This study is designed to permit adequately powered tests of these hypotheses (details appear in the Statistical Methods and Data Analysis section below). The study is adequately powered (.80) to detect clinically meaningful (“medium”) differences using conventional standards. The attention to multiple outcomes including antidepressant response, switch rates and side effect profiles and antidepressant response rates will provide a clinical “cost-benefit” perspective.

Condition	Intervention	Phase
Bipolar II Depression	Drug: Sertraline  Drug: Lithium	Phase III

Further study details as provided by University of Cincinnati:

Expected Total Enrollment:  70

This proposal outlines a multi-institutional collaborative research project to investigate the impact of mood stabilizer monotherapy, antidepressant monotherapy and mood stabilizer/antidepressant combination therapy in treating bipolar II depression. We have chosen a mood stabilizer (lithium) with known antidepressant properties, and an established antidepressant (sertraline) in a drug class (SSRI) where there are positive data regarding efficacy in the treatment of bipolar II depression. The study proposed is a double-blind randomized comparison of lithium monotherapy vs. sertraline monotherapy vs. lithium plus sertraline combination therapy in 207 patients with bipolar II depression. The proposed study will be the first, to our knowledge, to compare these treatments for acute depression in patients with bipolar II disorder. The use of three sites is essential to rapidly accumulate a large sample size in a relatively short period of time. This representative sample will provide data needed to answer critical clinical questions.

Bipolar disorder is a recurrent illness that affects up to three percent of the population (1-5). Bipolar disorder is chronic, disabling and is the 6th leading cause of disability worldwide (6). Bipolar II disorder (BD II) (the focus of this application) is recognized as a distinct subtype from Bipolar I disorder (BD I), differentiated by the severity of the manias (7). Whereas BD I is defined by manias that last longer than 7 days or result in a hospitalization, BD II is characterized by a lifetime history of depressive episodes with one or more hypomanic episodes lasting for at least 4 days (7). The two disorders are similar regarding the presentation of depressive episodes, although patients with BD II may have greater depressive episode recurrence and equal or greater rates of disability as patients with the BD I variant (4;8-11). The prevalence specifically of BD II has been conservatively estimated in the U.S. at 0.5% (12), representing over 1,000,000 American adults as of the 2000 census (13). The existence of BD II distinct from BD I and unipolar major depressive disorder (MDD) has been confirmed based on family history or inheritance pattern, course of illness, and lack of change of diagnostic category over time (14-18). Patients with BD II rarely convert to BD I – that is, the illness is stable over time with hypomanic episodes rarely evolving into manic episodes (14;15;19).

It is now well-recognized that most patients with either BD I or BD II spend much more time in the depressed than the manic phase of their illness (ratio estimates ~ 3:1) over their lifetime (4;20-23) (Kupka et al., unpublished data). The illness is associated with high morbidity and mortality, with suicide attempts and completed suicides occurring at high rates in this population (24-29). Despite these facts, there have been very few double-blind placebo controlled trials comparing the efficacy of different treatments for the depressed pole of bipolar disorder, and, to date, there are almost no FDA approved treatments for acute bipolar depression. Thus, clinicians are often faced with the dilemma of needing to treat a phase of the illness in which there are very few empirical studies regarding the optimal treatment approach.

Psychotropic medications have played a pivotal role in reducing both manic and depressive episodes in patients with bipolar illness. For BD I, switch rates into mania occur at high rates in subjects treated with antidepressant monotherapy (30;31). Thus, antidepressant monotherapy is not recommended. Rather, treatment with a mood stabilizer alone (e.g. lithium) or with an antidepressant in addition to a mood stabilizer is recommended for BD I depression (32-40). There are no clear recommendations for patients with BD II depression based on data. The clinical management dilemma can be complex when patients with BD II present with depression. These patients often do not consider their hypomanic symptoms to be in need of treatment. Thus, while a first recommendation may be to try a mood stabilizer (lithium) alone or a mood stabilizer in combination with an antidepressant, many patients with BD II, in fact, prefer not to take a mood stabilizer and prefer instead to take only an antidepressant. While it is unclear if treatment with antidepressant monotherapy would lead to an increased risk for switch into hypomania/mania or increased risk for mood cycling for patients with BD II depression, there is clinical concern that this could occur. However, as stated above, patients with BD II rarely develop a change over time from having only hypomanic episodes to having more severe manic episodes. Additionally, while no controlled double-blind studies have been performed, several recent reports have indicated that short-term selective serotonin re-uptake inhibitor (SSRI) monotherapy treatment is effective in BD II major depressive episode (41-44), and that SSRI treatment for BD II depression given as either monotherapy (43;45;46) or as adjunctive to a mood stabilizer (47;48) may be associated with a relatively low hypomanic or manic switch rate. Recent work by our group (see Preliminary Studies) and others (49;50) has demonstrated lower antidepressant-induced acute switch rates in persons with BD II vs. BD I when antidepressants are given in combination with a mood stabilizer, suggesting perhaps less vulnerability to switching. Thus, whether SSRI monotherapy would be reasonable treatment for BD II depression or whether, as in BD I, antidepressant monotherapy would destabilize patients with BD II compared to treatment with a mood stabilizer remains to be tested. The optimal approach to treating persons with BD II depression remains to be evaluated.

This project will focus on the safety, tolerability and efficacy of three treatment approaches to BD II depression. Whether patients with BD II disorder could do well (without switching) on antidepressant monotherapy, could do better with mood stabilizer monotherapy, or could do best with combination mood stabilizer plus antidepressant therapy requires investigation, and is the purpose of this grant application. Treatment research for this population is not a priority to the pharmaceutical industry, since formal indication for BD I is likely to generalize to all bipolar diagnoses. In particular, competition between companies has to date focused on BD I and it is unlikely that a research question specifically regarding BD II will be answered outside of a federal grant mechanism.

This acute sixteen-week trial will assess switch rates, side effect rates (tolerability) and rates of anti-depressant response without switching between these three treatment strategies. We have not included simple antidepressant response rates (without regard for switching or side effects) in the aims or hypotheses because we do not consider an antidepressant response that is accompanied by increased risk of manic switch or intolerable side effects to be a good clinical outcome. We also do not expect the drugs to differ in antidepressant response rates per se. We will thus assess treatments for clinically meaningful “good outcomes” that will be measured as a good antidepressant response without switching and without frequent clinically problematic side effects (that would most likely lead to noncompliance). As it is of concern that antidepressant monotherapy may be associated with either a higher risk of manic or hypomanic switch episodes, we will specifically evaluate the occurrence of any syndromal hypomanic symptoms during sertraline monotherapy versus treatments involving lithium. Additionally, we will carefully track subthreshold hypomanic and depressive symptoms to collect data on mood variability. Even if antidepressants do not trigger a syndromal switch into hypomania/mania, there has been concern that this class of medications can destabilize patients by increasing subthreshold symptoms and mood variability (cycling). We will thus also track patients for subthreshold hypomanic symptoms – the kind that may not be reported to a patient’s physician (nor would they be exit criteria for this study), but nonetheless would point to a variability in mood that could, in time, be a harbinger of destabilization.

This will be the largest (and thus most adequately powered) randomized acute trial ever completed to date in this understudied population. We believe that the frequency and prominence of depressive symptoms in BD II warrant special attention. Both sertraline and lithium have documented antidepressant effects, and are likely to be beneficial for patients with BD II disorder in a depressive episode. Whether lithium will have added prophylactic antimanic benefit as monotherapy or in combination treatment with sertraline will be tested. Both acute and prophylactic treatment trials for BD II, while limited, suggest that the medications chosen for study in this grant application warrant further controlled study of their effectiveness and tolerability in this population.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

1. Age 18-65
2. English speaking (as assessment sales are not validated in other languages)
3. DSM-IV Criteria for BD II by Structured clinical Interview for DSM-IV (SCID)
4. DSM-IV criteria for current depressive episode
5. IDS-C > 22 (moderately ill)
6. CGI-BP depression subscale > 3 (mildly ill or greater)
7. YMRS < 8 and CGI-BP mania subscale = 1 (not ill)
8. Currently on no other antidepressant medication (5 ½-lives) x 2 weeks (6 weeks fluoxetine)*
9. If currently on antidepressant medication, are having an inadequate response after 6 weeks of treatment and are willing to discontinue it
10. If has another Axis I disorder, currently stable and not requiring adjustments in treatment (e.g. if panic/anxiety disorder on stable benzodiazepine; if alcoholism, currently sober for > 3 months)
11. Negative urine pregnancy test if female
12. Willing to be treated with either sertraline, a standardized FDA-approved treatment for major depression or lithium, an FDA-approved treatment for bipolar disorder (mood stabilizer)

13. Able to provide informed consent

    • With respect to patients who are on antidepressant medication when they are first seen by us: they will be allowed to participate if their current trial has lasted 6 weeks and they have had an inadequate response (and still meet DSM-IV criteria for BD II disorder, depressive episode and had an IDS > 22). These patients will complete a taper of existing medications prior to randomization.

Exclusion Criteria:

1. Prior treatment failure with an adequate trial (> 6 weeks at adequate doses) with sertraline or lithium for depression 2. Current suicidal ideation operationalized as > 2 on item 18 of the IDS (e.g. has current suicidal ideation or has ideation and a plan) 3. Current active Axis I alcohol or drug use comorbidity assessed by SCID (see 2.b. below) 4. Significant alcohol or substance abuse or dependence within the past 3 months (see D.2.b. below) 5. Axis II Borderline personality Disorder 6. YMRS > 8 7. Rapid cycling (> 4 episodes/year) within the last year 8. Current psychotic symptoms 9. Organic mood disorder (e.g. head trauma or CVA preceding mood episode) 10. Active hepatitis, hepatic encephalopathy, or renal failure 11. Creatinine > 1 12. Liver function tests > 3 times the upper limit of normal (AST, ALT, GGT) 13. Abnormal TSH 14. Unstable medical condition 15. Currently pregnant or breastfeeding 16. Not practicing a reliable form of birth control 17. Unable to provide informed consent

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Please refer to this study by ClinicalTrials.gov identifier  NCT00276965

Susan L. McElroy, MD      513-558-1199    susan.mcelroy@uc.edu

Ohio
      University of Cincinnati Medical Center, Cincinnati,  Ohio,  45267-0559,  United States

Study chairs or principal investigators

Susan L. McElroy, MD,  Principal Investigator,  University of Cincinnati   

Study ID Numbers:  R01 MH074707-R01
Last Updated:  January 12, 2006
Record first received:  January 12, 2006
ClinicalTrials.gov Identifier:  NCT00276965
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2006-01-17