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Heart Disease, Cancer Shorten Lifespans in Schizophrenia

5 February 2013. Undiagnosed heart disease and cancer steal 12 to 15 years from the lives of people with schizophrenia, reports a study published online January 15 in the American Journal of Psychiatry. Led by Casey Crump of Stanford University, in collaboration with a team from Lund University in Sweden, the study tracked over six million people in Sweden and found that undiagnosed medical conditions—but not unnatural causes of death like suicide—accounted for the shortened lifespans in schizophrenia.

The study suggests that these medical conditions go undetected in people with schizophrenia, even though they tend to have more contacts with the healthcare system. Though antipsychotic drugs themselves were not associated with death (see SRF related news story), the study was unable to say whether the higher rates of smoking by people with schizophrenia were to blame for these.

Premature mortality is a well-known, albeit distressing, finding for people with schizophrenia (see SRF related news story and SRF news story), and narrowing this “mortality gap” means finding its causes. The new study provides one of the most comprehensive surveys of these using Swedish national databases. With data available from both inpatient and outpatient records, the researchers could track diagnoses—whether schizophrenia or other comorbid conditions that didn’t necessarily land someone in the hospital—to obtain a fuller picture of a person’s health.

Swedish counts
The study population was all people aged 25 or older living in Sweden, and who had lived there for two or more years, as of January 2003. This amounted to 6,097,834 people, 8,277 of whom were diagnosed with schizophrenia. The researchers followed this cohort for seven years, tracking specific diagnoses recorded in either the Swedish Outpatient Registry or the Swedish Hospital Registry, and deaths recorded in the Swedish Death Registry.

On average, women with schizophrenia died 12 years earlier, and men 15 years earlier, than their counterparts without the disorder. This difference was not accounted for by “unnatural” deaths, meaning suicide or accidents: although unnatural deaths occurred more frequently in schizophrenia, when the subset of people who had died from natural causes was analyzed, the stark gap in mortality remained.

The most common causes of death among people with schizophrenia were ischemic heart disease and cancer. Among all people who died from these conditions, those with schizophrenia were less likely to have received a diagnosis of these conditions. For example, of those people who died from ischemic heart disease, 26.3 percent of people with schizophrenia had been diagnosed with the condition, compared to 43.7 percent of people in the general population. Similarly, of those who died from cancer, 73.9 percent of people with schizophrenia had received that diagnosis, compared to 82.3 percent of those in the general population. This suggested that these conditions went undetected in schizophrenia, since as a whole, the schizophrenia group was seeing doctors, clocking twice as many outpatient clinic visits and hospital admissions per year. Also, when the researchers looked exclusively at those people with schizophrenia who had received a diagnosis of ischemic heart disease or cancer prior to their death, their risk of dying from those conditions fell to general population levels.

Behind the causes
Because smoking is a risk factor for these conditions, it could be that they stem from the prolific smoking habits of people with schizophrenia. The databases, however, did not have information on an individual’s smoking status. To measure what the effect of smoking might be on their risk estimates, the researchers adjusted their calculations by the prevalence of smoking in schizophrenia (70 percent) and the general population (25 percent). This revised their estimates downward, though risk from dying from something like ischemic heart disease was still elevated compared to the general population. This suggests smoking may modulate risk, but information about individual smoking behavior will be needed to better estimate its contribution.

Although the metabolic syndrome induced by second-generation antipsychotic drugs could spur many of these conditions, the study did not find an association between any particular antipsychotic and increased mortality. In fact, not taking antipsychotics increased risk of death from any cause, and aripiprazole and olanzapine use were associated with decreases in risk.

Whether these comorbid conditions reflect something about the cause of schizophrenia, or the consequences of living with it, the study argues that the primary healthcare needs of people with schizophrenia sorely deserve attention.—Michele Solis.

Reference:
Crump C, Winkleby MA, Sundquist K, Sundquist J. Comorbidities and Mortality in Persons With Schizophrenia: A Swedish National Cohort Study. Am J Psychiatry. 2013 Jan 15. Abstract

Comments on Related News


Related News: A Burden on the Heart—Schizophrenia and Coronary Heart Disease

Comment by:  Kiumars Lalezarzadeh
Submitted 27 December 2005
Posted 28 December 2005
  I recommend the Primary Papers

The relation between fatty acid and dopamine needs basic consideration. Two-week-old pups of mother rats fed n-3 polyunsaturated fatty acid-deficient diets (3 weeks before and 2 weeks after birth) showed an increase of D2 (and D1) receptors in the mesolimbic-mesocortical pathways of mothers and many brain areas of the pups (Kuperstein et al., 2005). The depressing effects of increased cholesterol level may be seen in reverse.

The effects of different antipsychotics on the immune system and fungal pathogens need consideration also. Antipsychotics reduce calcineurin protein levels and elevate phosphatase activity of calcineurin in striatum and prefrontal cortex (Rushlow et al., 2005). Calcineurin increases fungal pathogens and its inhibition is related to immune suppression (Cruz et al., 2001). Antipsychotics need further study in relation to calcineurin, immune suppression, and fatty acids.

References:
Kuperstein F, Yakubov E, Dinerman P, Gil S, Eylam R, Salem N Jr, Yavin E. Overexpression of dopamine receptor genes and their products in the postnatal rat brain following maternal n-3 fatty acid dietary deficiency. J Neurochem. 2005 Dec;95(6):1550-62. Epub 2005 Nov 23. Abstract Rushlow WJ, Seah YH, Belliveau DJ, Rajakumar N. Changes in calcineurin expression induced in the rat brain by the administration of antipsychotics. J Neurochem. 2005 Aug;94(3):587-96. Abstract Cruz MC, Fox DS, Heitman J. Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans. EMBO J. 2001 Mar 1;20(5):1020-32. Abstract

View all comments by Kiumars Lalezarzadeh

Related News: A Burden on the Heart—Schizophrenia and Coronary Heart Disease

Comment by:  Robert Peers
Submitted 30 December 2005
Posted 31 December 2005

In what may be a landmark study of lifestyle intervention in schizophrenia, Australian dietitian Sherryn Evans was highly successful in limiting weight gain in newly diagnosed schizophrenia patients treated with olanzapine (Evans et al., 2005). Nutritionally educated patients were only 2 kg heavier after 3 months and 6 months, and were happier; controls were 6 kg and 9.9 kg heavier at the same time points.

The key to nutritional success is close supervision, best provided in community centers accessible to schizophrenia patients. A gym would help. F. M. Baker once ran a program in a poor area of Baltimore, in which the patients were collected daily and brought in, to cook their own (healthy) meals and take part in psychosocial therapy; medication compliance improved, and readmission rates fell dramatically.

The adverse metabolic effects of most newer antipsychotic drugs have stimulated a renaissance of interest in nutritional factors and physical health in schizophrenia that will hopefully encourage the entry of dietitians and exercise physiologists into the treatment arena. They have much to offer.

A well-planned low-fat, grain- and legume-rich diet, as in the Australian study, will improve cell membrane structure in brain and body by allowing omega-3 and -6 essential fatty acid levels to rise (the key to controlling diabetes and heart risk). The same diet also provides the key nutrient inositol, a seed-derived glucose isomer that imitates the anxiolytic action of clozapine-type drugs, and so would treat the comorbid anxiety seen in a third of patients with schizophrenia (which promotes hypertension, diabetes, cardiac mortality, smoking, negative symptoms, and suicide).

The inositol hexaphosphate in edible seeds is itself a potent iron-binding antioxidant (Graf et al., 1987), prominent in the diet of healthy centenarians, and in the whole grains is known to reduce coronary disease progression in the Iowa Women's Health Study (Erkkila et al., 2005): So here is a simple life-extender and artery protector for schizophrenia patients, too, anxious or not, who eat corn, grains, and beans.

Omega-3 fatty acids already look promising in schizophrenia (Puri and Richardson, 1998), so if oily fish intake is low, two or three fishoil capsules a day—costing little—might help both brain and cardiac risk.

View all comments by Robert Peers

Related News: A Burden on the Heart—Schizophrenia and Coronary Heart Disease

Comment by:  Patricia Estani
Submitted 3 January 2006
Posted 4 January 2006
  I recommend the Primary Papers

More studies must be designed to research variables that affect heart disease in schizophrenia. I think that integrating medical services, for example, adding nutritional treatment or dietary services to psychiatric support is essential to prevent the metabolic syndrome commonly observed in schizophrenic patients.

View all comments by Patricia Estani

Related News: A Burden on the Heart—Schizophrenia and Coronary Heart Disease

Comment by:  SuSanne Henriksen
Submitted 10 January 2006
Posted 10 January 2006
  I recommend the Primary Papers

Is there any evidence of an increased incidence of arrhythmias, especially tachycardia, in schizophrenia?

View all comments by SuSanne Henriksen

Related News: Mortality Gap Growing for People With Schizophrenia

Comment by:  Ezra Susser, SRF Advisor
Submitted 11 December 2007
Posted 11 December 2007
  I recommend the Primary Papers

I would like to underscore a point that emerges from the important paper by Saha and colleagues (an excellent summary is provided above by Victoria Wilcox). Currently the focus on inequalities/disparities in public health has paid attention mainly to socioeconomic and ethnic/racial disparities. This paper and some other recent papers draw attention to the disparities in health between people with and without severe mental illness. I view this disparity as being in large part rooted in discrimination experienced by people with mental illness, rather than being inherent in their illness. People with a severe mental illness should have the right to high quality health care and prevention, even if care and prevention has to be tailored to their special needs so that it can be utilized.

View all comments by Ezra Susser

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  John McGrath, SRF Advisor
Submitted 23 July 2009
Posted 23 July 2009
  I recommend the Primary Papers

The results of this study are surprising. In those with schizophrenia, those on clozapine had by far the lowest relative risk of death (compared to patients on other antipsychotics). Compared to older medications, atypical antipsychotics, to date, do not seem to be impacting on the relative risk of death.

I congratulate the authors on this impressive study. The study is another reminder of the utility of population-based record linkage studies. Thank heavens for the Nordic countries' health registers.

A few years ago we wondered if the differential mortality rate for schizophrenia was worsening over time (Saha et al., 2007). In addition to differential access to health care, we worried that the adverse effects of atypical antipsychotics might be a “ticking time bomb” for worsening mortality in the decades to come. The new Finnish study shows a more nuanced picture emerging.

While the results are thought provoking, let’s not forget about the main game. We all agree that there is still much more work to be done in optimizing the general physical health of people with schizophrenia.

References:

Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry . 2007 Oct 1 ; 64(10):1123-31. Abstract

View all comments by John McGrath

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Francine Benes, SRF Advisor
Submitted 4 November 2009
Posted 4 November 2009

Clozapine: A First-Line Antipsychotic?
Tiihonen et al., of the University of Kuopio in Finland, compared mortality rates in over 66,000 patients with schizophrenia with the entire population of Finland and concluded that clozapine should be used as a first-line drug in the treatment of this disorder. Clozapine is a very effective antipsychotic, and for patients who have received it for several years, the improvement in clinical status can be quite remarkable (Lindstrom, 1988; Agid et al., 2008). Additionally, the improved mortality rate of patients on clozapine may be attributable, at least in part, to the close monitoring of their white blood cell count (WBC).

The stipulation that weekly or biweekly blood samples must be drawn is not an issue that can be viewed lightly, because approximately 1-2 percent of patients on clozapine may show significant decreases in their WBC. This may be a harbinger of agranulocytosis, a potentially lethal form of morbidity in which the bone marrow loses its ability to generate leukocytes; death remains a significant risk for patients taking this drug (Taylor et al., 2009). To some, this may seem like a small price to pay for an improved quality of life. For others, however, it represents an unacceptable degree of risk. Additionally, many patients consider the requirement for frequent blood drawing as intrusive and/or painful and refuse to have it done (personal observation).

Perhaps the greatest source of resistance to using clozapine as a “first-line” drug is the psychiatrist who is faced with this decision. In general, most believe that they would be exposing their patient to unnecessary risk and prefer to look toward other, more “benign” antipsychotic drugs (APDs) for treatment options. In practice, however, the second-generation atypical APDs are not necessarily better candidates for “first-line” use, because they may be even more likely to cause excessive weight gain, diabetes mellitus, and cardiovascular disease (Wehring et al., 2003; Henderson et al., 2005) and result in increased mortality (Meatherall and Younes, 2002). In addition to the risk of agranulocytosis, clozapine may also cause unacceptable amounts of sedation, drooling, and weight gain. Typical APDs, on the other hand, are associated with other side effects that can be quite debilitating. These include extrapyramidal movement disorders, such as 1) akathisia, a condition that may cause a worsening of symptoms as a result of agitation; 2) drug-induced Parkinsonism, in which hypokinesia usually complicates the negative symptoms of schizophrenia; and 3) tardive dyskinesia, a syndrome in which there are involuntary movements of the tongue and lips that can result in significant disability and even disfigurement (Peacock et al., 1996).

In considering the choice of an APD for a “first-episode” patient with schizophrenia, all of these factors must be considered. It is impossible to know how a particular patient with no prior history of having taken an APD will respond to any given drug. What may be an excellent “first-line” drug for one patient may not be so for another. So, the choice of a “first-line” drug requires that the doctor and patient work together to identify the APD that is most appropriate at a particular time in the course of the illness, particularly if the patient has a treatment-sensitive or treatment-resistant form of schizophrenia (Wang et al., 2004).

References:

Agid O, Kapur S, Remington G. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs. 2008;13:479-95. Abstract

Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, Freudenreich O, Evins AE, Cather C, Goff DC. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66:1116-21. Abstract

Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988;77:524-9. Abstract

Meatherall R, Younes J. Fatality from olanzapine induced hyperglycemia. J Forensic Sci. 2002;47:893-6. Abstract

Peacock L, Solgaard T, Lublin H, Gerlach J . Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects. Psychopharmacology (Berl). 1996; 124:188-96. Abstract

Taylor DM, Douglas-Hall P, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry. 2009;194:165-7. Abstract

Wang PS, Ganz DA, Benner JS, Glynn RJ, Avorn J. Should clozapine continue to be restricted to third-line status for schizophrenia?: a decision-analytic model. J Ment Health Policy Econ. 2004;7:77-85. Abstract

Wehring HJ, Kelly DL, Love RC, Conley RR. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003;160:2241-2. Abstract

View all comments by Francine Benes

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Edward Orton (Disclosure)
Submitted 18 November 2009
Posted 18 November 2009
  I recommend the Primary Papers

Dr. Benes notes that clozapine is "...a very effective antipsychotic, and...improvement in clinical status can be quite remarkable." The mortality figures reported by Tihonen et al. have proved quite striking to schizophrenia researchers. The perception within the psychiatry community that clozapine is too risky for first-line therapy needs further assessment and discussion. Only about 5 percent of schizophrenics in the U.S. receive clozapine (Lieberman, 2009), leaving the vast majority of patients undermedicated because of this perception. The major issue with starting a patient on clozapine is WBC monitoring. I would like to call upon the NIMH to establish a major study in which schizophrenics are introduced to clozapine on an inpatient basis for 30-60 days to establish safety. It is well known that most WBC events associated with clozapine occur in the first few weeks of treatment. Also, I note that current prescribing practice with clozapine actually allows for monthly blood monitoring after 12 months of continuous clozapine use. Thus, the burden of monitoring diminishes sharply after one year.

References:

Lieberman J. A Beacon of Hope: Prospects for Preventing and Recovering from Mental Illness. NARSAD Research Quarterly 2 (1), Winter 2009.

View all comments by Edward Orton