Quetiapine monotherapy for bipolar depression
`
`EXPERT OPlNlON
`
`Michael E Thase
`
`Departments of Psychiatry. University
`of Pennsylvania School 01 Medicine.
`Philadelphia. PA. USA: the Philadelphia
`Veterans Nialrs Medical Center.
`Philadelphia. PA. USA: and the
`University ol Pittsburgh Medical
`Center. Pittsburgh. PA, USA
`
`CorrespondencezMichael EThase
`Department of Psydiiatry. University
`of Pennsylvania School oi Medicine.
`Room 689. 3535 Market Street.
`Philadelphia. PA USA
`Tel +l 2|5 746 6680
`Fax +l ZIS 573 0759
`Email thaseme@upmc.edu
`
`Abstract: Bipolar depression is more common, disabling, and difficult-to—trcat than the manic
`and hypomanic phases that define bipolardisorder. Unlike the treatment ofso—callcd “unipolar“
`depressions. anticlqircssants generally are not ind icutcd as mnothcrapios for bipolar depressions
`and recent studies suggest that even when used in combination with traditional mood stabiliz-
`ers -- antidepressants may have questionable value for bipolar depression. The current practice
`is that mood stabilizers are initiated first as monotlmpies; however, the antidepressant efficacy
`of lithium and valproatc is modest at best. Within this context the role ofatypical antipsychotics
`is being evaluated. The combination of olanzapinc and the antidepressant fiuoxctinc was the
`first treatment to receive regulatory approval in the US specifically for bipolar I depression.
`Quetiapinc was the second medication to be approved for this indication. largely as the result
`of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRcssion) l and II.
`Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily
`at bedtime) were significantly more effective than placebo. with no increased risk of patients
`switching into mania, Pooling the two studies, quetiapine was effective for both bipolar l and
`bipolar ll depressions and for patients with (and without) a history of rapid cycling. The two
`doses were comparably effective in both studies. Although the efficacy of quctiapinc mono-
`rhcrapy has been established. much additional research is necessary. Further studies are needed
`to more fully investigate dose—response relationships and comparing quctinpinc mouothcmpy to
`other mood stabilizers (lithium. valproatc, and lamotrigiuci in bipolar depression. both singly
`and in combination. l-lcad-ro-hcad studies are needed comparing quotiapine to the olanzapine-
`fluoxctine combination. Longer-term studies are needed to confirm the persistence of response
`and to better gauge effects on metabolic profiles across months of therapy. A prospective study
`of patients specifically seeking treatment for rapid cycling and those with a history of treat-
`ment-emergent affective sh itts also is needed. Despite the caveats. as treatment guidelines are
`revised to incorporate new data. the efficacy and tolerability of quctiapinc monotherapy must
`be given serious consideration.
`Keywords: bipolar disorder. manic depression. deprcsion. quctiapinc. mood stabilizer
`
`Introduction
`
`Bipolar disorder is a highly recurrent and not infrequently chronic illness that is
`rocognircd as one of the world’s 10 greatest public health problems {Murray and
`Lopez 1997). For the majority of patients. the periods of depression far exceed those
`of mania, in terms of both frequency and duration (Post et al 2003; Judd et al 2002.
`2003). For individuals with bipolar l disorder, for example, days spent with depres-
`sive symptoms are about three times more common than days spent with hypomanic
`or titanic symptoms (Judd cl al 2002). The dominanec of the depressed pole of the
`illness is even more dramatic individuals with bipolar ll disorder: in one prospective
`study conducted across nearly 13 years. patients with bipolar ll disorder spent almost
`40 tithes the days with depressive symptoms as compared to the days spent with
`hypomanic symptoms (Judd et a] 2003).
`Despite the dramatic and life-disrupting nature of mania, recent studies have also
`documented that it is the more long-lasting depressive episodes that have the greater
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`Neuropsychiatric Disease andTreatmcnt 1008:4(l) 2l—3l
`© 2008 Dove Medical Press Limited. All right: reserved
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`‘l'hasa
`
`deleterious efi‘ccts on quality of life and functionality (Judd
`et al 2005: Depp et a1 200(3). The burden imposed by bipolar
`depression on the family and loved ones exceeds that of
`bipolar mania or unipolar depression. perhaps all the more
`remarkable in view of the greater risk of psychosis, violent
`behaviour. and increased frequency of hospital i7ation associ-
`ated with mania (Post 2005: Hirschfeld 2004). The perceived
`stigma of the condition may also add to the burden placed
`on the fatnily or primary caregiver (Pcrlick et al 2004).
`The assessment of caregiver burden is further impeded by the
`unique characteristics of bipolar depression — including the
`unfortunate tendency for milder episodes to go unrecog-
`nized or untreated and the high incidence of subsyndromal
`inter-episode symptoms (Ogilvie et al 2005). Perhaps not
`surprisingly, the depressive episodes also are more directly
`linked to reduced longevity in bipolar disorder. particularly
`through suicide but perhaps also to increased risks of obesity
`and cardiovascular disease (Dilsaver et al 1.997; Fagiolini
`et al 2002; Mitchell and Malhi 2004).
`Despite the obvious clinical importance of the depressed
`phase of bipolar disorder, remarkably few controlled studies
`of first- and seeond~line treatments have been performed
`(Thase 2005). The paucity of well-designed studies essen-
`tially precludes the practice ofevidence-based medicine and
`for some important questions i cg. “if an antidepressant is
`used and appears to be effective, how long should it be main-
`tained?”l there is not consersus about best practices. which
`no doubt hampers clinical decision-making (Thasc 2005;
`Ostacher 2006). Indeed, in the largest placebo-controlled
`study of the role of antidepressants in bipolar depression
`conducted to date, the addition of paroxetine or bupropion
`to optimized therapy with mood stabilizers resulted in no
`added benefit as compared to therapy with mood stabilizers
`alone (Sachs et al 2007). For the prescribing physician, the
`need to swiftly deliver effective pharmaeotherapy to lessen
`suffering and minimize functional impairments is paramount.
`and appears to foster the continued use of antidepressants
`in bipolar depression despite the lack of clear-cut evidence
`that they improve outcomes. Nevertheless, the decision to
`initiate therapy with an antidepressant to hasten recovery is
`not without attendant risks, including treatment-emergent
`affective switches (TEAS) or acceleration of cycling and,
`as a result. the ranking of antidepressants in contemporary
`practice guidelines continues to drop in favor of other strate—
`gies (Tltase 2005; Yatham et al 2006).
`Many expert panels recommend initiating mood
`stabilizers alone, ie, before considering whether or not an
`antidepressant is indicated. lf one accepts the validity of
`
`the “mood stabilizer first" strategy. then lithium and three
`anticonvulsants (valproate. earbamazepine. and lamo-
`trigine) might be nominated as candidates for first line
`of therapy for bipolar depression (Thasc 2005: Grunzc
`2005). However. none of these medications is renowned
`
`for having powerful antidepressant effects (Thase 2005)
`and ~ primarily for reasons of tolerability and safety — few
`clinicians would use carbamazepine as the first step in a
`treatment algorithm. Even lithium salts. which arguably
`have the best evidence of efficacy from placebo-controlled
`studies (Zornberg and Pope 1993; Thase and Sachs 2000),
`do not exert particularly robust antidepressant effects
`(Thase 2005) . The search for an effective monotherapy for
`bipolar depression thus goes on.
`Emerging data suggest that the list of medications that
`are classified as mood stabilizers eventually may need to be
`expanded to include the class ofmedications known as atypi-
`cal antipsychotics. All five of the more widely prescribed
`atypical antipsychotics (in alphabetical order: aripiprazole.
`olanzapinc. quetiapine. rispcridonc. and ziprasidonc) inve
`established antimanic efficacy. Consistent with proposed
`criteria to define mood stabilizers (see. for example. Ketter
`and Calabrese 2002: Goodwin and Malhi 2007), atypical
`antipsychotics are unlikely to cause TEAS and two members
`of the class lolanzapine and aripiprazolc) have received a
`formal indication for prophylaxis against manic relapse fol-
`lowing successful acute therapy. Starting with observations
`from studies that included patients with mixed manic states.
`there is slowly increasing evidence to indicate that atypical
`antipsychotics also have antidepressant effects ( Keck 2005;
`Nemeroff 2005}. In fact, the first treatment to be approved
`by the United States Food and Drug Administration (FDA)
`specifically for bipolar depression is the proprietary com-
`bination of olanzapine and the selective serotonin reuptakc
`inhibitor (SSRI). fluoxetine. ln the pivotal trials that led to
`that indication, olanzapine monotherapy was also studied and
`found to have intermediate efficacy: greater than placebo but
`significantly less than the olanzapine—fluoxetine combination
`(OFC) (Tohen et al 2003).
`
`This review will focus on the second atypical antipsy-
`ehotic to be systematically studied as a monotherapy for
`bipolar depression. quetiapine. The results of the research
`program that led to the FDA approval of quctiapine mono-
`therapy for bipolar depression will be summarized in detail.
`Quetiapine, which isthe first —andcurrently only —monotherapy
`approved by the FDA to treat both the depressive and manic
`episodes associated with bipolar disorder. ins been ranked
`as a first-line treatment of bipolar depression in the recently
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`updated treatment guidelines published by the Canadian
`Network for Mood and Anxiety Treatments (CANMAT)
`(Yatham et al 2006).
`
`Efficacy against depressive
`
`symptoms
`Regulatory approval of quctiapinc monotherapy for bipolar
`depression was primarily based on two similar randomized
`controlled trials (RCTs) known by the acronyms BOLDER
`(BipOLar DEp Rossion) l and I]. Both of these 8—week.
`placebo-controlled, double-blind studies compared two doses
`of quctiapine — 300 mg per day and 600 mg per day. Both
`studies used once daily closing (at bedtime) and the same
`rapid titration schedule. with maximum study dose achieved
`by the 8th day of treatment. Both studies included patients
`with bipolar I and bipolar II depressive episodes and allowed
`otherwise eligible patients with histories oftapid cycling to
`enroll. Both studies used change in the Montgomery—Asberg
`Depression Rating Scale (MADRS) total score as the primary
`endpoint. Together. the BOLDER l (Calabrcsc ct al 2005)
`and BOLDER ll (Thase et al 2006) studiesrepresent the larg-
`est placebo-controlled data set to date that includes patients
`with bipolar l and bipolar II depressions.
`BOLDER l enrolled 542 patients meeting DSM-IV criteria
`for a current episode of bipolar l or bipolar H depression.
`according to DSM-IV criteria (Calabrese et al 2005) . In order
`to enter the study. outpatients had to score at least 20 on the
`l7-itcm Hamilton Depression Scale (HAM—DH). as well as
`have a score ofat least 2 on HAM-D item ] (depressed mood).
`Pretreatment MADRS scores indicated that the unmedicatcd
`
`study group presented with moderate-to-sevcre levels of
`depressive symptoms (see, for example, Muller et a1 2003).
`Both doses ofquctiapinc resulted in significant improve-
`ments in MADRS total scores at all time points measured.
`with statistical significance over placebo detected after only I
`week of treatment (the first assessment point ofthe study) and
`maintained at every time point thereafter (see Figure la). The
`proportion of patients classified as responders to treatment,
`defined as a 250% improvement in MADRS total score at
`study endpoint (using the “last observation carried forward
`[LOCF] convention" to estimate the final scores of study
`dropouts) was significantly higher in both groups receiving
`active quetiapine (58% in both groups) than in the group
`randomized to placebo (36%). Remission rates (defined as
`
`Quempine monotherapy for BP
`
`than those receiving placebo (median time to response was
`22 days for both doses of quetiapine versus 36 days for
`placebo. and median times to remission were 29. 27. and
`65 days for 300 mg quetiapine. 600 mg quetiapinc. and
`placebo, respectively).
`The results of the BOLDER ll trial (n : 509) fully
`replicated the first study in terms of the primary outcome
`variable. with quctiapinc-treated patients displaying signifi-
`cantly greater mean improvement in MADRS total scores
`than placebo-treated patients at all time points from Week
`1 onward (Figure lb) (Thase et al 200(3). Response rates for
`both doses of quetiapine monothcrupy were also similar to
`those observed in the original study after 8 weeks of treatment
`(60%. 58%. and 45% for the 300 mg. 600 mg. and placebo
`groups. respectively). as were remission rates (52% for both
`groups receiving active quctiapine as compared to 37% for
`the group receiving placebo). Looking across the two stud-
`ies, the only appreciable difference was the higher placebo
`response/remission rates observed in BOLDER ll. which
`could possibly be attributable to increased expectations from
`physicians and patients alike, in light of the positive findings
`arising from BOLDER I.
`In both BOLDER studies. improvements on the second-
`
`ary rater-administered measure, the HAM-D”. mirrored those
`reported on the MADRS scale. For example. both groups
`receiving active quetiapine again experienced significantly
`greater mean improvements from Week 1 onward compared
`with the group receiving placebo.
`
`With respect to the impact of quetiapine on specific
`depressive symptoms. at study endpoint improvements were
`detected in nine of the 10 individual items in BOLDER Land
`
`in nine individual items in BOLDER ll. Figure ’2 summarizes
`improvements in individual items of the MADRS scale in
`
`the BOLDER studies. lt is important to note that significant
`improvements were observed on the core symptoms of
`depression, including apparent sadness, reported sadness.
`suicidal thoughts. and pessimistic thoughts. in addition to
`improvements in sleep and anxiety.
`
`Efficacy in patient subgroups
`Since the patient populations enrolled in the BOLDER stud-
`ies included individuals with both bipolar I and bipolar II
`depression. and those with and without a rapid—cycling dis-
`ease course. the results of the BOLDER trials were examined
`
`a final MADRS total score $12) followed a similar pattem
`(53% for both 300 mg and 600 mg quctiapine. 28% for
`placebo). Individuals treated with either dose of quetiapine
`were faster to respond to treatment and to achieve remission
`
`to detenninc if quetiapine was particularly effective - or
`ineffective
`in various patient subgroups. Although there
`are important differences between bipolar l and bipolar II
`disorders (as well as between patients who meet criteria for
`
`
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`0
`
`1
`
`2
`
`Study Week
`4
`
`3
`
`5
`
`6
`
`7
`
`B
`
`I Quotient» 300 My 0:172!
`+ Owl-we 600 W (n21 70)
`‘233: Placebo (n—i 69)
`
`Least squares
`mean change
`{mm baseline
`
`0
`
`.5
`
`-10
`
`45 1
`
`a
`3‘
`l
`I
`
`SE 9 g
`
`—
`
`~20 J
`
`‘psOmi vs placebo
`
`Them
`
`Flgure la Least-squares nun change from baselne in Mercenary-Asher; Depression Rang Scale (HADES) total score at each assmment of outpatients with bipolar I
`or II disorder who expeaicnced : nujor deprudve episode (HOLDER ll
`
`rapid cycling and those who do not) (Yatham ct al 2005),
`dcmonstralionthatanoveltmalmcntiscompambly effective
`across the subgroups could greatly simplify clinical man-
`agement. The combined BOLDER data set shows that both
`
`bipolar l and bipolar ll patient groups exhibited significant
`improvements in MADRS total score following treatment
`with either dose of quotiapinc (300 mg per day or 600 mg
`per day) compared with placebo ( Figure 3).
`
`Study Week
`
`
`
`'Wnomw/daymasa
`4— Wino 600 wavy (vi-161)
`"$5 Hm cn=151§
`
`
`
`Least squares
`mean change
`from baseline
`
`.4
`
`lnwmvement
`
`‘pct‘mi. buxom 913 um
`
`Figure “I Lean-squares mean change fem baseline in MontgomrrAsberg Depression Rating Sale (MADRS) total score at each nssusment of outpan'ents with lipohr l
`or II disorder who experienced a maior depressive episode (BOLDER ll).
`
`I 4
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`I Ouatimim 300 mgx'day £n=327) i fluotimme 606 mgfdny in=321i
`
`23%,! Ptambo {M330}
`
`Quetiapine monotherapy for BP
`
`Apparent sadness
`
`Reported sadness
`inner lensrcm
`
`Roduced sloop
`
`Reciuced appetite
`Concentration difficulties
`
`Suicidal thoughts
`
`Lassitude »
`
`inability to feel
`
`Pessimistic thoughts
`
`0
`
`10
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`96 improvement from Baseline 'n Mean Score
`
`woos; 'pwm; ‘nsonoi vs pl mbo
`Figure 2 Pauling: improvtment from baseline in Montgomery-Asbeig Depression Rating Sui: (MADRS) indvidual item: won t: in outputiznls with hpolar I or II disor-
`der (data pooled hum BOLDEK l and BOLDER ll nudes: IT'E LOCF).
`
`Rapid cycling is associated with a poorer treatment
`response and long—term prognosis. and is associated with
`greater disability and a higher incidence of suicidal behavior
`(Schncck 2006). Currcntly available antidepressants may
`increase the risk of rapid cycling. and this uncertainty has
`
`limited their widespread use (Goldberg and Truman 2003i.
`Results ofa subanalysisof BOLDER l mdicutcdthat quctiap—
`his was as effective in patients with a history of rapid cycling
`as among with loss frequent cpisodcs ( V icta ct al 2007). A
`not yet published analysis of the combined data from the
`
`Bipolar disorder l
`(ii-55?;
`
`Bipolar disorder ll
`(rt-921)
`
`
`
`I Ouoflapins 300 mgfday
`fl Quotiaplne 600 mgldw
`Nam
`
`—4
`
`-3
`
`---1 2
`
`46
`
`420
`
`Least mums
`mean change
`from
`baseline
`
`E g
`
`3!
`9a.
`g
`
`fin-«0.01: 394mm vs placebo
`{n at baseline}
`
`Figun 3 Least mean squares change from baseline in Nonlgoma'rAsberg Depressron Kiting Scale (MADRS)tnuI score in outpatients with bpohr i or II dsorder (data
`pooled from BOLDER l and BOLDER || studim IT'E LOCF).
`
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`Time
`
`BOLDER studies echoed this result and demonstrated the
`
`broad applicability of quetiapine treatment by revealing a
`similar improvement in MADRS total scores in both patients
`with or without rapid cycling (Figure 4). As many experts
`consider antidepressants to be relatively contraindicated in
`rapid cycling because of an extremely high incidence of
`TEAS. the antidepressant activity of quetiapine could be
`partly offset if therapeutic response was associated with
`increased cycling or thc induction of hypomania/mania. It is
`thus noteworthy that the rapid cycling patients treated with
`quetiapine in BOLDER l and BOLDER H were no more
`likely to develop hypomania or mania than were patients
`receiving placebo. Although patients were also assessed for
`signs/symptoms of treatment-emergent mood elevation with
`the Young Mania Rating Scale, to date results on this measure
`have not been reported. Nevertheless. as described below, the
`proportion of patients developing diagnosablc episodes of
`hypomania or mania was actually higher among those treated
`with placebo than those receiving active quetiapinc.
`
`Efficacy against anxiety symptoms
`Anxiety disorders are highly comorbid with bipolar
`disorder and may predispose individuals to intensified
`symptoms. substance abuse. hospitalization, and suicide
`idcations (Gaudiano and Miller 2005: Keller 2006:
`
`McIntyre et al 2006). A cross-sectional sample from
`500 individuals with bipolar I or II disorder enrolled in the
`Systematic Treatment Enhancement Program For Bipolar
`Disorder ( STEP-8D) indicated that comorbid anxiety disor-
`ders, which were identified in over half of the sample, had a
`large and negative impact on role functioning and quality of
`life (Simon et ul 2004a). The patient’s response to treatment
`can be dampened by eomorbid anxiety (Frank ct a1 2002;
`Gaudiano and Miller 2005l. making pharmacothcrapy a
`challenge. Despite the high comorbidity, many patients with
`bipolar disorder and a coexisting anxiety disorder do not
`receive appropriately tailored drug therapy. In the STEP—BD
`population mentioned above. only 59% reported pharmaco-
`tlicrapy use meeting criteria for “minimally adequate“ mood
`stabilizer. regardless of comorbid diagnoses. rapid cycling.
`or bipolar l or it status (Simon et al 2004b). Moreover, even
`though anticonvulsants may have some utility for patients
`with comorbid anxiety. such patients are less responsive to
`therapy than min-anxious patients (Henry ct at 2003). Given
`the paucity of existing data and the clear need for improved
`treatment options in this patient subset, it was important to
`examine the etcht of quctiapinc monothcrapy on anxiety
`symptoms in the BOL DER studies.
`in the BOLDER 1 study, mixed model for repeated
`measurements ( MM R Ml analysis of anxiety symptoms, as
`
`Rapid eyetlng
`(mast)
`
`Non-rapid cycling
`(ii-727)
`
`
`
`.
`
`~20
`
`I mmsfioniglday
`U Wmfim mcyday
`:aa; Placebo
`
`Least squares
`mean change
`from
`baseline
`
`|ll
`
`l
`*a
`E l9
`2 l9 l
`5 l
`
`l
`
`‘p<0.001 vs bimbo
`(n at became)
`
`Figure 4 1.1351 mean squares change irom baselne in Hummerrksbetg Depression Rating Sula (HADRS) total score In outpatients with bipolar l or II disorder and
`valid or nomrapd qding (dab pooled tram BOLDER i and BOLIxR ll nudes lTE LOCF).
`
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`rated on the Hamilton Rating Scale for Anxiety (HAM-A).
`revealed that quetiapine monotherapy was associated with
`a rapid and pronounced improvement across individual
`and combined quetiapine treatment groups compared With
`placebo {—10.3 versus —6.7 for combined quctiapinc and pla-
`cebo groups. respectively). irrespective of baseline severity
`of depression (Hirschfeld ct a1 2000). Improvements were
`seen in eight ofthe 14 individual items on the HAM-A scale.
`which included the core items of “anxious mood" (—1.1
`
`versus —0.5, respectively; p < 0.001) and “tension” (—1.1
`versus -0.6 respectively; p < 0.001 ). This improvement
`was replicated in the BOLDER 11 study. in temts of both
`magnitude and significance (Thase et al 2006).
`Improvement in anxiety symptoms was observed in
`the subgroup of bipolar I patients in BOLDER I. in which
`HAM-A total score was significantly improved compared
`with placebo at Week 8 (—10.4 versus —5.l points. for
`combined quetiapine and placebo groups. respectively;
`p < 0.001 ) (Hirschfeld ct al 2006). Within the smaller sub-
`set of patients with bipolar ll disorder. patients treated with
`active quetiapinc or placebo showed comparable improve-
`ment in HAM-A total score (—9.8 versus ~9.0. respectively).
`Results from subgroup analyses from the BOLDER [1 trial
`and the pooled data set, not yet available, will be helpful in
`clarifying this unexpected finding.
`
`Effects on other secondary outcome
`measures
`
`Quality of sleep
`Sleep disturbance is a relatively common occurrence in
`psychiatric patients. with insomnia presenting as a primary
`symptom in 30%—90% of psychiatric disorders. (Becker
`2006) Again, the BOLDER I study was the first to explore
`the impact of quetiapine monothcrapy on sleep, using the
`Pittsburgh questionnaire ('PSQl) to rate quality of sleep. The
`PSQl is a 24-item questionnaire that includes 19 self-rated
`and 5 items rated by the patient's bed partner. The instrument
`is used to study sleep quality. latency, duration, efficiency.
`use of medication. and daytime dysfunction, and assesses
`sleep quality and disturbance in the preceding month.
`In BOLDER 1, participants showed moderate—to-severe
`sleep disruption at baseline according to the l’SQl. At last
`assessment. quality of sleep had improved significantly fol-
`lowing treatment with either dose of quetiapinc compared
`with placebo (p < 0.001 ) (Endicott et a1 2007). Mean values
`
`for quality of sleep, sleep latency, and sleep duration were
`0.5~0.7 points lower in quctiapine-trcated patients than in
`placebo-treated patients (Endicott et a1 2007).
`
`Quettapine monotherapy tor BP
`
`Quality of life
`To date. dedicated quality—of—li fc studies in individuals with
`bipolar disorder are relatively sparse. although a number of
`ongoing studies are attempting to redress this imbalance
`in response to increased recognition that recovery should
`be marked by a return to an acceptable quality of life and
`improved functionality for the patient (Miehalak et al 2005;
`Mitchell ct a1 2006; Kasper 2004). The depressive compo-
`nent of bipolar disorder is thought to be more detrimental to
`quality of life than the manic component (Vojta et a! 2001).
`Furthermore, the degree of functional impairment and loss
`of work productivity experienced by individuals with bipo-
`lar depression exceeds that experienced by patients with
`unipolar depression (Vornik and Hirschfeld 2005). There
`is also evidence to suggest that the delayed diagnosis or
`misdiagnosis experienced by many individuals with bipolar
`depression may further impact the quality of life they are
`able to enjoy since early and appropriate intervention can
`drastically enhance not only the symptomatic but also the
`subjective experience of individuals over the long term
`(Kasper 2004).
`Thus, any efficacious medication that can also exert
`positive effects on quality of life in bipolar depression is of
`obvious therapeutic value. Positive effects on health—related
`quality of life may be intrinsically linked with general
`tolerability. if a treatment is well-tolerated. a patient will be
`more likely to become satisfied with his treatment regimen.
`The superiority and increasing popularity of the atypical
`antipsychotics over the more conventional antipsychotics
`may derive from their improved tolerability (Vomik and
`Hirschfeld 2005).
`
`The BOLDERI study was the first large—scale investiga-
`tion ot‘quetiapinc monotherapy in bipolar depression to report
`quality of life as a secondary endpoint (Endicott ct a1 2007).
`Both BOLDER studies used the short-form version of the
`
`Quality of Life Enjoyment and Satisfaction Questionnaire
`(O-LESQ) to evaluate the impact of quetiapine on health-
`related quality of life. This version rates 16 items [physical
`health; mood; work; household activities: social relationships;
`family relationships: leisureotime activity; ability to function
`in daily life; sexual drive, interest and/or performance; eco-
`nomic status: living/housing situation: ability to get around
`physically without feeling dizzy or unsteady or falling; vision
`in terms of ability to work or do hobbies; overall sense of
`well—being; medications; and overall life satisfaction and
`contentment during the past week) on a 5—point scale.
`Consistent with their disease profile, BOLDER partici-
`pants scored poorly on quality—of—life scores at baseline.
`
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`Following 8 weeks of treatment with quctiapinc. significant
`improvements in Q-L ES-Q total score were evident in both
`BOLDER studies (Calabresc ct al 2005; Thase et al 2006:
`
`Endicott et al 2007). In BOLDER I. for example. mean
`Q-LES-Q percentage maximum scores at final assess-
`ment (LOCF) were 57.6. 57.4. and 48.] points for 300 mg
`quetiapinc. 600 mg quetiapine. and placebo. respectively
`[Endicott et al 2007). The improvements were significantly
`greater in both quctiapinc groups compared with placebo
`(p < 0.001 ) at final assessment. Interestingly. quality-of-
`life improvements were positively linked with MADRS
`response and remission status. If a patient responded to
`quetiapine treatment. quality of life also improved, whereas
`MADRS non-response was associated with negligible
`improvement in quality of life.
`The Shcehan Disability Scale (SDS), introduced as an
`additional outcome measure for BOLDER ll. quantified the
`impact of quetiapine on the interrelated domains of work.
`social life, and family life/home life/responsibilities. At the
`last mssment. the mean improvements in SDS scores from
`baseline were -7.3, —7.9. and 43.0 for 300 mg quctiapinc,
`600 mg quetiapine. and placebo. respectively (p < 0.05 for
`600 mg quetiapine versus placebo) (Thase et at 2006).
`
`Tolerability profile
`Good tolerability. as rated by physicians and patients alike, is
`integral to the success of any medication strategy. As toler—
`ability and treatment adherence tend to worsen as each new
`drug is added to a complex phannacotherapy regimen, a well-
`tolerated monotherapy would be expected to have multiple
`advantages. (Burton ct al 2005) Quetiapine monothcrapy
`was generally well-tolerated in the BOLDER studies. As
`detailed safety/tolerability data were presented in the source
`publ ications, (Calabrcsc et al 2005; Thase ct al 2006) only a
`brief summary follows below.
`
`Treatment discontinuations and adverse
`
`event (AE) incidence
`in the BOLDER studies. the proportions of quetiapine—treated
`patients completing the full 8 week treatment protocol was
`similar to that reported for placebo and ranged between 53%
`and 67%. The most common reasons for discontinuation were
`
`withdrawal ofconscnt, adverse events, loss to follow-up. and
`lack of perceived efficacy. with attrition due to AEs more
`common among the patients receiving active medication and
`dropouts due to lack ofefficacy more common in the placebo
`groups. None of the serious AEs reported in either BOLDER
`study was considered to have been drug-related.
`
`The majority of AH: were mild—to—modcratc in intensity
`and transient in nature. The most common adverse events
`
`experienced by 5% or more ot‘patients receiving quetiapine
`in both BOLDER studies were dry mouth. sedation. somno-
`lence, dizziness. and constipation (Table l; pooled data from
`HOLDER l and ll). Trends in tolerability tended to favor the
`group receiving the lower (300 mg per day) dose. although
`few of these differences were statistically significant.
`
`Weight change
`Weight gain in the BOLDER studies was greater among
`the patients receiving active quctiapinc. Across studies. the
`pooled weight-gain data showed a mean increase of 1.2 kg
`in the quetiapinc 300 mg per day group and LS kg in the
`600 mg per day group. as compared with a gain of 0.2 kg
`in the placebo group. A weight increase of greater than 7%
`was observed in 7.1% of patients receiving the 300 mg/day
`dose of quetiapine. l 0.0% receiving the 600 mg/day dose of
`quctiapinc, and 2.4% of those receiving placebo.
`The weight gain associated with some atypical antipsy-
`choties may ofien be accompanied by deleterious changes in
`serum lipids and increases in fasting glucose, both of which
`increase the risk for coronary artery disease. it is important
`to note that in the BOLDER trials, the mean change in fast-
`ing glucose and lipids with quctiapinc was not statistically
`significantly different to that with placebo.
`
`Treatment-emergent mania
`As discussed previously. the risk of precipitating a manic
`episode is a major concern when treating bipolar depression
`with traditional antidepressants. Treatment-emergent mania
`affects 2093—4093 of individuals with bipolar disorder receiv-
`ing long-term anti depressant therapy (Goldberg and Truman
`2003). Since combination therapy may reduce the risk of
`treatment-emergent mania. this is ofien the treatment approach
`
`Tabb I Most common adverse events associated with quetiap-
`ine treatment in outpau‘ents with bipolar I or II disorder (25%
`patients: data pooled from BOLDER I and BOLDER II studies)
`Adverse
`Quotiapine
`Quotiapine
`Placebo
`event (X)
`300 mg
`600 mg
`(n = 347)
`(n = 350)
`(n = 348)
`43.4
`43.7
`30.9
`29.9
`28.6
`27.0
`ISA
`l9. 5
`l0.0
`lO.6
`5.7
`5.2
`2.9
`5.7
`
`Dry mouth
`Sedation
`Somnolence
`Dizziness
`Constipation
`Lethargy
`Might. increase
`
`l 2.7
`8. l
`6.6
`6.9
`3.7
`l .7
`l .2
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`preferred by many psychiatrists (Grunze 2005). Therefore.
`when assessing the tolerability profile of a single agent, it is
`important to establish the propensity for manic switch.
`Data from the BOLDER studies showed a low incidence
`
`of treatment-emergent mania with quetiapine and placebo.
`Treatment-emergent mania was defined as an adverse event
`of mania or hypomania. or Young Mania Rating Scale
`(YMRS) score 2’ l 6 on any two consecutive visits or at the
`final visit. Data pooled from BOLDER I and [1 reveal that
`the proportion of patients with treatment-emergent manic
`symptoms was greater in the placebo group (5.2%) compared
`with both quctiapine treatment groups (both 2.9%).
`
`EPS-related AEs
`Historically. the atypical antipsychotics have been associated
`with a reduced risk ofextmpyramidal symptoms (BPS) within
`the recommended dose ranges compared with their conventional
`counterparts (Pierre 2005‘). This highl