Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry. 2015 Apr;72(4):334-41. doi: 10.1001/jamapsychiatry.2014.2502. Review. Erratum in: JAMA Psychiatry. 2015 Jul;72(7):736. Erratum in: JAMA Psychiatry. 2015 Dec;72(12):1259. PubMed PMID: 25671328; PubMed Central PMCID: PMC4461039.
De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011 Oct 18;8(2):114-26. doi: 10.1038/nrendo.2011.156. Review. PubMed PMID: 22009159.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. https://www.nice.org.uk/guidance/cg178. Published February 2014. Updated March 2014. Accessed August 2017.
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):1123-31. Review. PubMed PMID: 17909124.
Definitions, Etiology, EpidemiologyTop
Serious mental illness (SMI) is a term applied to those mental illnesses that either currently or in the previous year have been associated with serious functional impairment. SMI typically refers to cases of schizophrenia, bipolar disorder, and depression. The 12-month prevalence of SMI is estimated at 4% to 6% of the adult population.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (one geographic area with specific diagnostic criteria). Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005 Jun;62(6):617-27. Erratum in: Arch Gen Psychiatry. 2005 Jul;62(7):709. Merikangas, Kathleen R [added]. PubMed PMID: 15939839; PubMed Central PMCID: PMC2847357.
Compared with the general population, individuals with SMI have a 2-fold to 3-fold higher risk of death at a given age and their life expectancy is dramatically reduced. This difference is referred to as the “mortality gap,” and it is estimated to be approximately 10 years for individuals with schizophrenia and is greater in men than in women.Evidence 2High Quality of Evidence (high confidence that we know true effects of the intervention). 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):1123-31. Review. PubMed PMID: 17909124. Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry. 2015 Apr;72(4):334-41. doi: 10.1001/jamapsychiatry.2014.2502. Review. Erratum in: JAMA Psychiatry. 2015 Jul;72(7):736. Erratum in: JAMA Psychiatry. 2015 Dec;72(12):1259. PubMed PMID: 25671328; PubMed Central PMCID: PMC4461039. The mortality gap has remained stable at these levels despite overall improvements in life expectancy for the general population. The purpose of this chapter is to heighten the awareness of physicians about this alarming situation so that the factors contributing to this problem can be appropriately addressed.
Individuals with SMI who present for medical care may receive poor or delayed treatment because physicians attribute their physical symptoms to their mental illness. This phenomenon is referred to as “diagnostic overshadowing,” meaning that it may be difficult for physicians to recognize medical illness when they view the patient through the shadow cast by their mental illness.
SMIs are understood as being highly heritable disorders, with estimates of heritability ranging from over 80% for schizophrenia and bipolar disorder to 37% for major depression. For example, the risk of developing schizophrenia in people with a first-degree relative with schizophrenia is approximately 10-fold higher than in the general population.Evidence 3High Quality of Evidence (high confidence that we know true effects of the intervention). Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. Cambridge, England: Cambridge University Press; 1982. Mental illnesses may be chronic and persisting or remitting and relapsing in their course. It is estimated that 75% of cases of mental illnesses in adults have their onset by the age of 24 years. The impact of SMI on physical health problems reflects the cumulative effects of a range of determinants of health over many decades. Addressing the mortality gap requires appreciation of a host of health determinants early in the course of SMI.
Our understanding of the outcome from mental illness has changed dramatically over the past 60 years since psychotropic medications were first introduced for the treatment of schizophrenia, bipolar disorder, and major depression. These illnesses are highly treatable with the expectation of high rates of remission. While relapses are common and often result in rehospitalization, their rates can be dramatically reduced by maintenance medications. Recent attention to illness self-management and relapse prevention has the potential to alter the course of these illnesses. Concurrent substance use disorders and developmental disorders compound problems with treatment adherence and together contribute to the challenge of managing medical comorbidity in this population.
There are many factors that contribute to premature mortality (the mortality gap) observed in individuals with SMI (Table 16.13-1):
1) Causes of death: Both men and women with schizophrenia are more likely to die as a result of a number of medical causes compared with the general population. When expressed as standardized mortality ratio (SMR), individuals with schizophrenia are twice as likely to die of natural causes, including cardiovascular diseases (SMR, 1.88), digestive diseases (SMR, 3.34), endocrine diseases (SMR, 4.07), infectious diseases (SMR, 3.77), genitourinary diseases (SMR, 2.90), respiratory diseases (SMR, 3.51), nervous diseases (SMR, 3.55), and neoplastic diseases (SMR, 1.33).
2) Elevated risk factors for medical illness: Individuals with schizophrenia are much more likely to smoke tobacco, including cigarettes, relative to the general population (odds ratio, 5.3).Evidence 4High Quality of Evidence (high confidence that we know true effects of the intervention). de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005 Jul 15;76(2-3):135-57. PubMed PMID: 15949648. They are more likely to be heavy smokers with higher nicotine dependence scores and lower cessation rates. It has been estimated that persons with broadly defined mental illness consume over 40% of all cigarettes sold in the United States.Evidence 5Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness related to the definition of mental illness. Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: A population-based prevalence study. JAMA. 2000 Nov 22-29;284(20):2606-10. PubMed PMID: 11086367.
Individuals with schizophrenia have much higher rates of obesity, hypertension, hyperlipidemia and hypercholesterolemia, diabetes, and metabolic syndrome.Evidence 6High Quality of Evidence (high confidence that we know true effects of the intervention). Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull. 2013 Mar;39(2):306-18. doi: 10.1093/schbul/sbr148. Epub 2011 Dec 29. Review. PubMed PMID: 22207632; PubMed Central PMCID: PMC3576174. Increased rates of glucose intolerance and insulin resistance may be directly linked to schizophrenia. A combination of poor diet, sedentary behavior, obesity, and adverse effects of psychotropic medications over time compound this association. Most antipsychotics and mood stabilizers have the potential to cause weight gain, as do many antidepressant medications. Amongst antipsychotic agents, clozapine and olanzapine are considered to carry the greatest risk of weight gain.Evidence 7High Quality of Evidence (high confidence that we know true effects of the intervention). Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013 Sep 14;382(9896):951-62. doi: 10.1016/S0140-6736(13)60733-3. Epub 2013 Jun 27. Review. Erratum in: Lancet. 2013 Sep 14;382(9896):940. PubMed PMID: 23810019. Mean one-year weight gain from olanzapine in patients treated for their first episode of psychosis is estimated at 15.5 kg compared with 7.1 kg for those treated with haloperidol, a first-generation antipsychotic considered to have among the lowest risks of weight gain.Evidence 8Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (dropout rate). Zipursky RB, Gu H, Green AI, et al. Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol. Br J Psychiatry. 2005 Dec;187:537-43. PubMed PMID: 16319406. Antipsychotic medications may lead to abnormalities in glucose and lipid metabolism through molecular mechanisms that may be only partially accounted for by weight gain.
Current users of antipsychotic medications have been found to be at a significantly greater risk of sudden cardiac death, which has been found to be dose-related. The risk varies with first-generation antipsychotics (eg, haloperidol, perphenazine, chlorpromazine, thioridazine) from an incidence risk ratio of 1.31 with low doses to 2.42 with high doses; with second-generation antipsychotics (eg, risperidone, olanzapine, quetiapine, clozapine), the incidence risk ratio rises from 1.59 with low doses to 2.86 with high doses.Evidence 9Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data, increased due to the dose-effect response. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009 Jan 15;360(3):225-35. doi: 10.1056/NEJMoa0806994. Erratum in: N Engl J Med. 2009 Oct 29;361(18):1814. PubMed PMID: 19144938; PubMed Central PMCID: PMC2713724. It is thought the increased risk of sudden cardiac death is likely due to ventricular arrhythmias such as torsades de pointes secondary to the blockade of potassium channels and prolonged cardiac repolarization. Antipsychotic medications vary substantially in the degree to which they cause QTc prolongation, as do antidepressants and mood stabilizing medications. Despite the cardiac risks associated with the use of antipsychotic medications in patients with schizophrenia, epidemiologic evidence suggests that long-term use may be associated with reduced mortality.Evidence 10Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational studies. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009 Aug 22;374(9690):620-7. doi: 10.1016/S0140-6736(09)60742-X. PubMed PMID: 19595447.
Many antipsychotic medications have profound anticholinergic effects, which is also the case for antiparkinsonian medications and some antidepressant medications. These medications commonly lead to severe problems with constipation. Bowel obstruction and paralytic ileus are amongst the most common and severe complications of treatment for schizophrenia. In patients treated with clozapine, for example, severe constipation is associated with a very high mortality rate and is much more common than agranulocytosis or myocarditis—severe adverse events that receive more attention.
Individuals with SMI are less likely to receive good medical care, and this is thought to contribute substantially to their reduced life expectancy. The phenomenon can be understood as involving factors attributable to the behavior of patients and of health providers.
Patients with SMI may be less inclined to seek care and may have lower adherence to medical treatments. Approaches that facilitate health care–seeking and support treatment adherence in individuals with cognitive and motivational deficits are essential. Patients may have reduced access to care as a result of poverty, differences in insurance coverage, as well as stigma and discrimination.
There are ways in which medical providers may contribute to the poor care received by some patients with SMI. It may be challenging to obtain a history from some patients with SMI if they are uncooperative or have thought disorders. Behavior that is bizarre or aggressive as well as active features of psychosis, mania, or depression may also interfere with a proper assessment. Assessment is also likely to be more difficult and time-consuming, which further limits the likelihood that physicians working with severe time constraints, such as in an emergency department, will carry out a comprehensive assessment.
Many physicians are uncomfortable working with patients who have SMI (see Difficult Patient). This may be due to a perceived lack of knowledge about mental illness and its management, fear of violence, and the pervasive stigma associated with SMI. These factors likely contribute substantially to the lower intensity of care that patients with SMI often receive.Evidence 11Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and retrospective nature of data. Kurdyak P, Vigod S, Calzavara A, Wodchis WP. High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. Schizophr Res. 2012 Dec;142(1-3):52-7. doi: 10.1016/j.schres.2012.09.003. Epub 2012 Sep 27. PubMed PMID: 23021899. Ribe AR, Vestergaard M, Katon W, et al. Thirty-Day Mortality After Infection Among Persons With Severe Mental Illness: A Population-Based Cohort Study in Denmark. Am J Psychiatry. 2015 Aug 1;172(8):776-83. doi: 10.1176/appi.ajp.2015.14091100. Epub 2015 Feb 20. PubMed PMID: 25698437. Druss BG, Bradford DW, Rosenheck RA, Radford MJ, Krumholz HM. Mental disorders and use of cardiovascular procedures after myocardial infarction. JAMA. 2000 Jan 26;283(4):506-11. PubMed PMID: 10659877. Frayne SM, Halanych JH, Miller DR, et al. Disparities in diabetes care: impact of mental illness. Arch Intern Med. 2005 Dec 12-26;165(22):2631-8. PubMed PMID: 16344421. Patients with SMI are less likely to receive tests for diabetes monitoring, to have their blood pressure or cholesterol recorded during regular health visits, to have up-to-date cancer screening, and to receive chemotherapy, radiation, and surgery when diagnosed with cancer. Patients with schizophrenia who present with myocardial infarction have been found to be 50% less likely to see a cardiologist or to have a cardiac procedure and 56% more likely to die within 30 days of presentation. Similarly, patients with SMI who have been hospitalized for the treatment of infection have been reported to have a 30-day mortality rate that is approximately 50% higher than those without SMI.
When encountering patients with SMI, many physicians have difficulty separating physical illness from psychiatric illness and incorrectly assume that whatever physical complaints are being described can be explained by the person’s psychiatric problems. This diagnostic overshadowing results in patients with SMI receiving care of lower intensity and quality. It is important to appreciate that patients with SMI not only have all of the same potential medical problems that are observed in those without mental illness, but they are expected to have many of these problems at a higher frequency and younger age.
Higher rates of suicide and accidental and violent deaths account for one-third of the excess mortality associated with schizophrenia; people with schizophrenia are 8 times as likely to die of unnatural causes and 16 times more likely to die by suicide in particular.Evidence 12High Quality of Evidence (high confidence that we know true effects of the intervention). 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):1123-31. Review. PubMed PMID: 17909124.
Internists and family practitioners must be aware of the heightened risk of medical illness and the large reduction in life expectancy associated with having SMI. This awareness should lead to greater vigilance in ensuring that such patients receive a careful and comprehensive assessment notwithstanding the challenges they may present. Some experts recommend that individuals with SMI have a comprehensive physical assessment at least annually, including assessment of weight, waist circumference, pulse, blood pressure, and metabolic monitoring, as well as a review of gastrointestinal, cardiac, and respiratory functions. Electrocardiography (ECG) should be completed before administering an antipsychotic—or, if not feasible, early in the course of antipsychotic treatment—and then followed up when treatment has been stabilized. As it is very common for many individuals with SMI to be treated concurrently with multiple psychotropic medications, repeating ECG periodically should be considered, for example, when doses are increased or new medications are added. Communication with the patient’s psychiatrist and mental health team about concurrent medical problems and their management is critically important.
Health promotion initiatives have been introduced to improve the health of individuals with SMI and may be available through local family health teams or mental health services. Initiatives to enhance physical activity together with dietary counseling may contribute to the management of obesity and associated metabolic problems. Smoking cessation programs have been of great benefit to many individuals with SMI. Treatment with varenicline, bupropion, and nicotine patches have been demonstrated to be of benefit in helping patients with SMI to discontinue smoking, and we recommend efforts to help patients with SMI to quit smokingEvidence 13Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016 Jun 18;387(10037):2507-20. doi: 10.1016/S0140-6736(16)30272-0. Epub 2016 Apr 22. PubMed PMID: 27116918. (see Nicotine Addiction). Lifestyle changes may be particularly challenging for patients with SMI who experience illness-related deficits in cognition, organization, and motivation. Early use of medications to address problems with hypertension, glucose intolerance, cholesterol and lipid abnormalities, as well as antipsychotic-induced weight gain (eg, metformin) should be given consideration.
Individuals with SMI have dramatically lower life expectancies and a greatly increased risk of death due to a broad range of medical disorders. This can be understood as resulting from the confluence of a number of critical problems:
1) Lifestyle factors including poor diet, sedentary lifestyle, and high rates of obesity and smoking.
2) Adverse effects of antipsychotic and other psychotropic medications.
3) More limited access to health-care services, reduced health care–seeking behavior, and poor adherence to medical care.
4) Provision of lower-quality care.
The magnitude and complexity of this problem requires that internists and family practitioners be especially vigilant in assessing patients with SMI comprehensively, in guarding against the tendency to see physical symptoms as being due to mental illness, in ensuring that medical illness is identified early, and in confirming that the systems and supports are in place, so that patients with SMI are able to adhere to the recommended treatments.
Patients with serious mental illness:
– Have elevated risk of dying from cardiovascular, respiratory, gastrointestinal, endocrine, infectious, genitourinary, neurologic, and neoplastic causes
– Have higher rates of suicide and accidental and violent deaths
– Have higher rates of obesity, hypertension, hyperlipidemia, hypercholesterolemia, diabetes, and metabolic syndrome
– Have higher rates of smoking
– Have more difficulty accessing services
– Have more difficulty adhering to medical treatments
– Are less likely to receive a comprehensive medical assessment
– Are less likely to receive screening tests
– Are less likely to receive specialty consultations and diagnostic tests