clozapine for treatment resistant bipolar systematic review

Review Article

Clozapine for treatment-resistant bipolardisorder: a systematic review

Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment-resistant bipolar disorder: a systematic review.Bipolar Disord 2015: 17: 235247. 2014 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd.

Objective: To evaluate the ecacy and safety of clozapine for treatment-resistant bipolar disorder (TRBD).

Methods: A systematic review of randomized controlled studies, open-label prospective studies, and retrospective studies of patients withTRBD was carried out. Interventions included clozapine monotherapyor clozapine combined with other medications. Outcome measures wereecacy and adverse drug reactions (ADRs).

Results: Fifteen clinical trials with a total sample of 1,044 patients metthe inclusion criteria. Clozapine monotherapy or clozapine combinedwith other treatments for TRBD was associated with improvement in: (i)symptoms of mania, depression, rapid cycling, and psychotic symptoms,with many patients with TRBD achieving a remission or response; (ii)the number and duration of hospitalizations, the number ofpsychotropic co-medications, and the number of hospital visits forsomatic reasons for intentional self-harm/overdose; (iii) suicidal ideationand aggressive behavior; and (iv) social functioning. In addition, patientswith TRBD showed greater clinical improvement in long-term follow-upwhen compared with published schizophrenia data. Sedation (12%),constipation (5.0%), sialorrhea (5.2%), weight gain (4%), and bodyache/pain (2%) were the commonly reported ADRs; however, thesesymptoms but did not usually require drug discontinuation. Thepercentage of severe ADRs reported, such as leukopenia (2%),agranulocytosis (0.3%), and seizure (0.5%), appeared to be lower thanthose reported in the published schizophrenia literature.

Conclusion: The limited current evidence supports the concept thatclozapine may be both an eective and a relatively safe medication forTRBD.

Xian-Bin Lia,b, Yi-Lang Tanga,c,Chuan-Yue Wanga,b andJose de Leond,e,f

aBeijing Key Laboratory of Mental Disorders,

Department of Psychiatry, Beijing Anding

Hospital, Capital Medical University, bCenter of

Schizophrenia, Beijing Institute for Brain

Disorders, Laboratory of Brain Disorders (Capital

Medical University), Ministry of Science and

Technology, Beijing, China, cDepartment of

Psychiatry and Behavioral Sciences, Emory

University School of Medicine, Atlanta, GA,dMental Health Research Center at Eastern State

Hospital, University of Kentucky, Lexington, KY,

USA, ePsychiatry and Neurosciences Research

Group (CTS-549), Institute of Neurosciences,

University of Granada, Granada, fBiomedical

Research Centre in Mental Health Net

(CIBERSAM), Santiago Apostol Hospital,

University of the Basque Country, Vitoria, Spain

doi: 10.1111/bdi.12272

Key words: bipolar disorder clozapine

treatment-resistant

Received 11 February 2014, revised and

accepted for publication 11 August 2014

Corresponding author:

Chuan-Yue Wang, M.D., Ph.D.

Beijing Anding Hospital,

Capital Medical University

No. 5 Ankang Lane

Dewai Avenue, Xicheng District

Beijing 100088

China

Fax: +86-10-58303195

E-mail: [email protected]

Clozapine, an atypical antipsychotic, is primarilyused for the treatment of treatment-resistantschizophrenia in most parts of the world (1, 2).Long-term use of clozapine is associated withimprovement in clinical symptoms, measurablesocial and functional gains, and decreased hospi-talization as compared with typical antipsychoticagents (3, 4). Furthermore, meta-analyses of

randomized clinical trials (RCTs) (5, 6) and arecent review of eectiveness trials (7) supportedthe greater ecacy of clozapine among antipsy-chotics in schizophrenia.A growing number of reports, however, suggest

that clozapine may also have a role in other treat-ment-resistant psychotic conditions (810), such asschizoaective disorder and psychotic mood

235

Bipolar Disorders 2015: 17: 235247 2014 John Wiley & Sons A/SPublished by John Wiley & Sons Ltd.

BIPOLAR DISORDERS

disorders (1113). Furthermore, case reports andretrospective studies suggest that clozapine may beparticularly eective in the treatment of medica-tion-resistant unipolar depression and bipolar dis-order (BD); some even suggested it is moreeective than it is for schizophrenia (12, 1416).Compared with unipolar depression, BD is a

more serious type of mood disorder. BD is a recur-rent, potentially disabling, sometimes even fatalpsychiatric illness (1719), and the estimated life-time prevalence of various types of BD is over2.0% (20, 21). BD is often associated with high lev-els of unfavorable outcomes or treatment resis-tance (2224). In contrast to schizophrenia,denitions of treatment-resistant bipolar disorder(TRBD) vary greatly (17, 2527). However, a fail-ure to respond to at least two trials of dissimilartreatments, involving an adequate dose and dura-tion, could serve as a conservative denition(2831).Although mood disorder was traditionally con-

sidered a rather rare condition in China, recentlyconducted epidemiological studies in the countryshowed that it is one of the common mental disor-ders (32, 33), with a one-month prevalence of 6.1%(32). Unlike other countries, clozapine has beenwidely used for BD in China despite not havingbeen approved for mood disorders (3436), and itis indeed one of the most commonly used antipsy-chotics in the treatment of BD (34, 37, 38). Somepsychiatrists even preferred it as a rst-line treat-ment for mania (3840). Similar to ndings fromstudies in Western countries, RCTs showed thatclozapine was an eective add-on treatment to an-tidepressants for treatment-resistant depression(41). Clozapine was also eective for treatment-resistant mania in a case report (42) and an RCT(43).Clozapine is a drug of choice for TRBD in

China but the evidence for its use in Western coun-tries remains sparse, and the studies are limited tocase reports (44), open-label trials (11), and onlyone RCT with fewer than 20 patients in each group(45). As China has the largest population on cloza-pine (4648), the Chinese experience and studiesmay be of keen interest to Western psychiatrists(49). So far, no exhaustive systematic review onclozapine for TRBD has been published.The primary aim of this review was to evaluate

the ecacy and safety of clozapine for TRBD. Aspreviously mentioned, in addition to internationaldatabases, we also included Chinese databases thatare not usually reviewed in articles written byWestern psychiatrists. Particular attention waspaid to safety and tolerability, as the potentiallysevere adverse drug reactions (ADRs) associated

with clozapine are commonly a factor discouragingclinicians from prescribing it.

Methods

Before we conducted this systematic review, ourprotocol of reviewing clozapine use for TRBDwas published online (http://www.crd.york.ac.uk/prospero/); the registration number wasCRD42013004322 at the Preferred ReportingItems for Systematic Reviews and Meta-Analyses(PRISMA). PRISMA provides an evidence-basedminimum set of items for reporting in systematicreviews and meta-analyses (50).

Types of studies

All types of trials evaluating the ecacy and safetyof clozapine for TRBD were eligible for inclusion.We included RCTs (Table 1), open-label retrospec-tive studies (Table 2), and prospective trials(Table 3). We excluded meta-analyses and system-atic reviews. We also excluded from the compre-hensive review case series and reports, since theyoer a lower level of evidence, and are associatedwith a high suspicion of publication biases. How-ever, we have included them in Table 4 and pro-vided a brief statement on them for the sake ofentirety. The retrospective open study by Nielsenet al. (51) was included in this review (Table 2),although the sample also included patients withnon-TRBD; it was not possible to exclude them.All tables provided details of the contamination ofthe studies by other diagnoses when it was not pos-sible to separate the patients.

Study selection

We searched PubMed, Embase, and CochraneLibrary databases and the Cochrane ControlledTrials Register of clozapine for TRBD. We alsosearched the Chinese databases [the Chinese Bio-medical Literature and China National KnowledgeInfrastructure databases] using the same keywords.The search included all studies published betweenJanuary 1979 and June 2014, regardless of lan-guage. The keywords used for the searchesincluded: clozapine, bipolar disorder, manic, depres-sion, resistant/resistance/refractory, drug therapy,and trial. The keywords were used in combinationwith the Boolean operators AND, OR, and NOT.We supplemented the search by using the relatedarticle function. We also manually searched bibli-ographies of RCTs, meta-analyses, and systematicreviews for studies that were missed in the initialelectronic search (52).

236

Li et al.

One author (X-BL) independently inspectedcitations from the searches and identied relevantabstracts. A random 20% of the samples wereindependently re-inspected by author Y-LT toensure reliability. When disagreements arose, the

full report was acquired for more detailed scrutiny.Full reports of the abstracts meeting the reviewcriteria were obtained and inspected by X-BL.Again, a random 20% of reports were re-inspectedby Y-LT in order to ensure reliable selection.

Table 1. Clozapine randomized controlled trials for treatment-resistant bipolar disorder (TRBD)

Suppes et al. 1999 (45)

Population: 38 patients meeting the DSM-IV criteria for BD (n = 26) or SAD (n = 12) who were deemed treatment-resistant [failure ofadequate treatment with two mood stabilizers (lithium, valproate, or carbamazepine) at standard therapeutic levels]. Subjects wererandomly assigned to clozapine add-on treatment (n = 19) or TAU (no clozapine) (n = 19)Intervention: Clozapine (355 mg/day) add-on therapyComparison: TAUMeasures: Patients received monthly ratings on the BPRS, CGI, BRMS, HDRS, SAPS, SANS and AIMS, and a 40-item side-effectchecklistStudy design: Randomized, TAU-controlled study with follow-up of one yearResultsa: Significant between-group differences were found in scores on all rating scales except the HDRS. Total medication use overone year significantly decreased in the clozapine group. No significant differences in physical complaints between groups were noted

Tan 2010 (43)

Population: 71 patients with DSM-IV BD who were classified as having TRBD were randomly assigned to clozapine added to lithiumtreatment (n = 35) or clozapine added to valproate treatment (n = 36). Treatment resistance was defined as failure of adequatetreatment with two different antidepressantsIntervention: Clozapine (100300 mg/day) added to lithium (5001,500 mg/day)Comparisons: Clozapine (100300 mg/day) added to valproate (6001,800 mg/day)Measures: Patients received ratings on BPRS, HDRS, and TESS at Weeks 0, 1, 2, 4, and 6Study design: Randomized, open-controlled studyResultsa: In the study group, 89% of patients were responders (based on BPRS and HDRS) to clozapine added to lithium comparedwith 64% of patients receiving clozapine added to valproate (p < 0.05). No significant differences in adverse drug reactions betweenthe groups were found

AIMS = Abnormal Involuntary Movement Scale; BPRS = Brief Psychiatric Rating Scale; BRMS = BechRafaelsen Mania Scale;CGI = Clinical Global Impression; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HDRS = HamiltonDepression Rating Scale; SAD = schizoaffective disorder; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale forthe Assessment of Positive Symptoms; TAU = treatment-as-usual; TESS = Treatment Emergent Symptom Scale.aClinical remission and response were defined differently in each study.

Table 2. Clozapine retrospective studies for treatment-resistant bipolar disorder (TRBD)

McElroy et al. 1991 (12)

Sample: All patients were either inadequately responsive to or unable to tolerate standard biological therapiesMethods: Survey of treating clinicians and chart data for all 85 consecutive patients, including 39 with schizophrenia, 25 with SAD, and14 with psychotic BD, who received clozapine for at least six weeks at one centerResults: Compared to patients with schizophrenia, patients with SAD and psychotic BD had significantly higher response rates toclozapine (10% for schizophrenia versus 1520% for SAD and 43% for psychotic BD)

Chang et al. 2006 (58)

Sample: Patients with BD resistant to conventional treatmentMethods: Analysis of clinical data from medical records of 51 patients with DSM-IV BD treated with add-on clozapine for >6 monthsResults: The number of hospital days/year was reduced in 90% of patients after clozapine add-on treatment. The total number andduration of hospitalizations/year also decreased. Significant reductions were found in the number and duration of hospitalizationsassociated with manic, depressive, and hypomanic episodes. Long-term efficacy of clozapine add-on was supported by continuousdecreases in hospital days/year in the 27 selected patients

Nielsen et al. 2012 (51)

Sample: A total of 21,473 patients with a lifetime diagnosis of ICD-10 BD, of whom only 326 (1.5%) were treated with clozapine andwere included in a mirror-image analysisMethods: A pharmacy-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine inpatients with BD (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image designResults: Clozapine appeared to be an appropriate choice for TRBD. Compared to the pre-clozapine period, during clozapinetreatment, the mean number of bed-days decreased from 179 to 35. The mean number of admissions was reduced from 3.2 to 2.0.Overall, 240 patients (74%) had reduced bed-days and 130 (40%) were not admitted while treated with clozapine. Moreover, thenumber of psychotropic co-medications was reduced from 4.5 DDD (2575 percentiles: 2.48.2) to 3.9 DDD (2575 percentiles:2.46.1). The percentage of patients with hospital visits for intentional self-harm/overdose was reduced significantly from 8% to 3%

BD = bipolar disorder; DDD = defined daily doses; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition;ICD-10 = International Classification of Diseases, 10th edition; SAD = schizoaffective disorder.

237

Clozapine for treatment-resistant bipolar disorder

Table

3.Clozapineop

en-la

beltrialsfortrea

tmen

t-resistan

tbipolar

disorder

Study

Subjects

Resistancedefinition

(failure

of)

Treatm

ents

(mg/day)

Duration

(months)

Mainfindings

Suppesetal.

1992(16)

7with

dysphoric

mania

Standard

treatm

ents

includingACs

CLZ(50500)+

ACs

3660

Sym

ptomatic

andfunctionalimprovementwasassessed.Mostofthe

patientssustainedsubstantialgainsinpsychosocialfunctioninfollow-

upover3years.Nofurtherhosp

italizationswere

neededin6of

7patients

Banovetal.

1994(11)

52BD,81SAD,

14UD,40SCH

Undefined

CLZ

18.7

BDmanicandSADbipolarpatientshadsignificantly

betteroutcomes

thanUD,BD,andSADdepressedpatients.BDandSADpatientshad

significantly

greaterimprovementinsocialfunctioningthanSCHpatients.

Oneormore

episodesofdepressionpriortoCLZpredictedCLZ

discontinuation

Kimmeletal.

1994(62)

25manicwith

BDorSAD

Li,ACs,and

2APs,orintolerant

CLZ

13

18of25patientsdemonstrateda>50%

decrease

intheYMRS

Kowatchetal.

1995(65)

5childrenor

adolescents

with

BD

MultipletrialsofAPs

andACs,orintolerance

CLZ(75225)+

Li

2There

wasa42%

decrease

intheCGI.Treatm

entwasforaggressive

behaviorandpsychotic

symptoms

Zarateetal.

1995(61)

17mood

disorders

CombinationsofLi,

ACs,APs,andECT;

orhadtardivedyskinesia

CLZ

16.1

65%

(11/17)hadnosubsequentre-hosp

italizationormoodepisode.

SignificantimprovementinCGIscores

Calabrese

etal.

1996(44)

25acutelymanic

Li,ACs,andAPs,

intolerableADRs,orboth

CLZ(494)

472%

(18/25)improvedontheYMRSand32%

(8/25)improvedontheBPRS.

Thepatientswith

BDascomparedtothepatientswith

SAD,andthenon-

rapidcyclingpatientsascomparedtorapidcyclers,hadsignificantly

greaterimprovementintotalB

PRSscore

Greenetal.

2000(63)

22activemanic

500mg/dayofchlorpromazine

orits

equivalentand

Liofatleast6weeks

CLZ

357%

(13/22)improvedontheBPRS,57%

(12/22)ontheYMRS,and39%

(8/22)ontheCGI,and77%

(17/22)exp

eriencedatleasta20%

reductiononallthreescales

Ciapparellietal.

2000(59)

34psychotic

BD,

31SCH,26SAD,

bipolartype

Adequatetreatm

entwith

3differentclassesofAPs

CLZflexible

doses

24

Allpatientsshowedsignificantimprovement24monthsfromintake

(based

onBPRSandCGI).Thepresenceofsuicidalideationatintake

predicted

greaterimprovementatendpoint

Ciapparellietal.

2003(60)

37psychotic

BD,

34SCH,30SAD,

bipolartype

Adequatetreatm

entwith

3differentclassesofAPs

CLZflexible

doses

48

Patientswith

SADandBDshowgreaterclinicalimprovementthanthose

with

SCH.Patientswith

BDhadtheshortesttim

etoresp

onse

andthe

highestpsychosocialandoccupationalfunctioninglevels(based

onBPRS,CGI,andGAF)

Fehretal.

2005(64)

9BD

2ACs+APs

CLZ(156

77)

12

Threepatientsdemonstratedstrikingmoodstabilizationandreturnedto

previouslevelsoffunctioning(basedonBPRSandHDRS).Fivepatients

hadmoderateimprovementinmoodstabilizationandfunctioning(based

onBPRSandHDRS),andonepatientshowedaminimalresp

onse

AC=anticonvulsant;ADR=adversedrugreaction;AP=antip

sychotic;BD=bipolardisorder;BPRS=BriefPsychiatricRatingScale;CGI=ClinicalGlobalIm

pression;CLZ=clozapine;

ECT=electroconvulsivetherapy;GAF=GlobalA

ssessmentofFunctioning;HDRS=HamiltonDepressionRatingScale;Li=lithium;SAD=schizoaffectivedisorder;SCH=schizophrenia;

UD=unipolardepression;YMRS=YoungManiaRatingScale.

238

Li et al.

Where it was not possible to resolve disagreementby discussion, a third author (C-YW) mediated thedecision. If the matter was unresolved, an attemptwas made to contact the authors of the originalstudy for clarication (53).

Data extraction

Review authors X-BL and Y-LT considered allincluded studies initially, without seeing compari-son data, to judge clinical, methodological and sta-tistical heterogeneity and thereby decide whethereach study would be included for meta-analysis orother data synthesis. We then extracted data intostandard, simple forms. X-BL extracted data fromall included studies. In addition, to ensure reliabil-ity, Y-LT independently extracted data from a ran-dom sample of these studies, comprising 30% of

the total. Again, any disagreement was discussed,decisions were documented, and, if necessary,authors of studies were contacted for clarication.Data presented only in graphs and gures wereextracted whenever possible, but included only iftwo authors independently had the same result.We also attempted to contact authors through anopen-ended request in order to obtain missinginformation or for clarication whenever deemednecessary. If studies were multi-center, weextracted data relevant to each component centerseparately (53).

Assessment of reporting biases

Reporting biases arise when the dissemination ofresearch ndings is inuenced by the nature anddirection of results. We tried to locate the research

Table 4. Clozapine case series and reports for treatment-resistant bipolar disorder

Study Subjects Age, gender

Resistancedefinition(failure of)

Treatments(mg/day)

Duration(months) Main findings

Calabrese et al.1991 (74)

2 RC BD 47 years, F48 years, F

AC + AP CLZ (250350) 1.53.5 Remission

Suppes et al.1994 (15)

3 RC BD 43 years, F25 years, F45 years, F

AP + AC CLZ (150400) + Li 1220 2 remission,1 response

Antonacci &Swartz1995 (70)

4 euphoricmania

Unavailable Standardtreatments + AC

CLZ _ Enhanced functioningand insight

Poyurovsky &Weizman1996 (71)

2 mania 24 years, M41 years, F

AP + AC CLZ (250350)+ ECT

_ Remission

Lancon & Llorca1996 (75)

1 RC BD 42 years, F Conventionaltherapy

CLZ _ Successfully treated

Mahmood et al.1997 (72)

3 mania Unavailable AP + AC CLZ _ Successfully treated

Chanpattana2000 (73)

1 mania 26 years, M Conventionaltreatment

CLZ (200) + ECT 18 Complete remission

Xu 2003 (42) 1 mania 40 years, F AP + AC CLZ (600) +Li (1,500) +CBZ (600)

1 Remarkably effective

Chen et al.2005 (76)

1 RC BD 38 years, F Various biologicaltherapies

CLZ (350) +TPR (300)

36 Complete remission

Vijay Sagar2005 (79)

1 juvenile-onset BD

18 years, F AC combinations CLZ (200) 24 Remission

Quante et al.2007 (119)

3 BD, 2 UD Not provided Medications +ECT

CLZ (125 and 375) 12 4/5 patients showedsteady improvement

Gupta2009 (78)

1 BD 28 years, M Standard AC CLZ (350) 66 No hospitalization andno more episodes

Bastiampillaiet al. 2010 (77)

1 RC BD 52 years, F Standard APs +ACs

CLZ (150) +LTG (100)

60 Sustained remission

Bennedetti et al.2010 (29)

7 SAD andpsychotic BD

Three patients, mean36 years, MFour patients, mean40 years, F

Treatmentresistant

Aripiprazole (6.8) +CLZ (293)

Remission

AC = anticonvulsant; AP = antipsychotic; BD = bipolar disorder; CBZ = carbamazepine; CLZ = clozapine; ECT = electroconvulsivetherapy; F = female; Li = lithium; LTG = lamotrigine; M = male; RC = rapid cycling; SAD = schizoaffective disorder; TPR = topiramate;UD = unipolar depression.

239


protocols of included RCTs. If the protocol wasavailable, outcomes in the protocol and in thepublished report were compared. If the protocolwas not available, outcomes listed in the methodssection of the trial report were compared with theactually reported results (54).

Grading recommendations

We used the grading of recommendations assess-ment, development, and evaluation (GRADE) sys-tem to rate the quality of evidence and strength ofrecommendations of this systematic review follow-ing the guidelines of the Cochrane Collaboration.GRADE included systematic assessments of allincluded trials across six main domains for eachoutcome: limitations of the study design and exe-cution, inconsistency, indirectness, imprecision ofresults, publication bias, and large treatment eect.Accordingly, we graded the recommendation forthe outcome measure of clozapine for BD as verylow, low, moderate, or high (Table 5).

Results

The various combinations of the search clozapine,bipolar disorder, manic, depression, resistant orresistance, refractory yielded 342 articles, of which15 studies met the criteria. In total, 1,044 patientswith TRBD had received clozapine treatment(Fig. 1). There were two RCTs (Table 1); three ret-

rospective studies (Table 2), and 10 open-labelprospective trials (Table 3). These studies wereequally distributed across the years between 1991and 2012, which indicates that clozapine forTRBD has been a rather long-lasting, clinicallyimportant topic for the last 25 years.It was not possible to conduct a meta-analysis

because of the studys heterogeneity, including dif-ferences in illness phase (mania, depression, orrapid cycling BD), methodology (open-label trialor RCT) and outcome denition (response orremission). Although meta-analysis is a powerfultool for analyzing data (55), confounding inter-study variables that cannot be controlled may vio-late basic statistical assumptions, making this typeof analysis error-prone (56, 57). Therefore, we onlyextracted data onto standard, simple forms on acase-by-case basis and reported the ecacy ofclozapine for TRBD when available, as well asother descriptive statistics. Compared with e-cacy, there was less heterogeneity in ADRs. There-fore, we conducted data synthesis using this term,and all trials with ADR details were included; thepercentage of each ADR was computed in thisreview and is presented in Table 6.We were unable to locate the protocols for three

RCTs; therefore, we assessed the reporting bias bymeans of comparing outcomes listed in the meth-ods with the results, which indicated that thereported results were approximately consistentwith outcomes listed in the methods.

Table 5. Grading of recommendations assessment, development, and evaluation system (GRADE) analysis: quality assessment of clozapine fortreatment-resistant bipolar disorder

Critical outcomeParticipants(studies)

Risk ofbias Inconsistency Indirectness Imprecision Public bias

Largeeffect

Overallquality

of evidenced

Open studies

CGI score 236 (5) Seriousa No No No Undetected No Very lowBPRS score 248 (5) No No No No Undetected No LowYMRS score 47 (2) No No No No Undetected No LowSocial functioning 304 (4) Seriousb No No No Undetected No Very lowHospital days/year 377 (2) No No No No Undetected No LowMean no. of admissions 377 (2) No No No No Undetected No LowRandomized clinical trials

BPRS score 109 (2) Noc No No No Undetected No ModerateHDRS score 109 (2) Noc No No No Undetected No Moderate

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; HDRS = Hamilton Depression Rating Scale; YMRS = YoungMania Rating Scale.aIncomplete accounting of patients and outcome events.bRelatively few patients (n 10).cLack of allocation concealment.dThe quality of evidence was rated using the GRADE Working Group system. High quality indicates that further research is very unlikelyto change our confidence in the estimate of effect but none of the studies reached that level. Moderate quality indicates that furtherresearch is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality indi-cates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to changethe estimate. Very low quality indicates that we are very uncertain about the estimate.

240

Li et al.

Quality assessment of the included studiesbased on the GRADE approach showed manylimitations of the study designs, no obvious indi-rectness, imprecision in result reporting and largetreatment eect. Based on the above assessments,the quality of evidence presented for each outcomeranged from very low to moderate (Table 5).

Clozapine RCTs for TRBD

Our literature search yielded two clozapine RCTsfor TRBD (Table 1). In these RCTs, adjunctiveclozapine treatment was superior to treatment asusual for TRBD (45). In addition, clozapine withadded lithium was better than clozapine aug-mented with valproate in rapid cycling BD (43).

Clozapine retrospective trials for TRBD

Three clozapine retrospective trials for TRBD wereidentied (Table 2). Two trials described the num-ber and duration of hospitalizations, the numberof psychotropic co-medications and the number ofhospital visits for medical reasons and for inten-tional self-harm/overdose as signicantly reducedduring clozapine treatment (12, 29, 51, 58).Another retrospective study comparing patients

with schizophrenia and psychotic BD indicatedthat the latter had signicantly higher responserates to clozapine (12).

Clozapine open-label prospective trials for TRBD

The 10 clozapine open-label prospective studies forTRBD (Table 3) included ve long-term follow-upstudies (11, 16, 5961), four focused on mania (44,6264) and one focused on adolescent patients(65). The studies found that patients on clozapinedemonstrated a signicant decrease in the YoungMania Rating Scale (YMRS), Hamilton Depres-sion Rating Scale (HDRS), Brief Psychiatric Rat-ing Scale (BPRS), and Clinical Global ImpressionScale (CGI) scores (44, 66); the presence of suicidalideation and aggressive behavior at intake pre-dicted greater improvement at endpoint (59, 65)and improvement in social functioning (16). In

Table 6. Clozapine adverse drug reactions in treatment-resistantbipolar disorder

Adverse drug reactionn (% of797 total)

Blood cells Leukopenia 14 (1.7)Decreases in whiteblood cell count

6 (0.8)

Agranulocytosis 2 (0.3)Metabolic system Weight gain 31 (4.0)

Weight loss 1 (0.1)Hyperlipidemia 1 (0.1)Increased appetite 1 (0.1)Diabetes type 2 1 (0.1)

Endocrine system Sialorrhea 42 (5.2)Sweating 4 (0.5)Dry mouth 1 (0.1)Influenza-like syndrome 1 (0.1)

Cardiovascular

system

Abnormal EEG 6 (0.8)Orthostatic hypertension 6 (0.8)Tachycardia 6 (0.8)Orthostatic hypotension 2 (0.2)

Digestive system Constipation 40 (5.0)Diarrhea 8 (1.1)Nausea/vomiting 5 (0.6)Postprandial regurgitation 1 (0.1)Ileus 1 (0.1)

Nervous system Sedation 98 (12.2)Body ache and pain 15 (1.8)Dizziness 11 (1.4)Sleep cycle inversion 7 (1.1)Transient fever 8 (0.9)Urinary incontinence 6 (0.8)Seizure 4 (0.5)Tremors 2 (0.2)Fatigue 2 (0.2)Neuroleptic malignantsyndrome

1 (0.1)

Bradykinesia 1 (0.1)Enuresis 1 (0.1)Mental confusion 1 (0.1)

Fig. 1. Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) ow diagram.

241


addition, they also found that BD patients showedgreater clinical improvement than those withschizophrenia in the long-term follow-up (11, 60).

Clozapine ADRs in TRBD

ADRs are summarized in Table 6. The prevalencesof the most serious ADRs were leukopenia, 2%;agranulocytosis, 0.3%; and seizure, 0.5%. Therewere no cases of myocarditis. The most frequentclinically signicant ADRs were sedation (12%),constipation (5%), sialorrhea (5%), weight gain(4%), and any kind of pain (2%). Other ADRswith a frequency of 0.51.0% were dizziness, diar-rhea (1%), transient fever, urinary incontinence,abnormal EEG, tachycardia, orthostatic hyperten-sion, and nausea. Other ADRs are described inTable 6.

Discussion

This is the rst systematic review of clozapine forTRBD summarizing its ecacy and safety. Ourcomprehensive systematic review included 15 stud-ies with a total of 1,044 patients and suggests thatclozapine may be an eective therapy, safe andwell tolerated. Although we excluded all of the caseseries and case reports in this comprehensivereview, the literature search provided 13 casereports/series in which clozapine was used forTRBD (Table 4). The 13 articles included ve onmania (42, 7073), ve on rapid cycling BD (15,7477), and three on other TRBDs (29, 78, 79).Overall, almost all cases were treatment-resistantand had a remission after switching to clozapinemonotherapy or adding clozapine to other drugs.

Strengths of the study

While many patients with BD respond well to con-ventional medications (including antidepressants,mood stabilizers and antipsychotics), a substantialproportion do not achieve a satisfactory response(6769). This systematic review showed that cloza-pine may be an ecacious therapy for TRBD.First, RCTs showed that: (i) clozapine add-ontreatment was superior to treatment as usual inmania, and (ii) clozapine plus lithium was betterthan clozapine plus valproate in rapid cycling BD.Secondly, retrospective studies of clozapine forTRBD indicated that the total number and dura-tion of hospitalizations and the number of psycho-tropic co-medications were signicantly reducedduring clozapine treatment. Thirdly, in open-labelprospective studies, patients treated with clozapinedemonstrated a signicant decrease in the YMRS,

HDRS, BPRS, and CGI scores, evidencedimprovement in social functioning, suicidal idea-tion and aggressive behavior, and had fewer subse-quent aective episodes; furthermore, patients withTRBD showed greater clinical improvement thanthose with schizophrenia in the long-term follow-up in these trials. The current review also suggeststhat clozapine may have anti-manic properties insome children and adolescents with TRBD.In general, this review found that clozapine for

TRBD was safe and well tolerated (Table 6). Seda-tion, constipation, sialorrhea, weight gain, andpain were the common ADRs, which is consistentwith schizophrenia studies (80, 81), and they wererather mild and tolerable to most patients. Moder-ate ADRs included dizziness, diarrhea, transientfever, urinary incontinence, abnormal EEG, tachy-cardia, orthostatic hypertension, and nausea. RareADRs were sweating, hyperlipidemia, diabetestype 2, inuenza-like syndrome, postprandialregurgitation, ileus, and bradykinesia, which is alsocomparable with schizophrenia studies (80, 82).These ADRs were not severe enough to result indrug discontinuation. The ADRs in the metabolicsystem were obviously low; there is the possibilityof a major underreport in the included trials.Among all the reports, 17 patients had leukope-

nia (2%), two had agranulocytosis (0.2%), and vehad seizures (0.5%). These gures tend to be lowerthan averages reported in schizophrenia reviews(8389). We are not sure whether the lower ADRfrequency in BD versus schizophrenia trials is realor an artefact. Greater underreport and dierentmethodologies may contribute to an articially lowADR frequency. Some clozapine ADRs are dose-related; others are not. Doses in BD trials appearlower than doses in Western schizophrenia studies,but it was not possible to control doses for con-founders such as smoking [which induced cloza-pine metabolism probably by inducing thecytochrome P450 1A2 (CYP1A2)] and racial dier-ences (see the discussion in the section Limitationsof the study below) (64, 87, 89). The agranulocyto-sis risk is still a concern for clinicians, but manda-tory blood monitoring has been shown toconsiderably reduce the incidence of fully devel-oped cases of agranulocytosis (80). Thus, appropri-ate management of clozapine ADRs facilitatesmaximization of the benets of clozapine treat-ment, and physicians and patients alike should beaware that there are a range of benets to cloza-pine use that outweigh its risk (80, 90, 91).Clozapine treatment was associated with signi-

cant improvement in tardive dyskinesia in sevenpatients (9294); clozapine may be useful for long-term treatment to lower tardive dyskinesia risk (93,

242

Li et al.

95, 96). Furthermore, once tardive dyskinesia ordystonia is established, clozapine may be useful forboth control of the movement disorder and BD(93, 96).The main strength of this study is that we also

searched Chinese databases in the systematicreview, which included all TRBD clozapine trialsconducted in China, where clozapine is widelyused. Thus, it is the rst review to include all trialsavailable without applying any language restric-tions. We found RCTs of clozapine monotherapyor clozapine combined with other medications ver-sus other treatments in patients with TRBD; thecomparison treatments included a mood stabilizer(97, 98), other antipsychotics (99102), clozapineplus a mood stabilizer versus a mood stabilizer (97,103, 104), and clozapine plus a mood stabilizer ver-sus other antipsychotics plus a mood stabilizer(103109) in the treatment of BD in China. Wealso found two RCTs, one open-label prospectivestudy, and two case reports on the use of clozapinefor TRBD in the Chinese literature, including theonly placebo-controlled clozapine RCT forTRMD (41).

Limitations of the study

A few limitations of the current review need to beacknowledged. First, it was not possible to conducta meta-analysis because of the studys heterogene-ity, including dierences in illness phase (mania,depression or rapid cycling BD), methodology(open-label trials or RCTs) and outcome denition(response or remission). This great heterogeneitymay violate basic statistical assumptions and makethese analyses error-prone. Therefore, we onlyextracted data onto standard, simple forms on acase-by-case basis and reported the ecacy ofclozapine for TRBD when available. Comparedwith data on ecacy, there was lower heterogene-ity with ADR data, and therefore data synthesisusing ADRs was conducted and the percentage ofeach ADR was computed (Table 6).Secondly, most of the clinical trials included here

had major methodological problems. Althoughthis review included 15 clinical trials, most of themwere open-label observational trials; only twoRCTs were available. There were no obviousreporting biases in the RCTs, but reporting biasesin other studies are possible. Furthermore, theGRADE approach showed that the quality of theevidence was very low in CGI score and psycho-social function; other outcomes were from low tomoderate (Table 5). Therefore, the current reviewprovided limited evidence supporting clozapineuse. However, two strengths of the current review

also need to be mentioned: (i) all available trialswere included, without applying any languagerestrictions; and (ii) the ecacy case-by-caseanalysis and computation of the percentage of eachADR provided some evidence supporting the useof clozapine (Table 6).Thirdly, some trials were contaminated by

some patients with a diagnosis of schizoaectivedisorder or schizophrenia, which does not corre-spond to the population described as the targetpopulation of interest (those with TRBD). In sometrials, we could not separate patients with TRBDfrom the patients with schizoaective disorder orschizophrenia, but the tables provide details ofthese contaminated studies.A fourth limitation of this review and all the

studies reviewed in it is the lack of close attentionto issues regarding clozapine pharmacokineticsand dosing. Clozapine dosing is inuenced byracial dierences, drugdrug interactions andsmoking. In 1997, it was already reported that Chi-nese patients tended to receive approximately halfof the clozapine dosage used in Western counties(110, 111) but appeared to have roughly similarclozapine levels, which is indicative of lower cloza-pine metabolism in Chinese patients. The literaturehas not stressed this dierence nor provided anexplanation. Sirot et al. (112) carried out a veryimportant study that has not received enoughattention in the literature. They described cyto-chrome P450 2C19 (CYP2C19) poor metabolizers(PMs) as having 2.3-fold higher plasma clozapineconcentrations than patients with other CYP2C19genotypes. Approximately 25% of the Chinesepopulation are CYP2C19 PMs.Studies of adjunctive clozapine treatment in

TRBD usually ignore the major dierences inclozapine metabolism associated with co-med-ication. Carbamazepine is a major inducer ofclozapine metabolism (113) and it is possible thatvalproate may be a mild inducer (114). Fluvox-amine is a major inhibitor of clozapine metabolism(115) and paroxetine and uoxetine are mild inhib-itors (114, 115).In conclusion, future studies and meta-analyses

of clozapine for TRBD will need to pay attentionto important pharmacokinetic dierences associ-ated with racial dierences, co-medication andsmoking, which may have major inuences onclozapine dosing but at present are ignored in mostpublished articles.

Comparison with other studies

Poon et al. (17) performed a literature review onTRBD research ndings. It provided few promising

243


leads other than the use of clozapine for TRBDmania, which is comparable to our analysis. Theirreview was limited by: (i) inclusion of only twoclozapine trials (44, 45), (ii) lack of report on cloza-pine ADRs, and (iii) lack of inclusion of Chinesestudies which include larger numbers of patients.Gitlin (116) conducted a review on this topic.

That review indicated that combining multipleagents was the most commonly used clinical strat-egy for TRBD; an approach that may be eectivefor treatment-resistant patients included high-dosethyroid augmentation, clozapine, calcium channelblockers, and electroconvulsive therapy, which isconsistent with our ndings. However, only threestudies of clozapine treatment were included (45,60, 64), and none of the Chinese studies wereincluded. Similarly, there was no safety analysis ordata synthesis.Frye et al. (117) reviewed the use of atypical

antipsychotics in the treatment of BD, focusingon clozapine as the prototypical agent. Thatreview indicated that the early clinical experienceof clozapine as a potential mood stabilizer sug-gested greater anti-manic than antidepressantproperties. However, that review only includedsome trials conducted before 1998, whichexcluded most trials of clozapine for TRBD.Similarly, there was no safety analysis or datasynthesis in that analysis.

Conclusions

TRBD is a complex, often severe and disablingpsychiatric disorder and it often poses a thera-peutic challenge (17, 118). This systematic reviewshows that clozapine monotherapy or its combi-nation with other medications for TRBD may beboth safe and eective. Long-term use of cloza-pine appeared to be associated with improvementin clinical symptoms, measurable social andfunctional gains, and decreased hospitalization.Constipation, sedation, sialorrhea, weight gain,aches and pain were the most commonlyreported ADRs, though none were severe enoughto result in drug discontinuation. The percent-ages of patients with leukocytopenia, agranulocy-tosis and seizure were lower than in studies ofclozapine for schizophrenia, but the possibilitycannot be ruled out that they may be contami-nated by ADR underreporting. Clozapine forTRBD may increase treatment compliance,which may oer additional therapeutic benets.On the other hand, some patients may have pooradherence or may not be willing to start cloza-pine treatment due to the blood collectionsrequired for the prevention of agranulocytosis.

This comprehensive review has focused onTRBD, but future reviews need to focus on therole of clozapine for the treatment of BD ingeneral. Though clozapine is rarely used fornon-treatment-resistant BD elsewhere in theworld, emerging evidence from China is encour-aging (41, 97, 98). Since the early 1980s, fewclozapine RCTs for BD in general have beenpublished; once more clozapine RCTs have beenpublished, a meta-analysis of non-treatmentresistant BD, if supportive of clozapine use, willprovide clinicians with more choices.

Acknowledgements

The authors thank Lorraine Maw, M.A., for editorial assis-tance. This study was supported by the Beijing Science andTechnology Commission (grant D121100005012002). No com-mercial organizations had any role in the writing of this paperfor publication.

Disclosures

The authors of this paper report no nancial relationship withcommercial interests within the last three years.

Author contributions

X-BL and Y-LT contributed equally to the review of the arti-cles and to the writing of the rst draft. C-YW and JdL con-tributed by improving the rst and later drafts. All authorscontributed to and approved the nal manuscript.

References

1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine forthe treatment-resistant schizophrenic: a double-blindcomparison with chlorpromazine. Arch Gen Psychiatry1988; 45: 789796.

2. Marder SR, Van Putten T. Who should receive cloza-pine? Arch Gen Psychiatry 1988; 45: 865867.

3. Meltzer HY. Dimensions of outcome with clozapine. BrJ Psychiatry Suppl 1992; 17: 4653.

4. Meltzer HY, Okayli G. Reduction of suicidality duringclozapine treatment of neuroleptic-resistant schizophre-nia: impact on risk-benet assessment. Am J Psychiatry1995; 152: 183190.

5. Asenjo Lobos C, Komossa K, Rummel-Kluge C et al.Clozapine versus other atypical antipsychotics for schizo-phrenia. Cochrane Library 2010; CD006633.

6. Leucht S, Cipriani A, Spineli L et al. Comparative e-cacy and tolerability of 15 antipsychotic drugs in schizo-phrenia: a multiple-treatments meta-analysis. Lancet2013; 382: 951962.

7. Attard A, Taylor DM. Comparative eectiveness ofatypical antipsychotics in schizophrenia. CNS Drugs2012; 26: 491508.

8. Owen R Jr, Beake B, Marby D, Dessain E, Cole J.Response to clozapine in chronic psychotic patients. Psy-chopharmacol Bull 1989; 25: 253.

9. Naber D, Hippius H. The European experience with useof clozapine. Hosp Community Psychiatry 1990; 41:886890.

244

Li et al.

10. Leppig M, Bosch B, Naber D, Hippius H. Clozapine inthe treatment of 121 out-patients. Psychopharmacology1989; 99: S77S79.

11. Banov MD, Zarate CA Jr, Tohen M et al. Clozapinetherapy in refractory aective disorders: polarity predictsresponse in long-term follow-up. J Clin Psychiatry 1994;55: 295300.

12. McElroy SL, Dessain EC, Pope HG Jr et al. Clozapinein the treatment of psychotic mood disorders, schizoaf-fective disorder, and schizophrenia. J Clin Psychiatry1991; 52: 411414.

13. Lindstrom LH. The eect of long-term treatment withclozapine in schizophrenia: a retrospective study in 96patients treated with clozapine for up to 13 years. ActaPsychiatr Scand 1988; 77: 524529.

14. Frakenburg FR. Clozapine and bipolar disorder. J ClinPsychopharmacol 1993; 13: 289290.

15. Suppes T, Phillips KA, Judd CR. Clozapine treatment ofnonpsychotic rapid cycling bipolar disorder: a report ofthree cases. Biol Psychiatry 1994; 36: 338340.

16. Suppes T, McElroy SL, Gilbert J, Dessain EC, Cole JO.Clozapine in the treatment of dysphoric mania. Biol Psy-chiatry 1992; 32: 270280.

17. Poon SH, Sim K, Sum MY, Kuswanto CN, BaldessariniRJ. Evidence-based options for treatment-resistantadult bipolar disorder patients. Bipolar Disord 2012; 14:573584.

18. American Psychiatric Association. Practice guidelinesfor the treatment of patients with bipolar disorder (revi-sion). Am J Psychiatry 2002; 159 (Suppl. 4): 150.

19. Judd LL, Akiskal HS, Schettler PJ et al. The long-termnatural history of the weekly symptomatic status of bipo-lar I disorder. Arch Gen Psychiatry 2002; 59: 530537.

20. Merikangas KR, Akiskal HS, Angst J et al. Lifetime and12-month prevalence of bipolar spectrum disorder in theNational Comorbidity Survey replication. Arch GenPsychiatry 2007; 64: 543552.

21. Hwu H-G, Joyce PR, Karam EG et al. Cross-nationalepidemiology of major depression and bipolar disorder.JAMA 1996; 276: 293299.

22. McElroy SL, Frye M, Denico K et al. Olanzapine intreatment-resistant bipolar disorder. J Aect Disord1998; 49: 119122.

23. Goldberg JF, Burdick KE, Endick CJ. Preliminary ran-domized, double-blind, placebo-controlled trial of pram-ipexole added to mood stabilizers for treatment-resistantbipolar depression. Am J Psychiatry 2004; 161: 564566.

24. Ghaemi SN, Katzow JJ. The use of quetiapine for treat-ment-resistant bipolar disorder: a case series. Ann ClinPsychiatry 1999; 11: 137140.

25. DellOsso B, Mundo E, DUrso N et al. Augmentativerepetitive navigated transcranial magnetic stimulation(rTMS) in drug-resistant bipolar depression. BipolarDisord 2009; 11: 7681.

26. Erfurth A, Michael N, Stadtland C, Arolt V. Bupropionas add-on strategy in dicult-to-treat bipolar depressivepatients. Neuropsychobiology 2002; 45: 3336.

27. Pacchiarotti I, Mazzarini L, Colom F et al. Treatment-resistant bipolar depression: towards a new denition.Acta Psychiatr Scand 2009; 120: 429440.

28. Gitlin MJ. Treatment-resistant bipolar disorder. BullMenninger Clin 2001; 65: 2640.

29. Benedetti A, Di Paolo A, Lastella M et al. Augmenta-tion of clozapine with aripiprazole in severe psychoticbipolar and schizoaective disorders: a pilot study. ClinPract Epidemiol Ment Health 2010; 6: 3035.

30. Sachs GS. Treatment-resistant bipolar depression. Psy-chiatr Clin North Am 1996; 19: 215236.

31. Sharm V, Khan M, Corpse C. Role of lamotrigine in themanagement of treatment-resistant bipolar II depression:a chart review. J Aect Disord 2008; 111: 100105.

32. Phillips MR, Zhang J, Shi Q et al. Prevalence, treatment,and associated disability of mental disorders in fourprovinces in China during 200105: an epidemiologicalsurvey. Lancet 2009; 373: 20412053.

33. Tsai S-Y, Chen C-C, Yeh E-K. Alcohol problems andlong-term psychosocial outcome in Chinese patients withbipolar disorder. J Aect Disord 1997; 46: 143150.

34. Si TM, Shu L, Yu X et al. A cross-sectional study ontreatment patterns of bipolar disorders in China in 2006.Chin J Psychiatry 2012; 45: 2934.

35. Chen XL, Xing BP, Zhang YQ, Jin WD. Atypical anti-psychotics in the treatment of elder patients with mania.Herald Med 2008; 27: 672673.

36. Fan ZG, Chen JM, Lu GH. Comparison analysis ofclozapine treatment for 54 cases with mania Chin. J Neu-rol 1994; 39: 202.

37. Liu YQ, Zhun FY, Yang LZ, Wang RJ, Chen CM. Clin-ical treatment analysis of 528 cases of aective disorderspatients. Chin J Pharmacoepidemiol 1997; 5: 158161.

38. Wang GY, Dong YM. The investigation and analysis ofoutpatient drug use in psychiatry. Chin J Modern DrugApplication 2007; 1: 44.

39. Liu TB, Gao H, Shen QJ. Clozapine combined with lith-ium carbonate in the treatment of acute mania. J ClinPsychiatry 2000; 10: 350351.

40. Zhang L, Chen JD. A double-blind study of clozapinecombined with lithium carbonate. J Psychiatry 2002; 15:4041.

41. Yan JX. A double-blind clinical trial of add-on clozapinein the treatment of treatment-resistant depression. Clin JPsychol Med 2001; 11: 170171.

42. Xu XH. One case of treatment-resistant twin mania.J Clin Psychosom Dis 2003; 9: 26.

43. Tan J. The ecacy and safety of lithium and low-doseclozapine treatment for refractory bipolar. YoujiangMed 2010; 38: 150151.

44. Calabrese JR, Kimmel SE, Woyshville MJ et al. Cloza-pine for treatment-refractory mania. Am J Psychiatry1996; 153: 759764.

45. Suppes T, Webb A, Paul B, Carmody T, Kraemer H,Rush AJ. Clinical outcome in a randomized 1-year trialof clozapine versus treatment as usual for patients withtreatment-resistant illness and a history of mania. Am JPsychiatry 1999; 156: 11641169.

46. Si TM, Shu L, Yu X et al. Antipsychotic drug patternsof schizophrenia in China: a cross-sectioned study. ChinJ Psychiatry 2004; 37: 152155.

47. Zhang GP, Wang CY. The one-day survey on psychotro-pic drug use in 788 psychotic inpatients in Beijing An-ding Hospital. Chin J Clin Pharmacol 2001; 17: 287289.

48. Luo RL, Chen Q. Investigation and analysis of psycho-tropic in 296 inpatients in one day. J Chin People Health2009; 21: 17551756.

49. Tang YL, Mao PX, Jiang F et al. Clozapine in China.Pharmacopsychiatry 2008; 41: 19.

50. Moher D, Liberati A, Tetzla J, Altman DG. Preferredreporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151: 264269.

51. Nielsen J, Kane JM, Correll CU. Real-world eective-ness of clozapine in patients with bipolar disorder: results

245


from a 2-year mirror-image study. Bipolar Disord 2012;14: 863869.

52. Varadhan KK, Neal KR, Lobo DN. Safety and ecacyof antibiotics compared with appendicectomy for treat-ment of uncomplicated acute appendicitis: meta-analysisof randomised controlled trials. BMJ 2012; 344: e2156.

53. Higgins JP, Green S. Cochrane Handbook for System-atic Reviews of Interventions. Hoboken, NJ: WileyOnline Library, 2008.

54. Higgins JPT, Altman DG, Sterne JAC. Assessing risk ofbias in included studies. In: Higgins JP, Green S eds.Cochrane Handbook for Systematic Reviews of Inter-ventions. Hoboken, NJ: Cochrane Book Series, 2008:187241.

55. Leandro G. Meta-Analysis in Medical Research: TheHandbook for the Understanding and Practice of Meta-Analysis. Wiley.com, 2008. Available from: http://www.books.google.com [accessed October 2014].

56. Ried K. Interpreting and understanding meta-analysisgraphs: a practical guide. Aust Fam Physician 2006; 35:635638.

57. Hoer ZS, Roth RL, Mathews M. Evidence for the par-tial dopamine-receptor agonist aripiprazole as a rst-linetreatment of psychosis in patients with iatrogenic ortumorogenic hyperprolactinemia. Psychosomatics 2009;50: 317324.

58. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min AhnY. The eects of long-term clozapine add-on therapy onthe rehospitalization rate and the mood polarity patternsin bipolar disorders. J Clin Psychiatry 2006; 67: 461467.

59. Ciapparelli A, DellOsso L, Pini S, Chiavacci MC, FenziM, Cassano GB. Clozapine for treatment-refractoryschizophrenia, schizoaective disorder, and psychoticbipolar disorder: a 24-month naturalistic study. J ClinPsychiatry 2000; 61: 329334.

60. Ciapparelli A, DellOsso L, Bandettini di Poggio A et al.Clozapine in treatment-resistant patients with schizo-phrenia, schizoaective disorder, or psychotic bipolardisorder: a naturalistic 48-month follow-up study. J ClinPsychiatry 2003; 64: 451458.

61. Zarate CA Jr, Tohen M, Banov MD, Weiss MK, ColeJO. Is clozapine a mood stabilizer? J Clin Psychiatry1995; 56: 108112.

62. Kimmel SE, Calabrese JR, Woyshville MJ, Meltzer HY.Clozapine in treatment-refractory mood disorders. J ClinPsychiatry 1994; 55 (Suppl. B): 9193.

63. Green AI, Tohen M, Patel JK et al. Clozapine in thetreatment of refractory psychotic mania. Am J Psychia-try 2000; 157: 982986.

64. Fehr BS, Ozcan ME, Suppes T. Low doses of clozapinemay stabilize treatment-resistant bipolar patients. EurArch Psychiatry Clin Neurosci 2005; 255: 1014.

65. Kowatch RA, Suppes T, Gilllan SK, Fuentes RM,Granneman BD, Emlsie GJ. Clozapine treatment of chil-dren and adolescents with bipolar disorder and schizo-phrenia: a clinical case series. J Child AdolescPsychopharmacol 1995; 5: 241253.

66. Liu NH, Ying D. The clinical observation of clozapineadd valproate and propranolol for treatment-resistantdepression. Med J Chin People Health 2006; 18: 771.

67. Tohen M, Sanger TM, McElroy SL et al. Olanzapineversus placebo in the treatment of acute mania. Am JPsychiatry 1999; 156: 702709.

68. Ketter TA, Kimbrell TA, George MS et al. Eects ofmood and subtype on cerebral glucose metabolism intreatment-resistant bipolar disorder. Biol Psychiatry2001; 49: 97109.

69. Vieta E, Reinares M, Corbella B et al. Olanzapine aslong-term adjunctive therapy in treatment-resistant bipo-lar disorder. J Clin Psychopharmacol 2001; 21: 469473.

70. Antonacci DJ, Swartz CM. Clozapine treatment ofeuphoric mania. Ann Clin Psychiatry 1995; 7: 203206.

71. Poyurovsky M, Weizman A. Safety and eectiveness ofcombined ECT and clozapine in treatment-resistantmania. Eur Psychiatry 1996; 11: 319321.

72. Mahmood T, Devlin M, Silverstone T. Clozapine in themanagement of bipolar and schizoaective manic epi-sodes resistant to standard treatment. Aust N Z J Psychi-atry 1997; 31: 424426.

73. Chanpattana W. Combined ECT and clozapine in treat-ment-resistant mania. J ECT 2000; 16: 204207.

74. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapineprophylaxis in rapid cycling bipolar disorder. J Clin Psy-chopharmacol 1991; 11: 396397.

75. Lancon C, Llorca PM. Clozapine in the treatment ofrefractory rapid cycling bipolar disorder. Encephale1996; 22: 468469.

76. Chen CK, Shiah IS, Yeh CB, Mao WC, Chang CC.Combination treatment of clozapine and topiramate inresistant rapid-cycling bipolar disorder. Clin Neurophar-macol 2005; 28: 136138.

77. Bastiampillai TJ, Reid CE, Dhillon R. The long-termeectiveness of clozapine and lamotrigine in a patientwith treatment-resistant rapid-cycling bipolar disorder.J Psychopharmacol 2010; 24: 18341836.

78. Gupta M. Clozapine monotherapy for 66 months intreatment resistant bipolar disorder: a case report. J ClinPsychopharmacol 2009; 29: 501503.

79. Vijay Sagar KJ. Treatment-refractory, juvenile-onsetbipolar aective disorder. Ind J Psychiatry 2005; 47:124125.

80. Lieberman JA. Maximizing clozapine therapy: managingside eects. J Clin Psychiatry 1998; 59 (Suppl. 3): 3843.

81. Saerman A, Lieberman JA, Kane JM, Szymanski S, Ki-non B. Update on the clinical ecacy and side eects ofclozapine. Schizophrenia Bull 1991; 17: 247261.

82. Daniel DG, Goldberg TE, Weinberger DR, KleinmanJE. Dierent side eect proles of risperidone and cloza-pine in 20 outpatients with schizophrenia or schizoaec-tive disorder: a pilot study. Am J Psychiatry 1996; 153:417419.

83. Alvir JMJ, Lieberman JA, Saerman AZ, SchwimmerJL, Schaaf JA. Clozapine-induced agranulocytosisinci-dence and risk factors in the United States. N J EnglMed 1993; 329: 162167.

84. Idanpaan-Heikkila J, Alhava E, Olkinuora M, Palva I.Agranulocytosis during treatment with clozapine. Eur JClin Pharmacol 1977; 11: 193198.

85. Atkin K, Kendall F, Gould D, Freeman H, Liberman J,OSullivan D. Neutropenia and agranulocytosis inpatients receiving clozapine in the UK and Ireland. Br JPsychiatry 1996; 169: 483488.

86. Fan ZY, Cui HS, Shen AZ, Ju FY, Tang M, Bai SZ.3113 cases of WBC count of psychiatric patients afterclozapine treatment. New Drug Clin 1992; 10: 330331.

87. Devinsky O, Honigfeld G, Patin J. Clozapine-related sei-zures. Neurology 1991; 41: 369371.

88. Pacia SV, Devinsky O. Clozapine-related seizures: expe-rience with 5,629 patients. Neurology 1994; 44: 22472249.

89. Haller E, Binder RL. Clozapine and seizures. Am J Psy-chiatry 1990; 147: 10691071.

90. Miller DD. Review and management of clozapine sideeects. J Clin Psychiatry 2000; 61 (Suppl. 8): 1417.

246

Li et al.

91. Naber D, Holzbach R, Perro C, Hippius H. Clinicalmanagement of clozapine patients in relation to ecacyand side-eects. Br J Psychiatry Suppl 1992; 5459.

92. Lieberman JA, Saltz BL, Johns CA, Pollack S, Boren-stein M, Kane J. The eects of clozapine on tardive dys-kinesia. Br J Psychiatry 1991; 158: 503510.

93. Casey DE. Clozapine: neuroleptic-induced EPS and tar-dive dyskinesia. Psychopharmacology 1989; 99: S47S53.

94. Tamminga C, Thaker G, Moran M, Kakigi T. Clozapinein tardive dyskinesia: observations from human and ani-mal model studies. J Clin Psychiatry 1994; 55 (Suppl. B):102106.

95. Small JG, Milstein V, Marhenke JD, Hall DD. Treat-ment outcome with clozapine in tardive dyskinesia,neuroleptic sensitivity, and treatment-resistant psychosis.J Clin Psychiatry 1987; 48: 263267.

96. Simpson GM, Lee JH, Shrivastava RK. Clozapine in tar-dive dyskinesia. Psychopharmacology 1978; 56: 7580.

97. Liu TZ, Song SY. A comparative study of clozapine ver-sus lithium in the treatment of mania. Shandong ArchPsychiatry 1990; 3: 2123.

98. Liu HY, Gong CF, Ma ZL. A controlled study of cloza-pine, sodium valproate and carbamazepine in the treat-ment of 84 patients with mania. Health Psychol J 2002;10: 228230.

99. Wu YH. Comparative study of clozapine versus olanza-pine in the treatment of mania. Pract Chin Clin Med2004; 21: 3435.

100. Wei XY, Wang QM, Yang YJ, Liu MY. The compari-son of olanzapine and clozapine in the treatment ofmania. J Clin Psychol Med 2002; 12: 347348.

101. Xie WJ, Zhao YM, Li J, Zhou Y, Chen M. A study ofaripiprazole versus clozapine in the treatment of mania.Shandong Arch Psychiatry 2006; 19: 2.

102. Liao GS. A comparative study of quetiapine and cloza-pine in the treatment of mania episode. Med J Chin Peo-ple Health 2009; 21: 29932994.

103. Yan JX, Chu PH, Liu QH, Chu JF, Lv XS, Zhang YQ.Clozapine combined with lithium in the treatment ofmania. Chin J Nerv Ment Dis 1997; 23: 104106.

104. Tao Q, Yang XJ, Wang RQ. A comparative study oflithium and chlorpromazine versus lithium and clozapinein the treatment of mania. Sichuan Arch Psychiatry1999; 12: 5657.

105. Zhang GY, Xie QM, Wang YX, Liu CM. Antipsychot-ics combined with lithium in the treatment of mania.J Clin Psychol Med 2006; 16: 2.

106. Jing YL, Wang LT, Li J. A comparative study of olanza-pine and clozapine combined with lithium in the

treatment of mania. Shandong Arch Psychiatry 2005; 18:256257.

107. Tao H, Jin WD, Liu ZC, Qiu DS, Ma YC, Shen Y et al.Controlled studies on olanzapine or clozapine and stabi-lizer in patients with mania. J Clin Psychosom Dis 2004;10: 164166.

108. Dong YY, Gan JG. Randomized controlled study ofclozapine combined lithium versus ziprasidone combinedlithium in the treatment of mania. J Pract Med 2010; 26:18061807.

109. Tang XW, Wu H, Chen Q. Randomized controlled trialcomparing quetiapine with lithium and clozapine withlithium in the treatment of female patients with mania.Shanghai Arch Psychiatry 2011; 23: 291298.

110. Chang W, Lin S, Lane H, Hu W, Jann M, Lin H. Cloza-pine dosages and plasma drug concentrations. J FormMed Assoc 1997; 96: 599605.

111. Chong S-A, Tan C-H, Khoo Y-M et al. Clinical evalua-tion and plasma clozapine concentrations in Chinesepatients with schizophrenia. Ther Drug Monit 1997; 19:219223.

112. Sirot EJ, Knezevic B, Morena GP et al. ABCB1 andcytochrome P450 polymorphisms: clinical pharmacoge-netics of clozapine. J Clin Psychopharmacol 2009; 29:319326.

113. de Leon J, Santoro V, DArrigo C, Spina E. Interactionsbetween antiepileptics and second-generation antipsy-chotics. Expert Opin Drug Metab Toxicol 2012; 8: 311334.

114. Diaz F, Santoro V, Spina E et al. Estimating the size ofthe eects of co-medications on plasma clozapine con-centrations using a model that controls for clozapinedoses and confounding variables. Pharmacopsychiatry2008; 41: 8191.

115. Spina E, De Leon J. Metabolic drug interactions withnewer antipsychotics: a comparative review. Basic ClinPharmacol Toxicol 2007; 100: 422.

116. Gitlin M. Treatment-resistant bipolar disorder. Mol Psy-chiatry 2006; 11: 227240.

117. Frye MA, Ketter TA, Altshuler LL et al. Clozapine inbipolar disorder: treatment implications for other atypi-cal antipsychotics. J Aect Disord 1998; 48: 91104.

118. Ranjan R, Meltzer HY. Acute and long-term eective-ness of clozapine in treatment-resistant psychotic depres-sion. Biol Psychiatry 1996; 40: 253258.

119. Quante A, Zeugmann S, Bajbouj M, Anghelescu I.Clozapine in medication- and electroconvulsive therapy-resistant, depressed inpatients: a case series. J Clin Psy-chopharmacol 2007; 27: 715717.

247


clozapine for treatment resistant bipolar systematic review

Documents