Mood Disorders Research Unit, Psychiatric Hospital in Aarhus, Risskov, Denmark
Department of Psychiatric Demography, Psychiatric Hospital in Aarhus, Risskov, Denmark
Correspondence: Professor Per Vestergaard, Department of Clinical Psychiatry, Aarhus University Hospital, Skovagervej 2, DK-8240 Risskov, Denmark. Tel. +45 8617 7777; Fax: +45 8617 9124
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ABSTRACT |
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Aim To estimate mortality rates from a cohort of patients with affective disorder commenced on lithium with an observation period of two years and a follow-up after 16 years.
Method The mortality rates of patients were compared with those of the general Danish population, standardised for age, gender and calendar time with respect to death from all causes, suicide and death from cardiovascular disease.
Results Forty of the study's 133 patients died during the 16-year observation period (11 from suicide). Mortality among patients commenced on lithium was twice that of the general population. The statistically significantly elevated mortality was due largely to an excess of suicides; mortality from all other causes was similar to the background populations. Thirty-two patients died after the first two years of observation and were included in the analysis of the association between death and treatment compliance. Suicide occurred more frequently among those patients not complying with treatment.
Conclusion Mortality, especially suicide, was significantly increased in unselected patients with affective disorder commenced on lithium relative to the general population.
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INTRODUCTION |
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METHOD |
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The hospital's criterion for starting lithium prophylaxis in both unipolar and bipolar patients was the occurrence of 2-3 affective disorder episodes in a five-year period.
During their index admission and before the start of prophylactic lithium treatment the patients were examined and interviewed, and laboratory, clinical and socio-medical variables were recorded (Maarbjerg et al, 1988; Aagaard et al, 1988). Diagnosis of the index episode was established according to the criteria of Feighner et al (1972). An overall classification of the disease according to polarity was established from the description of the index episode, from notes concerning past episodes and from the quality of the intervals between episodes. The overall diagnostic classification comprised three subgroups: a unipolar depressed group where at least two depressive episodes and no manic or hypomanic episodes had occurred; a bipolar group where at least one manic episode had occurred; and a group of patients described as atypical because the index episode, although affective, did not fulfil the Feighner criteria or because the course of the illness was atypical.
After a 16-year observation period, date and cause of death for each patient were obtained from the National Registration Office, and death certificates from the Danish Central Death Register were examined. Compliance with lithium treatment during the first two years of prophylactic treatment was chosen as a key predictor variable for the analysis of mortality figures. Compliance was understood as the uninterrupted intake of lithium tablets as prescribed and adherence to the lithium treatment programme.
The two-year compliance period was chosen because this is the period offered for follow-up of patients with affective disorder in the hospital lithium clinic. After two years the patients are advised to continue lithium treatment with their general practitioner.
Statistical analysis
The mortality rates of patients receiving lithium were compared with those
of the general Danish population, standardised for age, gender and calendar
time (in four periods: 1981-85, 1986-89, 1990-93, 1994-97), with respect to
death from all causes, from suicide (ICD-8 E950-E959, ICD-10 X60-X84, Y87.0)
and from cardiovascular disease (ICD-8 390-458, ICD-10 100-199) (World Health
Organization, 1974,
1986). The standardised
mortality ratios (SMRs) were supplied with exact 95% confidence limits
(Breslow & Day, 1987). On
the basis of the first two years' observation, the 125 patients who survived
were grouped as either compliant or non-compliant with lithium treatment and
the suicide SMRs of these groups were compared as described in Breslow &
Day (1987).
Comparison of the time between two-year follow-up and death from any cause between compliant and non-compliant patients was performed by using Cox regression analysis, with adjustments made for age, gender, diagnosis at the start of the study and number of previous episodes. On the basis of Kaplan-Meier plots we also made a crude comparison of time to suicide between compliant and non-compliant patients, using the non-parametric log rank test (Klein & Moeschberger, 1997).
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RESULTS |
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Suicide
An autopsy was performed in 11 of the 40 cases of death. The nature of the
suicides as they were described on the death certificates is shown in
Table 2, together with the
available information about the patients' pattern of lithium intake until the
time of their suicides.
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Conservative estimates were applied when choices were made between suicide and natural death. No cases of other unnatural death on the death certificate were assigned to the suicides group; neither did the authors suspect that such cases were misclassified by the forensic authorities.
Standardised mortality ratios
Table 3 shows that the
standardised mortality ratio among patients who started lithium treatment was
elevated for death from all causes. This risk increase, however, was mainly
confined to a statistically significantly increased risk for suicide
(SMR=20.5). The mortality from all causes other than suicide was slightly
increased (SMR - 1.9), and statistically significant only for female patients.
The risk of death from cardiovascular disease did not differ from that in the
general population.
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Seventy-seven (62%) of the 125 patients who survived the first two years of observation were compliant with lithium treatment.
The intervals between two-year follow-up and death from any cause did not differ between compliant and non-compliant patients when compared by Cox regression (risk ratio 0.81, P=0.56). This result did not change much when adjusting for age, gender, diagnosis at study start and the number of previous episodes (risk ratio 0.88, P=0.74).
Suicide and patient compliance
Table 4 shows that eight
cases of suicide were recorded among the 125 patients who survived the
two-year observation period. One of these suicides had bipolar disorder (1.8%
of all bipolar disorder patients), another had unipolar disorder (4.4%), and
the remaining six (13.3%) were diagnosed as having atypical affective
disorders. The suicide risk was almost four times higher among those who were
non-compliant with treatment. This finding was only marginally significant
(P=0.06), presumably because of the limited sample size. However,
estimates of suicide SMR were considerably greater than unity among both
compliant (SMR 8.1) and non-compliant patients (SMR 30.7). Kaplan-Meier
estimates of time to suicide for the compliant and non-compliant groups are
shown in Fig. 1; a comparison
of time to suicide using the log rank test showed a value of P of
0.06.
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DISCUSSION |
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Suicide occurred more frequently among non-compliant than among compliant patients, although the difference reached only marginal statistical significance.
Strengths and limitations of study design
In this study all consecutively admitted patients who started lithium
treatment were followed up after 16 years and analysed according to the
intent-to-treat principle. The strength of this design is its ability to
examine mortality in patients with affective disorder under so-called
naturalistic conditions, where different doctors inside and outside hospital
participate in the treatment with various degrees of patient compliance,
co-medications and changes in the patients' life circumstances. The patients
are truly representative of the population of affective disorder patients in a
geographically well-defined catchment area with only one psychiatric hospital
(to which all patients were admitted) and a fixed number of general
practitioners available for their subsequent treatment.
A limitation of the design is the diagnostic heterogeneity of patients - they included both patients with unipolar and bipolar disorder and a considerable number of patients with affective disorder with atypical features (among whom the majority of recorded suicides occurred). This latter group included patients with schizoaffective disorder, bipolar II disorder, mixed episodes and rapid cycling.
Another limitation was the lack of knowledge of how many patients actually continued lithium treatment after the first-two years of observation. Only for 48 of the 93 patients who survived all 16 years of follow-up was adequate information available from case records and from personal and telephone interviews. Among these 48 patients, eight (15%) continued with lithium uninterrupted for the entire follow-up period, while approximately one half continued with lithium for more than nine years.
For the patients who died, information about lithium treatment is scarce, but it is estimated from case notes that 20-30% were taking it at the time of death. Among the 11 cases of suicide (Table 2), four patients were assumed to be taking lithium at the time of death.
Interpretation of results
The difference in suicide figures between lithium compliant and
non-compliant patients could reflect a suicide prophylactic effect of lithium
treatment. The association between lithium non-compliance and suicide could,
however, also reflect the disposition in a subgroup of affective disorder
patients that demonstrate concomitantly non-compliance, suicidal behaviour and
misuse of drugs and alcohol without any clear indication of the direction of
causation. The association between misuse and non-compliance with lithium
treatment has been observed in previous investigations
(Vestergaard et al,
1998).
The mortality figures illustrate the (lack of) ability of the health care system to protect patients with affective disorder effectively from premature death once prophylactic lithium treatment has been decided upon and initiated and compliance behaviour exercised for two years. The two-year period immediately after the start of prophylactic lithium treatment is a period in which non-compliance is highly expressed. Approximately 40% of the patients discontinued prophylactic treatment in this period (Aagaard & Vestergaard, 1990). It is estimated that after this period only 5-10% of the patients discontinue their treatment each year (Vestergaard & Schou, 1988).
The results in context
Our study supports the results of previous investigations
(Norton & Whalley, 1984; Nilsson, 1995) in which
mortality in unselected lithium-treated patient groups under so-called
naturalistic conditions was found to be significantly elevated compared with
the general population. Suicide was the main reason for the elevated mortality
figures and was closely associated with lithium non-compliance. Our results
may also be compatible with figures from certain lithium clinics in which
selected and possibly well-motivated and compliant patients were followed
closely (Coppen et al,
1991;
Müller-Oerlinghausen
et al, 1992; Lenz
et al, 1994). Mortality among these patients was found
not to be different from that of the general population. However, our study
highlights the possibility that the results from these studies may give an
unduly optimistic outlook regarding the mortality-reducing effect of the
lithium treatment modality in daily clinical routine. These results may merely
reflect the preferential admission of patients with good prognoses to
specialised facilities where less motivated, non-compliant and non-responding
patients are not admitted or gradually expelled.
Implications for treatment
Mortality is increased for most or all major psychiatric disorders,
including affective disorders (Hansen
et al, 1997). This was so before the era of modern
psychopharmacology and is apparently still the case in Western societies,
where a considerable part of the population receives treatment with
psychoactive drugs. Lithium in conjunction with other psychotropic drugs,
psychotherapy and psychosocial measures may be able to reduce mortality in
some patients with affective disorder. It remains to be elucidated, for
patients who are not compliant with lithium treatment and non-responding
affective disorder patients, to what extent more precise diagnostic
sub-grouping, new treatments with anticonvulsants and atypical antipsychotics
and the establishment of lithium clinics or mood disorder clinics will enhance
compliance and reduce mortality.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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Aagaard, J., Vestergaard, P. (1990) Predictors of outcome in prophylactic lithium treatment: a two-year prospective study. Journal of Affective Disorders, 18, 259-266.[CrossRef][Medline]
Breslow, N. E. & Day, N. E. (1987) Statistical Methods in Cancer Research. The Design and Analysis of Cohort Studies. Lyon: IARC Science Publishers.
Coppen, A., Standish-Barry, H., Bailey, J., et al (1991) Does lithium reduce the mortality of recurrent mood disorders? Journal of Affective Disorders, 23, 1-7.[CrossRef][Medline]
Feighner, J. P., Robins, E., Guze, B., et al (1972) Diagnostic criteria for use in psychiatric research. Archives of General Psychiatry, 26, 57-63.[CrossRef][Medline]
Goodwin, F. K. & Jamison, K. R. (1990) Manic-Depressive Illness. New York: Oxford University Press.
Hansen, V., Arnesen, E. & Jacobsen, B. K. (1997) Total mortality in people admitted to a psychiatric hospital. British Journal of Psychiatry, 170, 186-190.[Abstract]
Klein, J. P. & Moeschberger, M. L. (1997) Survival Analysis. Techniques for Censored and Truncated Data. New York: Springer-Verlag.
Lenz, G., Ahrens, B., Denk, E., et al (1994) In Ziele und Ergehnisse der medikamentösen Prophylaxe affektiver Psychosen (eds B. Müller-Oerlinghausen & B. Berghöfer), pp. 49-52. Stuttgart: Thieme.
Maarbjerg, K., Aagaard, J. & Vestergaard, P. (1988) Adherence to lithium prophylaxis: I. Clinical predictors and patients' reasons of non-adherence. Pharmacopsychiatry, 21, 121-125.[Medline]
Müller-Oerlinghausen, B., Ahrens, B., Grof, E., et al (1992) The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness. Acta Psychiatrica Scandinavica, 86, 218-222.[Medline]
Nilsson, A. (1995) Mortality in recurrent mood disorders during periods on and off lithium. A complete population study in 362 patients. Pharmacopsychiatry, 28, 8-13.[Medline]
Norton, B. & Whalley, L. J. (1984) Mortality of a lithium-treated population. British Journal of Psychiatry, 145, 277-282.[Abstract]
Schou, M. (1998) The effect of prophylactic lithium treatment on mortality and suicidal behavior: a review for clinicians. Journal of Affective Disorders, 50, 253-259.[CrossRef][Medline]
Vestergaard, P. & Schou, M. (1988) Prospective studies on a lithium cohort. I. General features. Acta Psychiatrica Scandinavica, 78, 421-426.[Medline]
Vestergaard, P. & Aagaard, J. (1991) Five-year mortality in lithium-treated manic-depressive patients. Journal of Affective Disorders, 21, 33-38.[CrossRef][Medline]
Vestergaard, P., Licht, R. W., Brodersen, A., et al (1998) Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels. Acta Psychiatrica Scandinavica, 98, 310-315.[Medline]
World Health Organization (1974) The Eighth Revision of the International Classification of Diseases and Related Health Problems (ICD-8). Geneva: WHO.
World Health Organization (1986) The Tenth Revision of the International Classification of Diseases and Related Health Problems (ICD-10). Geneva: WHO.
Received for publication April 23, 1999. Revision received July 29, 1999. Accepted for publication August 17, 1999.