Schizophrenia Research Forum - A Catalyst for Creative Thinking

Mortality Gap Growing for People With Schizophrenia

4 December 2007. It comes as no surprise that people with schizophrenia tend to die sooner than those without it, but a meta-analysis of 37 research papers from 25 nations shows that the mortality difference between the two groups has burgeoned in recent decades. This alarming finding comes from a report in the October Archives of General Psychiatry by John McGrath and others at the Queensland Centre for Mental Health Research in Brisbane, Australia. Although suicide deaths garner most of the research attention, the researchers write, “Less widely appreciated is the fact that people with schizophrenia are at increased risk for premature death associated with comorbid somatic conditions.”

To compare death rates in two populations, researchers often compute the standardized mortality ratio, or SMR. In this context, they divide the number of deaths observed in subjects with schizophrenia by the number expected in an age- and sex-matched cohort from the general population. Two earlier meta-analyses—one based on studies published between 1969 and 1996 (Brown, 1997), the other on studies from 1973 to 1995 (Harris and Barraclough, 1998)—found an SMR of 1.5 to 1.6, meaning that people with schizophrenia are about one and a half times more likely than the general population to die during a given period.

It may not be a coincidence that the later review found a greater risk. A Swedish study published after the prior meta-analyses revealed that the added death risk associated with schizophrenia rose from 1976 to 1995. In the one meta-analysis that explored time trends, the mortality gap widened from the 1970s to the 1980s, although it narrowed in the 1990s. Since those decades brought stepped-up efforts to treat mental illness, along with the introduction of second-generation antipsychotic drugs, McGrath and colleagues wanted to clarify whether the death disparity has worsened.

To do so, McGrath, first author Sukanta Saha, and David Chant conducted a meta-analysis of studies released between 1980 and early 2006 that examined mortality in schizophrenia. The studies came from countries at various stages of economic development; they spanned the globe from North and South America to Europe, Australia, and Asia. Overall, the studies furnished information on 22,296 deaths.

McGrath and his collaborators zeroed in on research reports that gave either the SMR or the data needed to compute it. When possible, they also determined the annual all-cause case fatality rate, or CFR. The CFR indicates the percentage of persons diagnosed with a particular illness who died during a given time frame.

Not just suicide, but physical diseases, too
In comparing cohorts with schizophrenia to the general population, the analysis found an all-cause SMR of 2.58, consistent with the 2006 review. When Saha and colleagues looked at the studies’ follow-up dates, they found a significant rise in the SMRs, from 1.84 in the 1970s, to 2.98 in the 1980s, and even 3.20 in the 1990s. They note that this trend runs counter to the decline in age-standardized mortality rates seen in the general population of most nations. Since CFRs stayed constant, “These findings suggest that people with schizophrenia have not fully benefited from the improvements in health outcomes available to the general population,” they write.

As for causes of death, subjects with schizophrenia were eight times more likely than others to die of unnatural causes such as homicide, suicide, and accidents. Indeed, they were 12 times more likely to die by suicide. These numbers, although tragic, belie the fact that natural causes such as heart disease kill the majority of people with schizophrenia, who are twice as likely as those in the larger community to die of natural causes.

That excess death risk extended to all categories of disease except cerebrovascular diseases. The highest median SMRs occurred for infectious (4.29), nervous (4.22), genitourinary (3.70), and respiratory disease (3.19). The median SMR for deaths due to cardiovascular disease, a top cause of death in many countries, was 1.79, and from endocrine disease, 2.63.

What’s going on?
Saha and colleagues did not probe the reasons for the widening mortality gap, but they hint that second-generation antipsychotic drugs may further amplify the differences (see SRF related news stories on heart disease, glucose metabolism, and weight gain). They note, “Compared with typical antipsychotics, several of the second-generation antipsychotics are more likely to cause weight gain and metabolic syndrome,” two big risk factors for death across all causes and particularly from heart disease. In fact, the National Hospital Discharge Survey found that the prevalence of diabetes in people with schizophrenia versus those without mental illness soared, after a lag period, following the debut of atypical antipsychotics. Because these risk factors may take decades to steal a life, the authors warn that the future may bring an even grimmer reality.

“Apart from adverse effects related to medication, schizophrenia can trigger a cascade of socioeconomic and lifestyle factors that, in turn, can translate into adverse physical health outcomes,” Saha and colleagues write. For instance, people with schizophrenia tend to receive inadequate care for their physical health needs and to engage in unhealthy behaviors such as smoking. Furthermore, the same environmental and genetic factors that may foster schizophrenia could contribute to other medical problems.

This meta-analysis shows the need for more research to find ways to prevent suicide by people with schizophrenia, as well as to pinpoint the causes of the added risk of somatic illness that also threatens their lives. As Saha and colleagues write, “Given the potential for an even greater disease burden as a result of the introduction of second-generation antipsychotic medications, research aimed at optimizing the physical health of people with schizophrenia needs to be undertaken with a sense of urgency.”—Victoria L. Wilcox.

Reference:
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; 64(10):1123-1131. Abstract

Comments on News and Primary Papers
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

Comments on Related News


Related News: Some Antipsychotic Drugs Impair Glucose Metabolism

Comment by:  James Manning IV
Submitted 25 November 2005
Posted 25 November 2005

This study is thoughtful and balanced, and driven by evidence.

View all comments by James Manning IV

Related News: Some Antipsychotic Drugs Impair Glucose Metabolism

Comment by:  Patricia Estani
Submitted 27 November 2005
Posted 28 November 2005
  I recommend the Primary Papers

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: Food for Thought—Weight Gain and Mortality in the Mentally Ill

Comment by:  Mary Reid
Submitted 12 March 2007
Posted 14 March 2007

Atmaca and colleagues report that atypical antipsychotic-, especially clozapine- and olanzapine-induced weight gain is related to increased levels of leptin. How does this tie in with the study by Sangwon Kim and colleagues, who found that clozapine and olanzapine lower levels of active AMPK in mouse hypothalamus tissue while leptin activates hypothalamic AMPK?

Wannamethee et al. conclude, "Plasma leptin is associated with insulin resistance, inflammation, and disturbances in homeostasis independent of waist circumference, suggesting possible pathways by which leptin may influence risk of cardiovascular disease." They also report that leptin is lowered in cigarette smokers.

It is of interest that De Rosa and colleagues report reduced activation of FOXP3 by leptin. Is this a positive or a negative in schizophrenia? Is there a predisposition to develop autoimmune disease with long-term use of these drugs?

View all comments by Mary Reid

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