Progress in Neuro-Psychopharmacology and Biological Psychiatry
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☆
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
References (68)
- et al.
Is chronic pain a variant of depressive disease? The case of primary fibromyalgia syndrome
Pain
(1987) - et al.
Antidepressant treatment of fibromyalgia. A meta-analysis and review
Psychosomatics
(2000) - et al.
A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia
Am J Med
(2002) - et al.
A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder
Pain
(2005) - et al.
The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research
Psychiatry Res
(1989) - et al.
Autonomic dysfunction in patients with fibromyalgia: application of power spectral analysis of heart rate variability
Semin Arthritis Rheum
(2000) - et al.
Psychiatric disorders in patients with fibromyalgia. A multicenter investigation
Psychosomatics
(1999) - et al.
Autonomic nervous system dysfunction may explain the multisystem features of fibromyalgia
Semin Arthritis Rheum
(2000) - et al.
Psychological aspects of Brazilian women with fibromyalgia
J Psychosom Res
(1995) - et al.
What is the effect of selective serotonin reuptake inhibitors on temperament and character in patients with fibromyalgia?
Compr Psychiatry
(2009)
Recognition of emotional distress in physically healthy primary care patients who perceive poor physical health
Gen Hosp Psychiatry
Factors that affect the number of tender points in fibromyalgia and chronic widespread pain patients who did not meet the ACR 1990 criteria for fibromyalgia: are tender points a reflection of neuropathic pain?
Semin Arthritis Rheum
A randomized, controlled, trial of controlled release paroxetine in fibromyalgia
Am J Med
Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome
Pain
A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder
Arthritis Rheum
Comorbidity of fibromyalgia and psychiatric disorders
J Clin Psychiatry
Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled clinical trials
J Womens Health (Larchmt)
An inventory for measuring depression
Arch Gen Psychiatry
An inventory for measuring clinical anxiety: psychometric properties
J Consult Clin Psychol
The fibromyalgia impact questionnaire: development and validation
J Rheumatol
Assessing depression in fibromyalgia patients
Arthritis Care Res
Sexual and physical abuse in women with fibromyalgia syndrome: a test of the trauma hypothesis
Clin J Pain
Disseminating and implementing trauma-focused CBT in community settings
Trauma Violence Abuse
A global measure of perceived stress
J Health Soc Behav
Temperament and stress response in children with juvenile primary fibromyalgia syndrome
Arthritis Rheum
The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome
Z Rheumatol
Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial
Arthritis Rheum
Fibromyalgic syndrome: depression and abnormal illness behavior. Multicenter investigation
Psychother Psychosom
Efficacy of milnacipran in patients with fibromyalgia
J Rheumatol
Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit
Arch Gen Psychiatry
A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia
Arthritis Rheum
Management of fibromyalgia syndrome
Jama
Psychotropic treatment of chronic fatigue syndrome and related disorders
J Clin Psychiatry
Mindfulness training as an intervention for fibromyalgia: evidence of postintervention and 3-year follow-up benefits in well-being
Psychother Psychosom
Cited by (12)
Effectiveness of a psychoeducational treatment program implemented in general practice for fibromyalgia patients: A randomized controlled trial
2011, Clinical Journal of PainCitation Excerpt :In fact, comorbid anxiety has also emerged as one of the most important outcome predictors in medical illnesses.39 In contrast, anxiety has been shown to have no influence on the outcome in FM for pharmacologictreatments.40 Our findings indicate that an intervention including education and relaxation, made by an interdisciplinary team, is an effective treatment for FM, at least in the short term, as some investigators had suggested earlier.41
Paroxetine’s effect on the proinflammatory cytokine stimulation and intracellular signaling pathways in J774.2 cells
2023, Naunyn-Schmiedeberg's Archives of PharmacologyThe impact of depressive and bipolar symptoms on socioeconomic status, core symptoms, function and severity of fibromyalgia
2017, International Journal of Rheumatic DiseasesThe effects of inflammatory tooth pain on anxiety in adult male rats
2016, Basic and Clinical Neuroscience
- ☆
This work was supported by a Collaborative Research Grant from GlaxoSmithKline.