Testing Interventions for Patients With Fibromyalgia and Depression
Testing Interventions for Patients With Fibromyalgia and Depression
Chronic pain is a major health problem. It causes high economic and social costs around the
 world and severely impairs the quality of life of those who suffer from it. Chronic pain and
 major depression frequently co-occur. Patients with both conditions have a worse prognosis
 and higher disability, and their treatment options are scarce. Behavioral activation (BA) may
 be an especially useful intervention for these patients. This intervention targets mechanisms
 of action that seem to be common to both disorders. In spite of this, the efficacy of this
 intervention has not been yet examined in people with both conditions. Therefore, the purpose
 of the present study is to examine the efficacy of BA compared to usual care among Chilean
 women with fibromyalgia and mayor depression (N = 90). Women will be randomized to an
 experimental arm (n = 45) who will receive usual care (UC) for fibromyalgia with comorbid
 depression plus BA; and a comparison arm, who will receive only UC for fibromyalgia with
 comorbid depression (n =45). Primary and secondary outcomes will be assessed before, during,
 and after the intervention, as well as at a three month follow-up. The investigators expect
 to find that, after treatment, the group receiving BA will experience higher statistical and
 clinical significant reductions in depressive symptom severity (primary outcome), as well as
 in their levels of some pain-related variables (namely pain intensity, fibromyalgia impact,
 pain-related anxiety, catastrophism, and physical health symptoms severity). In addition, the
 percentage of women in remission from the diagnosis of depression (as well as the percentage
 of women responding to treatment) will be greater in the experimental arm than in the
 comparison arm. Also, the percentage of women who show a clinically significant reduction in
 pain intensity (decreases greater than two units in the pain intensity scale) will be greater
 in the experimental arm than in the comparison arm. Finally, the investigators hypothesize
 that the decrease observed in the pain-related variables will be mediated by the decrease
 observed in depressive symptoms severity. Regarding the outcomes assessed at a three months
 follow-up, the investigators expect to find that the differences found after treatment
 between the two arms will be maintained at follow-up. In order to test our hypothesis,
 Hierarchical Linear Models (HLM) and Cochran-Mantel-Haenszel tests will be performed. The
 results of these study might contribute to facilitate the integrated treatment of
 fibromyalgia and depression, and to reduce the burden on the health system due to the lack of
 effective therapeutic strategies to treat these comorbidity.
Chronic pain is a word-wide major health problem, which seriously affects the quality of life
 of those who experience it and causes important socio-economical costs (Tsang et al., 2008).
 According to the results of the last Chilean National Health Survey (2010), 34.2% of Chileans
 older than 15 years present pain ranging from moderate to severe. The pain experienced by a
 considerable proportion of these individuals (73.5%) is chronic. Among Chileans, chronic pain
 has been found to be related to more sickness leaves, a five-time increase in the use of
 primary care services, and the presence of depressive disorders (Miranda et al., 2013). In
 fact, around 35% patients with chronic pain suffer from depression (Gracely, Ceko, &
 Bushnell, 2012). In the case of some specific pain disorders such as fibromyalgia, this
 comorbidity is even greater (life prevalence around 90% for depressive symptomatology and
 62-86% for major depressive disorder; Gracely et al., 2012). As a result, some authors posit
 that fibromyalgia and depression are two manifestations of a single affective spectrum
 disorder (Gracely et al., 2012). In fact, according to some evidence, both disorders share
 pathophysiological aspects. For example, pharmacological treatment of both fibromyalgia and
 depression includes the same dual serotonergic and noradrenergic agonists, namely,
 amitriptyline and duloxetine (Maletic & Raison, 2009).

 Depressive symptoms impair chronic pain treatment and are associated with a worse chronic
 pain prognosis (Li, 2015). The increasing and concomitant prevalence of depression and
 chronic pain represents a burden for the primary care systems. Providing effective and
 appropriate primary care interventions to address this comorbidity is indeed needed,
 considering that chronic pain and depression lead to great disability. Taking into account
 that reducing disability is part of the second strategic objective of the Health Goals of the
 Decade 2011-2020 for Chile, the design and dissemination of therapeutic strategies aimed at
 the treatment of these problems is a priority in this country.

 Behavioral Activation (BA) is an evidence-based psychological intervention for depression
 (Cuijpers, Van Straten, & Warmerdam, 2007; Dimidjian, Barrera, Martell, Muñoz, & Lewinsohn,
 2011). It has been shown to be as effective as comprehensive cognitive behavioral therapy
 (Cuijpers et al., 2007) and antidepressant therapy (Dimidjian et al., 2006), with a lower
 dropout rate than the latter (Dimidjian et al., 2006). There is also evidence that BA works
 as well as medication and better than cognitive behavioral therapy in the treatment of severe
 depression (Dimidjian et al., 2006). Moreover, several meta-analyses support the efficacy of
 BA for the treatment of depression (Cuijpers et al., 2007; Ekers, Webster, Van Straten,
 Cuijpers, Richards, & Gilbody, 2014; Mazzucchelli, Kane, & Rees, 2009). According to the
 result of the last meta-analysis conducted (Ekers et al., 2014) - in which 26 randomized
 controlled trials (RCTs) were analyzed with a total of 1,524 participants - the treatment
 with BA is superior to the control condition (usual treatment, placebo, or waiting list),
 showing a high effect size (standardized mean difference, SMD: -0.74, 95% CI -0.91 a - 0.56).
 In addition, the examination of four RCTs with 283 participants showed that CT is also
 superior to medication. In this case the effect size was moderate (SMD -0.42, IC -0.83 to
 -0.00). Finally, according to the results of different studies conducted with several
 populations, BA can be used in multiple contexts and populations (Dimidjian et al., 2011)
 such as adolescents (Jacob, Keeley, Ritschel, and Craighead, 2013), seniors (Quijano et al.,
 2007), university students (Gawrysiak, Nicholas, & Hopko, 2009), and primary care patients
 (Uebelacker, Weisberg, Haggarty, & Miller, 2009).

 More research on the efficacy of BA is still needed, especially with regard to its effect
 after follow-up; however the results reported so far are promising. Furthermore, BA is much
 easier to apply and disseminate than other psychological treatments. For these reasons, there
 is now an increasing interest in examining the efficacy of this intervention in populations
 with different comorbidities such as obesity, cancer, anxiety, borderline personality,
 substance abuse, childhood abuse history, smoking, and post-traumatic stress disorder, among
 others (Dimidjian et al., 2011).

 BA could be particularly suitable for treating depression among patients with chronic pain,
 as some of its main purposes are fighting inactivity, increasing environmental reinforces,
 and decreasing aversive experiences. Indeed, inactivity, loss of reinforces, and excessive
 unpleasant experiences seem to play a key role in the etiology of both depressive disorders
 and chronic pain (Dimidjian et al., 2011, Leeuw et al. 2007). According to Lewinsohn's
 integrative model of depression (Lewinsohn, Hoberman, Teri, & Hautzinger, 1985), when a
 person with certain vulnerabilities faces a stressful event, that event and the emotions
 associated with it interrupt their normal behavior patterns, reduce the availability of the
 reinforcers in the environment, and increase the rate of aversive experiences. All this
 finally leads to depression. Depressive symptoms have a series of behavioral, cognitive, and
 emotional correlates that make the subject more vulnerable to new stressful events, thus
 creating a pathological cycle that is self-perpetuating in time. Something similar occurs
 when a person suffers a painful injury. According to Vlayen and Linton's Fear and Avoidance
 Model (FAM, 2000), in the face of a painful injury, vulnerable individuals (with increased
 pain catastrophizing or increased pain-related fear) develop strategies aimed at avoiding
 pain and the activities that cause it. This leads to inactivity, loss of reinforcers,
 disability, and depression, and consequently, to the exacerbation of the pain intensity and
 pain-related anxiety and catastrophizing. The patient is trapped in a vicious circle of
 symptoms that feed-back each other and perpetuate over time. Taking into account the FAM
 assumptions, as well as the purpose of the BA, this treatment may likely not only be useful
 for reducing depression in patients suffering from pain, but also for reducing the intensity
 of their pain and the anxiety and catastrophism associated with it. BA could break the chain
 of perpetuation in both disorders. In fact, there are preliminary data that support this
 premise. In a case study, in which BA was used with a woman who had been suffering from
 chronic pain associated with a diagnosis of fibromyalgia for 11 years, a clinically
 significant decrease in depressive symptoms was observed after treatment. In addition, the
 degree in which the pain interfered with the patient's daily activities was reduced (in a
 100%), as well as pain-related anxiety and the use of pain medication use. These results
 (with the exception of reduction in medication use) were maintained within three months of
 the intervention (Lundervold, Talley, & Buermann, 2006). These same authors replicated these
 findings in another study, in which they applied the same treatment to another woman who had
 been suffering from fibromyalgia for 22 years. In this case, the decreases of pain intensity,
 pain-related anxiety, depression, and medication use were maintained three and six months
 after the intervention (Lundervold, Talley, & Buermann, 2008).

 Behavioral activation is part of some cognitive behavioral pain management treatments (Ehde,
 Dillworth, & Turner, 2014) that include - in addition to BA - cognitive re-structuring. There
 is evidence that such treatments are effective in reducing symptoms associated with chronic
 pain (Ehde et al, 2014; Williams, Eccleston, & Morley, 2012). The size of the effect of such
 treatments varies from small to moderate, depending on the outcome variable analyzed. Thus,
 according to the results of the meta-analysis conducted by Williams and colleagues (2012),
 compared with the usual treatment, cognitive-behavioral interventions developed for pain
 management have small but significant effects on pain (SMD = -0.21, CI 95% CI = -0.37 to
 -0.05, Z = 2.35, p <0.05) and disability (DME = - 0.26, CI 95% = -0.47 a -0.04, Z = 2.35, p <
 0.05), and moderate effects on mood (DME = -0.38, 95% CI = -0.57 to -0.18, Z = 3.84, p <0.01)
 and catastrophism (DME = -0.53, 95% CI = -0.76 to -0.31, Z = 4.58, P <0.01). However, in
 relation to other active treatments, their effects on disability (DME = -0.19, 95% CI = -0.33
 to -0.05, Z = 2.66, p <0.01) and catastrophism (SMD = -0.18, 95 % = -0.36 to 0.00, Z = 1.92,
 p = 0.05) appear to be small, and no significant effects have been found for pain and mood.
 In addition, further studies are needed to examine the active components of cognitive
 behavioral therapy for pain (Ehde et al., 2014). Although BA may be one of the effective
 components of cognitive behavioral therapy, the intensity and emphasis placed on behavioral
 activation within cognitive behavioral treatments is small, and is generally limited to use
 in one session, so it is not known yet whether BA in isolation could have beneficial effects
 on pain. Furthermore, to our knowledge, no studies have been conducted to examine the
 efficacy of BA to reduce depressive symptoms in patients with chronic pain (beyond the
 abovementioned case studies).

 Finally, it is important to highlight that BA has multiple advantages that make it very
 efficient in terms of costs and benefits. First, it is a brief therapy, very easy to apply
 and disseminate (Dimidjian et al., 2011). In addition, it can be implemented by
 non-psychologists after appropriate training (e. g., nurses or social workers; Ekers,
 Richards, McMillan, Bland, & Gilbody, 2011). It can also be implemented in group format
 (Houghton, Curran, & Saxon, 2008; Porter, Spates, & Smitham, 2004) and in the context of
 primary care (Dimidjian et al., 2011). Finally, there are preliminary results that support
 its effectiveness in the Latino population (Bianchi & Henao, 2015; Kanter, Santiago-Rivera,
 Rusch, Busch, & West, 2010). Taken together, these advantages make BA of particular interest
 in the Latin American context, where economic limitations often do not allow for long and
 complex treatments, and access to trained therapists is usually limited. Therefore, the
 purpose of the present study is to examine the effectiveness of BA in a sample of Chilean
 women with chronic pain and comorbid mayor depression. For several reasons, the investigators
 will study the efficacy of this treatment in women with the same diagnosis of chronic pain,
 namely fibromyalgia. First, because this is the first RCT examining the efficacy of BA in
 patients with chronic pain, it is advisable to include patients with the same diagnosis to
 increase the homogeneity of the sample. Secondly, BA may be more effective in this type of
 patients, as there is a high comorbidity between fibromyalgia and depression and both
 disorders have been hypothesized to be manifestations of a single affective spectrum disorder
 (Gracely et al., 2012), Finally, preliminary results on the effects of BA in patients with
 pain have been reported in women with fibromyalgia.

 The investigators expect to find that, after treatment, the women in the experimental arm
 will experience greater decreases in depressive symptoms severity as well as in the
 pain-related variables assessed (pain intensity, fibromyalgia impact, pain-related anxiety,
 catastrophism, and physical health symptoms severity) than women in the comparison arm. In
 addition, the percentage of women in remission from the diagnosis of depression (as well as
 the percentage of women responding to treatment) will be greater in the experimental arm than
 in the comparison arm. Similarly, the percentage of women who show a clinically significant
 reduction in pain intensity (decreases greater than two units in the pain intensity scale)
 will be greater in the experimental arm than in the comparison arm. Finally, the
 investigators hypothesize that the decreases observed in the pain-related variables will be
 mediated by decreases observed in depressive symptoms severity.

 Regarding the outcomes assessed at a three months follow-up, the investigators expect to find
 that the differences found between the two groups in the depressive symptoms severity and the
 pain-related variables decreases will be maintained at follow-up. Furthermore, at follow-up
 the percentage of women in remission from the diagnosis of depression (as well as the
 percentage of women responding to treatment) will continue to be greater in the experimental
 arm than in the comparison arm. Similarly, after follow-up, the percentage of women who show
 a clinically significant reduction in pain intensity will continue to be greater in the
 experimental arm than in the comparison arm. The differences found after the follow-up in the
 pain-related variables will be mediated by the differences found in depressive symptoms
 severity.

 Method

 Participants:

 Women diagnosed with fibromyalgia and major depression attended at the Service of Family
 Medicine, Reumathology or Traumatology of the UC-Christus Health Network (N = 90) will
 participate.

 The study sample size was calculated for a Hierarchical Linear Model (HLM) in which the
 primary outcome (changes in depressive symptoms severity) was the dependent variable. Using
 Mplus, the investigators determined that a sample of 90 participants was needed to reach a
 power of .80. In this power analysis, the correlation between the intercept and the slope was
 specified to be -0.4. The average slope was assumed to be negative, as depression scores are
 expected to drop, and was specified as -0.5. To simplify the model, the variances of the
 intercept, slope, and scores of all the variables in the model (depressive symptoms severity,
 and covariates) were specified as 1, so as to have the standardized model solution. The
 treatment effect on the slope (standardized Beta) was specified as 0.45. This corresponds to
 a medium-to-large effect size (Cohen, 1992). In addition, the effect of two covariates was
 included. The effect of each of the covariates on the slope was specified as 0.1. The
 correlation between treatment and each covariate was specified as 0.1, and the correlation
 between covariates was specified as 0.3.

 Design The present study is a randomized clinical trial with a parallel design. After the
 diagnosis interview, participants will be randomly assigned to two intervention arms: an
 experimental arm - that will be treated with BA in a group setting in addition to usual care
 (UC) for fibromyalgia and comorbid depression- and a comparison arm that will receive only UC
 for fibromyalgia with comorbid depression. The research design is longitudinal and mixed
 (within and between subjects repeated measures). Outcomes will be assessed in both groups
 before, during and after the intervention, as well as after a three-month follow-up, by a
 research assistant who will be blind to group assignment.

 Procedure Participants will be recruited through several procedures. First, posters and
 brochures with information about the study will be available at the medical attention boxes,
 so that patients interested in participation could contact the research team by email or
 phone. In addition, one of the nurses of the medical center will contact by phone all the
 fibromyalgia patients registered in the medical center to ask them for permission to put them
 in contact with the study research team. Participants who agree to be contacted will received
 a phone call by a research assistant, who will provide them with further information about
 the study and - in order to corroborate that they indeed meet the inclusion criteria for
 fibromyalgia and mayor depression -ask them to respond to the Fibromyalgia Survey
 Questionnaire (FSQ; Wolfe et al., 2011; Carrillo de la Peña et al., 2015) and the Patients
 Health Questionnaire-9 (PHQ-9; Baader et al., 2008). Participants who meet inclusion criteria
 will be scheduled for a diagnoses interview according to Diagnostic and Statistical Manual of
 Mental Disorders IV (DSM-IV) criteria. The Mini-International Neuropsychiatric Interview
 (MINI; Ferrando, Bobes, & Gilbert, 1999; Sheehan & Lecrubier, 1999) will be applied in order
 to make the diagnoses. In addition, the Mini-Mental State Examination (Folstein, Folstein, &
 Mchugh, 1975, González-Hernández et al., 2009) will be administered. All participant will be
 asked for informed consent before participation. Participants who meet all the inclusion
 criteria after this interview will be randomized to the two arms. Randomization will be
 conducted by a research assistant (other than those who will perform the assessments,
 treatment and data analysis) using a computer program. As a compensation, patients will
 receive gift card (with a value of 10.000 Chilean pesos) after each outcome assessment
 interview.

 Data analyses In order to test whether there are differences between the groups in the
 sociodemographic and clinical characteristics assessed at baseline, Student's t-tests will be
 performed for continuous variables and Chi-square test for categorical variables. If there
 are small or empty cells in the categorical tests, the Chi-square test will be replaced by an
 Exact Fisher's Test. Those variables in which statistically significant differences are found
 will be introduced in the analyses as covariates.

 In order to examine the differences between the groups in the reduction of the primary and
 secondary outcome, HLM will be performed using MPlus. This analysis involves two levels of
 analysis: intra-subject (Level 1, which analyzes the change of subjects over time) and
 inter-subject (Level 2, through which the effect of treatment is examined). Repeated measures
 of symptoms are nested in each subject, and the analysis allows estimating a change parameter
 along repeated measurements. The analysis tests whether the change parameter varies according
 to the treatment group, and other covariates. HLM allows to consider in the analyses all
 participants (including those who abandoned the study). Therefore, these analyses will be
 conducted according to the principle of intention to treat.

 In order to examine whether there are differences between the groups in the remission of the
 diagnosis of depression, the investigators will perform two Cochran-Mantel-Haenszel tests
 (one for the results obtained after the intervention and another for the results obtained
 after the follow-up). Similarly, in order to examine whether there is a response to treatment
 (reduction of at least 50% in the severity of depressive symptoms; Dimidjian et al., 2006),
 two other Cochran-Mantel-Haenszel testse will be carried out. Finally, in order to examine
 whether there are any differences between the groups in the percentage of women responding to
 treatment with regard to the intensity of pain, two more Cochran-Mantel-Haenszel tests will
 be performed. Treatment response will be considered if there are reductions of at least two
 units on the pain scale from 0 to 10, as this is the criteria usually employed for clinically
 significant pain improvement (Michener, Snyder, & Leggin, 2011). Finally, in order to test
 whether the decreases found after the follow-up in the pain-related variables are mediated by
 the decrease in depressive symptoms severity, regression analysis with bootstrapping will be
 conducted (Preacher & Hayes, 2008).
Inclusion criteria:

 1. Being 18 years old or older

 2. Understanding Spanish

 3. Meeting the diagnostic criteria for fibromyalgia according to the Fibromyalgia Survey
 Questionnaire (FSQ)

 4. Have a primary diagnosis of major depression according to the MINI International
 Neuropsychiatric Interview (MINI).

 5. Being receiving usual care for fibromyalgia and depression in the Medical Center San
 Joaquín (Red Salud UC Christus, Santiago Chile).

 6. Being under treatment with duloxetine.

 Exclusion criteria:

 1. Having past or present history of psychosis, bipolar disorder, or substance use
 disorder

 2. Presenting risk of suicide according to the suicide module of the MINI

 3. Presenting a lower score than the cut-off point in the Minimental Cognitive
 Examination

 4. Being participating simultaneously in another therapy for the depression or pain

 5. Being treated with antidepressants other than duloxetine

 6. Being diagnosed with Rheumatoid arthritis or other connective tissue diseases.