History of depressive and/or anxiety disorders as a predictor of treatment response: A post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release in patients with fibromyalgia

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Abstract

Background

Despite of a high comorbidity of depressive and/or anxiety disorders with fibromyalgia, information on the clinical implications of this comorbidity is limited but antidepressants are commonly prescribed to treat fibromyalgia in clinical practice. We investigated whether a history of depressive and/or anxiety disorders was associated with response to paroxetine controlled release (CR) in the treatment of fibromyalgia.

Methods

One hundred sixteen (116) fibromyalgia subjects were randomized to receive paroxetine CR or placebo for 12 weeks. The primary outcome was treatment response defined as ≥ 25% reduction in the Fibromyalgia Impact Questionnaire (FIQ) score. In multivariate logistic regression, we determined if a history of depression and/or anxiety disorders was an independent predictor of response to paroxetine CR.

Results

In logistic regression, the history of depression and/or anxiety did not predict treatment response as measured by ≥ 25% reduction in Fibromyalgia Impact Questionnaire (FIQ) score (OR = 0.66, 95% CI = .29–1.49, Wald = 0.97, p = 0.32), while the drug status (paroxetine CR) was significantly associated with treatment response (OR = 2.57, CI = 1.2–5.61, Wald = 5.5, p = 0.02).

Conclusion

A significant proportion of patients with fibromyalgia had a history of anxiety and or depressive disorders. However response to treatment of fibromyalgia symptoms with paroxetine CR was not associated with a history of depressive and/or anxiety disorders. Our findings need to be confirmed in more adequately-powered and well-designed subsequent studies.

Introduction

The prevalence rates for current and lifetime diagnoses of depressive disorders in fibromyalgia range from 22 to 90% (Ahles et al., 1987, Burckhardt et al., 1994, Epstein et al., 1999, Ercolani et al., 1994, Guven et al., 2005, Kurland et al., 2006). The differences in prevalence across various studies may be explained by variations in assessment scales for depression, differences in definitions of depression and fibromyalgia, sampling bias and reliance on treatment-seekers as opposed to community samples. The high prevalence of depression in fibromyalgia and shared pathophysiological characteristics have led some authors to suggest that it may be a depressive spectrum disorder (Ahles et al., 1987, Meyer-Lindenberg and Gallhofer, 1998). Major depression is likely the most common psychiatric illness comorbid with fibromyalgia; one study indicates that 46% of fibromyalgia patients have been diagnosed with depression, and 23% of fibromyalgia patients report a family history positive for depression (Offenbaecher et al., 1998). Less attention has been paid to the prevalence of anxiety disorders in fibromyalgia, but they also appear to be common. Arnold et al. (2006) found that patients with fibromyalgia were significantly more likely than those without fibromyalgia to have comorbid anxiety disorders including posttraumatic stress disorder (PTSD) (Odds Ratio [OR] = 12), panic disorder (OR = 5.0), obsessive compulsive disorder (OR = 14) and social phobia (OR = 8.9): any anxiety disorders (OR = 6.7) (Arnold et al., 2006). Other studies have also supported the high prevalence of anxiety disorders in patients with fibromyalgia with rates ranging from 13% to 64%, PTSD being the most common (Arnold et al., 2006, Martinez et al., 1995, Sherman et al., 2000, Thieme et al., 2004).

There is considerable evidence of pathophysiological link between fibromyalgia, major depressive disorder and anxiety disorders with shared genetic loading (Hudson et al., 1985, Pae et al., 2008), abnormal sensitization of pain (Staud et al., 2001), dysregulation of neurotransmitters (Goodnick and Sandoval, 1993), stress-response abnormalities (Crofford, 1998, Van Houdenhove and Luyten, 2006), clinical symptoms (Meyer-Lindenberg and Gallhofer, 1998), autonomic nervous system dysfunction (Martinez-Lavin and Hermosillo, 2000), and psychosocial factors (Wolfe and Hawley, 1998). The clinical overlap between the disorders is also striking. There is a marked female preponderance in fibromyalgia, similar to depression. Patients with fibromyalgia often suffer from a variety of pain syndromes (Pamuk et al., 2006) such as chronic headaches, menstrual disturbances, chronic fatigue, irritable bowel syndrome and sleep problems which are also more common in patients with major depressive disorder and anxiety disorder (Lecrubier, 2006, Pae et al., 2007, Rubio and Lopez-Ibor, 2007). In addition, patients with these disorders show similarities in character and temperament: i.e., higher harm avoidance and self-criticism, and lower self-directedness (Conte et al., 2003, Luyten et al., 2007, Mazza et al., 2009). The evidence indicates that fibromyalgia, depressive and anxiety disorders may have a bidirectional relationship in etiology, pathophysiological mechanisms and clinical manifestations. There is some evidence that comorbid depression and anxiety may increase the level of emotional distress, reduce coping abilities and possibly be related to severity of pain symptoms in fibromyalgia (Thieme et al., 2004, Turk et al., 1998). Neuro-endocrine factors are also important in fibromyalgia, which has been characterized as a stress related disorders mediated by changes in both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (Cohen et al., 2000, Pae et al., 2008, Wingenfeld et al., 2008), which are also observed in posttraumatic stress disorder (PTSD) and depressive disorders (Pae et al., 2008).

Antidepressant medications are commonly prescribed to treat fibromyalgia. The evidence from controlled clinical trials indicates that tricyclic antidepressants (amitriptyline), selective serotonin uptake inhibitors (fluoxetine and paroxetine controlled release), and dual norepinephrine and serotonin uptake inhibitors (duloxetine, milnaciran) may be effective to treat fibromyalgia (Arnold et al., 2002, Arnold et al., 2000, Arnold et al., 2007, Arnold et al., 2005, Gendreau et al., 2005, O'Malley et al., 2000, Patkar et al., 2007, Vitton et al., 2004). It is worth noting that medications with different biological mechanisms such as pregabalin and sodium oxybate have also been found to be effective in fibromyalgia (Crofford et al., 2005, Rooks, 2007, Scharf et al., 2003), suggesting that pain modulation can be influenced through a variety of neurotransmitter systems.

As of yet the treatment implications of the comorbidity between depression, anxiety and fibromyalgia have not been fully clarified, but is seems likely that fibromyalgia sufferers are comprised of a heterogeneous group of people who may differ in their levels of pain, psychological distress, comorbid conditions and adaptive coping responses. There is continuing research into examining the role of clinical variables as predictors of treatment response in order to improve treatment-outcome and to optimize treatments based on symptoms profiles. There is emerging evidence that effective control of depressive and anxiety symptoms may enhance the positive outcome in patients with fibromyalgia (Grossman et al., 2007, Stratz et al., 2003).

We investigated whether a history of major depression and/or anxiety disorders was associated with response to treatment in a 12-week, RCT of paroxetine controlled release (CR) in fibromyalgia. The results of the primary efficacy analysis have been previously published (Patkar et al., 2007). For the purpose of this analysis we decided to combine subjects with history of depressive and anxiety disorders because there was a substantial overlap between the two disorders, both disorders have been shown to respond to paroxetine and the combined group increased the power to detect an effect.

Section snippets

Design

This was a randomized, double-blind, placebo-controlled trial of paroxetine controlled release (CR) (dose 12.5 to 62.5 mg/day) in fibromyalgia. The study was approved by the Institutional Review Boards of Duke University, Durham, North Carolina, and Thomas Jefferson University, Philadelphia, Pennsylvania and performed under an IND assigned by the Food and Drug Administration.

Subjects

All subjects provided written informed consent prior to participating in the protocol. Subjects were recruited through

Outcome measures

The protocol-specified primary outcome measure was proportion of responders as defined by ≥ 25% reduction on the Fibromyalgia Impact Questionnaire (FIQ) total score. The FIQ is a 10-item, self-report instrument that measures physical function, pain, depression, anxiety, fatigue, morning tiredness, stiffness, work record, job difficulty and overall well-being. The scores range from 0 to 100 (maximum). The FIQ has been found to have good reliability and validity in clinical trials (Burckhardt et

Comorbid depressive and anxiety disorders

Out of 983 subjects who were prescreened over the phone, 180 subjects were asked to come in for an on-site screening visit. Fifty six subjects failed the on-site screening, 124 subjects met the entry criteria and entered the placebo-run phase, and 116 were randomized to receive paroxetine CR or placebo.

43.4% of the 983 telephone screen failures had current depressive and/or anxiety disorders. About 48% of the 56 on-site screen failures had current anxiety and/or depressive disorders. Of the 116

Discussion

This post hoc analysis was conducted after the initial randomized controlled trial showed a beneficial effect of paroxetine CR in fibromyalgia (Patkar et al., 2007). The results failed to demonstrate a significant effect for history of anxiety and/or depression to predict treatment response based on the primary and secondary outcome measures. Subjects with or without history of depression and/or anxiety were equally likely to respond to paroxetine CR. There could be several explanations for the

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    This work was supported by a Collaborative Research Grant from GlaxoSmithKline.

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