Bipolar Disorders 2014 © 2014 John Wiley & Sons A/S

Published by John Wiley & Sons Ltd.
BIPOLAR DISORDERS

Review Article

Clozapine for treatment-resistant bipolar
disorder: a systematic review
Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment- Xian-Bin Lia,b, Yi-Lang Tanga,c,
resistant bipolar disorder: a systematic review. Chuan-Yue Wanga,b and
Bipolar Disord 2014: 00: 000–000. © 2014 John Wiley & Sons A/S. Jose de Leond,e,f
Published by John Wiley & Sons Ltd. a
Beijing Key Laboratory of Mental Disorders,
Department of Psychiatry, Beijing Anding
Objective: To evaluate the efficacy and safety of clozapine for treatment- Hospital, Capital Medical University, bCenter of
resistant bipolar disorder (TRBD).
Schizophrenia, Beijing Institute for Brain
Disorders, Laboratory of Brain Disorders (Capital
Methods: A systematic review of randomized controlled studies, open-
Medical University), Ministry of Science and
label prospective studies, and retrospective studies of patients with Technology, Beijing, China, cDepartment of
TRBD was carried out. Interventions included clozapine monotherapy
Psychiatry and Behavioral Sciences, Emory
or clozapine combined with other medications. Outcome measures were University School of Medicine, Atlanta, GA,
efficacy and adverse drug reactions (ADRs). d
Mental Health Research Center at Eastern State
Hospital, University of Kentucky, Lexington, KY,
Results: Fifteen clinical trials with a total sample of 1,044 patients met
USA, ePsychiatry and Neurosciences Research
the inclusion criteria. Clozapine monotherapy or clozapine combined Group (CTS-549), Institute of Neurosciences,
with other treatments for TRBD was associated with improvement in: (i)
University of Granada, Granada, fBiomedical
symptoms of mania, depression, rapid cycling, and psychotic symptoms, Research Centre in Mental Health Net
with many patients with TRBD achieving a remission or response; (ii)
(CIBERSAM), Santiago Apo
stol Hospital,
the number and duration of hospitalizations, the number of University of the Basque Country, Vitoria, Spain
psychotropic co-medications, and the number of hospital visits for
somatic reasons for intentional self-harm/overdose; (iii) suicidal ideation
doi: 10.1111/bdi.12272
and aggressive behavior; and (iv) social functioning. In addition, patients
with TRBD showed greater clinical improvement in long-term follow-up
Key words: bipolar disorder – clozapine –
when compared with published schizophrenia data. Sedation (12%),
treatment-resistant
constipation (5.0%), sialorrhea (5.2%), weight gain (4%), and body
ache/pain (2%) were the commonly reported ADRs; however, these
Received 11 February 2014, revised and
symptoms but did not usually require drug discontinuation. The
accepted for publication 11 August 2014
percentage of severe ADRs reported, such as leukopenia (2%),
agranulocytosis (0.3%), and seizure (0.5%), appeared to be lower than
Corresponding author:
those reported in the published schizophrenia literature.
Chuan-Yue Wang, M.D., Ph.D.
Beijing Anding Hospital,
Conclusion: The limited current evidence supports the concept that
Capital Medical University
clozapine may be both an effective and a relatively safe medication for
No. 5 Ankang Lane
TRBD.
Dewai Avenue, Xicheng District
Beijing 100088
China
Fax: +86-10-58303195
E-mail: wang.cy@163.net

Clozapine, an atypical antipsychotic, is primarily randomized clinical trials (RCTs) (5, 6) and a
used for the treatment of treatment-resistant recent review of effectiveness trials (7) supported
schizophrenia in most parts of the world (1, 2). the greater efficacy of clozapine among antipsy-
Long-term use of clozapine is associated with chotics in schizophrenia.
improvement in clinical symptoms, measurable A growing number of reports, however, suggest
social and functional gains, and decreased hospi- that clozapine may also have a role in other treat-
talization as compared with typical antipsychotic ment-resistant psychotic conditions (8–10), such as
agents (3, 4). Furthermore, meta-analyses of schizoaffective disorder and psychotic mood

1

and are associated (32). was published online (http://www. and systematic paid to safety and tolerability. In contrast to schizophrenia. and it vided a brief statement on them for the sake of is indeed one of the most commonly used antipsy. a fail- Types of studies ure to respond to at least two trials of dissimilar treatments. reviews and meta-analyses (50). disorders (11–13). PRISMA provides an evidence-based els of unfavorable outcomes or treatment resis. could serve as a conservative definition of clozapine for TRBD were eligible for inclusion. Clozapine is a drug of choice for TRBD in We searched PubMed.0% (20. particularly effective in the treatment of medica- tion-resistant unipolar depression and bipolar dis- Methods order (BD). 21). definitions of treatment-resistant bipolar disorder (TRBD) vary greatly (17. since they ders (32. the studies by other diagnoses when it was not pos- tidepressants for treatment-resistant depression sible to separate the patients. we have included them in Table 4 and pro- been approved for mood disorders (34–36). So far. psychiatrists even preferred it as a first-line treat. as the potentially reviews for studies that were missed in the initial severe adverse drug reactions (ADRs) associated electronic search (52). hensive review case series and reports.ac. and the studies are limited to Trials Register of clozapine for TRBD. 25–27). We included RCTs (Table 1). 14–16). Furthermore. (PRISMA). BD is a recur. (28–31). and Cochrane China but the evidence for its use in Western coun. bipolar disorder. regardless of lan- (49). As China has the largest population on cloza. We excluded meta-analyses and system- conducted epidemiological studies in the country atic reviews. (41). open-label retrospec- Although mood disorder was traditionally con. with a one-month prevalence of 6. Library databases and the Cochrane Controlled tries remains sparse. 38). the efficacy and safety of clozapine for TRBD. and prospective trials sidered a rather rare condition in China. Similar to findings from non-TRBD.Li et al. some even suggested it is more effective than it is for schizophrenia (12. minimum set of items for reporting in systematic tance (22–24). However. sometimes even fatal prospero/).crd. although the sample also included patients with ment for mania (38–40). We also case reports (44). All types of trials evaluating the efficacy and safety tion. clozapine has been with a high suspicion of publication biases. and the estimated life. meta-analyses. entirety. databases. the Chinese experience and studies The search included all studies published between may be of keen interest to Western psychiatrists January 1979 and June 2014. open-label trials (11). Unlike other countries. our Compared with unipolar depression. tive studies (Table 2). potentially disabling. included: clozapine. Embase. in addition to international with the Boolean operators AND. 33). CRD42013004322 at the Preferred Reporting time prevalence of various types of BD is over Items for Systematic Reviews and Meta-Analyses 2. we also included Chinese databases that We supplemented the search by using the ‘related are not usually reviewed in articles written by article’ function. depres- The primary aim of this review was to evaluate sion. the registration number was psychiatric illness (17–19). involving an adequate dose and dura. resistant/resistance/refractory. it was not possible to exclude them. How- widely used for BD in China despite not having ever. Before we conducted this systematic review. case reports and with clozapine are commonly a factor discouraging retrospective studies suggest that clozapine may be clinicians from prescribing it. no exhaustive systematic review on guage. Infrastructure databases] using the same keywords. and only searched the Chinese databases [the Chinese Bio- one RCT with fewer than 20 patients in each group medical Literature and China National Knowledge (45).1% offer a lower level of evidence. BD is often associated with high lev. The keywords were used in combination previously mentioned. We also manually searched bibli- Western psychiatrists. Clozapine was also effective for treatment- resistant mania in a case report (42) and an RCT Study selection (43). pine (46–48). RCTs showed that All tables provided details of the contamination of clozapine was an effective add-on treatment to an. recently (Table 3). drug therapy. Particular attention was ographies of RCTs. The keywords used for the searches clozapine for TRBD has been published.uk/ rent. studies in Western countries. OR. 37. BD is a protocol of reviewing clozapine use for TRBD more serious type of mood disorder. and NOT. As and trial. (51) was included in this review (Table 2).york. We also excluded from the compre- showed that it is one of the common mental disor. manic. 2 . Some et al. The retrospective open study by Nielsen chotics in the treatment of BD (34.

One author (X-BL) independently inspected full report was acquired for more detailed scrutiny. using a two-year mirror-image design Results: Clozapine appeared to be an appropriate choice for TRBD. who received clozapine for at least six weeks at one center Results: Compared to patients with schizophrenia.2 to 2. 10th edition. and 6 Study design: Randomized. SANS = Scale for the Assessment of Negative Symptoms. HDRS.800 mg/day) Measures: Patients received ratings on BPRS. Subjects were randomly assigned to clozapine add-on treatment (n = 19) or TAU (no clozapine) (n = 19) Intervention: Clozapine (355 mg/day) add-on therapy Comparison: TAU Measures: Patients received monthly ratings on the BPRS. 240 patients (74%) had reduced bed-days and 130 (40%) were not admitted while treated with clozapine. 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 lithium treatment (n = 35) or clozapine added to valproate treatment (n = 36). and TESS at Weeks 0. patients with SAD and psychotic BD had significantly higher response rates to clozapine (10% for schizophrenia versus 15–20% for SAD and 43% for psychotic BD) Chang et al. SANS and AIMS. Compared to the pre-clozapine period. 1999 (45) Population: 38 patients meeting the DSM-IV criteria for BD (n = 26) or SAD (n = 12) who were deemed treatment-resistant [failure of adequate treatment with two mood stabilizers (lithium. DDD = defined daily doses.0. BRMS. Clozapine retrospective studies for treatment-resistant bipolar disorder (TRBD) McElroy et al. independently re-inspected by author Y-LT to Again. a Clinical remission and response were defined differently in each study. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders.4–8. citations from the searches and identified relevant Full reports of the abstracts meeting the review abstracts.5 DDD (25–75 percentiles: 2. 4th edition. Long-term efficacy of clozapine add-on was supported by continuous decreases in hospital days/year in the 27 selected patients Nielsen et al. ICD-10 = International Classification of Diseases. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders. TAU-controlled study with follow-up of one year Resultsa: Significant between-group differences were found in scores on all rating scales except the HDRS. 2006 (58) Sample: Patients with BD resistant to conventional treatment Methods: Analysis of clinical data from medical records of 51 patients with DSM-IV BD treated with add-on clozapine for >6 months Results: The number of hospital days/year was reduced in 90% of patients after clozapine add-on treatment.473 patients with a lifetime diagnosis of ICD-10 BD. HDRS. depressive. and 14 with psychotic BD. BRMS = Bech–Rafaelsen Mania Scale. the number of psychotropic co-medications was reduced from 4. open-controlled study Resultsa: In the study group.5%) were treated with clozapine and were included in a mirror-image analysis Methods: A pharmacy-epidemiologic database study was carried out in Denmark. including 39 with schizophrenia. The total number and duration of hospitalizations/year also decreased. 25 with SAD. between 1996 and 2007. TAU = treatment-as-usual. the mean number of bed-days decreased from 179 to 35. Moreover. 2012 (51) Sample: A total of 21. 4. and a 40-item side-effect checklist Study design: Randomized. 2. HDRS = Hamilton Depression Rating Scale. 1991 (12) Sample: All patients were either inadequately responsive to or unable to tolerate standard biological therapies Methods: Survey of treating clinicians and chart data for all 85 consecutive patients. Table 2. and hypomanic episodes.9 DDD (25–75 percentiles: 2. Overall. Clozapine randomized controlled trials for treatment-resistant bipolar disorder (TRBD) Suppes et al. during clozapine treatment.4–6. CGI. 4th edition. 3 . investigating the effectiveness of clozapine in patients with BD (without a schizophrenia-spectrum disorder). 89% of patients were responders (based on BPRS and HDRS) to clozapine added to lithium compared with 64% of patients receiving clozapine added to valproate (p < 0. BPRS = Brief Psychiatric Rating Scale. 1. No significant differences in adverse drug reactions between the groups were found AIMS = Abnormal Involuntary Movement Scale. Treatment resistance was defined as failure of adequate treatment with two different antidepressants Intervention: Clozapine (100–300 mg/day) added to lithium (500–1.500 mg/day) Comparisons: Clozapine (100–300 mg/day) added to valproate (600–1. Significant reductions were found in the number and duration of hospitalizations associated with manic. SAPS = Scale for the Assessment of Positive Symptoms. Total medication use over one year significantly decreased in the clozapine group. CGI = Clinical Global Impression. The percentage of patients with hospital visits for intentional self-harm/overdose was reduced significantly from 8% to 3% BD = bipolar disorder. the by Y-LT in order to ensure reliable selection. valproate. Clozapine for treatment-resistant bipolar disorder Table 1. TESS = Treatment Emergent Symptom Scale. SAD = schizoaffective disorder. SAPS. When disagreements arose.1). A random 20% of the samples were criteria were obtained and inspected by X-BL.05). of whom only 326 (1. The mean number of admissions was reduced from 3. or carbamazepine) at standard therapeutic levels]. a random 20% of reports were re-inspected ensure reliability. SAD = schizoaffective disorder.2) to 3.

Clozapine open-label trials for treatment-resistant bipolar disorder Li et al. 1996 (44) intolerable ADRs. and 39% 2000 (63) or its equivalent and (8/22) on the CGI.7 BD manic and SAD bipolar patients had significantly better outcomes 1994 (11) 14 UD. 52 BD. No further hospitalizations were needed in 6 of 7 patients Banov et al. YMRS = Young Mania Rating Scale. 25 manic with Li. and SAD depressed patients. SAD = schizoaffective disorder. Significant improvement in CGI scores or had tardive dyskinesia Calabrese et al. or intolerance Li behavior and psychotic symptoms with BD Zarate et al. BPRS = Brief Psychiatric Rating Scale. UD = unipolar depression. Most of the 1992 (16) mania treatments ACs patients sustained substantial gains in psychosocial function in follow- including ACs up over 3 years. ACs. . and the non- rapid cycling patients as compared to rapid cyclers. ADR = adverse drug reaction. and CLZ 13 18 of 25 patients demonstrated a > 50% decrease in the YMRS 1994 (62) BD or SAD ≥2 APs. 1995 (61) disorders ACs. or intolerant Kowatch et al. 3 different classes of APs doses with SCH. AP = antipsychotic. had significantly greater improvement in total BPRS score Green et al. BD = bipolar disorder. Five patients had moderate improvement in mood stabilization and functioning (based on BPRS and HDRS). CLZ (494) 4 72% (18/25) improved on the YMRS and 32% (8/25) improved on the BPRS. 26 SAD. Resistance definition Treatments Duration Study Subjects (failure of) (mg/day) (months) Main findings Suppes et al. Patients with BD had the shortest time to response and the bipolar type highest psychosocial and occupational functioning levels (based on BPRS. CGI. or both The patients with BD as compared to the patients with SAD. 22 active manic 500 mg/day of chlorpromazine CLZ 3 57% (13/22) improved on the BPRS. Treatment was for aggressive 1995 (65) adolescents and ACs. BD. 25 acutely manic Li. 81 SAD. One or more episodes of depression prior to CLZ predicted CLZ discontinuation Kimmel et al. Adequate treatment with CLZ flexible 24 All patients showed significant improvement 24 months from intake (based 2000 (59) 31 SCH. Li = lithium. and ECT.1 65% (11/17) had no subsequent re-hospitalization or mood episode. 3 different classes of APs doses on BPRS and CGI).4 Table 3. ECT = electroconvulsive therapy. 9 BD 2 ACs + APs CLZ (156  77) 12 Three patients demonstrated striking mood stabilization and returned to 2005 (64) previous levels of functioning (based on BPRS and HDRS). 7 with dysphoric Standard CLZ (50–500) + 36–60 Symptomatic and functional improvement was assessed. and one patient showed a minimal response AC = anticonvulsant. SCH = schizophrenia. 17 mood Combinations of Li. 57% (12/22) on the YMRS. 34 psychotic BD. 5 children or Multiple trials of APs CLZ (75–225) + 2 There was a 42% decrease in the CGI. HDRS = Hamilton Depression Rating Scale. 30 SAD. and 77% (17/22) experienced at least a 20% Li of at least 6 weeks reduction on all three scales Ciapparelli et al. APs. The presence of suicidal ideation at intake predicted bipolar type greater improvement at endpoint Ciapparelli et al. CLZ 16. CLZ = clozapine. Undefined CLZ 18. CGI = Clinical Global Impression. 40 SCH than UD. GAF = Global Assessment of Functioning. BD and SAD patients had significantly greater improvement in social functioning than SCH patients. and GAF) Fehr et al. 37 psychotic BD. ACs. and APs. Adequate treatment with CLZ flexible 48 Patients with SAD and BD show greater clinical improvement than those 2003 (60) 34 SCH.

we son data. any disagreement was discussed. 1 RC BD 38 years. F AC = anticonvulsant. methodological and sta. M AP + AC CLZ (250–350) _ Remission Weizman 41 years.8) + – Remission 2010 (29) psychotic BD 36 years. F AC combinations CLZ (200) 24 Remission 2005 (79) onset BD Quante et al. gender (failure of) (mg/day) (months) Main findings Calabrese et al. to ensure reliabil. AP = antipsychotic. If studies were multi-center. SAD = schizoaffective disorder. M = male. ECT = electroconvulsive therapy. F + ECT 1996 (71) Lancon & Llorca 1 RC BD 42 years. 2 UD Not provided Medications + CLZ (125 and 375) 12 4/5 patients showed 2007 (119) ECT steady improvement Gupta 1 BD 28 years. if necessary. F 1 response 45 years. mean Treatment Aripiprazole (6. each study would be included for meta-analysis or other data synthesis. M Conventional CLZ (200) + ECT 18 Complete remission 2000 (73) treatment Xu 2003 (42) 1 mania 40 years. TPR = topiramate. F AP + AC CLZ (600) + 1 Remarkably effective Li (1. to judge clinical. extracted data relevant to each component center tistical heterogeneity and thereby decide whether separately (53). but included only if two authors independently had the same result. an attempt authors of studies were contacted for clarification. BD = bipolar disorder. without seeing compari. M Standard AC CLZ (350) 66 No hospitalization and 2009 (78) no more episodes Bastiampillai 1 RC BD 52 years. a third author (C-YW) mediated the decisions were documented. We also attempted to contact authors through an Data extraction open-ended request in order to obtain missing Review authors X-BL and Y-LT considered all information or for clarification whenever deemed included studies initially.5–3. and. CBZ = carbamazepine. 2010 (77) ACs LTG (100) Bennedetti et al. In addition. If the matter was unresolved. LTG = lamotrigine. F = female. Li = lithium. F Antonacci & 4 euphoric Unavailable Standard CLZ _ Enhanced functioning Swartz mania treatments + AC and insight 1995 (70) Poyurovsky & 2 mania 24 years. 3 BD. comprising 30% of direction of results. 7 SAD and Three patients. F Conventional CLZ _ Successfully treated 1996 (75) therapy Mahmood et al. 18 years. Where it was not possible to resolve disagreement the total. M resistant CLZ (293) Four patients. extracted whenever possible.5 Remission 1991 (74) 48 years. RC = rapid cycling. F Suppes et al. by discussion. 3 RC BD 43 years. F AP + AC CLZ (150–400) + Li 12–20 2 remission. decision. mean 40 years. F Standard APs + CLZ (150) + 60 Sustained remission et al. Again. 3 mania Unavailable AP + AC CLZ _ Successfully treated 1997 (72) Chanpattana 1 mania 26 years. 2 RC BD 47 years. We tried to locate the research 5 . We then extracted data into Assessment of reporting biases standard. research findings is influenced by the nature and dom sample of these studies. F AC + AP CLZ (250–350) 1. Reporting biases arise when the dissemination of ity. was made to contact the authors of the original Data presented only in graphs and figures were study for clarification (53). F Various biological CLZ (350) + 36 Complete remission 2005 (76) therapies TPR (300) Vijay Sagar 1 juvenile. necessary. Clozapine case series and reports for treatment-resistant bipolar disorder Resistance definition Treatments Duration Study Subjects Age.500) + CBZ (600) Chen et al. 1994 (15) 25 years. X-BL extracted data from all included studies. Y-LT independently extracted data from a ran. Clozapine for treatment-resistant bipolar disorder Table 4. UD = unipolar depression. simple forms. CLZ = clozapine.

and evaluation system (GRADE) analysis: quality assessment of clozapine for treatment-resistant bipolar disorder Overall Participants Risk of Large quality Critical outcome (studies) bias Inconsistency Indirectness Imprecision Public bias effect of evidenced Open studies CGI score 236 (5) Seriousa No No No Undetected No Very low BPRS score 248 (5) No No No No Undetected No Low YMRS score 47 (2) No No No No Undetected No Low Social functioning 304 (4) Seriousb No No No Undetected No Very low Hospital days/year 377 (2) No No No No Undetected No Low Mean no. we graded the recommendation for other descriptive statistics. rapid cycling BD). 1. clinically actually reported results (54). low. important topic for the last 25 years. as well as Accordingly. confounding inter- ing the guidelines of the Cochrane Collaboration. CGI = Clinical Global Impression. indirectness. protocols of included RCTs. The various combinations of the search ‘clozapine. resistant or RCTs. High quality indicates that further research is very unlikely to change our confidence in the estimate of effect but none of the studies reached that level. methodology (open-label trial ment. and evaluation (GRADE) sys. Table 5. or high (Table 5). which indicates that clozapine for section of the trial report were compared with the TRBD has been a rather long-lasting. 6 . Therefore. a Incomplete accounting of patients and outcome events. outcomes in the protocol and in the prospective trials (Table 3). of admissions 377 (2) No No No No Undetected No Low Randomized clinical trials BPRS score 109 (2) Noc No No No Undetected No Moderate HDRS score 109 (2) Noc No No No Undetected No Moderate BPRS = Brief Psychiatric Rating Scale.Li et al. three ret. There were two RCTs (Table 1). simple forms on a cution. which indicated that the with TRBD had received clozapine treatment reported results were approximately consistent (Fig. extracted data onto standard. moderate. the percentage of each ADR was computed in this Results review and is presented in Table 6. making this type included trials across six main domains for each of analysis error-prone (56. Compared with effi- the outcome measure of clozapine for BD as very cacy. 1). HDRS = Hamilton Depression Rating Scale. b Relatively few patients (n ≤ 10). or We used the grading of recommendations assess. Grading of recommendations assessment. there was less heterogeneity in ADRs. If the protocol equally distributed across the years between 1991 was not available. inconsistency. and large treatment effect. refractory’ yielded 342 articles. YMRS = Young Mania Rating Scale. In total. d The quality of evidence was rated using the GRADE Working Group system. 57). with outcomes listed in the methods. we conducted data synthesis using this term. we assessed the reporting bias by resistance. clozapine for TRBD when available. of which means of comparing outcomes listed in the meth- 15 studies met the criteria. 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 change the estimate. or RCT) and outcome definition (response or tem to rate the quality of evidence and strength of remission). fore. publication bias. c Lack of allocation concealment. depression. development. If the protocol was rospective studies (Table 2). study variables that cannot be controlled may vio- GRADE included systematic assessments of all late basic statistical assumptions. Although meta-analysis is a powerful recommendations of this systematic review follow. including dif- Grading recommendations ferences in illness phase (mania. imprecision of case-by-case basis and reported the efficacy of results. we only outcome: limitations of the study design and exe. and all trials with ADR details were included. manic. tool for analyzing data (55). outcomes listed in the methods and 2012. depression. Moderate quality indicates that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. development. therefore. These studies were published report were compared. We were unable to locate the protocols for three bipolar disorder.044 patients ods with the results. and 10 open-label available. Very low quality indicates that we are very uncertain about the estimate. It was not possible to conduct a meta-analysis because of the study’s heterogeneity. There- low.

Scale (CGI) scores (44. Mania Rating Scale (YMRS).1) treatment effect.2) Body ache and pain 15 (1.1) Cardiovascular Abnormal EEG 6 (0.2) Digestive system Constipation 40 (5. Two trials described the num. Brief Psychiatric Rat- of psychotropic co-medications and the number of ing Scale (BPRS).1) Diabetes type 2 1 (0.5) Quality assessment of the included studies Tremors 2 (0.1) Fig.4) Sleep cycle inversion 7 (1. In addition. for TRBD (Table 1). 58). imprecision in result reporting and large Bradykinesia 1 (0. Clozapine adverse drug reactions in treatment-resistant bipolar disorder n (% of Adverse drug reaction 797 total) Blood cells Leukopenia 14 (1. 66). adjunctive clozapine treatment was superior to treatment as Clozapine open-label prospective trials for TRBD usual for TRBD (45). 16. The 10 clozapine open-label prospective studies for mented with valproate in rapid cycling BD (43).1) limitations of the study designs.0) Diarrhea 8 (1. the number sion Rating Scale (HDRS). four focused on mania (44.2) based on the GRADE approach showed many Fatigue 2 (0.1) Nausea/vomiting 5 (0.1) Endocrine system Sialorrhea 42 (5. In 7 . dicted greater improvement at endpoint (59. TRBD (Table 3) included five long-term follow-up studies (11. Preferred Reporting Items for Systematic Reviews and Transient fever 8 (0. 59–61).7) Decreases in white 6 (0. 62–64) and one focused on adolescent patients Clozapine retrospective trials for TRBD (65).0) Weight loss 1 (0. 51. Clozapine for treatment-resistant bipolar disorder Table 6.1) Ileus 1 (0.1) Nervous system Sedation 98 (12.8) blood cell count Agranulocytosis 2 (0. Hamilton Depres- ber and duration of hospitalizations. the presence of suicidal tional self-harm/overdose as significantly reduced ideation and aggressive behavior at intake pre- during clozapine treatment (12. clozapine with added lithium was better than clozapine aug. syndrome rectness.3) Metabolic system Weight gain 31 (4. In these RCTs.1) Increased appetite 1 (0.8) Orthostatic hypotension 2 (0.8) Seizure 4 (0. no obvious indi.1) ranged from ‘very low’ to ‘moderate’ (Table 5).8) Tachycardia 6 (0.2) Neuroleptic malignant 1 (0. The studies found that patients on clozapine Three clozapine retrospective trials for TRBD were demonstrated a significant decrease in the Young identified (Table 2). Urinary incontinence 6 (0. 29. with schizophrenia and psychotic BD indicated Clozapine RCTs for TRBD that the latter had significantly higher response Our literature search yielded two clozapine RCTs rates to clozapine (12).1) Hyperlipidemia 1 (0.2) Sweating 4 (0.5) Dry mouth 1 (0. 1. Based on the above assessments.9) Meta-Analyses (PRISMA) flow diagram. 65) Another retrospective study comparing patients and improvement in social functioning (16).1) Influenza-like syndrome 1 (0.1) the quality of evidence presented for each outcome Mental confusion 1 (0. Enuresis 1 (0.8) Dizziness 11 (1. and Clinical Global Impression hospital visits for medical reasons and for inten.8) system Orthostatic hypertension 6 (0.6) Postprandial regurgitation 1 (0.

Other ADRs are described in fever. maximization of the benefits of clozapine treat- Secondly. tory blood monitoring has been shown to First. 78. or an artefact. diar. which is also This is the first systematic review of clozapine for comparable with schizophrenia studies (80. and they were rhea (1%). aware that there are a range of benefits to cloza- tion of hospitalizations and the number of psycho. and five review. frequency in BD versus schizophrenia trials is real 74–77). and (ii) clozapine plus lithium was better ate management of clozapine ADRs facilitates than clozapine plus valproate in rapid cycling BD. patients with TRBD showed greater clinical improvement than Clozapine ADRs in TRBD those with schizophrenia in the long-term follow- ADRs are summarized in Table 6. pine metabolism probably by inducing the ventional medications (including antidepressants. We are not sure whether the lower ADR mania (42. 89). five on rapid cycling BD (15. abnormal EEG. TRBD was safe and well tolerated (Table 6). tion and aggressive behavior. cardia. furthermore. This systematic review showed that cloza. ate ADRs included dizziness. influenza-like syndrome. 87. tropic co-medications were significantly reduced Clozapine treatment was associated with signifi- during clozapine treatment. Rare ADRs were sweating.5%). 79). orthostatic hypertension. These figures tend to be lower reports/series in which clozapine was used for than averages reported in schizophrenia reviews TRBD (Table 4). Greater underreport and different Overall.0% were dizziness. tachycardia.Li et al. Thirdly. diabetes type 2. 2%. BPRS. well tolerated. related. urinary incontinence. and nausea. a substantial ences (see the discussion in the section ‘Limitations proportion do not achieve a satisfactory response of the study’ below) (64. transient fever.5%. hyperlipidemia. there is the possibility clozapine may be an effective therapy. The agranulocyto- (67–69). were no cases of myocarditis. pine use that outweigh its risk (80.5–1. orthostatic hyperten. appropri- mania. sialorrhea. Some clozapine ADRs are dose- monotherapy or adding clozapine to other drugs. 90. 0. Seda- constipation (5%).3%.2%). The most frequent In general. others are not. Other ADRs pain were the common ADRs. suicidal idea- schizophrenia in the long-term follow-up (11. weight gain. Our These ADRs were not severe enough to result in comprehensive systematic review included 15 stud. 0. which is consistent with a frequency of 0. constipation. and had fewer subse- quent affective episodes. sialorrhea (5%). RCTs showed that: (i) clozapine add-on considerably reduce the incidence of fully devel- treatment was superior to treatment as usual in oped cases of agranulocytosis (80). cytochrome P450 1A2 (CYP1A2)] and racial differ- mood stabilizers and antipsychotics). 70–73). sis risk is still a concern for clinicians. but it was not possible to control doses for con- Strengths of the study founders such as smoking [which induced cloza- While many patients with BD respond well to con. postprandial Discussion regurgitation. that clozapine may have anti-manic properties in agranulocytosis. The 13 articles included five on (83–89). with schizophrenia studies (80. The current review also suggests of the most serious ADRs were leukopenia. rather mild and tolerable to most patients. 8 . drug discontinuation. evidenced greater clinical improvement than those with improvement in social functioning. The ADRs in the metabolic ies with a total of 1. this review found that clozapine for clinically significant ADRs were sedation (12%). and any kind of pain (2%). but manda- pine may be an efficacious therapy for TRBD. in open-label cant improvement in tardive dyskinesia in seven prospective studies. There some children and adolescents with TRBD. and nausea. Thus. they also found that BD patients showed HDRS. TRBD summarizing its efficacy and safety. 82). weight gain tion. 60). and physicians and patients alike should be TRBD indicated that the total number and dura. diarrhea. Doses in BD trials appear lower than doses in Western schizophrenia studies. and (4%). the literature search provided 13 case had seizures (0. and seizure. 17 patients had leukope- series and case reports in this comprehensive nia (2%). patients treated with clozapine patients (92–94). addition. 91). urinary incontinence. clozapine may be useful for long- demonstrated a significant decrease in the YMRS. retrospective studies of clozapine for ment. and CGI scores. Moder- abnormal EEG. two had agranulocytosis (0. and bradykinesia. transient sion. The prevalences up in these trials. tachy- Table 6. term treatment to lower tardive dyskinesia risk (93. ileus. safe and of a major underreport in the included trials. 81). almost all cases were treatment-resistant methodologies may contribute to an artificially low and had a remission after switching to clozapine ADR frequency.044 patients and suggests that system were obviously low. and three on other TRBDs (29. Although we excluded all of the case Among all the reports.

This great heterogeneity genotypes. it is the first review to include all trials disorder or schizophrenia. the clozapine dosing but at present are ignored in most GRADE approach showed that the quality of the published articles. we could not separate patients with TRBD sus other treatments in patients with TRBD. only two to important pharmacokinetic differences associ- RCTs were available. the from the patients with schizoaffective disorder or comparison treatments included a mood stabilizer schizophrenia. review. but reporting biases smoking. (112) carried out a very acknowledged. Sirot et al. attention in the literature. Although In conclusion. We found RCTs of clozapine monotherapy population of interest (those with TRBD). Therefore. spond to the population described as the target tions. other outcomes were from ‘low’ to Comparison with other studies ‘moderate’ (Table 5). Furthermore. Therefore. Thus. two strengths of the current review TRBD research findings. clozapine may be useful for were included. chrome P450 2C19 (CYP2C19) poor metabolizers depression or rapid cycling BD). Furthermore. 115). which included all TRBD clozapine trials Thirdly. (17) performed a literature review on use. most of the clinical trials included here itors (114. We and dosing. without applying any language both control of the movement disorder and BD restrictions. Compared ication. 96). including differences in illness phase (mania. (110. In some or clozapine combined with other medications ver. 96). First. and two case reports on the use of clozapine smoking. trials. drug–drug interactions and study. and therefore data synthesis valproate may be a mild inducer (114). some trials were ‘contaminated’ by conducted in China. There were no obvious ated with racial differences. 104). other antipsychotics (99–102). It provided few promising 9 . simple forms on a TRBD usually ignore the major differences in case-by-case basis and reported the efficacy of clozapine metabolism associated with co-med- clozapine for TRBD when available. Fluvox- using ADRs was conducted and the percentage of amine is a major inhibitor of clozapine metabolism each ADR was computed (Table 6). co-medication and reporting biases in the RCTs. had major methodological problems. They described cyto- ity. most of them of clozapine for TRBD will need to pay attention were open-label observational trials.3-fold higher plasma clozapine (open-label trials or RCTs) and outcome definition concentrations than patients with other CYP2C19 (response or remission). which may have major influences on in other studies are possible. 98). the current review provided limited evidence supporting clozapine Poon et al. studies reviewed in it is the lack of close attention sus other antipsychotics plus a mood stabilizer to issues regarding clozapine pharmacokinetics (103–109) in the treatment of BD in China. analysis and computation of the percentage of each The main strength of this study is that we also ADR provided some evidence supporting the use searched Chinese databases in the systematic of clozapine (Table 6). it was already reported that Chi- for TRBD in the Chinese literature. (115) and paroxetine and fluoxetine are mild inhib- Secondly. future studies and meta-analyses this review included 15 clinical trials. and clozapine plus a mood stabilizer ver. and (ii) the efficacy case-by-case (93. which does not corre- available without applying any language restric. plus a mood stabilizer versus a mood stabilizer (97. one open-label prospective racial differences. which is indicative of lower cloza- pine metabolism in Chinese patients. including the nese patients tended to receive approximately half only placebo-controlled clozapine RCT for of the clozapine dosage used in Western counties TRMD (41). where clozapine is widely some patients with a diagnosis of schizoaffective used. evidence was ‘very low’ in CGI score and psycho- social function. 111) but appeared to have roughly similar clozapine levels. A fourth limitation of this review and all the 103. In 1997. but the tables provide details of (97. However. Carbamazepine is a major inducer of with data on efficacy. The literature Limitations of the study has not stressed this difference nor provided an A few limitations of the current review need to be explanation. we only Studies of adjunctive clozapine treatment in extracted data onto standard. clozapine metabolism (113) and it is possible that ity with ADR data. there was lower heterogene. these analyses error-prone. methodology (PMs) as having 2. once tardive dyskinesia or also need to be mentioned: (i) all available trials dystonia is established. Approximately 25% of the Chinese may violate basic statistical assumptions and make population are CYP2C19 PMs. it was not possible to conduct important study that has not received enough a meta-analysis because of the study’s heterogene. Clozapine dosing is influenced by also found two RCTs. clozapine these ‘contaminated’ studies. Clozapine for treatment-resistant bipolar disorder 95.

Leucht S. and decreased hospitalization. there was no safety analysis or Technology Commission (grant D121100005012002).. clozapine treatment of neuroleptic-resistant schizophre- Constipation. Comparative effectiveness of nated by ADR underreporting. Clozapine for atypical antipsychotics in schizophrenia. which is comparable to our analysis. Kane J. Br pine appeared to be associated with improvement J Psychiatry Suppl 1992. antipsychotics in the treatment of BD. 7. but future reviews need to focus on the review was limited by: (i) inclusion of only two role of clozapine for the treatment of BD in clozapine trials (44. That Disclosures review indicated that the early clinical experience of clozapine as a potential mood stabilizer sug. Singer J. The percent. Hosp Community Psychiatry 1990. world. will thyroid augmentation. Marder SR. Their TRBD. 98). Meltzer HY.Li et al. 118). 45). few That review indicated that combining multiple clozapine RCTs for BD in general have been agents was the most commonly used clinical strat. C-YW and JdL con- synthesis in that analysis. aging (41. calcium channel provide clinicians with more choices. Attard A. Similarly. CNS Drugs TRBD may increase treatment compliance. 6. Owen R Jr. Naber D. ages of patients with leukocytopenia. once more clozapine RCTs have been egy for TRBD. 152: 183–190. Conclusions References TRBD is a complex. Beake B. blockers. focusing on clozapine as the prototypical agent. published. 3. 9. 17: 46–53. 886–890. leads other than the use of clozapine for TRBD This comprehensive review has focused on mania. and electroconvulsive therapy. nation with other medications for TRBD may be 2. reported ADRs. an approach that may be effective published. which is consistent with our findings. Meltzer HY. Van Putten T. sialorrhea. measurable social and 4. However. Dessain E. Arch Gen Psychiatry shows that clozapine monotherapy or its combi. X-BL and Y-LT contributed equally to the review of the arti- Similarly. Who should receive cloza- both safe and effective. Taylor DM. 5. (ii) lack of report on cloza. Hippius H. CD006633. Psy- chopharmacol Bull 1989. Cole J. This study was supported by the Beijing Science and included. However. Honigfeld G. phrenia. which Author contributions excluded most trials of clozapine for TRBD. 97. sedation. agranulocy. properties.A. No com- data synthesis. 382: 951–962. there was no safety analysis or data cles and to the writing of the first draft. a meta-analysis of non-treatment for treatment-resistant patients included high-dose resistant BD. mercial organizations had any role in the writing of this paper Frye et al. Clozapine for psychiatric disorder and it often poses a thera. the treatment-resistant schizophrenic: a double-blind peutic challenge (17. 26: 491–508. and none of the Chinese studies were The authors thank Lorraine Maw. weight gain. Okayli G. 1988. 25: 253. The authors of this paper report no financial relationship with gested greater anti-manic than antidepressant commercial interests within the last three years. 8. Meltzer H. often severe and disabling 1. emerging evidence from China is encour- Gitlin (116) conducted a review on this topic. which may offer additional therapeutic benefits. Rummel-Kluge C et al. general. that review only included some trials conducted before 1998. if supportive of clozapine use. Long-term use of cloza. Cochrane Library 2010. 45: 865–867. cannot be ruled out that they may be contami. Since the early 1980s. 10 . Marby D. Komossa K. All authors contributed to and approved the final manuscript. 2012. though none were severe enough Clozapine versus other atypical antipsychotics for schizo- to result in drug discontinuation. On the other hand. 64). Reduction of suicidality during functional gains. Asenjo Lobos C. Comparative effi- tosis and seizure were lower than in studies of cacy and tolerability of 15 antipsychotic drugs in schizo- clozapine for schizophrenia. (117) reviewed the use of atypical for publication. 41: required for the prevention of agranulocytosis. some patients may have poor Response to clozapine in chronic psychotic patients. This systematic review comparison with chlorpromazine. and (iii) lack of inclusion of Chinese non-treatment-resistant BD elsewhere in the studies which include larger numbers of patients. adherence or may not be willing to start cloza. but the possibility phrenia: a multiple-treatments meta-analysis. Dimensions of outcome with clozapine. 45: 789–796. clozapine. 60. The European experience with use pine treatment due to the blood collections of clozapine. pine? Arch Gen Psychiatry 1988. Spineli L et al. only three Acknowledgements studies of clozapine treatment were included (45. nia: impact on risk-benefit assessment. M. Am J Psychiatry aches and pain were the most commonly 1995. Though clozapine is rarely used for pine ADRs. for editorial assis- tance. tributed by improving the first and later drafts. Cipriani A. Lancet 2013. in clinical symptoms.

Sachs GS. Wang RJ. One case of treatment-resistant twin mania. as add-on strategy in difficult-to-treat bipolar depressive 48. Gitlin MJ. ium carbonate in the treatment of acute mania. Carmody T. Merikangas KR. Am J ment-resistant bipolar disorder: a case series. Clozapine treatment of Herald Med 2008. treatment. 46: 143–150. Bipolar 47. Chin J Modern Drug 573–584. Tohen M et al. Xing BP. 55: 295–300. Neuropsychobiology 2002. 32: 270–280. 59: 530–537. ness of clozapine in patients with bipolar disorder: results 11 . 10: 350–351. 19: 215–236. Ann Intern Med 2009. Acta treatment patterns of bipolar disorders in China in 2006. 45: 33–36. 28. Chin J Clin Pharmacol 2001. Kraemer H. Liu YQ. Arch Gen Psychol Med 2001. 37. Wang CY. rol 1994. Akiskal HS. Ghaemi SN. 2009. Chen JM. 36: 338–340. Xu XH. Hwu H-G. Erfurth A. Clin- chiatry 1992. Am J Psychiatry 2002. 161: 564–566. Dong YM. 17: 287–289. 52: 411–414. Dell’Osso B. Bosch B. 27: 672–673. J Psychiatry 2002. Woyshville MJ et al. response in long-term follow-up. Poon SH. Di Paolo A. Tsai S-Y. Correll CU. and schizophrenia. 19. Si TM. D’Urso N et al. Zarate CA Jr. Atypical anti- Psychopharmacol 1993. treatment-resistant illness and a history of mania. bipolar and schizoaffective disorders: a pilot study. Sum MY. 373: 2041–2053. Cloza- 1998. Youjiang 22. Karam EG et al. The one-day survey on psychotro- Disord 2009. 41: 1–9. 11: 137–140. Gilbert J. Augmenta. Yang LZ. reporting items for systematic reviews and meta- 29. Suppes T. Bull 50. Psychiatry 2007. combined with lithium carbonate. pic drug use in 788 psychotic inpatients in Beijing An- 26. analyses: the PRISMA statement. Liu TB. Gao H. 31. Shi Q et al. Psy- the treatment of 121 out-patients. Wang GY. ical treatment analysis of 528 cases of affective disorders 17. Arolt V. Treatment-resistant bipolar depression. Clozapine for treatment-resistant bipolar disorder 10. The investigation and analysis of adult bipolar disorder patients. J Clin sion). Preliminary ran. 159 (Suppl. 11: 170–171. Treatment. Corpse C. Lancet 2009. 153: 759–764. RJ. 276: 293–299. Chin J Pharmacoepidemiol 1997. 49: 119–122. Khan M. Burdick KE. A double-blind study of clozapine natural history of the weekly symptomatic status of bipo. Mundo E. Kuswanto CN. ipexole added to mood stabilizers for treatment-resistant Rush AJ. Chen JD. Jin WD. Jiang F et al. Fan ZG. Biol Psy. 11: 76–81. Frakenburg FR. Lifetime and 41. Chen C-C. Si TM. 5: 158–161. Clozapine combined with lith- for the treatment of patients with bipolar disorder (revi. Chen XL. psychotics in the treatment of elder patients with mania. 15. Judd CR. Suppes T. Tan J. Yu X et al. Phillips KA. Pharmacopsychiatry 2008. of clozapine versus treatment as usual for patients with 24. Zhun FY. clozapine in schizophrenia: a retrospective study in 96 34. 6: 30–35. long-term psychosocial outcome in Chinese patients with 13. Psychopharmacology chiatr Clin North Am 1996. J Affect Disord 2008. Clozapine in 30. Clinical outcome in a randomized 1-year trial bipolar depression. 13: 289–290. Leppig M. Acta Psychiatr Scand 2009. 21: 1755–1756. A double-blind clinical trial of add-on clozapine 12-month prevalence of bipolar spectrum disorder in the in the treatment of treatment-resistant depression. 1: 44. Comparison analysis of three cases. Am J Psychiatry 23. 64: 543–552. 1996. 21. J Affect Disord 44. J Clin 35. 4): 1–50. Lindstr€ om LH. Sim K. 49. Practice guidelines 39. 45: 29–34. 32. Ann Clin Psychiatry 1999. Preferred Menninger Clin 2001. Clin 51. Lu GH. The use of quetiapine for treat. tropic in 296 inpatients in one day. 20. Real-world effective- Pract Epidemiol Ment Health 2010. Calabrese JR. nonpsychotic rapid cycling bipolar disorder: a report of 36. Judd LL. Pope HG Jr et al. Katzow JJ. treatment-resistant bipolar disorder. clozapine treatment for refractory bipolar. Clozapine management of treatment-resistant bipolar II depression: therapy in refractory affective disorders: polarity predicts a chart review. Naber D. Shu L. Zhang GP. Denicoff K et al. 38: 150–151. Luo RL. Psychiatry 2000. 45. 9: 26. Olanzapine in Med 2010. Phillips MR. Liberati A. resistant bipolar depression: towards a new definition. 77: 524–529. Arch Gen Psychiatry 2002. Mao PX. clozapine treatment for 54 cases with mania Chin. McElroy SL. Hippius H. Clozapine in the treatment of dysphoric mania. Yu X et al. 156: 1164–1169. pine for treatment-refractory mania. (rTMS) in drug-resistant bipolar depression. 40–41. American Psychiatric Association. Suppes T. 15: lar I disorder. J Clin Psychiatry 1994. Joyce PR. and associated disability of mental disorders in four 12. Role of lamotrigine in the 11. Altman DG. Zhang J. Baldessarini patients. Sharm V. Nielsen J. 46. Prevalence. Chin J Psychiatry 2012. tion of clozapine with aripiprazole in severe psychotic 151: 264–269. Clozapine provinces in China during 2001–05: an epidemiological in the treatment of psychotic mood disorders. Lastella M et al. Endick CJ. 111: 100–105. 99: S77–S79. 14. Chen CM. Application 2007. Colom F et al. 42. double-blind. Banov MD. Cole JO. Webb A. Am J Psychiatry 2004. Cross-national J Clin Psychosom Dis 2003. placebo-controlled trial of pram. Pacchiarotti I. Stadtland C. Zhang YQ. Antipsychotic drug patterns 25. Clozapine and bipolar disorder. schizoaf. 65: 26–40. Dessain EC. 18. Goldberg JF. Chen Q. Investigation and analysis of psycho- patients. Psychiatry 1999. Angst J et al. Moher D. Schettler PJ et al. Frye M. Shu L. McElroy SL. Evidence-based options for treatment-resistant 38. J Clin Psychiatry 33. J Affect Disord 1997. The efficacy and safety of lithium and low-dose JAMA 1996. Clin J National Comorbidity Survey replication. Paul B. Augmentative of schizophrenia in China: a cross-sectioned study. Zhang L. Tetzlaff J. J Chin People Health 27. Biol Psychiatry 1994. Yan JX. 43. Alcohol problems and 1991. A cross-sectional study on patients treated with clozapine for up to 13 years. J Neu- 16. Kimmel SE. Benedetti A. Mazzarini L. 1989. Michael N. domized. 120: 429–440. The effect of long-term treatment with bipolar disorder. Bipolar Disord 2012. The long-term 40. Bupropion ding Hospital. Tang YL. 37: 152–155. McElroy SL. 39: 202. Yeh E-K. Chin repetitive navigated transcranial magnetic stimulation J Psychiatry 2004. Shen QJ. 14: outpatient drug use in psychiatry. Akiskal HS. Treatment-resistant bipolar disorder. Dessain EC. survey. epidemiology of major depression and bipolar disorder. Psychiatr Scand 1988. fective disorder. Clozapine in China. Kane JM.

Weizman A. Arch Psychiatry Clin Neurosci 2005. Haller E. Weinberger DR. Palva I. 61: 329–334. treatment resistant bipolar disorder: a case report. Suppes T. The long-term 50: 317–324. 329: 162–167. Bai SZ. Dell’Osso L. Green S. 3): 38–43. schizoaffective disorder. 44: 2247– Psychiatry 1999. Biol Psychiatry 90. Alhava E. 156: 702–709. New Drug Clin 1992. Psychiatry 2003. side effects. Safferman A. Llorca PM. 3113 cases of WBC count of psychiatric patients after 66. Hoboken. Aust N Z J Psychi- Cochrane Handbook for Systematic Reviews of Inter. combined ECT and clozapine in treatment-resistant atic Reviews of Interventions. Safferman AZ. 29: 501–503. Psychopharmacol 1995. Liberman J.com.google. Ju FY. Roth RL. Meltzer HY. Calabrese JR. Different side effect profiles of risperidone and cloza- JO. Bipolar Disord 2012. Sanger TM. Neurology 1991. J Clin Psy- Analysis. Am J Psy- mood and subtype on cerebral glucose metabolism in chiatry 1990. NJ: Wiley mania. 635–638. 24: 1834–1836. 12 . Maximizing clozapine therapy: managing 60. Interpreting and understanding meta-analysis refractory rapid cycling bipolar disorder. Tohen M. Green AI. Med 1993. Altman DG. Clozapine and seizures. Daniel DG. try 2000. Gilfillan SK. Dell’Osso L. Bastiampillai TJ. 18: 771. Shiah IS. BMJ 2012. Woyshville MJ. Devlin M. 7: 203–206. Antonacci DJ. Eur Psychiatry 1996. Combined ECT and clozapine in treat- 187–241. J Clin Psychiatry 2006. 153: 62. Neal KR. 255: 10–14. Chanpattana W. Swartz CM. Szymanski S. Id€anp€a€ an-Heikkil€a J. JL. patients receiving clozapine in the UK and Ireland. Eur J may stabilize treatment-resistant bipolar patients. Silverstone T. J Clin Psychiatry 1998. 2008. 49: 97–109. Chen CK. Liu NH. Schizophrenia Bull 1991. Psychiatry 1996. 5: 241–253. Vijay Sagar KJ. Clozapine monotherapy for 66 months in in bipolar disorders. Med J Chin People Health 2006. 84. Olanzapine as 14: 863–869. Tohen M. Clozapine treatment of chil. The effects of long-term clozapine add-on therapy on J Psychopharmacol 2010. 17: 247–261. 2008. sodes resistant to standard treatment. Devinsky O. 59 (Suppl. 72. Shen AZ. Suppes T. Corbella B et al. Cui HS. 67: 461–467. Alvir JMJ. Leandro G. 80. Ind J Psychiatry 2005. Higgins JPT. 21: 469–473. effects. Olkinuora M. Poyurovsky M. Min Ahn with treatment-resistant rapid-cycling bipolar disorder. 64. Kimmel SE. Clozapine in the treatment of 56. and psychotic bipolar affective disorder. Cole JE. 55 (Suppl. J Clin 83. Gupta M. Clozapine treatment of ment of uncomplicated acute appendicitis: meta-analysis euphoric mania. Ried K. B): 91–93. prophylaxis in rapid cycling bipolar disorder. treatment-resistant bipolar disorder. Vieta E. 10: 330–331. Psychosomatics 2009. Ciapparelli A. Ann Clin Psychiatry 1995. Miller DD. J Clin 59. Clin Neurophar- treatment of psychosis in patients with iatrogenic or macol 2005. 2008: 73. 344: e2156. effectiveness of clozapine and lamotrigine in a patient 58. 41: 369–371. Higgins JP. Hoboken. Yeh CB. 71. Chang CC. Meltzer HY. Cassano GB. Markovitz PJ. 11: 193–198. Zarate CA Jr. 85. Reinares M. 11: 319–321. Clozapine in the dence and risk factors in the United States. Clozapine Handbook for the Understanding and Practice of Meta. 82. Freeman H. Pini S. Combination treatment of clozapine and topiramate in tial dopamine-receptor agonist aripiprazole as a first-line resistant rapid-cycling bipolar disorder. Emlsie GJ. Varadhan KK.629 patients. Bandettini di Poggio A et al. Mathews M. Banov MD. 61 (Suppl. 47: bipolar disorder: a 24-month naturalistic study. N J Engl treatment of refractory psychotic mania. 8): 14–17. 31: 424–426. J Clin Psychiatry 2000. Green S eds. books. Fenzi Psychopharmacol 2009. Tang M. Binder RL. Safety and efficacy lar disorder. add valproate and propranolol for treatment-resistant 87. 67. Encephale graphs: a practical guide. Kowatch RA. J Clin Psychopharmacol 2001. Lieberman JA. O’Sullivan D.Li et al. J Clin 124–125. Chiavacci MC. Fan ZY. Clozapine in treatment-refractory mood disorders. Effects of 89. McElroy SL et al. 147: 1069–1071. the rehospitalization rate and the mood polarity patterns 78. Clozapine-related seizures: expe- versus placebo in the treatment of acute mania. juvenile-onset schizophrenia. Aust Fam Physician 2006. Lieberman JA. Clozapine in treatment-resistant patients with schizo. 75. 68. Evidence for the par. Online Library. George MS et al. 11: 396–397. 22: 468–469. Dhillon R. tive disorder: a pilot study. Wiley. The clinical observation of clozapine clozapine treatment. Schaaf JA. Treatment-refractory. Low doses of clozapine Agranulocytosis during treatment with clozapine. Reid CE. Kimbrell TA. Weiss MK. In: Higgins JP. J ECT 2000. Pacia SV. J Child Adolesc 86. Honigfeld G. 69. Ketter TA. 57. 2249. chopharmacol 1991. phrenia: a clinical case series. Update on the clinical efficacy and side effects of disorder: a naturalistic 48-month follow-up study. ment-resistant mania. 76. Olanzapine 88. Sik Kim Y. Kane JM. of randomised controlled trials. Calabrese JR. Safety and effectiveness of 53. Patin J. Schwimmer Psychiatry 1994. Eur Clin Pharmacol 1977. 56: 108–112. Clozapine for treatment-refractory 79. Hoffer ZS. Tohen M. Ying D. Lieberman JA. Fuentes RM. atry 1997. Ozcan ME. J Clin clozapine. Sterne JAC. Br J dren and adolescents with bipolar disorder and schizo. Review and management of clozapine side 2001. Available from: http://www. zures. Clozapine in the 54. Chang JS. 55. Kendall F. Lobo DN. M. Lancon C. Assessing risk of management of bipolar and schizoaffective manic epi- bias in included studies. from a 2-year mirror-image study. long-term adjunctive therapy in treatment-resistant bipo- 52. Clozapine-related sei- depression. Mahmood T. Psychiatry 2000. Ha KS. 16: 204–207. or psychotic bipolar non B. Mao WC. Fehr BS. Am J Psychiatry 1996. 157: 982–986. Young Lee K. schizoaffective disorder. Y. NJ: Cochrane Book Series. 35: 1996. 169: 483–488. Neurology 1994. 81. 417–419. Meta-Analysis in Medical Research: The 74. 64: 451–458. Goldberg TE. of antibiotics compared with appendicectomy for treat. 28: 136–138. Clozapine-induced agranulocytosis–inci- 63. Kleinman 61. Ciapparelli A. Cochrane Handbook for System. ventions. Am J Psychia. Neutropenia and agranulocytosis in Granneman BD. Devinsky O. Is clozapine a mood stabilizer? J Clin Psychiatry pine in 20 outpatients with schizophrenia or schizoaffec- 1995. Am J rience with 5. tumorogenic hyperprolactinemia. Gould D. Ki- phrenia.com [accessed October 2014]. 70. 77. Atkin K. Patel JK et al. 65.

newer antipsychotics: a comparative review. Zhou Y. 16: 2. Liu CM. J Pract Med 2010. 115. Basic Clin ple Health 2009. Small JG. J Clin Psychiatry 1994. Liu HY. Pharmacol Toxicol 2007. Interactions pine in the treatment of mania. Xie WJ. B): 109. kinesia. Ma ZL. Spina E. A comparative study of bipolar disorder: treatment implications for other atypi- lithium and chlorpromazine versus lithium and clozapine cal antipsychotics. Wang QM. Chang W. Jing YL. Anghelescu I. Clozapine for treatment-resistant bipolar disorder 91. tion and plasma clozapine concentrations in Chinese sus lithium in the treatment of mania. doses and confounding variables. Santoro V. Spina E. Thaker G. Dong YY. 41: 81–91. sodium valproate and carbamazepine in the treat. Lee JH. Yang YJ. Clinical treatment of mania. Clozapine in tar. Clozapine in 104. 112. Moran M. Controlled studies on olanzapine or clozapine and stabi- stein M. Milstein V. resistant. Tamminga C. Shen Y et al. ABCB1 and pine. 40: 253–258. Mol Psy- Clozapine combined with lithium in the treatment of chiatry 2006. 19: Psychiatry 1990. the effects of co-medications on plasma clozapine con- 101. J Clin Psy- pine and clozapine combined with lithium in the chopharmacol 2007. 48: 91–104. Gan JG. lizer in patients with mania. 113. 27: 715–717. 96: 599–605. Wu H. J Affect Disord 1998. Acute and long-term effective- 1999. Br J Psychiatry Suppl 1992. Bajbouj M. Meltzer HY. Randomized controlled trial 102–106. 11: 227–240. Yan JX. Santoro V. Zeugmann S. J Clin Psychol Med 2006. 117. Ranjan R. Health Psychol J 2002. Clozapine in medication. Pract Chin Clin Med between antiepileptics and second-generation antipsy- 2004. A comparative study of olanza. Song SY. Marhenke JD. Jann M. Naber D. pine dosages and plasma drug concentrations. Chen Q. Liu ZC. 19: 2. Khoo Y-M et al. 93. Tang XW. The effects of clozapine on tardive dys. Metabolic drug interactions with pine in the treatment of mania episode. netics of clozapine. Treatment-resistant bipolar disorder. 102. Comparative study of clozapine versus olanza. Cloza- J Clin Psychiatry 1987. Tao Q. de Leon J. 3: 21–23. in the treatment of mania. 108. Psychopharmacology 1978. 13 . 29: 10: 228–230. Tao H. Holzbach R. A study of centrations using a model that controls for clozapine aripiprazole versus clozapine in the treatment of mania. J Clin Psychopharmacol 2009. Chong S-A. ment outcome with clozapine in tardive dyskinesia. Yang XJ. 119. Simpson GM. Treat. 103. 26: in tardive dyskinesia: observations from human and ani. Liu QH. A comparative study of quetiapine and cloza. Gong CF. 12: 56–57. Med J Chin Peo. Wu YH. 1806–1807. Altshuler LL et al. Wang YX. Liu MY. Clinical evalua- 97. Antipsychot. J Clin Psychosom Dis 2004. comparing quetiapine with lithium and clozapine with 95. Hall DD. Liao GS. Chu JF. Lieberman JA. neuroleptic sensitivity. 21: 34–35. Spina E et al. Saltz BL. Johns CA. Chin J Nerv Ment Dis 1997. Lin S. De Leon J. 18: management of clozapine patients in relation to efficacy 256–257. 110. Lane H. mal model studies. Ketter TA. dive dyskinesia. Li J. Shandong Arch Psychiatry 2005. 2008. D’Arrigo C. 158: 503–510. Lv XS. 92. 99: S47–S53. Hu W. J Form 96. Wei XY. Ma YC. Morena GP et al. Knezevic B. Perro C. 48: 263–267. Expert Opin Drug Metab Toxicol 2012. Xie QM. clozapine combined lithium versus ziprasidone combined 94. Zhao YM. Wang LT. mania. 107. Shrivastava RK. Frye MA. Gitlin M. 55 (Suppl. sion. Clozapine lithium in the treatment of mania. Sirot EJ. 319–326. Lin H. Psychopharmacology 1989. Wang RQ. 54–59. Pollack S. Tan C-H. lithium in the treatment of female patients with mania. Quante A. ness of clozapine in treatment-resistant psychotic depres- 105. 10: 164–166.and electroconvulsive therapy- 106. A controlled study of cloza. Chu PH. and treatment-resistant psychosis. 23: 291–298. 21: 2993–2994. A comparative study of clozapine ver. J Clin Psychol Med 2002. 99. 12: 347–348. Br J Psychiatry 1991. 334. Liu TZ. Clozapine: neuroleptic-induced EPS and tar. 100: 4–22. Hippius H. 111. Qiu DS. 8: 311– 100. Shandong Arch patients with schizophrenia. Zhang GY. 56: 75–80. Ther Drug Monit 1997. Kakigi T. Boren. Pharmacopsychiatry Shandong Arch Psychiatry 2006. Med Assoc 1997. Casey DE. Zhang YQ. Randomized controlled study of dive dyskinesia. The compari. 23: 104–106. Sichuan Arch Psychiatry 118. Shanghai Arch Psychiatry 2011. Li J. depressed inpatients: a case series. 116. 98. son of olanzapine and clozapine in the treatment of 114. Chen M. Biol Psychiatry 1996. Kane J. and side-effects. cytochrome P450 polymorphisms: clinical pharmacoge- ment of 84 patients with mania. chotics. ics combined with lithium in the treatment of mania. Estimating the size of mania. Diaz F. Jin WD. 219–223.