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
Nov116(5)317-33
2
Increased Mortality Rates for Medical Disorders
in schizophrenia

• 50 increased risk of death from medical causes
  in schizophrenia, and 20 shorter
  lifespan(Harris et al. Br J Psychiatry
  199817311)

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
Method

• 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
  

5
Bacterial Infections and Mycoses, virus diseases,
parasitic diseases
Surprisingly little on bacterial infections and
mycoses (a few studies on tuberculosis) Parasitic
diseases toxoplasma gondii, 21 reports, most of
them found increased rates of toxoplasma gondii
antibody titers in people with schizophrenia,
mainly etiological thoughts Virus diseases 1.
borna virus disease, influenca virus (etiological
studies) 2. Hepatitis B and C, HIV (20
studies) Most in US, most in East coast cities,
mixed populations (e.g. drug addicts included)
very high prevalence rates 1.3-22.9, no
population based studies. Paradox reduced
sexual interest high rates of HIV. Drug abuse,
lack of insight. Epidemiological studies of
better methodology still warranted
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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
• Paradoxreduced sexual interesthigh 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

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Neoplasms
Probably the best studied area with a number of
population based studies available (n13), 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.
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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.

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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)
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Prevalence of overweight in US adults
1. Behvioral Risk Factor Surveillance System
(BRFSS, BMI gt30)
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Only in America... ?
12
Meta-analysis of weight gain liabilities
4 10 week studies, N72
Allison et al., J Clin Psychiatry 2001 62 (suppl
7)22-31
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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)
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BMI Distributions for General Population and
Those With Schizophrenia (1989)
30
Obese
Overweight
Acceptable
Under-weight
20
Percent
10
0
lt 18.5
18.5-20
20-22
22-24
24-26
26-28
28-30
30-32
32-34
gt 34
BMI Range
Allison DB et al. J Clin Psychiatry.
199960215-220.
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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.
  199817311-53. 2. Hennekens et al. 2005

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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).
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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.
18
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.

19
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.
2006113298-305. Chafetz L et al. Community
Ment Health J. 200541169-84.
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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).
21
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
22
Nervous System Diseases
Amyotrophic lateral sclerosis two case report
about schizophrenic symptoms in a patient with
ALS Alzheimers 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)
23
Nervous System Diseases
Pain insensitivity A number of case series and
many experimental studies showed a decreased pain
sensitivity in people with schizophrenia. Importa
nt, 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
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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)

25
Female Genital Diseases and Pregnancy
Complications
Galactorrhea very little epidemiological
studies, rates between 10 -57. RCTs 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 RCTs 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
26
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
27
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
28
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) 155158)
29
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) 155158)
30
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
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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

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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

33
Origin of 225 epidemiological studies on the
association between schizophrenia and physical
illness
Leucht et al. 2006
34
Medical Comorbidity With Schizophrenia Is Very
Common
Physical Disease With Increased Frequency in
Schizophrenia

• 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

() very good evidence for increased risk (eg,
population-based studies).
35
Summary
Summary of physical diseases which occur with
increased frequency in schizophrenia according to
our review

MeSH disease category Physical disease with increased frequency in schizophrenia
Bacterial infections and mycoses Tuberculosis ()
Virus diseases HIV (), hepatitis B/C ()
Neoplasms Cancer in general (-)1
Musculoskeletal diseases Osteoporosis/decreased bone mineral density ()
Stomatognathic diseases Poor dental status ()
Respiratory tract diseases Impaired lung function ()
Nervous system diseases Extrapyramidal side-effects of antipsychotic drugs (), motor signs in antipsychotic naive patients (), altered (reduced) pain sensitivity ()
Urological and male genital diseases Sexual dysfunction (), prostate cancer (-)
Female genital diseases and pregnancy complications Obstetric complications (), sexual dysfunction (), hyperprolactinemia related side-effects of antipsychotics (irregular menses, galactorrhea etc.) ()
Cardiovascular diseases Cardiovascular problems ()
Skin and connective tissue diseases Hyperpigmentation ()2, rheumatoid arthritis (-)
Nutritional and metabolic diseases Obesity (), diabetes (), hyperlipidemia (), metabolic syndrome including hyperlipidemia (), polydipsia ()
Endocrine system diseases Thyroid dysfunction (), hyperprolactinemia () (side-effect of a number of antipsychotics)
() 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, otorhinolaryngologic
al 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.
36
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

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38
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
39
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