Elsevier

Journal of Affective Disorders

Volume 227, February 2018, Pages 379-383
Journal of Affective Disorders

Research paper
Residual anxiety may be associated with depressive relapse during continuation therapy of bipolar II depression

https://doi.org/10.1016/j.jad.2017.11.028Get rights and content

Highlights

  • Relative to lithium, venlafaxine had a large effect on symptoms of depression.

  • Superiority of venlafaxine over lithium in terms of anxiety reduction was more modest.

  • Baseline depression severity did not predict changes in depression.

  • Baseline anxiety severity negatively predicted change in anxiety.

  • Residual anxiety, but not depression, predicted relapse.

Abstract

Background

Anxiety symptoms are common in bipolar disorder. We explored the effect of anxiety on the outcome of acute and continuation pharmacotherapy of bipolar II depression.

Methods

Data were derived from a randomized double-blind 12-week acute (N = 129) and 6-month continuation (N = 55) comparison of venlafaxine versus lithium monotherapy in bipolar II depression in adults. We distinguished between the items of the Hamilton Rating Scale for Depression (HRSD) that capture depression vs. anxiety (i.e., psychomotor agitation, psychic anxiety, somatic anxiety, hypochondriasis, and obsessive-compulsive concerns) and examined the effect of treatment on depression and anxiety. Additionally, we explored whether baseline anxiety or depression predicted changes over time in depression and anxiety ratings or moderated treatment outcomes. We also explored whether residual depressive and anxious symptoms predicted relapse during continuation therapy.

Results

Venlafaxine was superior to lithium in reducing both depression and anxiety, though its effects on anxiety were more modest than those on depression. Baseline anxiety predicted change over time in anxiety, but not depression. By contrast, baseline depression did not predict change over time in depression or anxiety. Residual anxiety, specifically uncontrollable worry, was a stronger predictor of relapse than residual depression.

Conclusion

Successful treatment of symptoms of anxiety in bipolar depression may protect against depressive relapse.

Introduction

A hallmark of bipolar disorders are their high co-morbidity with other forms of psychopathology, especially substance use and anxiety disorders (Akiskal et al., 1989, Endicott et al., 1985). Historically, unipolar depression has been most often associated with the presence of co-morbid anxiety symptoms. However, a recent meta-analysis suggested that anxiety symptoms in bipolar disorders may be more common than previously thought (Pavlova et al., 2015). Specifically, Pavlova et al. reported that 45% of individuals with bipolar disorder also met criteria for an anxiety disorder, a rate comparable to the co-morbidity of anxiety in unipolar depression.

Anxiety co-morbidity may be a poor prognostic factor in the treatment of bipolar depression. In a sample of patients with bipolar I disorder, Feske (2000) reported that baseline symptoms of anxiety in the panic spectrum predicted longer time to remission as well as higher levels of depression throughout treatment. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, Simon et al. (2004) reported that lifetime anxiety co-morbidity predicted decreased likelihood of recovery. Similarly, Tohen et al. (2007) reported that anxiety co-morbidity predicted overall worse depression outcomes in treatment with olanzapine, olanzapine plus fluoxetine, or placebo. These findings support studies of unipolar depression suggesting that anxiety may be an indicator of risk for relapse (Forand and DeRubeis, 2013). Frank et al. (2002) reported that having a predominantly depressive presentation with more symptoms on the panic-agoraphobia spectrum predicted time to remission of bipolar I disorder. Because bipolar II disorder is inherently characterized by a highly recurrent predominantly depressive illness course, the additional risk of relapse conferred by the presence of anxiety symptoms may further increase the likelihood of a poor treatment outcome. The effects of co-morbid anxiety symptoms during the depressive phase of bipolar II disorder poses a substantial challenge to clinicians, especially because the mainstay pharmacological therapies for treating anxiety including serotonin reuptake inhibitors (SSRIs) (Ghaemi et al., 2001, Ghaemi et al., 2004, Leverich et al., 2006) and benzodiazepines (Perlis et al., 2010) may adversely impact the course of bipolar disorder.

The main objectives of this exploratory study were to: (1) compare the relative effectiveness of acute venlafaxine versus lithium monotherapy on depressive versus anxiety symptoms in subjects with bipolar II major depressive episode; (2) explore the relationship between baseline co-morbid anxiety symptoms and treatment outcome in depressive and anxiety symptoms in bipolar II subjects: and, (3) explore the effect of residual depressive and anxiety symptoms on the likelihood of depressive relapse in subjects who have recovered from their depression.

Section snippets

Methods

This was an exploratory study using data derived from a randomized, controlled comparison of venlafaxine versus lithium monotherapy of bipolar II depression (ClinicalTrials.gov identifier: NCT00602537). Informed consent was obtained in accordance with the ethical standards of the Institutional Review Board, using Good Clinical Practice guidelines (Baber, 1994) with oversight by the local Office of Human Research and an independent Data and Safety Monitoring Board. Blocked randomization was

Results

Baseline characteristics for the 129 subjects who entered acute treatment are summarized in Table 1. As reported previously (Amsterdam et al., 2015, Amsterdam et al., 2016), there were no statistically significant differences between the treatments any of these variables (ps > 0.08). The correlation between anxious and depressive symptoms on the baseline HRSD-17 assessment was relatively low (r = 0.35, p < 0.001), providing support for the distinction of anxious vs. depressive symptoms.

Discussion

Anxiety symptoms are common among patients with bipolar disorder and may adversely impact treatment outcome. The results of this exploratory analysis suggest that: (1) depressive and anxious symptom clusters in bipolar II disorder can be dissociated; (2) venlafaxine's superiority over lithium is more pronounced in symptoms of depression than anxiety symptoms; (3) the more severe the baseline symptoms of anxiety are, the harder they are to treat; and, (4) residual symptoms of anxiety, especially

Conclusion

Our findings suggest that, at least in bipolar II depression, anxiety symptoms play a different prognostic role than depressive symptoms: a greater severity predicts less change in anxiety and residual anxiety predicts relapse. While depressive and anxiety symptoms form part of the internalizing cluster of psychopathology (Wright et al., 2013), there are differences in these symptoms in terms of associated brain areas (Murphy et al., 2003), environmental triggers (Mennin et al., 2008),

Acknowledgements

Gratitude is expressed to the funding sources as well as our colleagues. We also thank the patients for contributing their time and energy into participating in the research.

Role of the funding sources

This research was supported by NIMH grant MH060353. Additional support for the preparation of this manuscript was provided by NIH grant MH080097 and The Jack Warsaw Fund for Research in Biological Psychiatry of the University of Pennsylvania Medical Center. The ClinicalTrials.gov identifier for the study is NCT00602537.

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