 |
 |
|
|
|
Affective disorders are characterized, first, by a high risk of recurrence and, second, by mortality rates that are 2 to 3 times higher than rates in the general population (1–4). Excess mortality among those with affective disorders is attributable primarily to suicide-induced mortality, for which rates are possibly 30 to 70 times higher (5)—and 100% higher in patients with a history of suicide attempts (6,7)—but it is also attributable to cardiovascular excess mortality. According to Goodwin and Jamison, who analyzed 21 existing studies (n = 6000 patients) to investigate the association of suicide and affective disorders, 30% of patients with affective disorders died from suicide (8). Further, a long-term study from Iceland reports that 52% of patients examined ended their lives (9). Guze and Robins’ often-quoted metaanalysis calculated a lifetime suicide risk of 15% for individuals with affective disorders (10), whereas Goodwin and Jamison reported an overall risk of 19%, based on more recent literature (11). When samples of patients with milder forms of affective disorders were analyzed—for example, those who were never hospitalized—the lifetime suicide rates appeared to be much lower (12,13). In a detailed metaanalysis, Harris and Barraclough calculated the relative contribution of various mental illnesses to the occurrence of suicide (14). The suicide-related standardized mortality rate (SMR; 15) was 21.24 in patients with major depression, 11.73 in those with bipolar disorder (BD), and 9.84 in those with schizophrenia. Although some studies found a somewhat lower suicide rate in BD patients, compared with unipolar disorder patients (for example, 16,17), others found higher rates in BD patients (18–20). Against this background, therefore, effective prophylaxis is of utmost importance for patients with affective disorders, and suicide prevention must be regarded as a decisive endpoint for assessing the outcome of long-term treatment of affective disorders. As we outline below, strong evidence has accumulated during the last decade that lithium prophylaxis can prevent suicidal acts and reduce the excess mortality of patients with affective disorders. It is therefore provoking and irritating to observe that a great many—perhaps most—patients with unipolar disorder or BD are not maintained on a proper, state-of-the-art prophylactic drug regimen (21). It has been estimated that up to 50% of these patients, including those who suffer multiple relapses and may therefore bear an increased suicide risk, do not receive prophylactic treatment (22). The American Psychiatric Association guidelines for the treatment of depressive disorder do not even mention lithium as a prophylactic agent (23). Assuming a population prevalence of 1% for BDs, at least 820 000 patients in Germany need prophylactic treatment. Lithium salts could probably be considered as first-line treatment for about one-half of them. Yet, according to a reasonable estimate for the year 2001, about 50 000 patients in Germany received lithium medication within the National Health Scheme (24). The question, then, is whether this discrepancy does not reflect some sort of malpractice. The Effect of Long-Term Lithium Medication on Mortality and Suicide Rates of Patients With Affective DisordersWhether uninterrupted medication with lithium salts can prevent suicide and lower mortality, thereby improving the course of manic depressive disorder, of recurrent depression, or even of schizoaffective disorders, is an intriguing question that was given little attention until the 1980s. Barraclough was perhaps one of the first investigators to postulate an association between long-term lithium medication and suicide prevention (25). He analyzed the charts of 100 suicide victims: 64 victims had suffered a major depression. Of these, 44 had episodic depression. Barraclough concluded that about 20% of the suicides could have been prevented by adequate lithium medication. Kline reported on 3 cases in which lithium medication as crisis intervention impressively changed suicidal thoughts or suicidal behaviour (26). Müller-Oerlinghausen and others published the first systematic retrospective analysis to demonstrate a highly significant reduction in suicide attempts in a sample of high-risk patients receiving long-term lithium treatment (27). The authors emphasized that suicides and suicide attempts occurred almost exclusively in a group of 13 patients who had taken lithium irregularly or had stopped the medication.
Felber and Kyber analyzed suicide attempts during accumulated periods on and off lithium: 90% of suicide attempts occurred in the off-lithium period (28). Coppen and others (29) and the International Group for the Study of Lithium-Treated Patients (IGSLI; 30,31) studied mortality among patients with affective disorders during long-term lithium treatment. These studies demonstrated that, during adequate lithium medication, the standardized mortality in this patient population is normalized down to the level in the general population. Coppen reviewed studies existing in the mid-1990s on suicide rates in patients both on and off long-term lithium treatment (32) (Table 1). According to Coppen, adequate lithium medication reduces the suicide-related mortality by 82%. Studies investigating potential effects of a therapeutic intervention on suicide rates display a common methodological problem: estimating how many deaths are to be expected in a matched, nontreated patient sample. Since it is not ethically possible to treat a control group of patients suffering from affective disorders with long-term placebo, the IGSLI used a reference group from the general population in its studies. This makes it possible to calculate the standardized mortality rate either for any causes of death or for specific causes such as cardiovascular disease, accident, and suicide. The IGSLI StudiesThe IGSLI studies began after the lithium research group in Berlin observed that suicidal behaviour was clearly decreased or even abolished in lithium-treated patients, including those not showing a satisfactory episode-preventive effect (27). The IGSLI main study evaluated detailed and well-documented data on the illness course of 827 patients from lithium clinics in Austria, Canada, Denmark, and Germany who had been treated with lithium for at least 6 months (30,15). These patients had the following diagnoses: 55% BD, 25% unipolar disorder, 2% unipolar-manic depression, 16% schizoaffective disorder, and 2% “other.” At the onset of lithium prophylaxis, patients were aged 41 years, on average. The mean duration of lithium treatment was 81 months (range, 6 to 21 years), equalling 5600 patient years. As can be seen from Table 2, the ratio of 44 observed to 38 expected deaths is not statistically different from 1.0, which is the mortality rate in the general population. Thus, the expected 2 to 3 times higher excess mortality in patients with affective disorders (see above) does not exist in this lithium-treated patient sample.
Although the suicide-related SMR is still higher than the general population rate (Table 2; 15) it can be clearly shown that it is definitely lower in all diagnostic groups, compared with that expected in untreated patient samples. Interestingly, the cardiovascular SMR also appeared to be normalized in the lithium-treated patients. It could be argued that patients who accept a lithium prophylaxis generally benefit from a better prognosis. If so, the specific patient selection would be primarily responsible for the normalization of the SMR. (Conversely, it could be assumed that patients for whom lithium prophylaxis is indicated suffer from a higher suicide risk, owing to the higher morbidity.) To study this issue, Müller-Oerlinghausen and others further analyzed 270 German and Danish patients from the original IGSLI sample, comparing the initial SMR with the SMR after treatment of more than 1 year (33). During the first year, overall mortality was 2 times higher, and suicide-related mortality 17 times higher, compared with the general population. However, the SMR normalized after the first year of treatment, suggesting that patients for whom lithium prophylaxis is indicated are in fact patients with a high risk of suicide. Studies Supporting the IGSLI Findings: the Effect of DiscontinuationCoppen and others presented one of the first systematic studies showing reduced mortality, mainly in patients with uni-polar disorders treated with lithium over particularly long periods (29). Norton and Whalley were not able to demonstrate reduced mortality in cohorts of lithium-treated patients (34), nor were Vestergaard and Aagaard (35). In both studies, however, lithium treatment duration was on average shorter than in the IGSLI study, and treatment compliance may not have been sufficiently controlled. For example, in Vestergaard and Aagaard’s study, one-third of the deaths took place after patients had discontinued lithium (35). Nilsson’s study is noteworthy: investigating in a different setting (specifically, an open field with no specialized lithium clinics, as in most IGSLI centres), this author did not observe a full normalization of the SMR (36). However, as observed in studies reviewed by Schou (37), the SMR rose to the expected level after patients with untreated affective disorders discontinued lithium (Table 3). Studies in a Sardinian patient sample (38) and a recent Swedish study (39) further support the evidence for lithium’s antisuicidal effect. The Swedish study is particularly interesting because it suggests that the suicide- preventing effect may be more marked among patients in specialized lithium clinics than in patients treated with routine medical care. A metaanalysis of about 17 000 patients with BD demonstrated that patients treated without lithium had an 8.6 times higher mortality from suicide, compared with patients receiving long-term lithium treatment (40).
Methodological Problems in Calculating Mortality RatesAlthough most existing studies suggest that lithium prophylaxis reduces suicide and mortality, a few apparently contradictory findings also exist (see above). One reason for this discrepancy may be differences in the therapeutic setting and in treatment duration. Another reason may be different ways of computing mortality rates. To study this issue, Wolf and others enlarged the database of the IGSLI study by adding mortality data from 2 associated centres and reanalyzed the data, using 3 different mathematical approaches (41). We studied the outcome of 3 different approaches: 1. the “cumulative approach,” used by most authors, in which the accumulation of the individual treatment duration is used and SMR calculated as the total number of observed deaths divided by the total number of expected deaths; 2. the “cumulative year-by-year approach,” in which SMR is calculated for successively accumulated treatment years (that is, patients with 6 to 11 months of treatment, patients with 6 to 20 years of treatment, patients with 6 to 35 years of treatment, and so on); 3. the “year-by-year approach,” in which SMR is calculated for all patients in the first year of treatment and then calculated for all patients in the second year of treatment, leaving out the data of the patients with fewer than 2 years of treatment, and so on. Using the cumulative approach, one has to make the unproven assumption that mortality remains stable throughout any treatment period. However, clinical experience indicates that the prophylactic effect of lithium is not fully developed until after at least 6 months of treatment; that is, the effect’s onset is gradual, and it seems possible that any mortality-lowering effect of lithium is also time-dependent. Unfortunately, the cumulative approach blurs possible effects of treatment duration on mortality. Step 2 of Wolf and others’ analysis reveals that the cumulative year-by-year-approach involves a remarkable distortion originating from the data accumulation process: the number of deaths observed in the first year is counted again for the following year, and so on, artificially increasing the number (41). This effect was not statistically significant in the enlarged IGSLI sample, because of the large number of cases and the long observation periods. However, if the IGSLI sample had accidentally consisted of patients with fewer than 19 years of treatment, this mathematical procedure would have shown no reduction in mortality during prophylactic treatment. Thus, the cumulative approach can lead to disastrous misinterpretation of the data. Another problem with the cumulative strategy is its neglect of a basic rule of probability theory: only probabilities of independent events may be added up. Being alive in later years of treatment is dependent on being alive in earlier years of treatment. In the Norton and Whalley (34) and Vestergaard and Aagaard (35) samples, the observation periods were too small to neutralize the distorting effect of the applied cumulative approach. Therefore, the year-by-year approach is obviously the scientifically sounder method of calculation, demonstrating clearly the normalized mortality of lithium-treated patients during practically all treatment periods. Survival analysis would be a reasonable and probably more appropriate method. However, this approach is hardly feasible because ethical considerations exclude recruiting an untreated control group of patients with a clear indication for lithium prophylaxis. For this reason, some uncertainties about studies on the mortality of patients with manic depression cannot be overcome. Antisuicidal Effects of Agents Other Than Lithium?Although it has been claimed that the reduced suicide rates recently observed in various European countries may be attributable to the increased use of modern antidepressive agents (42,43), evidence does not exist that long-term anti- depressant treatment in affective disorders lowers the lifetime suicide risk (44). A preliminary report by Angst and others pointed to a potential mortality-reducing effect of anti- depressant treatment; however, many questions regarding details of treatment conditions remain unanswered in this paper (19). A post hoc analysis from a controlled study comparing lithium and carbamazepine in BD and schizoaffective disorder over 2.5 years provides strong evidence for the antisuicidal effect of lithium, contrasted with carbamazepine: in the carbamazepine group, 4 completed suicides and 5 suicidal acts occurred. Conversely, no suicidal act was observed in the lithium group (45–47). No comparable data exist for other anticonvulsants used as mood stabilizers or for atypical neuroleptics. The only exception is clozapine, which has shown convincing evidence of an antisuicidal effect in schizophrenia patients (48). Although Baldessarini and others postulated that the reduction of the suicide risk by lithium prophylaxis is primarily caused by its depression-preventing effect (49), other authors point to the serotonin-agonistic and antiaggressive effects of lithium. For example, Ahrens and Müller-Oerlinghausen recently reanalyzed data from the IGSLI study and suggested that lithium’s antisuicidal property may be rather specific; that is, it is not shared by other mood stabilizers and does not depend fully on the prevention of depressive episodes (50). The intriguing issue of a potential specificity of the lithium effect will be clarified in an ongoing double-blind, placebo-controlled study on the antisuicidal effect of lithium in patients with a history of suicide attempts but without formal indication for long-term lithium prophylaxis. This study is being conducted within the German Network for Depression and supported by the Federal Ministry of Research and Technology.
How Many Suicides in the Population Can Be Prevented by Lithium Prophylaxis?Based on data collected within the Epidemiological Catchment Area Study (ECA; 51) and the epidemiological data of Weeke (41), as well as on the assumption that approximately 60% of all suicides in the population are committed by patients with affective disorders, Ahrens and Müller-Oerlinghausen constructed a model for calculating deaths and suicides to be expected in the general population and in patients with affective disorders (50). Table 4 shows that, for a sample of 827 subjects in the general population (matched with patients from the IGSLI sample) 1.34 suicides should be expected; in a corresponding sample of patients with affective disorders, 31 to 37 (average, 34) suicides were predicted. In the lithium-treated IGSLI sample, 7 suicides were observed. In other words, 27 predicted suicides did not occur. Based on this model, we can conclude that 5 suicides yearly per 1000 treated patients can be prevented. This would result in approximately 250 suicides prevented yearly in Germany. The IGSLI data also show that the average age of patients who committed suicide was 44 years. Thus, without these suicides, gross national productivity in Germany would gain 3060 working years before age 65 years. This positive effect adds to the net gain of about 110 million EURO yearly in Germany resulting from lithium prophylaxis within the National Health Scheme, although, as outlined above, the number of lithium-treated patients in this country appears to be very low (52). Figure 1 Algorithm for prophylaxis in unipolar depressive disorders (52). Integrating Mortality Findings Into Operationalized Treatment DecisionsIn the treatment of affective disorders, the devastating course of illness and the high mortality demand an effective, safe, and evidence-based strategy. In this context, psychiatrists may listen to a comment on existing mortality studies made by Mogens Schou in 1998: Owing to the special problems of mortality research this observation cannot prove definitely that lithium treatment has a mortality-lowering, antisuicidal effect. But they are compatible with such an assumption. As scientists we concede that such an action of lithium remains a possibility. As clinicians we cannot afford to disregard that possibility. It must be the duty of psychiatrists to keep this in mind when they choose prophylactic treatment for patients with severe depressions or suicidal thoughts or suicide attempts in the past (37). Consequently, our research group has developed suitable and rational algorithms for selecting an appropriate prophylactic strategy to treat either unipolar disorder or BD (53). Figure 1 offers an example. References1. Lundquist G. Prognosis and cause of manic depressive psychosis. Acta Psychiatr Neurol Scand 1945;35:1–96. 2. Kay DWK, Petterson U. Mortality. In: Petterson U, editor. Manic depressive illness: a clinical, social and genetic study. Acta Psychiatr Scand 1977;(Suppl 269):55–60. 3. Tsuang MT, Woolson RF. Excess mortality in schizophrenia and affective disorders. Do suicides and accidental deaths solely account for this excess? Arch Gen Psychiatry 1978;35:1181–5. 4. Weeke A. Causes of death in manic depressives. In: Schou M, Strömgren E, editors. Origin, prevention and treatment of affective disorders. London: Academic Press; 1979. p 289–99. 5. Hagnell O, Lanke J, Rorsman B. Suicide rates in the Lundby study: mental illness as a risk factor for suicide. Neuropsychobiology 1981;7:248–53. 6. Tuckman J, Youngman W. Identifying suicide with groups among attempted suicide. Public Health Rep 1963;78:763–6. 7. Motto I. Suicide attempts: a longitudinal view. Arch Gen Psychiatry 1965;13:516–20. 8. Goodwin FK, Jamison KR, editors. Manic depressive illness. Oxford: Oxford University Press; 1983. 9. Helgason T. Epidemiology of mental disorders in Iceland. Acta Psychiatr Scand 1964;40 (Suppl 173):1–258. 10. Guze SB, Robins E. Suicide in primary affective disorders. Br J Psychiatry 1970;117:437–8. 11. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press; 1990. 12. Blair-West GW, Cantor CH, Mellsop GW, Eyeson-Annan ML. Lifetime suicide risk in major depression: sex and age determinants. J Affect Disord 1999;55:171–8. 13. O’Leary D, Paykel E, Todd C, Vardulaki K. Suicide in primary affective disorders revisited: A systematic review by treatment era. J Clin Psychiatry 2001;62:804–11. 14. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998;173:11–53 15. Ahrens B, Müller-Oerlinghausen B, Schou M, Wolf T, Alda M, Grof E, and others. Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium-prophylaxis. J Affect Disord 1995;33:67–75. 16. Newman S, Bland R. Suicide risk varies by subtype of affective disorder. Acta Psychiatr Scand 1991;83:420–6. 17. Ösby U, Brandt L, Correia N, Ekbom A, Sparen P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001;58:844–50. 18. Lester D. Suicidal behavior in bipolar and unipolar affective disorders: a meta-analysis. J Affect Disord 1993;27:117–21. 19. Angst J, Sellaro R, Angst F. Long-term outcome and mortality of treated vs untreated bipolar and depressed patients: a preliminary report. Int J Psychiatr Clin Pract 1998;2:115–9. 20. Bottlender R, Jager M, Strauss A, Möller HJ. Suicidality in bipolar compared to unipolar depressed inpatients. Eur Arch Psychiatry Clin Neurosci 2000;250:257–61. 21. Fieve RR. Lithium therapy at the millennium: a revolutionary drug used for 50 years faces competing options and possible demise. Bipolar Disord 1999;1:67–70. 22. Solomon DA, Keller MB, Leon AC, Müller TI, Lavori PW, Shea T, and others. Multiple recurrences of major depressive disorder. Am J Psychiatry 2000;157:229–33. 23. APA. Practice guidelines for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000;157(Suppl 4):1–45. 24. Müller-Oerlinghausen B, Lohse MJ. Psychopharmaka. In: Schwabe U, Paffrath D, editors. Arzneiverordnungs-Report 2002. Berlin, Heidelberg, New York: Springer-Verlag; 2003. 25. Barraclough B. Suicide prevention, recurrent affective disorder and lithium. Br J Psychiatry 1972;121:391–2. 26. Kline NA Lithium and crisis intervention; damping affective overload. Psychosomatics 1978;19:401–5. 27. Müller-Oerlinghausen B, Müser-Causemann B, Volk J Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. J Affect Disord 1992;25:261–70. 28. Felber W, Kyber A. Suizide und Parasuizide während und außerhalb einer Lithiumprophylaxe. In: Müller-Oerlinghausen B, Berghöfer A, editors. Ziele und Ergebnisse der medikamentösen Prophylaxe affektiver Psychosen. Stuttgart, New York: Georg Thieme Verlag; 1994. p 53–9. 29. Coppen A, Standish-Barry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the mortality of recurrent mood disorders? J Affect Disord 1991;23:1–7. 30. Müller-Oerlinghausen B, Ahrens B, Grof E, Grof P, Lenz G, Schou M, and others. The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizo-affective illness. Acta Psychiatr Scand 1992;86:218–22. 31. Ahrens B, Müller-Oerlinghausen B. Die antisuizidale und mortalitätssenkende Wirkung von Lithium. In: Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Berlin, Heidelberg, New York: Springer-Verlag; 1997. p 262–77. 32. Coppen A. Depression as a lethal disease: prevention strategies. J Clin Psychiatry 1994;55 (Suppl 4):37–45. 33. Müller-Oerlinghausen B, Wolf T, Ahrens B, Schou M, Grof E, Grof P, and others. Mortality during initial and during later lithium treatment: a collaborative study by IGSLI. Acta Psychiatr Scand 1994;90:295–7. 34. Norton B, Whalley LJ. Mortality of a lithium-treated population. Br J Psychiatry 1984;145:277–82. 35. Vestergaard P, Aagaard J. Five-year mortality in lithium-treated manic-depressive patients. J Affect Disord 1991;21:33–8. 36. Nilsson A. Mortality in recurrent mood disorders during periods on and off lithium. A complete population study in 362 patients. Pharmacopsychiatry 1995;28:8–13. 37. Schou M. The effect of prophylactic lithium treatment on mortality and suicidal behavior: a review for clinicians. J Affect Disord 1998;50:253–9. 38. Tondo L, Baldessarini RJ, Floris G, Silvetti F, Rudas N.Lithium maintenance treatment reduces risk of suicidal behavior in bipolar disorder patients. In: Gallicchio VS, Birch NJ, editors. Lithium: biochemical and clinical advances. Cheshire (CT): Weidner Publishing Group; 1996. p 161–71. 39. Kallner G, Lindelius R, Petterson U, Stockman O, Tham A. Mortality in 497 patients with affective disorders attending a lithium clinic of after having left it. Pharmacopsychiatry 2000;33:8–13. 40. Tondo L, Jamison KR, Baldessarini RJ. Effect of lithium maintenance on suicidal behavior in major mood disorders. In: Stoff DM, Mann JJ, editors. The neurobiology of suicide: from the bench to the clinic. Ann NY Acad Sci 1997;836:339–51. 41. Wolf T, Müller-Oerlinghausen B, Ahrens B, Grof P, Schou M, Felber W, and others. How to interpret findings on mortality of long-term lithium treated manic-depressive patients? Critique of different methodological approaches. J Affect Disord 1996;39:127–32. 42. Isacsson G, Holmgren P, Druid H, Bergman U. The utilization of antidepressants a key issue in the prevention of suicide. An analysis of 5,281 suicides in Sweden 1992–94. Acta Psychiatr Scand 1997;96:94–100 43. Isacsson G. Frequency of suicides reduced with 25 percent: probably by the increased use of antidepressive agents. Lakartidningen 2000;97:1644–50. 44. Müller-Oerlinghausen B, Berghöfer A. Antidepressants and suicidal risk. J Clin Psychiatry 1999;60 (Suppl 2):94–9. 45. Thies-Flechtner K, Müller-Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Pharmacopsychiatry 1996;29:103–7. 46. Greil W, Ludwig-Mayerhofer W, Erazo N, Schöchlin C, Schmidt S, Engel RR, and others. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders a randomised study. J Aff Diord 1997;43:151–61. 47. Goodwin FK. Anticonvulsant therapy and suicide in affective disorders. J Clin Psychiatry 1999;60 (Suppl 2):89–93. 48. Meltzer HY. Suicide and schizophrenia: clozapine and the InterSePT study. International Clozaril/Leponex Suicide Prevention Trial. J Clin Psychiatry 1999;60(Suppl 12):47–50. 49. Baldessarini RJ, Tondo L, Hennen J. Reduced suicide risk during long-term treatment with lithium. Ann NY Acad Sci 2001;932:24–43. 50. Ahrens B, Müller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001;34:132–6. 51. Weissman MM, Leaf PJ, Tischler GL, Blazer DG, Karno M, Bruce ML, Florio LP. Affective disorders iin five United States communities. Psychol Med 1988;18:141–53. 52. Lehmann K, Ahrens B, Müller-Oerlinghausen B. Pharmakoökonomie der Lithiumprophylaxe. In: Müller-Oerlinghausen B, Greil W, Berghöfer A, editors. Die Lithiumtherapie. Berlin, Heidelberg, New York: Springer-Verlag; 1997. p 262–77. 53. Berghöfer A, Bauer M, Müller-Oerlinghausen B. Antisuicidal effect of lithium as a criterion for the selection of appropriate long-term medication in bipolar patients. In: Kaschka WP, editor. Perspectives in affective disorders. Advanced Biological Psychiatry. Vol. 21. Basel: Karger; 2002. p 1–9. 54. Goldacre M, Seagroan V, Hawton K.. Suicide after discharge from psychiatric inpatients care. Lancet 1993;342:283–6. 55. Lee AS, Murray RM. The long-term outcome of Maudsley depressives. Br J Psychiatry 1988; 153:741–51. 56. Kiloh I-G, Andrews G, Neilson M. The long-term outcome of depressive illness. Br J Psychiatry 1988;153:752–7. 57. Lehmann HE, Fenton FR, Deutsch M, Feldman S, Engelsmann F. An 11-year follow-up study of 1110 depressed patients. Act Psychiatr Scand 1988;78:57–65. 58. Lenz G, Ahrens B, Denk E, Müller-Oerlinghausen B, Schratzberger-Topitz A, Simhandl C, and others. Mortalität nach Ausscheiden aus der Lithiumambulanz. In: Müller-Oerlinghausen B, Berghöfer A, editors. Ziele und Ergebnisse der medikamentösen Prophylaxe affektiver Psychosen. Stuttgart, New York: Georg Thieme Verlag; 1994. p 49–52. Author(s)Manuscript received and accepted May 2003. 1. Former Research Group Clinical Psychopharmacology, Freie Universität, Berlin, Germany; Chair, Drug Commission of the German Medical Association, Cologne-Berlin, Germany. 2. Institute of Social Medicine, Epidemiology and Health Economics, Charité Hospital, Humboldt University, Berlin, Germany. 3. Department of Psychiatry, Universität Lübeck, Lübeck Germany. Address for correspondence: Prof B Müller-Oerlinghausen, Drug Commission of the German Medical Association, Jebensstr. 3, 10623 Berlin, Germany e-mail: bmoe@zedat.fu-berlin.de
1 | 2
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
