Research reportBipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine
Introduction
Among psychiatric disorders, bipolar disorder ranks highest in suicidality with a relative risk ratio of completed suicide of about 25 compared to the general population (Baldessarini and Tondo, 2003) and a lifetime risk of suicide between 6 and 15% (Guze and Robins, 1970, Sharma and Markar, 1994, Amaddeo et al., 1995, Harris and Barraclough, 1997, Inskip et al., 1998, O'Leary et al., 2001, Qin et al., 2003, Baldessarini and Tondo, 2003). Bipolar patients also have disproportionately higher risk of suicide attempts. It is estimated that 25–50% of bipolar patients attempt suicide during their lifetime (Baldessarini et al., 2006a). Furthermore, suicide attempts in bipolar patients are more lethal as one in three attempts end up with completed suicide compared to a ratio of 30:1 in the general population. (Baldessarini et al., 2006a). Compared with unipolar patients, suicide attempts in bipolar patients tend to be more lethal, particularly in males (Zalsman et al., 2006). Therefore, all suicidal behavior in bipolar patients needs to be considered with high potential for lethality in mind.
Treatment effectiveness in mood disorders may not necessarily translate into reduction in suicide risk. Recent concerns about the pro-suicidal potential of antidepressants (Fergusson et al., 2005, Gibbons et al., 2005), specially among children and adolescents (Hammad et al., 2006), have highlighted this issue. To date, lithium carbonate is the only medication convincingly shown to reduce suicidal risk in bipolar disorder, although included subjects in most longitudinal studies have been diagnosed with either bipolar or unipolar (“Major affective”) disorder. Previous reviews have shown a dramatic suicide reduction risk with long-term lithium use (Schou, 2000, Baldessarini and Tondo, 2003, Tondo et al., 2003), with the most recent meta-analysis clarifying the fact that lithium reduces suicide risk by a factor of about 5 compared to no treatment (Baldessarini et al., 2006b). A recent review of 32 controlled trials also found a 4–5 fold reduction in the risk of both completed suicide and deliberate non-fatal self harm in patients receiving lithium, compared with those receiving either placebo or other active treatment (Cipriani et al., 2005). Despite this, over the past decade, the use of lithium has declined and the use of anticonvulsants, particularly divalproex, has increased steadily and become more commonly prescribed than lithium (Goodwin et al., 2003, Davis et al., 2004). Unfortunately, very little data has accumulated about the role of anticonvulsants in suicide prevention. Indirect assessments of the suicide prevention potential of carbamazepine (e.g., Thies-Flechtner et al., 1996) have largely implied that it may not be as good as lithium in preventing suicidal behavior. The first formal study to address the question (Yerevanian et al., 2003) did not find a significant difference between lithium, divalproex and carbamazepine in suicide attempts and hospitalizations for suicidal intent. Furthermore, a potential protective role was implied for all three mood stabilizers by the fact that discontinuation of any of them resulted in significantly heightened risk for suicidal behavior. In contrast, in a large study of bipolar patients in two HMO settings, Goodwin et al. (2003) found that the adjusted risk of death by suicide was 2.7 times higher in the divalproex group compared with the lithium treated group. The corresponding risk ratio for non-fatal suicide attempts was 1.7. Furthermore, suicide risk without treatment was 0.116%, about 9 times the base rates for that population (0.012% per year). During a controlled clinical trial comparing Li, divalproex and placebo no significant difference in the rate of suicide attempts between lithium and divalproex was found (Bowden et al., 2000). Methodologic differences between the three studies that to date have provided empirical evidence about the relative effects of lithium and divalproex may account for differences in outcome. In our earlier study (Yerevanian et al., 2003), we reported retrospective chart review observations of bipolar patients treated with mood stabilizer monotherapy in the private practice of a single mood disorders specialist. Thus, diagnosis, treatment prescribed and compliance were deemed reliable but the study was limited in magnitude. In contrast, Goodwin et al. (2003) retrospectively obtained health plan data on prescriptions and suicide deaths or attempts, providing data from a very large sample. However, in that study, concomitant treatment with antidepressants was not excluded, and medication adherence was not assessed. Finally, in the Bowden et al. (2000) study, systematic diagnosis was insured, monotherapy was used, and compliance was assessed, but the observation period was only 12 months.
The current study was designed as an attempt to replicate our earlier study (Yerevanian et al., 2003) but in a significantly different patient population and clinical setting, to provide additional data on the relationship between lithium, anticonvulsants and suicidal behavior in bipolar disorder. The study was approved by the Institutional Review Board of the VA Greater Los Angeles Healthcare System.
Section snippets
Patients
The study is a retrospective chart review analysis of bipolar patients seen in a large Veterans Administration healthcare system in Southern California (VA Greater Los Angeles Healthcare System or VAGLAHS). The Computerized Patient Record System (CPRS) in use at the facility since 1994 includes progress notes of ALL treating personnel, discharge summaries of any hospitalizations, laboratory tests, records of medications dispensed including refills with dates, patient problem lists, demographic
Results
Table 1 describes demographic characteristics of the sample. From our total sample of 405 bipolar subjects, 192 (47.4%) were treated with mood stabilizer monotherapy for at least 1 month during the study. Of these, 40 (9.9% of total sample) were treated with ONLY mood stabilizer monotherapy during our study, while the remaining 152 also received other treatments before or after their period of mood stabilizer monotherapy treatment. Thus, 213 subjects in our overall sample (52.6%) never received
Main findings
This paper examines the relationship between mood stabilizer treatment and suicidal behavior in bipolar patients treated naturalistically in a large VA outpatient mental health clinic. The subjects in this report represent patients who were either treated with mood stabilizer monotherapy exclusively or contributed to MS monotherapy periods during the treatment of their bipolar disorder. We analyzed the data in this subgroup in order to have as pure a comparison between the three mood
Role of funding source
Abbott laboratories provided funding for a research assistant. The funding source had no role in the design of the study; nor in the collection, analysis and interpretation of data,writing of the report; and in the decision to submit the paper for publication.
Conflict of interest
Dr. Yerevanian has served as a consultant to Abbott Laboratories and has been on the speaker's bureau of Astra Zeneca. Dr. Koek has been on the speaker's bureau of Janssen Pharmaceutica.
Acknowledgements
The study was partially funded by Abbott Laboratories.
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