Quetiapine monotherapy for bipolar depression
`
`EXPERT OPINION
`
`Michael E Thase
`
`Departments of Psychiatry, University
`of Pennsylvania School of Medicine,
`Philadelphia. PA, USA; the Philadelphia
`Veterans Affairs Medical Center,
`Philadelphia, PA, USA; and the
`University of Pittsburgh Medical
`Center, Pittsburgh, PA, USA
`
`Correspondence: Michael £ Thase
`Department of Psychiatry, University
`of Pennsylvania School of Medicine,
`Room 689, 3535 Market Street,
`Philadelphia, PA, USA
`Tel +1 215 746 6680
`Fax +1 215 573 0759
`Ernail thaseme@upmc.edu
`
`Abstract: Bipolar depression is more common,disabling, and difficult-to-treat than the manic
`and hypomanic phasesthat define bipolar disorder. Unlike the treatmentof so-called “unipolar”
`depressions,antidepressants generallyare not indicated as monotherapies for bipolar depressions
`and recent studies suggest that -even when used in combination with traditional mood stabiliz-
`crs ~ antidepressants may have questionable value for bipolar depression. The current practice
`is that mood stabilizers are initiated first as monotherapies; however, the antidepressantefficacy
`oflithiumand valproate is modest at best. Within this context the role ofatypical antipsychotics
`is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the
`first treatment to receive regulatory approval in the US specifically for bipolar I depression.
`Quetiapine wasthe second medication to be approved forthis indication, largelyas the result
`of two pivotal trials knownby the acronyms of BOLDER (BipOLar DEpRession) I and I].
`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 | and
`bipolar I] depressions and for patients with (and without) a historyof rapid cycling. The two
`doses were comparably effective in both studies. Although the efficacy of quetiapine mono-
`therapy has been established, much additional research is necessary. Further studies are needed
`to more fully investigate dose-response relationships and comparing quetiapine monotherapy to
`other moodstabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly
`and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-
`fluoxetine 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 oftreat-
`ment-emergentaffective shifts also is needed. Despite the caveats, as treatment guidelines are
`revised to incorporate newdata, the efficacy and tolerability of quetiapine monotherapy must
`be given serious consideration.
`Keywords: bipolar disorder, manic depression, depression, quetiapine, mood stabilizer
`
`Introduction
`Bipolar disorder is a highly recurrent and not infrequently chronic illness that is
`recognized 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 I disorder, for example, days spent with depres-
`sive symptomsare about three times more common than days spent with hypomanic
`or manic symptoms (Judd et al 2002). The dominance of the depressed pole of the
`illness is even more dramatic individuals with bipolar II disorder: in one prospective
`study conducted across nearly 13 years, patients with bipolar I] disorder spent almost
`40 times the days with depressive symptoms as compared to the days spent with
`hypomanic symptoms(Judd et al 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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`Thase
`
`deleterious effects on quality of life and functionality (Judd
`et al 2005; Depp et al 2006). 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 greaterrisk of psychosis, violent
`behaviour, and increased frequency of hospitalization associ-
`ated with mania (Post 2005; Hirschfeld 2004). The perceived
`stigma of the condition may also add to the burden placed
`on the family or primary caregiver (Perlick ct 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 perhapsalso to increased risks ofobesity
`and cardiovascular disease (Dilsaver et al 1997; Fagiolini
`et al 2002; Mitchell and Malhi 2004).
`Despite the obvious clinical importance ofthe depressed
`phase ofbipolar disorder, remarkably few controlled studies
`of first- and second-line treatments have been performed
`(Thase 2005). The paucity of well-designed studies essen-
`tially precludesthe practice of evidence-based medicine and
`for some important questions (eg, “If an antidepressant is
`used and appearsto beeffective, how long should it be main-
`tained’?)”) there is not consensus aboutbestpractices, which
`no doubt hampers clinical decision-making (Thase 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 moodstabilizers
`alone (Sachs et al 2007). For the prescribing physician, the
`need to swiftly deliver effective pharmacotherapy 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 dropin favor of other strate-
`gies (Thase 2005; Yatham et al 2006).
`Many expert panels recommendinitiating mood
`stabilizers alone, ie, before considering whether or not an
`antidepressant is indicated. If one accepts the validity of
`
`the “moodstabilizerfirst” strategy, then lithium and three
`anticonvulsants (valproate, carbamazepine, and lamo-
`trigine) might be nominated as candidates for first line
`of therapy for bipolar depression (Thase 2005; Grunze
`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. Evenlithium salts, which arguably
`have the best evidenceofefficacy from placebo-controlled
`studies (Zomberg and Pope 1993; Thase and Sachs 2000),
`do not exert particularly robust antidepressant effects
`(Thase 2005}. The searchfor an effective monotherapy for
`bipolar depression thus goes on.
`Emerging data suggest that the list of medications that
`are classified as moodstabilizers eventually may need to be
`expanded to includethe class ofmedications known asatypi-
`cal antipsychotics. All five of the more widely prescribed
`atypical antipsychotics (in alphabetical order: aripiprazole,
`olanzapine, quetiapine, risperidone, and ziprasidone) have
`established antimanic efficacy. Consistent with proposed
`criteria to define moodstabilizers (see, for example, Ketter
`and Calabrese 2002; Goodwin and Mathi 2007), atypical
`antipsychotics are unlikely to cause TEAS and two members
`of the class (olanzapine and aripiprazole) 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 antidepressanteffects (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 reuptake
`inhibitor (SSRI), fluoxetine. In 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-
`chotic to be systematically studied as a monotherapy for
`bipolar depression, quetiapine. The results of the research
`programthat led to the FDA approval of quetiapine mono-
`therapy for bipolar depression will be summarized in detail.
`Quetiapine, whichis the first —and currently only —monotherapy
`approved by the FDAto treat both the depressive and manic
`episodes associated with bipolar disorder, has been ranked
`as a first-line treatment of bipolar depressionin 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 quetiapine monotherapy for bipolar
`depression was primarily based on two similar randomized
`controlled trials (RCTs) knownby the acronyms BOLDER
`(BipOLar DEpRession) | and I]. Both of these 8-week,
`placebo-controlled, double-blind studies compared two doses
`of quetiapine — 300 mg per day and 600 mg per day. Both
`studies used once daily dosing (at bedtime) and the same
`rapid titration schedule, with maximum studydose achieved
`by the 8th day of treatment. Both studies included patients
`with bipolar I and bipolar I] depressive episodes and allowed
`otherwise cligible patients with histories of rapid cycling to
`enroll. Both studies used change in the Montgomery-Asberg
`Depression Rating Scale(MADRS)total score as the primary
`endpoint. Together, the BOLDER | (Calabrese ct al 2005)
`and BOLDERII {Thase et al 2006) studies representthe larg-
`est placebo-controlled data set to date that includespatients
`with bipolar | and bipolar If depressions.
`BOLDER I enrolled 542 patients meeting DSM-IVcriteria
`for a current episode of bipolar I or bipolar II depression,
`according to DSM-IVcriteria (Calabrese et al 2005). In order
`to enter the study, outpatients had to score at least 20 on the
`17-item Hamilton Depression Scale (HAM-D17), as well as
`have a score ofat least 2 0n HAM-Ditem 1 (depressed mood).
`Pretreatment MADRS scoresindicated that the unmedicated
`
`study group presented with moderate-to-severe levels of
`depressive symptoms(see, for example, Muller et al 2003).
`Both doses ofquetiapine resulted in significant improve-
`ments in MADRStotal scores at all time points measured,
`with statistical significance over placebo detected after only 1
`weekof treatment(the first assessment point ofthe study) and
`maintained at every time point thereafter (see Figure 1a). The
`proportionof patients classified as respondersto treatment,
`defined as a =50% improvement in MADRStotal scoreat
`study endpoint (using the “last observation carried forward
`{LOCF] convention” to estimate the final scores of study
`dropouts) wassignificantly higher in both groupsreceiving
`active quetiapine (58% in both groups) than in the group
`randomized to placebo (36%). Remission rates (defined as
`a final MADRS total score =12) followed a similar patter
`(53%for both 300 mg and 600 mg quetiapine, 28% for
`placebo). Individuals treated with either dose of quetiapine
`were faster to respond to treatment and to achieve remission
`
`Quetiapine monotherapy for BP
`
`than those receiving placebo (mediantime 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 quetiapine, and
`placebo,respectively}.
`The results of the BOLDER II trial (n = 509) fully
`replicated the first study in terms of the primary outcome
`variable, with quetiapine-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 1b) (Thase et al 2006). Responserates for
`both doses of quetiapine monotherapy were also similar to
`those observedin the original study after 8 weeks of treatment
`(60%, 58%, and 45% for the 300 mg, 600 mg, and placebo
`groups, respectively}, as were remissionrates (52%for both
`groupsreceiving active quetiapine 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 I, which
`could possibly be attributable to increased expectations from
`physicians andpatients alike,in light of the positive findings
`arising from BOLDERI.
`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 individualitems in BOLDERI, and
`in nine individual ttems in BOLDERIT. Figure 2 summarizes
`improvements in individual items of the MADRSscale in
`the BOLDER studies.It 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
`improvementsin 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 BOLDERtrials were examined
`
`to determine if quetiapine was particularly effective — or
`ineffective -- in various patient subgroups. Although there
`are important differences between bipolar [ and bipolarIl
`disorders (as well as betweenpatients who meet criteria for
`
`
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`8
`
`1
`
`2
`
`0
`
`Study Week
`4
`
`3
`
`5
`
`6
`
`ft
`
`8
`
`Least squares
`mean change
`from baseline
`
`-10
`
`“W Quetiapine 300 mosclay (n=172}
`~@- Quetiapine 600 mg/day (n=170)
`“a Placebo iret 69)
`
`“15 7
`
`ii
`i
`
`eo
`
`e
`
`§& $&
`
`=
`
`20 -
`
`92<0.001 ¥s placebo
`
`Figure {a Least-squares mean change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS)total score at each assessment of outpatients with bipolar |
`orIl disorder who experienced a major depressive episode (BOLDER1).
`
`bipolar | and bipolar II patient groups exhibited significant
`rapid cycling and those who do not) (Yatham et al 2005),
`improvements in MADRStotal score following treatment
`demonstrationthat a novel treatment is comparably effective
`with cither dose of quetiapine (300 mg per day or 600 mg
`across the subgroups could greatly simplify clinical man-
`agement. The combined BOLDERdata set shows that both_per day) compared with placebo (Figure 3).
`
`Study Week
`
`mean change
`from baseline
`
` —-—4
`
`
`“HE Oustiopine 200 mgétay (n=155)
`~#- Custiapine B00 mgycay (n=151}
`owe Placebo (n=181)
`
` Least squares
`
`improvement
`
`“p<0.01, 'p<6.001 vs placebo
`
`Figure tb Least-squares mean change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS)total score at each assessmentof outpatients with bipolar |
`or Il disorder who experienced a major depressive episode (BOLDER I}.
`
`14
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`@ Quetiaping S00 mg/day in=327) 8 Quetiapine G00 mg/day in=321)
`
`= Placebo in=3305
`
`Quetiapine monotherapy for BP
`
`Apparent sadness
`
`Reported sadness
`Innertension
`
`Recliced sleep
`
`Redueed appetite
`Concentration difficulties
`
`Lassitude
`
`Inability to feel
`
`Passimistic thoughts
`
`9 3084010 20 50 «68 70 80
`
`
`
`
`
`
`
`Suicidal thoughts
`
`
`
`
`
`
`
`
`
`*2s0.06; 'p<0.01; #p<0.001 vs placebo
`Figure 2 Percentage improvement from baseline in Montgomery-Asberg Depression Rating Scale (MADRS)individual items scores in outpadents with bipolar for I disor
`der (data pooled from BOLDER | and BOLDER Hi studies: TT. LOCF).
`
`% Improvement fram Baseline in Mean Score
`
`limited their widespread use (Goldberg and Truman 2003).
`Rapid cycling is associated with a poorer treatment
`response and long-term prognosis, and is associated with—Results of a subanalysis of BOLDER I indicatedthat quetiap-
`greater disability and a higher incidence of suicidal behavior
`ine was aseffective in patients witha history of rapid cycling
`(Schneck 2006). Currently available antidepressants may
`as among with less frequent episodes (Vieta et al 2007). A
`increase the risk of rapid cycling, and this uncertainty has
`not yet published analysis of the combined data from the
`
`Bipolar disorder|
`(n-657}
`
`Bipolar disorder If
`
`(n=921} Least scuiares
`
`@ uetianine 300 mg/day
`§& Quetianine 600 mg/day
`Plaashe
`
`-4
`
`-B
`
`42
`
`~16
`
`~20
`
`mean change
`from
`baseline
`
`=#
`
`x2a £
`
`tpe0.01; $p<0.001 ¥s placebo
`én at baseline)
`
`Figure 3 Least mean squares change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS)total score in outpatients with bipolar| or Il disorder (data
`pooled from BOLDER I and BOLDER1| suidies: ITT LOCF).
`
`
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`15
`
`

`

`Thase
`
`BOLDER studies echoed this result and demonstrated the
`
`broad applicability of quetiapine treatment by revealing a
`similar improvement in MADRStotal scoresin 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 the induction of hypomania/mania. It is
`thus noteworthy that the rapid cycling patients treated with
`quetiapine in BOLDER [ and BOLDERII were no more
`likely to develop hypomania or mania than were patients
`receiving placebo. Althoughpatients were also assessed for
`signs/symptomsof 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 diagnosable episodes of
`hypomania or mania wasactually higher amongthosetreated
`with placebothan those receiving active quetiapine.
`
`Efficacy against anxiety symptoms
`Anxiety disorders are highly comorbid with bipolar
`disorder and may predispose individuals to intensified
`symptoms, substance abuse, hospitalization, and suicide
`ideations (Gaudiano and Miller 2005; Keller 2006:
`
`McIntyre et al 2006). A cross-sectional sample from
`500 individuals with bipolar | or Idisorder enrolled in the
`Systematic Treatment Enhancement Program for Bipolar
`Disorder (STEP-BD) indicated that comorbid anxiety disor-
`ders, which were identified in over half of the sample, hada
`large and negative impacton role functioning and quality of
`life (Simonet al 2004a). The patient’s response to treatment
`can be dampened by comorbid anxiety (Frank et al 2002;
`Gaudiano and Miller 2005), making pharmacotherapya
`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-
`therapy use mecting criteria for “minimally adequate” mood
`stabilizer, regardless of comorbid diagnoses, rapid cycling,
`or bipolar | orII status (Simonet a! 2004b). Moreover, even
`though anticonvulsants may have some utility for patients
`with comorbid anxiety, such patients are less responsive to
`therapy than non-anxiouspatients (Henry et al 2003). Given
`the paucity of existing data and the clear need for improved
`treatment optionsin this patient subset, it was important to
`examine the effect of quetiapine monotherapy on anxiety
`symptoms in the BOLDERstudies.
`In the BOLDER | study, mixed model for repeated
`measurements (MMRM) analysis of anxiety symptoms, as
`
`Rapid cycling
`(n=251}
`
`Non-rapid cysting
`
`(n=F27)
`
`@ Custinpine 200 mg/day
`& Quetiapine 600 mosciay
`88 Placebo
`
`.
`
`-20
`
`Least squares
`mean change
`from
`baseline
`
`| |
`
`=)
`e |x
`@ |
`2 |
`= |
`
`\
`
`+p<0.001 vs placebo
`(n at Daseline)
`
`Figure 4 Least mean squares change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS} total score in outpatients with bipolar | or I! disorder and
`rapid or non-rapid cycling (data pooled from BOLDER ! and BOLDERHi studies: ITT 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 quetiapine and pla-
`cebo groups, respectively), irrespective of baseline severity
`of depression (Hirschfeld et al 2006). Improvements were
`seen in eight ofthe 14 individual items on the HAM-Ascale,
`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 II study, in terms of both
`magnitude and significance (Thase et al 2006).
`Improvement in anxicty symptoms was observed in
`the subgroup of bipolar | patients in BOLDER[, in which
`HAM-Atotal score was significantly improved compared
`with placebo at Weck 8 (—10.4 versus —5.1 points, for
`combined quetiapine and placebo groups, respectively;
`p < 0.001) (Hirschfeld ct al 2006). Within the smaller sub-
`set of patients with bipolar II disorder, patients treated with
`active quetiapine or placebo showed comparable improve-
`ment in HAM-Atotal score (~9.8 versus ~9.0, respectively).
`Results from subgroup analyses from the BOLDER II triai
`and the pooled dataset, not yet available, will be helpful in
`clarifying this unexpectedfinding.
`
`Effects on other secondary outcome
`measures
`Quality of sleep
`Sleep disturbance is a relatively common occurrence in
`psychiatric paticnts, with insomnia presenting as a primary
`symptom in 30%-90%of psychiatric disorders. (Becker
`2006) Again, the BOLDER | study wasthefirst to explore
`the impact of quetiapine monotherapy on sleep, using the
`Pittsburgh questionnaire (PSQI]) to rate quality of sleep. The
`PSQIis a 24-item questionnaire that includes 19 self-rated
`and 5 itemsrated 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 I, participants showed moderate-to-severe
`sleep disruption at baseline according to the PSQL. At last
`assessment, quality of sleep had improved significantly fol-
`lowing treatment with either dose of quetiapine compared
`with placebo (p < 0.001) (Endicott et al 2007). Mean values
`for quality of sleep, sleep latency, and sleep duration were
`0.5--0.7 points lower in quetiapine-treated patients than in
`placebo-treated patients (Endicott et al 2007).
`
`Quetiapine monotherapy for BP
`
`Quality oflife
`To date, dedicated quality-of-life 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 (Michalak et al 2005;
`Mitchell et al 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 al 2001).
`Furthermore, the degree of functional impairment and loss
`of work productivity experienced by individuals with bipo-
`lar depression exceeds that experienced by paticnts with
`unipolar depression (Vornik and Hirschfeld 2005). There
`is also evidence to suggest that the delayed diagnosis or
`misdiagnosis experienced by manyindividuals with bipolar
`depression mayfurther impact the quality of life they are
`able to enjoy since carly and appropriate intervention can
`drastically enhance not only the symptomatic but also the
`subjective experience of individuals over the long term
`(Kasper 2004).
`Thus, anyefficacious medication that can also exert
`positive effects on quality oflife in bipolar depressionis of
`obvious therapeutic value. Positive effects on health-related
`quality of life may be intrinsically linked with general
`tolerability. If a treatmentis well-tolerated, a patient will be
`more likely to becomesatisfied with his treatment regimen.
`The superiority and increasing popularity of the atypical
`antipsychotics over the more conventional antipsychotics
`may derive from their improved tolerability (Vornik and
`Hirschfeld 2005).
`
`The BOLDERI study wasthefirst large-scale investiga-
`tion ofquetiapine monotherapyin bipolar depression to report
`quality oflife as a secondary endpoint (Endicott et al 2007).
`Both BOLDERstudies used the short-form version of the
`
`Quality of Life Enjoyment and Satisfaction Questionnaire
`(Q-LES-Q)to evaluate the impact of quetiapine on health-
`related quality oflife. This version rates 16 items (physical
`health; mood; work; household activities; social relationships;
`family relationships; leisure-timeactivity; 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 orfalling; vision
`in terms of ability to work or do hobbies; overall sense of
`well-being; medications; and overail life satisfaction and
`contentment during the past week) ona 5-pointscale.
`Consistent with their disease profile, BOLDERpartici-
`pants scored poorly on quality-of-life scores at baseline.
`
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`Thase
`
`Following 8 wecks of treatment with quetiapine, significant
`improvements in Q-LES-Q total score were evident in both
`BOLDER studies (Calabrese et al 2005; Thase et al 2006;
`
`Endicott et a] 2007). In BOLDERI, for example, mean
`Q-LES-Q percentage maximum scores at final assess-
`ment {(LOCF) were 57.6, 57.4, and 48.1 points for 300 mg
`quetiapine, 600 mg quetiapine, and placebo, respectively
`(Endicott et al 2007). The improvements were significantly
`greater in both quetiapine 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
`quetiapinetreatment, quality of life also improved, whereas
`MADRS non-response was associated with negligible
`improvement in quality oflife.
`The Sheehan Disability Scale (SDS), introduced as an
`additional outcome measure for BOLDER II, quantified the
`impact of quetiapine on the interrelated domains of work,
`social life, and family life/homelife/responsibilities. At the
`last assessment, the mean improvements in SDSscores from
`baseline were —7.3, -7.9, and —6.0 for 300 mg quetiapine,
`600 mg quetiapine, and placebo, respectively (p < 0.05 for
`600 mg quetiapine versus placebo) (Thase et al 2006).
`
`Tolerability profile
`Good tolerability, as rated by physicians andpatientsalike,is
`integral to the success of any medicationstrategy. As toler-
`ability and treatment adherence tend to worsen as each new
`drug is added to a complex pharmacotherapy regimen,a well-
`tolerated monotherapy would be expected to have multiple
`advantages. (Burton et al 2005) Quetiapine monotherapy
`was generally well-tolerated in the BOLDER studies. As
`detailed safety/tolerability data were presented inthe source
`publications, (Calabrese et al 2005; Thase et al 2006) only a
`brief summary follows below.
`
`Treatment discontinuations and adverse
`event (AE) incidence
`In the BOLDERstudies, 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 ofconsent, adverse events,loss to follow-up, and
`lack of perceived efficacy, with attrition due to AEs more
`common amongthe patients receiving active medication and
`dropouts due to lack ofefficacy more commonin the placebo
`groups. None of the serious AEsreported in either BOLDER
`study was considered to have been drug-related.
`
`The majority of AEs were mild-to-moderate in intensity
`and transient in nature. The most common adverse events
`
`experienced by 5% or more ofpatients receiving quetiapine
`in both BOLDERstudies were dry mouth, sedation, somno-
`lence, dizziness, and constipation (Table 1; pooled data from
`BOLDER | and I). Trendsin 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 quetiapine. Across studies, the
`pooled weight-gain data showed a mean increase of 1.2 kg
`in the quetiapine 300 mg per day group and 1.5 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%
`wasobserved in 7.1% of patients receiving the 300 mg/day
`dose of quetiapine, | 0.0%receiving the 600 mg/day dose of
`quetiapine, and 2.4%of those receiving placebo.
`The weight gain associated with some atypical antipsy-
`chotics may often be accompanied by deleterious changes in
`serum lipids and increases in fasting glucose, both of which
`inerease the risk for coronary artery disease. It is important
`to note that in the BOLDERtrials, the mean changein fast-
`ing glucose andlipids with quetiapine wasnotstatistically
`significantly different to that with placebo.
`
`Treatment-emergent mania
`As discussed previously, the risk of precipitating a manic
`episode is a major concern whentreating bipolar depression
`with traditional antidepressants. Treatment-emergent mania
`affects 20%-40%of individuals with bipolardisorder receiv-
`ing long-term antidepressant therapy (Goldberg and Truman
`2003). Since combination therapy may reduce the risk of
`treatment-emergent mania,thisis often the treatment approach
`
`Table 1 Most common adverse events associated with quetiap-
`ine treatmentin outpatients with bipolar | or Il disorder (=5%
`patients; data pooled from BOLDER | and BOLDERII studies)
`Adverse
`Quetiapine
`Quetiapine
`Placebo
`event (%)
`306 mg
`600 mg
`(n =347)
`(n =350)
`(n = 348)
`434
`43.7
`30.9
`29.9
`28.6
`27.0
`154
`19.5
`10.0
`10.6
`5.7
`5.2
`29
`5.7
`
`Dry mouth
`Sedation
`Somnolence
`Dizziness
`Constipation
`Lethargy
`Weight increase
`
`12.7
`8.1
`66
`69
`37
`7
`12
`
`Neuropsychiatric Disease and Treatment 2008:4(1)
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`

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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 BOLDERstudies 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 ==16 on any two consecutive visits or at the
`final visit. Data pooled from BOLDERI and II reveal that
`the proportion of patients with treatment-emergent manic
`symptomswas greater in the placebo group (5.2%) compared
`with both quetiapine treatment groups (both 2.9%).
`
`EPS-related AEs
`Historically, the atypical antipsychotics have been associated
`with a reduced risk of extrapyramidal symptoms (EPS) within
`the recommended dose rangescompared with their conventional
`counterparts (Pierre 2005). This highly desirable characteristic
`is thoughtto derive directly from their mechanism ofaction,
`specifically by less