Preliminary communication
Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression—lack of manic induction

https://doi.org/10.1016/j.jad.2005.02.018Get rights and content

Abstract

Objective

Current guidelines for the initial treatment of bipolar type I (BP I) and bipolar type II (BP II) major depressive episode (MDE) recommend avoiding the use of antidepressant drugs due to concerns over drug-induced manic switch episodes. However, recent evidence suggests that the manic switch rate during SSRI therapy of BP MDE may be lower than previously thought. This preliminary, placebo-controlled study examines the relative rates of treatment-emergent manic symptoms during fluoxetine monotherapy, olanzapine monotherapy, and combined fluoxetine plus olanzapine therapy of BP I and BP II MDE.

Methods

32 BP I and 2 BP II MDE patients were randomized to receive double-blind therapy with fluoxetine monotherapy 10–30 mg daily, olanzapine monotherapy 5–20 mg daily, combined therapy with fluoxetine 10–40 mg plus olanzapine 5–15 mg daily, or placebo for up to 8 weeks. Outcome measures included the 17-item HAM-D, 17-item HAM-D “atypical” symptom profile (HAM-D 17-R), 28 item HAM-D, Montgomery–Asberg Depression Rating Scale (MADRS), and the Young Mania Rating (YMR) scale.

Results

There were significant reductions over time in mean HAM-D 28 and MADRS ratings for all treatment groups (p < 0.006). However, there were no differences among treatment conditions (p = ns). There was no significant increase in YMR scores over time in any treatment group. In contrast, there was a significant reduction in the mean YMR score in the fluoxetine-treated patients over time (p = 0.008). No patient met DSM IV criteria for a manic episode.

Limitations

Cohort sizes were limited and the study was not powered to detect statistical differences in efficacy or mania symptoms among treatment conditions. The dose of fluoxetine was modest and the treatment duration was limited to 8 weeks.

Conclusion

These observations support earlier findings of a low manic switch rate during fluoxetine monotherapy of BP I and BP II MDE, and suggest that fluoxetine may be a safe initial treatment of BP MDE alone or in combination with olanzapine.

Section snippets

Background

The treatment of bipolar (BP) major depressive episode (MDE) remains a major challenge (Ghaemi et al., 2000b, Soares, 2000, Post et al., 2003). Most patients with BP disorder will experience a preponderance of depressive episodes during the course of their illness. These MDEs may increase in frequency with increasing age, and may become more resistant to antidepressant treatment—eventually dominating the clinical picture (Goodwin and Jamison, 1990, Post et al., 2003). BP MDE carries a

Patient selection

All patients were provided with a detailed description of the purpose and procedures of the study in accordance with the ethical standards of the Institutional Review Board of the University of Pennsylvania. All subjects provided signed informed consent before enrolling in the trial.

Outpatients ≥ 18 years old with a DSM IV Axis I diagnosis of BP I or BP II disorder and a current DSM IV Axis I diagnosis of MDE were eligible for the trial. All patients had a screen and baseline 17-item Hamilton

Study enrollment

A total of 41 patients were entered into the trial. Of these, 5 patients (12.2%) were screen failures and did not have a baseline study visit. Two patients did have a baseline study visit but withdrew consent before receiving double-blind therapy. 34 patients received double-blind therapy: 8 received fluoxetine monotherapy, 8 received olanzapine monotherapy, 9 received combined fluoxetine plus olanzapine therapy, and 9 received placebo for at least one outcome evaluation. 32 patients (94%) met

Discussion

We compared the safety and efficacy of fluoxetine monotherapy, olanzapine monotherapy, and combined fluoxetine plus olanzapine therapy for the initial treatment of BP I and BP II MDE. We specifically examined the frequency of treatment-emergent manic symptoms in these groups using the YMR scale. The YMR is a sensitive instrument that is capable of detecting sub-clinical increases in manic symptoms. We observed no significant increase in YMR scores over time in any of the fluoxetine-treated

Conclusion

The present study demonstrates a low manic switch rate during fluoxetine monotherapy and during the combined use of fluoxetine plus olanzapine in BP I and BP II MDE patients. These findings support earlier observations suggesting that fluoxetine may result in a low manic induction rate during initial treatment of BP I and BP II MDE when used alone or in combination with olanzapine.

Acknowledgements

This study was supported by an Investigator Initiated Trial grant from Lilly Research Laboratories (Eli Lilly & Company) and by the Jack Warsaw Endowment for Research in Biological Psychiatry (Depression Research Unit, University of Pennsylvania School of Medicine).

References (50)

  • American Psychiatric Association

    Practice guidelines for the treatment of patients with bipolar disorder (revision)

    Am. J. Psychiatry

    (2002)
  • J. Amsterdam

    Efficacy and safety of venlafaxine in bipolar type-II major depressive episode

    J. Clin. Psychopharmacol.

    (1998)
  • J. Amsterdam et al.

    Fluoxetine and bipolar II major depressive episode

    J. Clin. Psychopharmacol.

    (1998)
  • J.D. Amsterdam et al.

    Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression—low manic switch rate

    Bipolar Disord.

    (2004)
  • C.F. Baldassano et al.

    What drugs are best for bipolar depression?

    Ann. Clin. Psychiatry

    (2003)
  • P. Benfield et al.

    Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

    Drugs

    (1986)
  • H.L. Boerlin et al.

    Bipolar depression and antidepressant-induced mania: a naturalistic study

    J. Clin. Psychiatry

    (1998)
  • J.B. Cohn et al.

    A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder

    Int. Clin. Psychopharmacol.

    (1989)
  • D.L. Dunner

    Sub-types of bipolar affective disorder with particular regard to bipolar II

    Psychiatr. Dev.

    (1983)
  • Expert Consensus Panel for Bipolar Disorder

    Treatment of bipolar disorder

    J. Clin. Psychiatry

    (1996)
  • M.B. First et al.

    Structured Clinical Interview for Axis I DSM-IV Disorders—Patient Edition

    (1994)
  • S.N. Ghaemi et al.

    Diagnosing bipolar disorder and the effect of antidepressants: A naturalistic study

    J. Clin. Psychiatry

    (2000)
  • N. Ghaemi et al.

    What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness

    World J. Biol. Psychiatr.

    (2000)
  • S.N. Ghaemi et al.

    Effectiveness and safety of long-term antidepressant treatment in bipolar disorder

    J. Clin. Psychiatry

    (2001)
  • S.N. Ghaemi et al.

    Antidepressant treatment in bipolar versus unipolar depression

    Am. J. Psychiatry

    (2004)
  • Cited by (86)

    • Adjunctive antidepressants for the acute treatment of bipolar depression: A systematic review and meta-analysis

      2022, Psychiatry Research
      Citation Excerpt :

      Our meta-analysis included 2587 patients with bipolar disorder, of which 1267 had BD-I, 280 had BD-II, and 1040 were unspecified. Eight studies recruited patients from outpatient clinics,(Altshuler et al., 2017; Amsterdam and Shults, 2005; Nemeroff et al., 2001; Nolen et al., 2007; Sachs et al., 2007; Schaffer et al., 2006; Shelton and Stahl, 2004; Yatham et al., 2016) three from outpatient and inpatient settings,(Brown et al., 2006; Niu and Mu, 2013; Tohen et al., 2003) the other studies did not specify the setting. Ten studies were double-blinded(Altshuler et al., 2017; Amsterdam and Shults, 2005; Brown et al., 2006; Nemeroff et al., 2001; Sachs et al., 2007; Schaffer et al., 2006; Shelton and Stahl, 2004; Tohen et al., 2003; Yatham et al., 2016) and nine were open-label(AstraZeneca, 2012; Chen et al., 2017; Kostyukova et al., 2018; Niu and Mu, 2013; Nolen et al., 2007; Pang, 2015; Qiu, 2013; Shen et al., 2011; Tu, 2012), including all of the studies from China.

    • Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis

      2020, Journal of Affective Disorders
      Citation Excerpt :

      The median duration of acute treatment was 8 weeks (interquartile range = 6–8). Eight (McElroy et al., 2010, Young et al., 2010, Amsterdam and Shults, 2005, Tohen et al., 2003, Agosti and Stewart, 2007, Cohn et al., 1989, Altshuler et al., 2017, Frye et al., 2000) trials involved three or more groups. After exclusion of closed-loop networks from four studies (Park et al., 2017, Riesenberg et al., 2012, De Wilde and Doogan, 1982, Grossman et al., 1999), 46 studies—involving 22 interventions and 63 comparisons—were eligible for network meta-analysis.

    • Bipolar I Mania and Atypical Depression

      2020, Psychotic Disorders: Comorbidity Detection Promotes Improved Diagnosis and Treatment
    View all citing articles on Scopus
    View full text