© 2015 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2015
BIPOLAR DISORDERS
Original Article
Life expectancy in bipolar disorder Kessing LV, Vradi E, Andersen PK. Life expectancy in bipolar disorder. Bipolar Disord 2015:00:000–000. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Lars Vedel Kessinga, Eleni Vradib and Per Kragh Andersenb a
Psychiatric Center Copenhagen, Department O, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
b
Objective: Life expectancy in patients with bipolar disorder has been reported to be decreased by 11 to 20 years. These calculations are based on data for individuals at the age of 15 years. However, this may be misleading for patients with bipolar disorder in general as most patients have a later onset of illness. The aim of the present study was to calculate the remaining life expectancy for patients of different ages with a diagnosis of bipolar disorder. Methods: Using nationwide registers of all inpatient and outpatient contacts to all psychiatric hospitals in Denmark from 1970 to 2012 we calculated remaining life expectancies for values of age 15, 25, 35 ... 75 years among all individuals alive in year 2000. Results: For the typical male or female patient aged 25 to 45 years, the remaining life expectancy was decreased by 12.0–8.7 years and 10.6– 8.3 years, respectively. The ratio between remaining life expectancy in bipolar disorder and that of the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood. Conclusions: Life expectancy in bipolar disorder is decreased substantially, but less so than previously reported. Patients start losing life-years during early and mid-adulthood.
Bipolar disorder is often conceptualized as a neuroprogressive disorder with an increasing risk of recurrence for every new affective episode (1–4) and with increasing cognitive disabilities during the course of illness (5–7). Mortality among patients with bipolar disorder or schizophrenia has consistently been found to be increased twoto threefold compared to that in the general population (8–11). Similarly, life expectancy has been reported to be decreased by 11 to 20 years for these patients compared to the general population (12–14). Whereas these figures may be correct for a typical patient with schizophrenia, they do not reflect the life expectancy for a typical patient with bipolar disorder. Calculations of life expectancy in these reports were based on data for patients having a first diagnosis below the age of 15 years (12–14). While the typical age at onset of schizophrenia may well be during the teenage
doi: 10.1111/bdi.12296 Key words: age – bipolar disorder – gender – life expectancy – mania – mortality Received 3 October 2014, revised 2 January 2015, revised and accepted for publication 23 January 2015 Corresponding author: Lars Vedel Kessing, MD, DMSc Psychiatric Center Copenhagen Department O, 6233 Blegdamsvej 9, 2100 CopenhagenDenmark Fax: 0045 38647077 E-mail: [email protected]
period, this is not the case for bipolar disorder. In European countries, the mean age at bipolar disorder onset (from population-based studies) has been estimated to be 25 years (15), and approximately 34% of individuals have an onset below the age of 19 years (16). Several studies have found a bimodal distribution of age at onset, with a large peak in early adult life (mid-20s) and a minor, but still substantial, peak in mid-life (mid40s) (17–21). Further, the onset of bipolar disorder below the age of 20 years is associated with a poor outcome, such as more frequent suicide attempts, comorbidity of alcohol abuse and drug addiction, and a rapid-cycling course (22–25) that may be associated with increased mortality. Consequently, calculations of life expectancy based on data for individuals at the age of 15 years may be misleading for patients with bipolar disorder in general. Other than the three studies of life
1
Kessing et al. expectancy cited above, which included samples from a secondary health care case register in London (12), Danish register-based data (13), and population-based register data from Denmark, Sweden, and Finland, no studies have been published on life expectancy that include data on bipolar disorder, (14) – and none of the aforementioned studies focused specifically on bipolar disorder. The aim of the present study was to calculate the remaining life expectancy of patients of different ages with a diagnosis of bipolar disorder, using similar data, design, and analyses as in the two previous studies, including Danish register-based data on life expectancy (13, 14). Methods
We used the same methods as used in the two previous studies, including Danish register-based data on life expectancy in bipolar disorder (13, 14). Thus, we used the same data, from the same nationwide register (however, updated to 2012, inclusive). Further, we used the same criteria for inclusion of patients and similar statistical analyses; however, we included additional analyses of remaining life expectancy based on patients with bipolar disorder at seven different ages (and not only for patients who were below the age of 15 when they were first diagnosed with bipolar disorder). The register
The Danish Psychiatric Central Research Register (DPCRR) is a nationwide registration of all psychiatric hospitalizations for the 5.4 million inhabitants of Denmark (26). From 1970 to 1993, the International Classification of Diseases (ICD)-8 was used and, up to 1995, only inpatient stays at psychiatric hospitals and wards were included. From 1 January 1995, the register also included information on patients in psychiatric ambulatory settings and community psychiatric centers. Since 1 January 1994, the ICD-10 has been in use in the register (27). General practitioners and private practicing psychiatrists do not report to the DPCRR. No private psychiatric inpatient hospitals or departments are in operation in Denmark; they are all are organized within public services, and report to the DPCRR. All inhabitants of Denmark have a unique person identification number [Civil Person Registration (CPR) number] that can be logically checked for errors, so that it can be established with certainty if a patient has had previous contact with any psychiatric service, irrespective of changes in name, for example.
2
The sample
The patient sample was defined as all individuals aged 1–110 years who had been seen in an outpatient (psychiatric ambulatory settings and community psychiatry centers) or inpatient (patients admitted during daytime or overnight to a psychiatric hospital) setting, with at least one main index diagnosis of mania/bipolar disorder (ICD-8: 296.19 or 296.39 and ICD-10: F30 or F31) during the study period from 1 April 1970 to 31 December 2012. Only patients who were alive in 2000 were included (so that updated mortality data were used). Data on the entire Danish general population of 5.4 million people were available from Statistics Denmark (28), including data on gender, age, and death. Statistical analysis
Life expectancies for patients with bipolar disorder were computed in the following way: patients with bipolar disorder were followed from their initial diagnosis until death or end of study (31 December 2012). From these life histories, age- and genderspecific mortality rates were calculated, thereby obtaining survival curves for male and female patients with bipolar disorder. The remaining life expectancies at ages x = 15, 25, 35 . . . 75 years were obtained as the area under the conditional survival curve, given survival until age x. The standard error of the remaining life expectancy was estimated as described by Andersen et al. (29). Life expectancies for the general Danish population were obtained from published Danish lifetables (28). Death was identified from 2000 to 2012 only to get updated mortalities (i.e., the cohort included only patients alive in 2000). The remaining life expectancy both for patients with bipolar disorder and the general population would clearly decrease with age simply as life expectancy decreases with age. To investigate the difference between the remaining life expectancy in patients with bipolar disorder and that for the general population according to age, we consequently calculated the ratio of life expectancy for patients with bipolar disorder and that for the general population at the different age categories. If this ratio decreased with age it would reflect that relatively more life-years are lost in bipolar disorder relative to the general population early in life compared to later in life, and consequently that patients with bipolar disorder start losing life-years earlier in life than the general population.
Life expectancy in bipolar disorder decreased with age. Further, the ratio of life expectancy for patients with bipolar disorder and that for the general population decreased steadily with age (Table 1: from 79.2% at the age of 15 years to 71.2% at the age of 75 years; Table 2: from 84.2% at the age of 15 years to 75.5% at the age of 75 years).
Results
During the study period from 1970 to 2012, we identified a total of 22,752 patients (men = 9,102 and women = 13,650) who were aged 1–110 years and had had contact with outpatient or inpatient services with at least one main diagnosis of mania/ bipolar disorder and who were alive in 2000. On average, the age at the index diagnosis of bipolar disorder was 46.3 years [standard deviation (SD) = 16.6] and the median age was 45.6 (quartiles: 33.3–57.8). Tables 1 and 2 present data on the remaining life expectancy for men and women with bipolar disorder compared to the general population. The remaining life expectancy for patients with bipolar disorder at the age of 15 years was based on a substantially lower number of person-years at risk than the remaining life expectancies for later values of age. For the typical male patient aged 25– 45 years at the time of diagnosis in the register, the remaining life expectancy was based on a larger number of person-years at risk and was decreased by 8.7–12.0 years compared to the general population. Similarly, for the typical women aged 25– 45 years, the remaining life expectancy was decreased by 8.3–10.6 years. As can be seen from Tables 1 and 2 and as illustrated in Figures 1 and 2, in general, the difference in remaining life expectancy between patients with bipolar disorder and the general population
Discussion
Life expectancy in bipolar disorder is decreased substantially, although less so than has been previously reported. For the typical male and female patient aged 25–45 years, the remaining life expectancy was decreased by 8.7–12.0 years and 8.3– 10.6 years, respectively. Regarding calculations based on data on patients at the age of 15 years, we found similar, although slightly increased, life expectancies as in previous Danish studies (13, 14). In the present study, using updated data to 2012, inclusive, the life expectancy for patients with a diagnosis of bipolar disorder at 15 years of age was decreased by 12.8 years for men and 10.4 years for women compared to life expectancies for the general population. These are slightly lower than the life expectancies found in previous Danish studies which included data up to 2006, inclusive (13.6 years for men and 12.1 years for women) (13, 14). This suggests that life expectancy
Table 1. Remaining life expectancy for men with bipolar disorder compared to men in the general population Bipolar disorder
General population
Age, years
Person-years at risk
Deaths
Life expectancy
15 25 35 45 55 65 75
1450.6 5443.5 10498.9 15929.9 18426.6 11151.3 5691.4
6 28 93 250 552 638 832
48.7 39.8 31.7 24.1 17.3 11.6 6.9
Difference in life expectancy
Ratio of life expectancies (%)
12.8 12.0 10.5 8.7 6.7 4.6 2.8
79.2 76.8 75.1 73.5 72.1 71.6 71.1
Life expectancy 61.5 51.8 42.2 32.8 24.0 16.2 9.7
Table 2. Remaining life expectancy for women with bipolar disorder compared to women in the general population Bipolar disorder
General population
Age, years
Person-years at risk
Deaths
Life expectancy
15 25 35 45 55 65 75
2129.6 7594.8 14361.5 22140.1 25753.1 19285.5 16144.8
0 26 67 242 514 779 1933
55.4 45.4 36.7 28.2 20.8 14.2 8.8
Difference in life expectancy
Ratio of life expectancies (%)
10.4 10.6 9.5 8.3 6.6 4.8 3
84.2 81.1 79.4 77.3 75.9 74.7 74.5
Life expectancy 65.8 56.0 46.2 36.5 27.4 19.0 11.8
3
Kessing et al. 80
Men
50 40 30 0
5
10
20
Life expectancy
60
70
General population Bipolar New born
0
5
10
15
20
25
30
35 40 Age
45
50
55
60
65
70
75
Fig. 1. Remaining life expectancy for men with bipolar disorder and men in the general population.
Women
50 40 0
5 10
20
30
Life expectancy
60
70
80
General population Bipolar New born
0
5
10
15
20
25
30
35 40 Age
45
50
55
60
65
70
75
Fig. 2. Remaining life expectancy for women with bipolar disorder and women in the general population.
has improved slightly over recent years (2006– 2012). In the study from a secondary health care case register in London, life expectancy at the age of 15 years for patients with bipolar disorder was decreased by 10.1 years for males and 11.2 years for females compared to the general population (12) – although life expectancy was reported at birth in this study, it was calculated based on data at the age of 15 years for patients. The calculations of life expectancy in the present study and previous Danish studies (13, 14), as well as the London study (12), were based on a population of patients who had had contact with psychi-
4
atric health care services (as inpatients or outpatients). It has previously been shown that the mean age at first contact with the mental health system is relatively high (30); in the present study, the mean age was 46.3 years (SD = 16.6) and the median age was 45.6 (quartiles: 33.3–57.8), in accordance with previous findings based on the case register (19) and with the London study [mean age 43 years for men and 45 years for women (12)]. Further, such patients who had had contact with a psychiatric hospital suffered from more severe types of disorder, and presumably also had more comorbid physical disorders, and may consequently have had a larger decrease in life expectancy, than patients treated for bipolar disorder by private psychiatrists. In addition, as illustrated by the results from the present study, life expectancy is even more decreased if it is based on data from patients at the age of 15 years. This finding is in accordance with a number of publications suggesting a poor outcome among patients with earlyonset bipolar disorder (22–25). A decrease in life expectancy in bipolar disorder compared to that in the general population may reflect a combination of: (i) a higher occurrence of risk factors, including lifestyle factors, for many chronic diseases, including cardiovascular diseases and some types of cancer; (ii) the iatrogenic effects of some psychotropic medication; (iii) higher rates of suicide, accidental, and violent death; and (iv) poorer access to physical healthcare and decreased attention toward and diagnosis of physical disorders (31). Interestingly, the ratio between the remaining life expectancy in bipolar disorder patients and that of the general population decreased with age (Tables 1 and 2), indicating that patients with bipolar disorder start losing life-years early after onset of the disorder – that is, during their 20s, 30s, and 40s – and that the loss of life-years in bipolar disorder is more pronounced early in life than later, compared to the general population. This may be partly due to the increased rate of suicide during the first years after onset of the illness (10, 32), but also to metabolic factors such as the chronic low-grade inflammation that may be particularly salient in the early stages of bipolar disorder (33–36), and to factors including increased oxidative stress [oxidative DNA and RNA damage (K. Munkholm, L.V. Kessing, M. Vinberg, unpublished report)] and altered levels of brainderived neurotropic factor (37). The long-term effects of lifestyle factors (smoking, alcohol, decreased exercise, drug abuse, etc.) associated with chronic diseases and the long-term effects of psychotropic drugs may also be risk factors for the
Life expectancy in bipolar disorder decreased life expectancy found in patients from 15 to 50 years of age. Accelerated aging has recently been proposed as a pathophysiological mechanism in bipolar disorder (38), and such a mechanism may in fact explain our finding that patients with bipolar disorder start losing life-years early during the course of illness. Clearly, this important area of research warrants further investigation.
previously reported. For the typical male and female patient aged 25–45 years, the remaining life expectancy was decreased by 12.0–8.7 years and 10.6–8.3 years, respectively. The ratio between the life expectancy in bipolar disorder and in the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood.
Advantages of the present study
Acknowledgements
The study population was ethnically and socially homogeneous, with a very low migration rate. The entire population (approximately 100%) of patients who had been treated in inpatient or outpatient psychiatric settings throughout the country was included. Psychiatric care is well developed in Denmark, so persons with mania or bipolar disorder can easily come into contact with psychiatric community centers or hospitals. Also, as psychiatric treatment in Denmark is free of charge, the study was not biased by socioeconomic differences.
Funding support was provided by an NARSAD Distinguished Investigator Grant 2012, Brain & Behavior Research Foundation, New York, NY, USA.
Limitations of the present study
It should be noted that the study included only patients who had passed the threshold for treatment in psychiatric outpatient settings (psychiatric ambulatory settings and community centers) or for psychiatric hospitalization. Patients who had been treated exclusively in private psychiatric practice or by general practitioners were not included in the study as these health facilities do not report to the DPCRR. It is likely that the inclusion of milder cases of bipolar disorder in the sample might have resulted in longer life expectancies. It should also be noted that the diagnosis of bipolar disorder in the ICD-10 includes both bipolar I and II disorders but does not discriminate between the two subtypes as ICD-10 defines bipolar disorder as a disorder with at least two mood episodes, of which at least one is a hypomanic or a manic episode. It should be stressed that the present study focused on the main diagnoses that were given for the illness that led to investigation and treatment. According to the ICD-10 diagnostic guidelines, a comorbid illness should be recorded as an auxiliary diagnosis only when the comorbid illness is independent of the primary illness. Auxiliary diagnoses are seldom recorded in Denmark. Conclusions
The remaining life expectancy in bipolar disorder is decreased substantially, although less so than
Author contributions LVK had full access to all of the data in the study and takes responsibility for its integrity and the accuracy of the data analysis. EV performed the statistical analyses in cooperation with PKA and LVK. LVK performed the initial data interpretation and drafted the first version of the manuscript. All authors have (i) made substantial contributions to the conception and design; (ii) been involved in revising the manuscript; (iii) given final approval of the version to be published; and (iv) agree to be accountable for all aspects of the work.
Disclosures In the last five years, LVK has been a consultant for BristolMyers Squibb, Eli Lilly & Co., Lundbeck, AstraZeneca, Servier, and Janssen-Cilag. EV and PKA do not have any financial disclosures or competing interests to report.
References 1. Kessing LV, Hansen MG, Andersen PK, Angst J. The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders - a life-long perspective. Acta Psychiatr Scand 2004; 109: 339–344. 2. Kessing LV, Hansen MG, Andersen PK. Course of illness in depressive and bipolar disorders. Naturalistic study, 1994–1999. Br J Psychiatry 2004; 185: 372–377. 3. Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res 2012; 46: 561–573. 4. Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler CM. Neuroprogression in bipolar disorder. Bipolar Disord 2012; 14: 356–374. 5. Kessing LV, Nilsson FM. Increased risk of developing dementia in patients with major affective disorders compared to patients with other medical illnesses. J Affect Disord 2003; 73: 261–269. 6. Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry 2004; 75: 1662–1666. 7. da Silva J, Goncalves-Pereira M, Xavier M, MukaetovaLadinska EB. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry 2013; 202: 177–186.
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Kessing et al. 8. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998; 173: 11–53. 9. Osby U, Correia N, Brandt L, Ekbom A, Sparen P. Mortality and causes of death in schizophrenia in Stockholm county. Sweden. Schizophr Res 2000; 45: 21–28. 10. Osby U, Brandt L, Correia N, Ekbom A, Sparen P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001; 58: 844–850. 11. Laursen TM, Munk-Olsen T, Nordentoft M, Mortensen PB. Increased mortality among patients admitted with major psychiatric disorders: a register-based study comparing mortality in unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 2007; 68: 899–907. 12. Chang CK, Hayes RD, Perera G et al. Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS ONE 2011; 6: e19590. 13. Laursen TM. Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophr Res 2011; 131: 101–104. 14. Laursen TM, Wahlbeck K, Hallgren J et al. Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries. PLoS ONE 2013; 8: e67133. 15. Post RM, Luckenbaugh DA, Leverich GS et al. Incidence of childhood-onset bipolar illness in the USA and Europe. Br J Psychiatry 2008; 192: 150–151. 16. Post RM, Altshuler L, Leverich G et al. More stressors prior to and during the course of bipolar illness in patients from the United States compared with the Netherlands and Germany. Psychiatry Res 2013; 210: 880–886. 17. Angst J, Preisig M. Course of a clinical cohort of unipolar, bipolar and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol Psychiatr 1995; 146 : 5–16. 18. Cassidy F, Carroll BJ. Vascular risk factors in late onset mania. Psychol Med 2002; 32: 359–362. 19. Kessing LV. Diagnostic subtypes of bipolar disorder in older versus younger adults. Bipolar Disord 2006; 8: 56– 64. 20. Kennedy N, Everitt B, Boydell J, Van OJ, Jones PB, Murray RM. Incidence and distribution of first-episode mania by age: results from a 35-year study. Psychol Med 2005; 35: 855–863. 21. Kroon JS, Wohlfarth TD, Dieleman J et al. Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study. Bipolar Disord 2013; 15: 306–313. 22. Carlson GA, Bromet EJ, Driessens C, Mojtabai R, Schwartz JE. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002; 159: 307–309.
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23. Carter TD, Mundo E, Parikh SV, Kennedy JL. Early age at onset as a risk factor for poor outcome of bipolar disorder. J Psychiatr Res 2003; 37: 97–303. 24. Leboyer M, Henry C, Paillere-Martinot ML, Bellivier F. Age at onset in bipolar affective disorders: a review. Bipolar Disord 2005; 7: 111–118. 25. Goodwin FK, Jamison KR. Manic Depressive Illness. Bipolar Disorder and Recurrent Depression, 2nd edn. New York, NY: Oxford University Press, 2007. 26. Munk-Jorgensen P, Mortensen PB. The Danish Psychiatric Central Register. Dan Med Bull 1997; 44: 82–84. 27. World Health Organisation. Klassifikation af sygdomme. Systematisk del. International Statistical Classification of Diseases and Health Related Problems. Tenth revision (Danish Edition). Copenhagen: Munksgaard, 1993. 28. Statistics Denmark. Statistics Denmark, 2014. Available from: http://www.dst.dk/HomeUK.aspx [accessed March 2015]. 29. Andersen PK, Borgan Ø, Gill RD, Keiding N. Statistical Models Based on Counting Processes. New York, NY: Springer Series in Statistics, 1993. 30. Almeida OP, Fenner S. Bipolar disorder: similarities and differences between patients with illness onset before and after 65 years of age. Int Psychogeriatr 2002; 14: 311–322. 31. Thornicroft G. Physical health disparities and mental illness: the scandal of premature mortality. Br J Psychiatry 2011; 199: 441–442. 32. Tsai SY, Kuo CJ, Chen CC, Lee HC. Risk factors for completed suicide in bipolar disorder. J Clin Psychiatry 2002; 63 : 469–476. 33. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 2009; 70: 1078–1090. 34. Munkholm K, Vinberg M, Vedel KL. Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Disord 2013; 144: 16–27. 35. Munkholm K, Brauner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 2013; 47: 1119–1133. 36. Munkholm K, Pedersen BK, Kessing LV, Vinberg M. Elevated levels of plasma brain derived neurotrophic factor in rapid cycling bipolar disorder patients. Psychoneuroendocrinology 2014; 47: 199–211. 37. Munkholm K, Poulsen HE, Kessing LV, Vinberg M. Elevated levels of urinary markers of oxidatively generated DNA and RNA damage in bipolar disorder. Bipolar Disord 2014, doi:10.1111/bdi.12245. 38. Rizzo LB, Costa LG, Mansur RB et al. The theory of bipolar disorder as an illness of accelerated aging: implications for clinical care and research. Neurosci Biobehav Rev 2014; 42C: 157–169.
Bipolar Disorders 2015
BIPOLAR DISORDERS
Original Article
Life expectancy in bipolar disorder Kessing LV, Vradi E, Andersen PK. Life expectancy in bipolar disorder. Bipolar Disord 2015:00:000–000. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Lars Vedel Kessinga, Eleni Vradib and Per Kragh Andersenb a
Psychiatric Center Copenhagen, Department O, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
b
Objective: Life expectancy in patients with bipolar disorder has been reported to be decreased by 11 to 20 years. These calculations are based on data for individuals at the age of 15 years. However, this may be misleading for patients with bipolar disorder in general as most patients have a later onset of illness. The aim of the present study was to calculate the remaining life expectancy for patients of different ages with a diagnosis of bipolar disorder. Methods: Using nationwide registers of all inpatient and outpatient contacts to all psychiatric hospitals in Denmark from 1970 to 2012 we calculated remaining life expectancies for values of age 15, 25, 35 ... 75 years among all individuals alive in year 2000. Results: For the typical male or female patient aged 25 to 45 years, the remaining life expectancy was decreased by 12.0–8.7 years and 10.6– 8.3 years, respectively. The ratio between remaining life expectancy in bipolar disorder and that of the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood. Conclusions: Life expectancy in bipolar disorder is decreased substantially, but less so than previously reported. Patients start losing life-years during early and mid-adulthood.
Bipolar disorder is often conceptualized as a neuroprogressive disorder with an increasing risk of recurrence for every new affective episode (1–4) and with increasing cognitive disabilities during the course of illness (5–7). Mortality among patients with bipolar disorder or schizophrenia has consistently been found to be increased twoto threefold compared to that in the general population (8–11). Similarly, life expectancy has been reported to be decreased by 11 to 20 years for these patients compared to the general population (12–14). Whereas these figures may be correct for a typical patient with schizophrenia, they do not reflect the life expectancy for a typical patient with bipolar disorder. Calculations of life expectancy in these reports were based on data for patients having a first diagnosis below the age of 15 years (12–14). While the typical age at onset of schizophrenia may well be during the teenage
doi: 10.1111/bdi.12296 Key words: age – bipolar disorder – gender – life expectancy – mania – mortality Received 3 October 2014, revised 2 January 2015, revised and accepted for publication 23 January 2015 Corresponding author: Lars Vedel Kessing, MD, DMSc Psychiatric Center Copenhagen Department O, 6233 Blegdamsvej 9, 2100 CopenhagenDenmark Fax: 0045 38647077 E-mail: [email protected]
period, this is not the case for bipolar disorder. In European countries, the mean age at bipolar disorder onset (from population-based studies) has been estimated to be 25 years (15), and approximately 34% of individuals have an onset below the age of 19 years (16). Several studies have found a bimodal distribution of age at onset, with a large peak in early adult life (mid-20s) and a minor, but still substantial, peak in mid-life (mid40s) (17–21). Further, the onset of bipolar disorder below the age of 20 years is associated with a poor outcome, such as more frequent suicide attempts, comorbidity of alcohol abuse and drug addiction, and a rapid-cycling course (22–25) that may be associated with increased mortality. Consequently, calculations of life expectancy based on data for individuals at the age of 15 years may be misleading for patients with bipolar disorder in general. Other than the three studies of life
1
Kessing et al. expectancy cited above, which included samples from a secondary health care case register in London (12), Danish register-based data (13), and population-based register data from Denmark, Sweden, and Finland, no studies have been published on life expectancy that include data on bipolar disorder, (14) – and none of the aforementioned studies focused specifically on bipolar disorder. The aim of the present study was to calculate the remaining life expectancy of patients of different ages with a diagnosis of bipolar disorder, using similar data, design, and analyses as in the two previous studies, including Danish register-based data on life expectancy (13, 14). Methods
We used the same methods as used in the two previous studies, including Danish register-based data on life expectancy in bipolar disorder (13, 14). Thus, we used the same data, from the same nationwide register (however, updated to 2012, inclusive). Further, we used the same criteria for inclusion of patients and similar statistical analyses; however, we included additional analyses of remaining life expectancy based on patients with bipolar disorder at seven different ages (and not only for patients who were below the age of 15 when they were first diagnosed with bipolar disorder). The register
The Danish Psychiatric Central Research Register (DPCRR) is a nationwide registration of all psychiatric hospitalizations for the 5.4 million inhabitants of Denmark (26). From 1970 to 1993, the International Classification of Diseases (ICD)-8 was used and, up to 1995, only inpatient stays at psychiatric hospitals and wards were included. From 1 January 1995, the register also included information on patients in psychiatric ambulatory settings and community psychiatric centers. Since 1 January 1994, the ICD-10 has been in use in the register (27). General practitioners and private practicing psychiatrists do not report to the DPCRR. No private psychiatric inpatient hospitals or departments are in operation in Denmark; they are all are organized within public services, and report to the DPCRR. All inhabitants of Denmark have a unique person identification number [Civil Person Registration (CPR) number] that can be logically checked for errors, so that it can be established with certainty if a patient has had previous contact with any psychiatric service, irrespective of changes in name, for example.
2
The sample
The patient sample was defined as all individuals aged 1–110 years who had been seen in an outpatient (psychiatric ambulatory settings and community psychiatry centers) or inpatient (patients admitted during daytime or overnight to a psychiatric hospital) setting, with at least one main index diagnosis of mania/bipolar disorder (ICD-8: 296.19 or 296.39 and ICD-10: F30 or F31) during the study period from 1 April 1970 to 31 December 2012. Only patients who were alive in 2000 were included (so that updated mortality data were used). Data on the entire Danish general population of 5.4 million people were available from Statistics Denmark (28), including data on gender, age, and death. Statistical analysis
Life expectancies for patients with bipolar disorder were computed in the following way: patients with bipolar disorder were followed from their initial diagnosis until death or end of study (31 December 2012). From these life histories, age- and genderspecific mortality rates were calculated, thereby obtaining survival curves for male and female patients with bipolar disorder. The remaining life expectancies at ages x = 15, 25, 35 . . . 75 years were obtained as the area under the conditional survival curve, given survival until age x. The standard error of the remaining life expectancy was estimated as described by Andersen et al. (29). Life expectancies for the general Danish population were obtained from published Danish lifetables (28). Death was identified from 2000 to 2012 only to get updated mortalities (i.e., the cohort included only patients alive in 2000). The remaining life expectancy both for patients with bipolar disorder and the general population would clearly decrease with age simply as life expectancy decreases with age. To investigate the difference between the remaining life expectancy in patients with bipolar disorder and that for the general population according to age, we consequently calculated the ratio of life expectancy for patients with bipolar disorder and that for the general population at the different age categories. If this ratio decreased with age it would reflect that relatively more life-years are lost in bipolar disorder relative to the general population early in life compared to later in life, and consequently that patients with bipolar disorder start losing life-years earlier in life than the general population.
Life expectancy in bipolar disorder decreased with age. Further, the ratio of life expectancy for patients with bipolar disorder and that for the general population decreased steadily with age (Table 1: from 79.2% at the age of 15 years to 71.2% at the age of 75 years; Table 2: from 84.2% at the age of 15 years to 75.5% at the age of 75 years).
Results
During the study period from 1970 to 2012, we identified a total of 22,752 patients (men = 9,102 and women = 13,650) who were aged 1–110 years and had had contact with outpatient or inpatient services with at least one main diagnosis of mania/ bipolar disorder and who were alive in 2000. On average, the age at the index diagnosis of bipolar disorder was 46.3 years [standard deviation (SD) = 16.6] and the median age was 45.6 (quartiles: 33.3–57.8). Tables 1 and 2 present data on the remaining life expectancy for men and women with bipolar disorder compared to the general population. The remaining life expectancy for patients with bipolar disorder at the age of 15 years was based on a substantially lower number of person-years at risk than the remaining life expectancies for later values of age. For the typical male patient aged 25– 45 years at the time of diagnosis in the register, the remaining life expectancy was based on a larger number of person-years at risk and was decreased by 8.7–12.0 years compared to the general population. Similarly, for the typical women aged 25– 45 years, the remaining life expectancy was decreased by 8.3–10.6 years. As can be seen from Tables 1 and 2 and as illustrated in Figures 1 and 2, in general, the difference in remaining life expectancy between patients with bipolar disorder and the general population
Discussion
Life expectancy in bipolar disorder is decreased substantially, although less so than has been previously reported. For the typical male and female patient aged 25–45 years, the remaining life expectancy was decreased by 8.7–12.0 years and 8.3– 10.6 years, respectively. Regarding calculations based on data on patients at the age of 15 years, we found similar, although slightly increased, life expectancies as in previous Danish studies (13, 14). In the present study, using updated data to 2012, inclusive, the life expectancy for patients with a diagnosis of bipolar disorder at 15 years of age was decreased by 12.8 years for men and 10.4 years for women compared to life expectancies for the general population. These are slightly lower than the life expectancies found in previous Danish studies which included data up to 2006, inclusive (13.6 years for men and 12.1 years for women) (13, 14). This suggests that life expectancy
Table 1. Remaining life expectancy for men with bipolar disorder compared to men in the general population Bipolar disorder
General population
Age, years
Person-years at risk
Deaths
Life expectancy
15 25 35 45 55 65 75
1450.6 5443.5 10498.9 15929.9 18426.6 11151.3 5691.4
6 28 93 250 552 638 832
48.7 39.8 31.7 24.1 17.3 11.6 6.9
Difference in life expectancy
Ratio of life expectancies (%)
12.8 12.0 10.5 8.7 6.7 4.6 2.8
79.2 76.8 75.1 73.5 72.1 71.6 71.1
Life expectancy 61.5 51.8 42.2 32.8 24.0 16.2 9.7
Table 2. Remaining life expectancy for women with bipolar disorder compared to women in the general population Bipolar disorder
General population
Age, years
Person-years at risk
Deaths
Life expectancy
15 25 35 45 55 65 75
2129.6 7594.8 14361.5 22140.1 25753.1 19285.5 16144.8
0 26 67 242 514 779 1933
55.4 45.4 36.7 28.2 20.8 14.2 8.8
Difference in life expectancy
Ratio of life expectancies (%)
10.4 10.6 9.5 8.3 6.6 4.8 3
84.2 81.1 79.4 77.3 75.9 74.7 74.5
Life expectancy 65.8 56.0 46.2 36.5 27.4 19.0 11.8
3
Kessing et al. 80
Men
50 40 30 0
5
10
20
Life expectancy
60
70
General population Bipolar New born
0
5
10
15
20
25
30
35 40 Age
45
50
55
60
65
70
75
Fig. 1. Remaining life expectancy for men with bipolar disorder and men in the general population.
Women
50 40 0
5 10
20
30
Life expectancy
60
70
80
General population Bipolar New born
0
5
10
15
20
25
30
35 40 Age
45
50
55
60
65
70
75
Fig. 2. Remaining life expectancy for women with bipolar disorder and women in the general population.
has improved slightly over recent years (2006– 2012). In the study from a secondary health care case register in London, life expectancy at the age of 15 years for patients with bipolar disorder was decreased by 10.1 years for males and 11.2 years for females compared to the general population (12) – although life expectancy was reported at birth in this study, it was calculated based on data at the age of 15 years for patients. The calculations of life expectancy in the present study and previous Danish studies (13, 14), as well as the London study (12), were based on a population of patients who had had contact with psychi-
4
atric health care services (as inpatients or outpatients). It has previously been shown that the mean age at first contact with the mental health system is relatively high (30); in the present study, the mean age was 46.3 years (SD = 16.6) and the median age was 45.6 (quartiles: 33.3–57.8), in accordance with previous findings based on the case register (19) and with the London study [mean age 43 years for men and 45 years for women (12)]. Further, such patients who had had contact with a psychiatric hospital suffered from more severe types of disorder, and presumably also had more comorbid physical disorders, and may consequently have had a larger decrease in life expectancy, than patients treated for bipolar disorder by private psychiatrists. In addition, as illustrated by the results from the present study, life expectancy is even more decreased if it is based on data from patients at the age of 15 years. This finding is in accordance with a number of publications suggesting a poor outcome among patients with earlyonset bipolar disorder (22–25). A decrease in life expectancy in bipolar disorder compared to that in the general population may reflect a combination of: (i) a higher occurrence of risk factors, including lifestyle factors, for many chronic diseases, including cardiovascular diseases and some types of cancer; (ii) the iatrogenic effects of some psychotropic medication; (iii) higher rates of suicide, accidental, and violent death; and (iv) poorer access to physical healthcare and decreased attention toward and diagnosis of physical disorders (31). Interestingly, the ratio between the remaining life expectancy in bipolar disorder patients and that of the general population decreased with age (Tables 1 and 2), indicating that patients with bipolar disorder start losing life-years early after onset of the disorder – that is, during their 20s, 30s, and 40s – and that the loss of life-years in bipolar disorder is more pronounced early in life than later, compared to the general population. This may be partly due to the increased rate of suicide during the first years after onset of the illness (10, 32), but also to metabolic factors such as the chronic low-grade inflammation that may be particularly salient in the early stages of bipolar disorder (33–36), and to factors including increased oxidative stress [oxidative DNA and RNA damage (K. Munkholm, L.V. Kessing, M. Vinberg, unpublished report)] and altered levels of brainderived neurotropic factor (37). The long-term effects of lifestyle factors (smoking, alcohol, decreased exercise, drug abuse, etc.) associated with chronic diseases and the long-term effects of psychotropic drugs may also be risk factors for the
Life expectancy in bipolar disorder decreased life expectancy found in patients from 15 to 50 years of age. Accelerated aging has recently been proposed as a pathophysiological mechanism in bipolar disorder (38), and such a mechanism may in fact explain our finding that patients with bipolar disorder start losing life-years early during the course of illness. Clearly, this important area of research warrants further investigation.
previously reported. For the typical male and female patient aged 25–45 years, the remaining life expectancy was decreased by 12.0–8.7 years and 10.6–8.3 years, respectively. The ratio between the life expectancy in bipolar disorder and in the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood.
Advantages of the present study
Acknowledgements
The study population was ethnically and socially homogeneous, with a very low migration rate. The entire population (approximately 100%) of patients who had been treated in inpatient or outpatient psychiatric settings throughout the country was included. Psychiatric care is well developed in Denmark, so persons with mania or bipolar disorder can easily come into contact with psychiatric community centers or hospitals. Also, as psychiatric treatment in Denmark is free of charge, the study was not biased by socioeconomic differences.
Funding support was provided by an NARSAD Distinguished Investigator Grant 2012, Brain & Behavior Research Foundation, New York, NY, USA.
Limitations of the present study
It should be noted that the study included only patients who had passed the threshold for treatment in psychiatric outpatient settings (psychiatric ambulatory settings and community centers) or for psychiatric hospitalization. Patients who had been treated exclusively in private psychiatric practice or by general practitioners were not included in the study as these health facilities do not report to the DPCRR. It is likely that the inclusion of milder cases of bipolar disorder in the sample might have resulted in longer life expectancies. It should also be noted that the diagnosis of bipolar disorder in the ICD-10 includes both bipolar I and II disorders but does not discriminate between the two subtypes as ICD-10 defines bipolar disorder as a disorder with at least two mood episodes, of which at least one is a hypomanic or a manic episode. It should be stressed that the present study focused on the main diagnoses that were given for the illness that led to investigation and treatment. According to the ICD-10 diagnostic guidelines, a comorbid illness should be recorded as an auxiliary diagnosis only when the comorbid illness is independent of the primary illness. Auxiliary diagnoses are seldom recorded in Denmark. Conclusions
The remaining life expectancy in bipolar disorder is decreased substantially, although less so than
Author contributions LVK had full access to all of the data in the study and takes responsibility for its integrity and the accuracy of the data analysis. EV performed the statistical analyses in cooperation with PKA and LVK. LVK performed the initial data interpretation and drafted the first version of the manuscript. All authors have (i) made substantial contributions to the conception and design; (ii) been involved in revising the manuscript; (iii) given final approval of the version to be published; and (iv) agree to be accountable for all aspects of the work.
Disclosures In the last five years, LVK has been a consultant for BristolMyers Squibb, Eli Lilly & Co., Lundbeck, AstraZeneca, Servier, and Janssen-Cilag. EV and PKA do not have any financial disclosures or competing interests to report.
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