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Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: A randomized, parallel group, open-label trial

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Abstract

Background

There is a paucity of controlled clinical data on the best initial therapy for treating patients with bipolar type II (BP II) major depressive episode (MDE). In this analysis, we examined the safety and antidepressant efficacy of short-term venlafaxine versus lithium monotherapy in rapid and non-rapid cycling patients with BP II MDE. We hypothesized that lithium would have superior efficacy to venlafaxine, with fewer syndromal and sub-syndromal hypomanic and mixed mood conversions in the rapid cycling BP II MDE patients.

Methods

Patients were randomized to monotherapy with either venlafaxine 37.5–375 mg daily or lithium 300–2100 mg daily for 12 weeks. The primary outcome measure was the 28-item Hamilton Depression Rating (HAM-D 28), with embedded ‘typical’ HAM-D 17 and ‘atypical’ HAM-D 17-R symptom scores. Secondary outcomes included the Young Mania Rating Scale (YMRS), clinical global impressions severity (CGI/S) and change (CGI/C) ratings, the proportion of responders (with ≥ 50% reduction in baseline HAM-D score) and remitters (with a final HAM-D score ≤ 8), and the proportion of patients with syndromal and sub-syndromal mood conversions.

Results

Forty-three patients received venlafaxine (12 rapid cycling) and 40 patients received lithium (15 rapid cycling): 48 (57.8%) were women and 69 (82.1%) were Caucasian. Thirty-three patients (39.8%) prematurely discontinued therapy: 11 for lack of efficacy, 13 for adverse events, 2 for non-compliance, and 7 who were lost to follow up. Venlafaxine produced a greater reduction in HAM-D 28 (p = 0.001) and HAM-D 17 (p = 0.002) scores (versus lithium) that was independent of cycling status (0.358). Venlafaxine also resulted in a higher rate of responders (p = 0.021) and remitters (p = 0.001) in rapid cycling patients. There was no significant difference in baseline mean YMRS scores, or mean YMRS change scores over time, between rapid and non-rapid cycling patients. Venlafaxine did not result in a higher proportion of mood conversions (versus lithium) in either the rapid or non-rapid cycling patients.

Limitations

This was a secondary analysis of rapid versus non-rapid cycling BP II MDE patients. The study was originally powered to detect differences in efficacy between treatment conditions, and was not specifically powered to detect differences in efficacy or mood conversion episodes between rapid and non-rapid cycling groups. We used a conservative life-time definition of rapid cycling (i.e., an average ≥ 4 affective episodes per year). We did not employ a patient-recorded daily chrono-record to identify ultra-short mood conversions. The study used a randomized, parallel group, open-label design.

Conclusion

These observations from this exploratory analysis suggest that venlafaxine monotherapy may be more effective than lithium monotherapy, with a similar mood conversion rate, in rapid and non-rapid cycling patients with BP II MDE. These data support prior observations that venlafaxine monotherapy may be effective initial treatment for BP II MDE.

Introduction

The most common phenotypic expression of bipolar illness is Bipolar II (BP II) disorder. It is highly recurrent, with the majority of episodes being depressive (Dunner et al., 1976, Simpson et al., 1993, Akiskal, 2005, Akiskal and Benazzi, 2005, Berk and Dodd, 2005, Sato et al., 2005). While antidepressant use has been associated with cycle acceleration in BP I disorder (Wehr and Goodwin, 1987, Goodwin and Jamison, 1990), the presence of antidepressant-induced rapid cycling in BP II disorder has been more difficult to establish (Akiskal and Benazzi, 2005, Benazzi, 1997). To date, most reports of drug-induced cycling in BP II disorder derive from uncontrolled studies or retrospective chart reviews of mixed BP I and BP II populations (Leverich et al., 2006, Stoll et al., 1994, Altshuler et al., 1995, Goodwin and Ghaemi, 1998, Ghaemi et al., 2003, Goldberg and Truman, 2003, Ghaemi et al., 2004, Marangell et al., 2004, Truman et al., 2007, Goldberg and McElroy, 2007). For example, several naturalistic studies have found higher manic switch rates during antidepressant (20%–84%) versus combined antidepressant plus mood stabilizer (32%) therapy (Goodwin and Ghaemi, 1998, Ghaemi et al., 2003, Goldberg and Truman, 2003, Ghaemi et al., 2004). More recently, Leverich et al. (2006) reported a higher frequency of syndromal and sub-syndromal hypomanic and mixed mood conversion episodes during venlafaxine (versus sertraline or bupropion) therapy in a study of mixed BP I, BP II, BP NOS, and BP schizo-affective patients. A recent retrospective, self-report study of 332 BP patients who had previously received antidepressant therapy found that 44% reported at least 1 mood conversion episode, and patients with a history of multiple antidepressant trials have an increased likelihood of reporting mood conversions. Moreover, the risk of mood conversion was more likely in BP patients who had ever experienced a mood conversion during tricyclic antidepressant (TCA), serotonin reuptake inhibitors (SSRI), or bupropion therapy (Truman et al., 2007).

In contrast, several prospective controlled clinical trials of fluoxetine monotherapy (Amsterdam et al., 1998, Amsterdam et al., 2004, Amsterdam and Shults, 2005, Parker et al., 2006) and venlafaxine monotherapy (Amsterdam, 1998, Amsterdam and Garcia-Espana, 2000, Parker et al., 2003) of BP II major depressive episode (MDE) have found relatively low hypomanic switch rates. None of these studies, however, have specifically examined efficacy and mood conversion rates in BP II MDE patients with rapid versus non-rapid cycling disorder.

In a primary analysis examining the safety and efficacy of initial venlafaxine versus lithium monotherapy of BP II MDE, we reported that venlafaxine monotherapy produced a greater reduction in depressive symptoms versus lithium (95% CI = (− 11.97,− 1.18)) (p = 0.017) and a greater proportion of treatment responders (58.1% versus 12.5%) (p < 0.0005) and treatment remitters (44.2% versus 7.5%) (p < 0.0005). Moreover, we found no difference over time in the rate of treatment-emergent hypomanic symptoms during venlafaxine versus lithium monotherapy (Amsterdam and Shults, 2008).

In the current analysis, we present additional comparative safety and efficacy results of venlafaxine versus lithium monotherapy in rapid and non-rapid cycling patients with BP II MDE. We hypothesize that lithium may have superior efficacy to venlafaxine monotherapy with a lower mood conversion rate in the rapid cycling patients relative to the non-rapid cycling patients.

Section snippets

Subjects

Outpatients ≥ 18 years old with a DSM IV Axis I diagnosis of BP II disorder and a current diagnosis of MDE were enrolled. All had a baseline 17-item Hamilton Depression Rating (HAM-D 17) (Williams, 1988) score ≥ 18. Patients with a co-morbid DSM IV Axis I diagnosis were not specifically excluded from the trial if the co-morbid condition did not constitute the primary disorder. Patients were excluded if they had a history of mania or psychosis, substance abuse or dependence in the preceding

Enrollment

Eighty-four patients were enrolled in the trial: 48 (57%) were women and 69 (82.1%) were Caucasian. Mean (SD) age was 37.2 (13.4) years (range 18–74 years); mean age at 1st MDE was 18.7 (8.7) years (range 5–57 years); mean age at 1st hypomanic episode was 20.7 (8.2) years (range 8–57 years). Mean illness duration was 18.5 (12.0) years (range 1–55 years); mean duration of current MDE was 15.0 (19.3) months (range 0.75–90 months). The mean number of prior MDEs was 7.7 (7.2) (range 0–35); mean

Discussion

To date, there have been few studies specifically examining the relative safety and efficacy of antidepressant versus mood stabilizer monotherapy of rapid and non-rapid cycling BP II patients. Several studies have suggested that antidepressant use may cause cycle acceleration in BP II patients (Wehr and Goodwin, 1987, Goodwin and Jamison, 1990, Altshuler et al., 1995, Goodwin and Ghaemi, 1998, Montgomery et al., 2000, Ghaemi et al., 2003, Goldberg and Truman, 2003, Ghaemi et al., 2004,

Conclusion

There has been a paucity of controlled studies examining the comparative safety and efficacy of antidepressant versus mood stabilizer therapy in rapid and non-rapid cycling BP disorder. The present analysis compared venlafaxine and lithium monotherapy in rapid and non-rapid cycling patients with BP II MDE. In contrast to initial expectations of lithium superiority in rapid cycling BP II patients, venlafaxine demonstrated significantly greater efficacy versus lithium, and a similar mood

Role of funding source

This research was supported by a grant from The Stanley Medical Research Institute, and by The Jack Warsaw Fund for Research in Biological Psychiatry of the University of Pennsylvania Medial Center. Funding sources had no further involvement in study design; in the collection, analysis and interpretation of data; in writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

At the time this research work was conducted, Dr. Amsterdam received support from NIMH grants 1R01MH060353, 1R34MH070753, 1R01MH060998, 1R01MH63818; from NIH/NCCAM grants 1R21AT002289 and 1R21AT001916; and from Lilly Research Laboratories, Forest Laboratories, and Organon, Inc. He was a member of the speaker's bureau of Wyeth, Inc. and Bristol-Myers-Squibb. Dr. Shults received research support from NIH grant 1R01CA096885.

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