is because a much larger number of people overall die from CVD2 • Harris EC, Barraclough B. Br J Psychiatry. 1998;173:11-53. 2. Hennekens et al. 2005

15. Digestive System Diseases, Nutritional and Metabolic Diseases Endocrine System Diseases Polydipsia: Surprisingly large literature (14 studies) showing quite clearly increased rates of polydipsia in schizophrenia (reviewed e.g. by Leon et al. 1994) Suggesting that this phenomenon is present in more than 20% of chronic psychiatric patients Not considered enough by psychiatrists, although consequences can be fatal (delirium, water intoxication, death) The problem is that most studies used rather soft definitions to define polydipsia, e.g. just simple hyponatremia. How often dangerous polydipsia occurs is not clear (case reports exist).

16. Digestive System Diseases, Nutritional and Metabolic Diseases Endocrine System Diseases Thyroid dysfunction: There is a large spectrum of thyroid function test abnormalities in schizophrenia and in psychiatric patients in general, although the alterations have been described often to be transient and that cases of clinically manifest thyroid disease are rare. A screening test for thyroid function at admission should be part of any baseline work on newly admitted patients.

17. Stomatognathic Diseases • A number of studies highlight the poor dental status of people with schizophrenia. • Poor dental status can be a source of infections and endocarditis.

18. Respiratory Tract Diseases • 62% smoke (meta-analysis Leon 2006) • A population-based study by Filik et al (2006) found higher rates of lung impairment in people with schizophrenia compared with a UK national sample • Chafetz et al (2005) also reported that people with schizophrenia have high rates of chronic respiratory problems Filik R et al. Acta Psychiatr Scand. 2006;113:298-305. Chafetz L et al. Community Ment Health J. 2005;41:169-84.

19. Otorhinolaryngologic Diseases Middle ear disease and vestibular disease may be etiological factors contributing to the development of schizophrenia. A number of experimental studies are available, although Levy and colleagues 1983 concluded that the role of vestibular disease in schizophrenia is overestimated. Deafness: Some evidence that hardness of hearing is overrepresented in people with late life schizophrenia, but this is mainly discussed as an etiological factor (old review by Cooper 1976).

20. Nervous System Diseases Extrapyramidal side-effects, akathisia, tardive dyskinesia:wide range of prevalence 2%-90% (Casey 1993) 14 studies showing that even antipsychotic naïve people with schizophrenia show fine motor symptoms Multiple sclerosis: Geographical similarities of distribution (Templer et al. 1985) Myasthenia gravis: Negative association in a couple of case reports Epilepsy: Huge literature, but only in the other direction CNS infections: see above

21. Nervous System Diseases Amyotrophic lateral sclerosis: two case report about schizophrenic symptoms in a patient with ALS Alzheimer’s disease: Equal or slightly less than in the general population (Murphy et al. 1998), more studies are needed Blindness: very rare in schizophrenia (Riscalla 1980) Creatinine phospokinase activity (CPK): increased together with morphological changes of muscles of schizophrenics (Meltzer 1976) Sleep problems: sleep is disturbed in people with schizophrenia (Benca et al. 1992)

22. Nervous System Diseases Pain insensitivity: A number of case series and many experimental studies showed a decreased pain sensitivity in people with schizophrenia. Important, because this may explain the decreased rates of some medical illnesses (polyarthritis) due to underreporting, but also why people with schizophrenia develop these diseases Hypotheses: Analgetic effects of antipsychotic drugs, basic deficit of schizophrenia for example as the expression of a disturbed psycho-physiological development, inability of sensing and communicating pain

23. Urologic and Male Genital Diseases Female Genital Diseases and Pregnancy Complications • Urinary incontinence: two reports on the association with clozapine • Sexual dysfunction: frequently in schizophrenia, but further studies seem to be warranted • Prostate cancer: the only specific cancer that was consistently decreased in the individual studies (explained by effects of medication and decreased sexual activity)

24. Female Genital Diseases and Pregnancy Complications Galactorrhea: very little epidemiological studies, rates between 10% -57%. RCT’s were not screened, they should underestimate the risk by their nature. Amenorrhea: typical antipsychotics 18,8% - 78%, literature on atypical antipsychotics is mainly based on RCT’s Cancer of breast, ovary, cervix uteri and corpus uteri: prolactin may be a promoter of breast cancer. The results of the population based cancer studies about all these forms of cancer are contradictory with some studies finding increased risk, some reduced risk and some equal risk in schizophrenia. Nulliparity and sexual activity are known risk factors for female cancers

25. Female Genital Diseases and Pregnancy Complications Obstetrical complications: large literature (32 studies included), the vast majority of which show increase rates of obstetrical complications in women with schizophrenia. Hypotheses: environmental factors (smoking, drugs), socioeconomic factors (low income), pharmacological factors (medication), disease related (cognitive function, self neglect) Unclear: parental risk, which risk factors are the most important ones, is the risk also increased in other psychiatric disorders, what is the best form of care for pregnant women with schizophrenia

26. Cardiovascular Diseases Many risk factors in the population: smoking (62%!), obesity, diabetes, dyslipidemia, antipsychotic medication (QTc prolongation), little exercise 21 studies were included and showed that overall the people with schizophrenia have high rates of cardiovascular problems such as ECG changes, arhythmias, cardiac infarction or sudden cardiac death. More evidence can be derived from mortality studies Stigma may play an important role

27. Increased death rates of mentally ill people Death Rates in People with Mental Illness Compared to the Rest of the Population, Western Australia, 1980-1998 (Lawrence and Coghlan N S W Public Health Bull 2002; 13(7): 155–158)

28. Reduced access to services of mentally ill IHD Hospitalisation Revascularisation Procedure and Death rates, by Principal Psychiatric Diagnosis, Western Australia, 1980-1998 (Lawrence and Coghlan N S W Public Health Bull 2002; 13(7): 155–158)

29. Cardiovascular Diseases Many risk factors in the population: smoking (62%!), obesity, diabetes, dyslipidemia, antipsychotic medication (QTc prolongation), little exercise 28 epidemiological studies were included and showed that overall the people with schizophrenia have high rates of cardiovascular problems such as ECG changes, arhythmias, cardiac infarction or sudden cardiac death. More evidence can be derived from mortality studies Stigma may play an important role

30. Miscellaneous topics • Eye Diseases • Hemic and Lymphatic Diseases • Congenital, Hereditary, and Neonatal Diseases and Abnormalities • Immune System Diseases • Disorders of Environmental Origin • Animal Diseases • Pathological Conditions, Signs and Symptoms

31. Limitations • Despite the enormous amount of references (44202) identified by our review may not be complete. Most of the studies came from Europe and the US. • Modern systematic review methods such as meta-analysis were not possible, often due to the methodological heterogeneity of the studies identified

32. Origin of 225 epidemiological studies on the association between schizophrenia and physical illness Leucht et al. 2006

33. Tuberculosis HIV++ Hepatitis B/C Osteoporosis/decreased bone mineral density Poor dental status Impaired lung function Sexual dysfunction Extrapyramidal side effects of antipsychotic drugs; motor signs in antipsychotic-naive patients Obstetric complications++ Hyperprolactinemia-related side effects of antipsychotics (eg, irregular menses, galactorrhea) Cardiovascular problems++ Hyperpigmentation (side effect of chlorpromazine) Obesity++, diabetes, hyperlipidemia, metabolic syndrome Thyroid dysfunction Medical Comorbidity With Schizophrenia Is Very Common Physical Disease With Increased Frequency in Schizophrenia (++) very good evidence for increased risk (eg, population-based studies).

34. Summary Summary of physical diseases which occur with increased frequency in schizophrenia according to our review (++) very good evidence for increased risk (e.g. population based studies), (+) good evidence for increased risk, (-) at least good evidence for decreased risk. 1 the results on specific forms of cancer were mostly inconclusive due to contradictory results and limited power 2 a side-effect of chlorpromazine, probably not a problem of most other antipsychotics The table does not list physical diseases that have only been shown to be related to the etiology of schizophrenia (e.g. influenza virus). There were no clearly increased rates of physical diseases in the categories “parasitic diseases”, “digestive system diseases”, “otorhinolaryngological diseases”, “eye diseases”, “hemic and lymphatic diseases”, “congenital, hereditary, and neonatal diseases and abnormalities”, “immune system diseases”, “disorders of environmental origin”, “animal diseases”, “pathological conditions, signs and symptoms” or these diseases were listed in another category.

35. Conclusions • Morbidity in terms of rates of a number of physical illnesses is clearly increased in schizophrenia. • The amount and quality of epidemiolgical studies found in some areas – especially some hot topics – could be better (e.g. obesity where more work is underway) • Surprising medical particularities such as decreased risk of cancer exist • Future studies should focus on life style and stigma issues and prevention programmes are necessary

37. Acknowledgement We thank the following experts for reviewing single chapters of publications that will be based on this review: Profs. and Drs. de Leon, Friedlander, Lawrence, Hatta, Templer, McCreadie, Perkins, Mortensen, Rybakowski, Steiner, Mondelli, Oken, Newcomer, and Cournos

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