ORIGINAL INVESTIGATION

Quetiapine extended-release (Seroquel-XR) versusamitriptyline monotherapy for treating patientswith fibromyalgia: a 16-week, randomized,flexible-dose, open-label trial

Elena P. Calandre & Fernando Rico-Villademoros & Jaime Galán &

Rocio Molina-Barea & Juan S. Vilchez & Carmen M. Rodriguez-Lopez &

Javier Hidalgo-Tallon & Piedad Morillas-Arques

Received: 11 September 2013 /Accepted: 16 December 2013# Springer-Verlag Berlin Heidelberg 2014

AbstractRationale Previous open-label studies have suggested thatquetiapine could be a valuable alternative for treatingfibromyalgia.Objective This study aims to compare the efficacy and toler-ability of extended-release quetiapine with amitriptyline fortreating fibromyalgia.Methods This study was a randomized, open-label, flexible-dose, non-inferiority trial. Patients with fibromyalgia wererandomized to receive quetiapine extended-release (XR) (N=45) (50 to 300 mg daily) or amitriptyline (N=45) (10 to 75 mgdaily) for 16 weeks. The primary endpoint was the changefrom baseline to endpoint in the Fibromyalgia ImpactQuestionnaire (FIQ) total score; the non-inferiority thresholdwas established at 8 points. The secondary outcomes includedsleep quality, anxiety, depression, and quality of life.Results Twenty-two (49 %) patients in the quetiapine groupand 34 (76 %) patients in the amitriptyline group completed thestudy. We found a reduction of 9.8 points in the total FIQ scoreat the endpoint for the quetiapine-treated patients compared to13.9 points for the amitriptyline-treated patients, for a differenceof 4.14 points (80% confidence interval (CI) −0.70 to 8.98). Nosignificant differences were found between the quetiapine XRand amitriptyline groups for any of the secondary outcomes.

The proportion of patients discontinuing treatment due toadverse events was higher in the quetiapine group (n=14,31.1 %) than the amitriptyline group (n=3, 6.6 %).Conclusions Our results appear to indicate that quetiapine XRdoes not provide similar efficacy to amitriptyline for treatingpatients with fibromyalgia. Quetiapine XR had a worse toler-ability than amitriptyline in this population, possibly due to arelatively high starting dose.

Keywords Fibromyalgia . Quetiapine XR . Amitriptyline .

Efficacy . Tolerability

Introduction

Fibromyalgia is a syndrome characterized by widespread painaccompanied by a wide array of symptoms, including chronicfatigue, sleep disturbances, morning stiffness, cognitive com-plaints, balance problems, and psychological distress. Severaldrugs are considered to be effective for treating fibromyalgia,including tricyclic antidepressants (amitriptyline andcyclobenzaprine), serotonin-noradrenaline reuptake inhibitors(duloxetine and milnacipran), the α2-δ ligands pregabalin andgabapentin, and sodium oxybate (Le Marshall and Littlejohn2011). However, none of these drugs have a significant effecton all dimensions of fibromyalgia symptomatology, and thenet benefit of these drugs is modest (Häuser et al. 2010, 2012).Therefore, further investigation of new drugs for treating thismultidimensional disease is needed.

Quetiapine is a second-generation antipsychotic with a com-plex mechanism of action, including weak D2 receptor antago-nism, 5-HT2A and 5-HT3 receptor antagonism, partial 5-HT1Areceptor agonism, H1 receptor antagonism, and moderate-to-

E. P. Calandre (*) : F. Rico-Villademoros : R. Molina-Barea :J. S. Vilchez : C. M. Rodriguez-Lopez : J. Hidalgo-Tallon :P. Morillas-ArquesInstituto de Neurociencias, Universidad de Granada, Avenida deMadrid 11, Granada, Spaine-mail: calandre@gmail.com

J. GalánHospital Quirón, Málaga, Spain

PsychopharmacologyDOI 10.1007/s00213-013-3422-0

high affinity for the α1- and α2-adrenoceptors. In addition, itsmain active metabolite, N-desalkyl-quetiapine, is a potent inhib-itor of the noradrenaline transporter (McIntyre et al. 2007).

In addition to schizophrenia, quetiapine is also licensed fortreating acute mania and bipolar depression and as add-ontreatment for refractory depression. Several controlled clinicaltrials have also shown that quetiapine is effective in treatinggeneralized anxiety disorder but has not yet been approved fortreating this condition (Bandelow et al. 2010; Katzman et al.2011). Quetiapine has been shown to exert a beneficial effecton sleep parameters in healthy subjects (Cohrs et al. 2004) andis commonly used on an off-label basis to treat insomnia (Coeand Hong 2012). All of these sleep-improving, antidepressant,and antianxiety characteristics suggest that quetiapine couldbe effective for treating several symptoms associated withfibromyalgia.

A congress communication published in abstract form in2003 (Shemo et al. 2003) reported an improvement in pain,mood, and sleep and/or cognition in seven fibromyalgia pa-tients with psychiatric comorbidities when treated withquetiapine as add-on therapy in a dose ranging from 25 to200mg daily. Hidalgo et al. (2007) evaluated the effectivenessof add-on treatment with quetiapine in a noncontrolled studythat included 35 patients with fibromyalgia, and they reportedsignificant improvements in sleep quality, fibromyalgia globalseverity, and the mental component of quality life, althoughthere was a lack of specific improvement in pain.

The present study aimed to compare the efficacy andtolerability of extended-release quetiapine (Seroquel-XR)with amitriptyline for treating fibromyalgia symptoms.

Patients and methods

Design

This was a single-center, randomized, open-label, flexible-dose, non-inferiority trial. After a 4-week washout period forthe previously prescribed medications for fibromyalgia, thepatients were randomized to receive extended-releasequetiapine (50 to 300 mg daily) or amitriptyline (10 to75 mg daily) over a 16-week period.

When this study was being prepared, the authors knew thatother double-blind, placebo-controlled trials with quetiapinefor treating fibromyalgia were planned; thus, the authors de-cided to use an active comparator in this study. Amitriptylinewas selected because this drug has been demonstrated to beeffective in managing fibromyalgia and because its sleep-improving and antidepressant properties parallel those ofquetiapine.

The randomization, which was performed with a computerprogram available online, was stratified for major depressivedisorder. When a patient was found to be eligible for

randomization, a fax was sent by the investigator to theheadquarters of the clinical research organization, which mon-itored the study, and the corresponding allocation code wasreturned by fax. The study medication was then provided bythe hospital pharmacy.

The daily minimum target efficacy doses were 100 mg forquetiapine and 25 mg for amitriptyline, although patients whodid not tolerate either dose could be reverted to the initial dose.Dose adjustments were performed according to the efficacyand tolerability of each drug at 7- to 14-day intervals, withstepwise increases of 50 mg of quetiapine or 10 to 15 mg ofamitriptyline. Both drugs were administered as a single dailydose at bedtime. During the trial, the patients were allowed totake medications prescribed for concomitant diseases that didnot exclude them for eligibility. As a rescue medication forpain, up to 3 g daily of paracetamol was permitted throughoutthe study. Up to 3 mg daily of bromazepam was allowed fortreating anxiety and/or insomnia only during the first 4 weeksafter randomization. The patients’ evaluations were performedat 2-week intervals from baseline to week 8 and at 4-weekintervals from week 8 to the end of the study.

Patients

The study included female andmale patients aged 18–70 yearswho fulfilled the 1990 American College of Rheumatologydiagnostic criteria (Wolfe et al. 1990) by scoring a minimumof 40 on the Fibromyalgia Impact Questionnaire (FIQ) totalscore and a minimum of 4 on the average pain severity item inthe Brief Pain Inventory (BPI). Patients were referred to ourinvestigation unit from general practitioners, rheumatologists,pain units, and/or fibromyalgia patient associations. Everypatient gave written informed consent to participate in thestudy, which was approved by the Ethics Committee of the“San Cecilio” University Hospital of Granada. The study wasconducted in accordance with the principles contained in theDeclaration of Helsinki. The trial registration number wasNCT-00766350.

The exclusion criteria were the following: (1) pregnancy,lactation, and women of childbearing age not using a validcontraception method; (2) patients with any DSM-IV-RAxis Ipsychiatric disorder other than major depression; (3) patientswith major severe depression as evidenced by a BeckDepression Inventory (BDI) score of ≥30; (4) substance and/or alcohol dependence; (5) current clinically relevant cardio-vascular, cerebrovascular, renal, hepatic, or respiratory diseaseor any other serious physical illness; (6) uncontrolleddiabetes mellitus; (7) unwillingness to discontinue drugsprescribed for fibromyalgia; (8) patients who had re-ceived quetiapine or amitriptyline within 1 year of random-ization; and (9) patients who at the randomization had achange in the FIQ total score of ≥20 % in relation to the valuedetermined at the screening visit.

Psychopharmacology

Outcome efficacy measures

The primary outcome was the change from baseline to theendpoint in the FIQ total score. We used the Spanish validatedversion (Esteve-Vives et al. 2007). The FIQ was administeredat the screening visit, at baseline and weeks 4, 8, 12, and 16.

The secondary outcomes were the following Spanish-validated scales: the BPI modified short form (Badia et al.2003), the Pittsburgh Sleep Quality Index (PSQI) (Royuelaand Macías 1997), the BDI (Vazquez and Sanz 1997), theState and Trait Anxiety Inventory (STAI) (Spielberger et al.2002), and the Short Form Health Survey (SF-36) (Alonsoet al. 1995); in addition, a Patient Global Improvement scale(PGI) was administered (Guy 1976).

Safety

The safety measurements included ECG, vital signs, completeblood count, blood chemistry, urinalysis, and adverse eventrecording. ECG, vital signs, and blood and urine analyseswere performed on the screening visit and at the end of thetrial. The adverse events were recorded at every visit follow-ing randomization and included those spontaneously reportedby the patient and those reported in response to a nonleadingquestion from the investigator.

Statistical analyses

The non-inferiority threshold was established at eight points.The randomized clinical trials of several drugs tested againstplacebo for treating fibromyalgia showed a mean difference inthe FIQ total score of 8,163 points between the last assessmentand baseline, with a mean variance of 317 (standard deviation(SD)=17.82). Based on those data and assuming a risk of10 % (confidence interval (CI)=90 %) and 80 % power, in aone-sided test, 45 subjects per group would be required to testnon-inferiority. The non-inferiority of quetiapine compared toamitriptyline was accepted when the upper limit of the confi-dence interval (80 %) for the observed difference excluded thenon-inferiority threshold.

Primary efficacy analyses were performed in the modifiedintention-to-treat (m-ITT) sample that included every random-ized patient who had at least one post-baseline visit; in addi-tion, analyses were also performed in the ITT sample thatincluded every randomized patient. Safety analyses were per-formed among the sample of patients who were randomizedand took at least one dose of the assigned drug.

The differences in the changes of the continuous efficacyoutcome measures were evaluated with repeated-measuresANCOVA using the baseline value as the independent variableand the change in the score as the dependent variable.Differences in the changes between quetiapine and amitriptylinewere assessed with Student’s t test or Wilcoxon Mann-Whitney

test. Frequency variables, such as the PGI and adverse events,were evaluated with the chi-squared test or Fisher’s exact test.All of the statistical analyses were performed with the statisticalpackage SAS version 8.02.

Results

Ninety-five patients were screened, 90 patients were random-ized, and 45 patients were allocated to each treatment group.There were no relevant differences between the demographicand clinical baseline data for either group (Table 1). Twenty-two (49 %) patients in the quetiapine group and 34 (76 %)patients in the amitriptyline group completed the study; thepatients’ disposition and reasons for discontinuation are shownin Fig. 1. Only three patients in the quetiapine group and twopatients in the amitriptyline group suffered major depressivedisorder. The m-ITT sample included 33 quetiapine-treatedpatients and 43 amitriptyline-treated patients. The final drugdoses ranged from 50 to 300 (121±86)mg/day for quetiapineXR and 10 to 75 (46±20)mg/day for amitriptyline.

The FIQ scores in the m-ITT sample are shown in Table 2,and secondary outcome scores for efficacy are shown inTable 3. The differences in the change in the FIQ total scorebetween the two study drugs were 4.14 (80 % CI −0.70 to8.98) for the m-ITT sample and 6.13 (80 % CI 1.97 to 10.29)for the ITT sample, discarding the non-inferiority ofquetiapine compared to amitriptyline (Fig. 2). No significantdifferences were found between quetiapine XR and amitrip-tyline for any of the evaluated parameters. The results werealso similar in the ITT sample and among completers.

Table 1 Demographic and baseline characteristics of the patients

Quetiapine(N=45)

Amitriptyline(N=45)

General data

Age (mean ± SD) 49.7±7.9 50.6±8.2

Women [N (%)] 45 (100) 43 (95.6)

Weight (mean ± SD) 71.7±13.2 69.8±11.5

Years since diagnosis (mean ± SD) 4.0±3.5 4.5±4.2

Current MDD [N (%)] 3 (6.7) 2 (4.4)

Baseline data [N (%)]

FIQ 75.4±11.4 76.6±12.2

BPI severity 7.25±1.5 7.32±1.6

BPI interference 7.46±1.6 7.68±1.4

PSQI 14.9±3.8 14.9±3.9

BDI 21.5±6.4 20.9±6.0

STAI state 40.3±9.4 39.2±10.1

STAI trait 39.7±6.3 39.3±9.8

SF-36 PCS 27.8±6.3 28.2±5.1

SF-36 MCS 29.7±11.0 30.7±10.7

Psychopharmacology

Among completers, 10 (45.5 %) of the quetiapine-treatedpatients and 18 (52.9 %) of the amitriptyline-treated patientswere reported to be much or very much improved. Details ofthe PGI scores are given in Fig. 3.

Tolerability

No patient died or experienced any serious adverse eventduring the study. Forty-five (100 %) of the quetiapine-treated patients and 42 (93.3 %) of the amitriptyline-treatedpatients reported at least one adverse event. Adverse eventsleading to drug discontinuation were more frequent in thequetiapine-treated group than the amitriptyline-treated group.The most common adverse events leading to withdrawal weresomnolence (17.8 %) and dizziness (11.1 %) among patientsreceiving quetiapine and dizziness (6.7 %) and headache(6.7 %) among patients receiving amitriptyline. Of note, 11(78.6 %) of the 14 patients who withdrew from the study dueto adverse events in the quetiapine-treated group did so be-tween the baseline and first follow-up visit when they received

only 50 mg/day of the drug. The adverse events reported by atleast 10 % of the patients in each group are shown in Table 4.Dizziness, somnolence, dry mouth, and constipation were themost frequently reported adverse events in both treatmentgroups; dizziness and somnolence were mainly reported bythe quetiapine-treated patients, whereas dry mouth and con-stipation were mainly reported by the amitriptyline-treatedpatients. A weight increase was observed in seven (15.6 %)patients treated with amitriptyline and five (11.1 %) patientstreated with quetiapine. One patient, treated with amitripty-line, had hyperglycemia. No other relevant changes in vitalsigns (including blood pressure), complete blood count, orblood biochemistry (including total cholesterol, LDL choles-terol, and triglycerides) were observed with either drug.

Discussion

This randomized clinical trial failed to show that quetiapineXR is non-inferior, in terms of efficacy, to amitriptyline fortreating patients with fibromyalgia. Moreover, quetiapine XR

Fig. 1 Patients’ disposition

Table 2 Changes from baseline to endpoint in the Fibromyalgia ImpactQuestionnaire scores (m-ITT sample)

Quetiapine XR(N=33)

Amitriptyline(N=43)

p

Total score −9.8±15.5 −13.9±16.7 0.3728

Physical impairment −0.32±1.9 −0.20±1.9 0.8575

Feel good −1.73±3.1 −2.43±3.0 0.9190

Missed work −0.43±3.2 −0.83±3.7 0.9047

Work difficulty −1.06±2.2 −1.88±2.9 0.4038

Pain −0.94±2.3 −1.40±2.4 0.8413

Fatigue −1.14±1.9 −1.30±2.3 0.7698

Morning tiredness −0.70±1.7 −1.27±2.7 0.3765

Stiffness −1.32±2.4 −1.31±2.5 0.9377

Anxiety −1.20±2.5 −1.59±2.6 0.5260

Depression −1.08±2.5 −1.60±2.5 0.4507

The mean values and SDs are provided

Table 3 Changes from baseline to endpoint in the secondary outcomevariables (m-ITT sample)

Quetiapine XR(N=33)

Amitriptyline(N=43)

p

BPI severity −1.21±2.0 −1.21±1.9 0.6199

BPI interference −1.34±2.3 −1.48±1.9 0.9874

PSQI −3.88±4.3 −3.79±4.1 0.6239

BDI −2.12±7.9 −4.19±7.6 0.2498

STAI state −5.45±11.2 −5.88±10.1 0.6234

STAI trait −1.70±7.9 −4.63±9.4 0.0952

SF-36 PCSa 2.34±7.3 0.94±6.6 0.3749

SF-36 MCSa 5.26±11.9 5.5±11.7 0.9395

The mean values and SDs are provideda The positive values indicate improvement

Psychopharmacology

showed a worse tolerability than amitriptyline in thispopulation.

In the primary analysis, we found a reduction of 9.8 pointsin the FIQ total score at the endpoint among the quetiapine-treated patients compared to 13.9 points in the amitriptyline-treated patients, for a difference of 4.14 points (80 % CI −0.70to 8.89); the upper limit of the corresponding 80% confidenceinterval for this difference reached the a priori establishedthreshold for non-inferiority (i.e., eight points), which doesnot support the non-inferiority hypothesis. The results of thesecondary outcomes were in the same direction and showedthat quetiapine did not provide any additional benefit overamitriptyline. In fact, the numerical differences between thetwo drugs favored amitriptyline in most outcomes.

The reduction in the FIQ total score (9.8 points; FIQ scorerange 0–100) was almost identical to the one we observed in aprevious uncontrolled study (10.2; FIQ score range 0–80)using the immediate release (IR) formulation of quetiapine

(0–80) (Hidalgo et al. 2007). These results may indicate thatquetiapine is active (i.e., better than placebo) in patients withfibromyalgia. However, in a recently published randomizedclinical trial comparing quetiapine XR with placebo, althoughquetiapine XR improved the overall symptomatology of fi-bromyalgia, the differences compared to placebo were onlysignificant for sleep quality (Potvin et al. 2012). In anothertrial that compared quetiapine XR with placebo in patientsexperiencing depression and concomitant fibromyalgia,quetiapine, administered as add-on treatment, improved notonly depression scores but also pain scores, total FIQ scores,and global functioning (McIntyre et al. 2013); however, in thattrial, most patients were receiving opioids, non-opioids anal-gesics, or anticonvulsants, and therefore, the amelioration ofpain cannot be solely attributed to quetiapine XR. Finally,preliminary data have been reported for another clinical trial;Moore et al. (2011), in a 12-week, randomized, double-blind,placebo-controlled, crossover trial evaluating the effect ofquetiapine XR in patients with fibromyalgia who had notresponded satisfactorily to previous treatment, reported a sig-nificant improvement over placebo in the FIQ total score andsleep measures for the first ten patients who entered into thestudy (Moore et al. 2011). Thus, it seems that the role ofquetiapine for the treatment of fibromyalgia deserves furtherstudy.

We think that our efficacy results are influenced by the poortolerability of quetiapine XR in this population. Fifty-onepercent of patients in the quetiapine group withdrew fromthe study prematurely; most of the withdrawals (31 %) weredue to adverse events. This poor tolerability of quetiapine XRwas somewhat unexpected. In a previous uncontrolled 12-week study of 35 patients with fibromyalgia treated withquetiapine IR, we found that only 14 % of the patients

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

m-ITT (Primary)

ITT (Secondary)

Amitriptylinebetter

Quetiapinebetter

δ

Fig. 2 Difference (quetiapine minus amitriptyline) in the mean changefrom baseline to endpoint in the FIQ total score and its 80 % confidenceinterval

Fig. 3 Patients Global Improvement Scale at endpoint

Table 4 Adverse events reported by ≥10 % of the patients

Adverse event [N (%)] Quetiapine(N=45)

Amitriptyline(N=45)

Dry mouth 14 (31.1) 28 (62.2)

Nausea/vomiting 6 (13.3) 8 (17.8)

Constipation 8 (17.8) 13 (28.9)

Increased appetite 3 (6.7) 6 (13.3)

Increased weight 5 (11.1) 7 (15.6)

Dizziness 17 (37.8) 12 (26.7)

Somnolence 15 (33.3) 13 (28.9)

Anxiety 8 (17.8) 4 (8.9)

Nightmares 4 (8.9) 7 (15.6)

Hypoesthesia 5 (11.1) 1 (2.2)

Headache 4 (8.9) 11 (24.4)

Palpitations 2 (4.4) 8 (17.8)

Tachycardia 2 (4.4) 6 (13.3)

Tinnitus 0 (0.0) 5 (11.1)

Psychopharmacology

withdrew from the study (6 % due to adverse events). Asmentioned above, most of the discontinuations of quetiapineXR in this trial occurred with the initial dose of quetiapine(i.e., 50 mg/day), suggesting that this dose could be too highfor these patients. This fact could explain the difference be-tween the results with quetiapine XR and those we found withquetiapine IR. In the latter trial, the initial dose was 25 mg/day; unfortunately, the lowest available strengths forquetiapine XR is 50 mg/day and, therefore, was the initialdose used in this trial. The tolerability of psychotropicsimproves when starting at a low dose and titrating slowly,which improves other outcomes, such as treatment persis-tence (Wu et al. 2012). Dose-dependent tolerability ofquetiapine has been shown in patients with bipolar de-pression and patients with major depression (Gao et al.2011), which supports our proposal of reducing thestarting dose of quetiapine used for patients with fibro-myalgia. Pharmacokinetic variability may have also con-tributed to this poor tolerability; a recent publication hasshown that the concentration/dose ratio for quetiapine andquetiapine sulfoxide significantly differed between the IRand XR formulations of the drug (Fisher et al. 2012).

Finally, in a previous uncontrolled study, quetiapine IRwasadded to the patient’s current treatment regimen (Hidalgo et al.2007), while in the present study, quetiapine XR was initiatedas monotherapy in patients who underwent a washout period.Because patients with fibromyalgia are especially sensitive todrug side effects (Barkhuizen 2002), those who are already ona treatment regimen are more likely to tolerate the addition ofa new drug because they are currently tolerating other drugs.The results of a trial investigating sequential treatment withtrazodone and pregabalin in patients with fibromyalgia sup-port this latter possibility (Calandre et al. 2011); in this trial,patients receiving trazodone as monotherapy withdrew be-cause of adverse events in a substantially higher proportionthan those who, having tolerated trazodone, receivedpregabalin as add-on treatment. In a placebo-controlled, ran-domized clinical trial with quetiapine XR (Potvin et al. 2012),only five (20 %) of the quetiapine-treated patients withdrewprematurely from the trial, and all of them were lost to follow-up; however, in this trial, quetiapine was administered as add-on therapy. Finally, the tolerability of quetiapine XR seems todiffer across its several indications (Gao et al. 2011; Wanget al. 2011). In a review of the literature (Wang et al. 2011), therisk of discontinuation due to adverse events with quetiapineXR was not significantly different from placebo in two ran-domized trials in patients with schizophrenia or mania andwas significantly increased in randomized trials of patientswith bipolar depression, refractory major depression, majordepression, and generalized anxiety disorder; the numberneeded to harm (NNH) for this outcomewas lower for patientswith generalized anxiety disorder (NNH=5) than patients withbipolar depression, refractory major depression, or major

depression (NNH ranging from 8 to 9). Therefore, patientswith fibromyalgia may be very sensitive to the side effects ofquetiapine XR, possibly much more sensitive than those withschizophrenia or mania.

Many antipsychotics have been shown to exert analgesicactivity in animal models. In addition, several antipsychotics,mainly the second generation ones, have been demonstrated inhumans to improve depression and/or anxiety features fre-quently associated to fibromyalgia. However, clinical dataregarding the effectiveness of antipsychotics for treating fi-bromyalgia come from case reports and uncontrolled studiesand have been generally disappointing. Only quetiapineshowed a clear beneficial effect and a good tolerability profilein a case report and an uncontrolled study and has beensubsequently investigated in randomized clinical trials(Calandre and Rico-Villademoros 2012).

Although not an objective of this study, we think that theresults of amitriptyline in this trial are remarkable. The tolera-bility of amitriptyline, the main concern with this drug, wasgood, and the efficacy results were consistent with those pre-viously reported in the literature, including those from a recentmeta-analysis of using antidepressants to treat fibromyalgia(Häuser et al. 2012). Interestingly, a recent randomized com-parison of amitriptyline, duloxetine, and pregabalin in patientswith neuropathic pain found no difference in pain ameliorationamong the three drugs (Boyle et al. 2012). In that trial, ami-triptyline did not compromise cognitive function, tolerability,or safety parameters and showed similar results to the compar-ators in terms of quality of life. To our knowledge, such acomparison has not been made in patients with fibromyalgia,but it is needed; therefore, the relative position of amitriptylinein the pharmacological armamentarium for this disease has notyet been established. However, our results support that this olddrug still plays a role in treating fibromyalgia.

Our study has several limitations; the major limitationis that the lack of blinding could have introduced anevaluation bias. While this fact is obviously true, this lackof blinding is expected to bias the results toward ourhypothesis. Looking at the results, this bias did not seemto have a major impact on our results. The non-inferioritythreshold and sample size could be additional limitations,but again, these factors did not have a major impact onour results or their interpretation.

In conclusion, despite the promising results with thestandard formulation of quetiapine in an uncontrolledstudy for this indication (Hidalgo et al. 2007), our resultsappear to indicate that quetiapine XR does not providesimilar efficacy to amitriptyline and is poorly tolerated inpatients with fibromyalgia. Whether quetiapine XR iseffective for this indication and/or may be useful for aspecific subpopulation (e.g., patients with fibromyalgiaand major depression) could be clarified by the resultsof other ongoing randomized trials.

Psychopharmacology

Acknowledgments Partial funding for this study was provided byAstraZeneca, as an investigator-sponsored study. The company had noinvolvement in writing the manuscript or interpreting the results.

Conflict of interest Dr. Rico-Villademoros has served as a freelanceconsultant for AstraZeneca Farmacéutica Spain. The remaining authorsdo not declare any conflict of interest.

References

Alonso J, Prieto L, Antó JM (1995) The Spanish version of the SF-36Health Survey (the SF-36 health questionnaire): an instrument formeasuring clinical results. Med Clin (Barc) 104:771–776

Badia X, Muriel C, Gracia A et al (2003) Validación española delcuestionario Brief Pain Inventory en pacientes con dolor de causaneoplásica. Med Clin (Barc) 120:52–59

Bandelow B, Chouinard G, Bobes J et al (2010) Extended-quetiapinefumarate (quetiapine XR): a one-daily monotherapy effective in gen-eralized anxiety disorder. Data from a randomized, double-blind,placebo- and active-controlled study. Int J Neuropsychopharmacol13:305–320

Barkhuizen A (2002) Rational and targeted pharmacologic treatment offibromyalgia. Rheum Dis Clin North Am 28:261–290

Boyle J, Eriksson ME, Gribble L et al (2012) Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalinin patients with chronic diabetic peripheral neuropathic pain: impacton pain, polysomnographic sleep, daytime functioning, and qualityof life. Diabetes Care 35:2451–2458

Calandre EP, Rico-Villademoros F (2012) The role of antipsychotics inthe management of fibromyalgia. CNS Drugs 6:135–153

Calandre EP, Morillas-Arques P, Molina-Barea R et al (2011) Trazodoneplus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study. BMCMusculoskeletal Disord 12:95

Coe HV, Hong IS (2012) Safety of low doses of quetiapine when used forinsomnia. Ann Pharmacother 46:718–22

Cohrs S, Rodenbeck A, Guan Z et al (2004) Sleep-promoting properties ofquetiapine in healthy subjects. Psychopharmacol (Berl) 174:421–429

Esteve-Vives J, Rivera Redondo J, Salvat Salvat MI et al (2007) Propuestade una versión de consenso del Fibromyalgia Impact Questionnaire(FIQ) para la población española. Reumatol Clin 3:21–24

Fisher DS, Handley SA, FlanaganRJ et al (2012) Plasma concentrations ofquetiapine, N-desalkylquetiapine, o-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide in relation to quetiapinedose, formulation and other factors. Ther Drug Monit 34:415–421

Gao K, Kemp DE, Fein E et al (2011) Number needed to treat to harm fordiscontinuation due to adverse events in the treatment of bipolardepression, major depressive disorder, and generalized anxiety dis-order with atypical antipsychotics. J Clin Psychiatry 72:1063–1071

Guy W (1976) ECDEU assessment manual for psychopharmacology—revised (DHEW Publ No ADM 76-338). U.S. Department ofHealth, Rockville

Häuser W, Petzke F, Sommer C (2010) Comparative efficacy and harmsof duloxetine, milnacipran and pregabalin in fibromyalgia syn-drome. J Pain 11:505–521

Häuser W, Wolfe F, Tölle T et al (2012) The role of antidepressants in themanagement of fibromyalgia syndrome: a systematic review andmeta-analysis. CNS Drugs 26:297–307

Hidalgo J, Rico-Villademoros F, Calandre EP (2007) An open-label study of quetiapine in the treatment of fibromyalgia.Prog Neuropsychopharmacol Biol Psychiatry 31:71–77

Katzman MA, Brawman-Mintzer O, Reyes EB et al (2011) Extended-release quetiapine fumarate (quetiapine XR) monotherapy as main-tenance treatment for generalized anxiety disorder: a long-term,randomized, placebo-controlled trial. Int Clin Psychopharmacol26:11–24

Le Marshall KF, Littlejohn GO (2011) Management strategies for fibro-myalgia. Open Access Rheumatol Res Rev 3:47–51

McIntyre RS, Soczynska JK, Woldeyoannes HO et al (2007) A preclin-ical and clinical rationale for quetiapine in mood syndromes. ExpertOpin Pharmacother 8:1211–1219

McIntyre A, Paisley D, Kuoassi E, Gendron A (2013) Quetiapine fuma-rate extended release or the treatment of major depression withcomorbid fibromyalgia syndrome a double-blind, randomized, pla-cebo controlled study. Arthritis Rheum. doi:10.1002/art38228

Moore N, McMillan P, Birur B, et al. (2011) Fibromyalgia: efficacy ofquetiapine compared with placebo [Abstract no. NR08–48:333]. In164th annual meeting of the American Psychiatric Association.Honolulu, Hawaii

Potvin S, Morin M, Cloutier C et al (2012) Add-on treatment ofquetiapine for fibromyalgia. A pilot, randomized, double-blind,placebo-controlled 12-week trial. J Clin Psychopharmacol 2:684–687

Royuela A, Macías JA (1997) Propiedades clinimétricas de la versióncastellana del cuestionario de Pittsburgh. Vigilia-Sueño 9:81–94

Shemo M, Shemo JPD, Anderson M (2003) Beneficial effects ofquetiapine treatment in patients with fibromyalgia [Abstract]. JNeuropsychiatry Clin Neurosci 15:282

Spielberger CD, Gorsuch RL, Lushene RE (2002) STAI Cuestionario deAnsiedad Estado-Rasgo. Manual (6ª edición). Publicaciones dePsicología Aplicada. Serie menor número 124. TEA EdicionesS.A, Madrid

Vazquez C, Sanz J (1997) Fiabilidad y valores normales de la versiónespañola del inventario para la depresión de Beck de 1978. ClinSalud 8:403–422

Wang Z, Kemp DE, Chan PK et al (2011) Comparisons of the tolerabilityand sensitivity of quetiapine-XR in the acute treatment of schizo-phrenia, bipolar mania, bipolar depression, major depressive disor-der, and generalized anxiety disorder. Int J Neuropsychopharmacol14:131–142

Wolfe F, Smythe HA, Yunus MB et al (1990) The American College ofRheumatology 1990 criteria for the classification of fibromyalgia:report of the multicenter criteria committee. Arthritis Rheum 33:160–172

Wu CH, Farley JF, Gaynes BN (2012) The association between antide-pressant dosage titration and medication adherence among patientswith depression. Depress Anxiety 29:506–514

Psychopharmacology