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. 2019 Jun 1;2019(6):CD004048. doi: 10.1002/14651858.CD004048.pub4

Niufan 2008.

Methods Study design: double‐blind, parallel, randomised, controlled study
Participants Diagnosis: bipolar disorder, manic or mixed episodes.
Method of diagnosis: DSM‐ IV criteria for an index manic or mixed episode of bipolar disorder (with or without psychotic features), based on a clinical assessment. Participants were required to have a YMRS total score ≥ 20
Age: for lithium, median =34.0 (SD = 13.77) years; for olanzapine, median = 31.2 (SD = 12.55) years
Sex: lithium 49.3% women, olanzapine 56.5% women.
Location: seven sites in China
Co‐morbidities: not described
Adjunctive therapy: none given
Adjunctive medication: "Concomitant medications with primarily central nervous system activity were excluded; however, the use of lorazepam (or lorazepam equivalent) up to 2 mg/ day was permitted to alleviate manic agitation, but not within 8 h of a psychiatric evaluation. Benzhexol hydrochloride (or equivalent) was permitted up to 6 mg/ day to alleviate extrapyramidal symptoms."
Interventions Participants were randomly assigned to either:
Experimental arm ‐ lithium
N = 71
Duration: 4 weeks
Treatment protocol: "Patients who met all enrolment criteria after a 2– 7 day screening period were randomised in a 1:1 ratio to double‐blind treatment with either oral olanzapine (5– 20 mg/day, starting dose 15 mg/day; n = 69) or lithium carbonate (600–1800 mg/day in a divided dose, starting dose 300–600 mg/day; n = 71) over a 4‐week period.
After 1 day on therapy, the olanzapine starting dose could be adjusted within the allowed dose range of 5– 20 mg/day, based on response (i.e., adverse events and efficacy).
Those participants who could not tolerate olanzapine 5 mg/day or lithium carbonate 600 mg/day after Day 3 of the double‐blind treatment phase were discontinued from the study. In order to maintain double‐blinding of non‐identical medications, participants also received placebo tablets similar in appearance to the treatment they had not been randomised to receive (double‐dummy treatment).
To further maintain the double‐blind nature of the study, all participants had serum specimens collected to test or lithium blood levels throughout the study, regardless of which treatment they were randomised to. An independent laboratory performed lithium blood level monitoring only for those participants randomised to receive lithium, although all participants received a laboratory report. Lithium blood levels were reported as “well below target” (below 0.60 mEq/L), “below target” (0.61–0.80 mEq/L), “within target” (0.81– 1.20 mEq/L), “above target” (1.21–1.40 mEq/L), or “well above target” (1.41–2.0 mEq/L), and corresponding recommendations were made to increase, decrease, or leave unchanged the daily “lithium” dose (regardless of whether the patient was actually receiving active lithium treatment). Olanzapine participants were randomly assigned to the various report categories."
Therapist/face‐to‐face contact: not described
Comparator arm ‐ olanzapine
N = 69
Duration: 4 weeks
Treatment protocol: "Patients who met all enrolment criteria after a 2– 7 day screening period were randomised in a 1:1 ratio to double‐blind treatment with either oral olanzapine (5– 20 mg/day, starting dose 15 mg/day; n = 69) or lithium carbonate (600–1800 mg/day in a divided dose, starting dose 300–600 mg/day; n = 71) over a 4‐week period.
After 1 day on therapy, the olanzapine starting dose could be adjusted within the allowed dose range of 5– 20 mg/day, based on response (i.e., adverse events and efficacy).
Those participants who could not tolerate olanzapine 5 mg/day or lithium carbonate 600 mg/day after Day 3 of the double‐blind treatment phase were discontinued from the study. In order to maintain double‐blinding of non‐identical medications, participants also received placebo tablets similar in appearance to the treatment they had not been randomised to receive (double‐dummy treatment).
To further maintain the double‐blind nature of the study, all participants had serum specimens collected to test or lithium blood levels throughout the study, regardless of which treatment they were randomised to. An independent laboratory performed lithium blood level monitoring only for those participants randomised to receive lithium, although all participants received a laboratory report. Lithium blood levels were reported as “well below target” (below 0.60 mEq/L), “below target” (0.61–0.80 mEq/L), “within target” (0.81– 1.20 mEq/L), “above target” (1.21–1.40 mEq/L), or “well above target” (1.41–2.0 mEq/L), and corresponding recommendations were made to increase, decrease, or leave unchanged the daily “lithium” dose (regardless of whether the patient was actually receiving active lithium treatment). Olanzapine participants were randomly assigned to the various report categories."
Outcomes Timepoints for assessment: at randomization, and at days 3, 7, 14, 21 and 28
Primary outcome:

  1. CGI‐BP (Overall Severity) Total Score


Secondary outcome:

  1. Trial completion + discontinuation

  2. Additional medications

  3. YMRS

  4. BPRS

  5. CGI‐BP Subscales

  6. MADRS

  7. Response – ≥ 50% decrease in YMRS score

  8. Remission rate (YMRS ≤ 12 at LOCF endpoint)

  9. Adverse events

  10. Weight gain/BMI

  11. Blood tests

  12. EPSEs
Notes Date of study: December 2003‐June 2005
Funding source: "Conflict of interest. This study was sponsored by Eli Lilly and Company. M. Tohen, A. Qiuqing, H. McElroy, and E. Pope are employees of Eli Lilly and Company. G. Niufan, Y. Fude, L. Ming, W. Gaohua, Z. Xinbao, L. Huichun, and S. Liang are clinical investigators for the F1D‐GH‐LOBV study (upon which the manuscript is based), for which their institutions were funded by Eli Lilly and Company for the time spent and assessment cost. The authors have no other potential conflicts of interest to disclose. Contributors. M. Tohen and A. Qiuqing were involved in the conception and design of the study. H. McElroy undertook the statistical analyses. E. Pope conducted the literature searches, and drafted the manuscript. G. Niufan, Y. Fude, L. Ming, W. Gaohua, Z. Xinbao, L. Huichun, and S. Liang were involved in the acquisition of data. All authors contributed to the interpretation of the data, critical revision of the manuscript for important intellectual content, and have approved the final manuscript. Role of funding source. Eli Lilly and Company (Lilly) provided funding for this study and was involved in the study conception and design. Lilly had no role in the collection of data for this particular manuscript, beyond the provision of clinical report forms and undertaking clinical monitoring of study sites. Lilly was involved in the analysis and interpretation of data for this manuscript, and in the drafting of the manuscript. Outside of the Lilly employees listed as authors (M. Tohen, A. Qiuqing, H. McElroy, and E. Pope), Lilly had no role in the decision to submit the paper for publication."
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk "randomised"
Allocation concealment (selection bias) Unclear risk Not described
Blinding (performance bias and detection bias) 
 All outcomes Low risk Double‐blind; "To further maintain the double‐blind nature of the study, all participants had serum specimens collected to test for lithium blood levels throughout the study, regardless of which treatment they were randomised to."
Incomplete outcome data (attrition bias) 
 All outcomes Low risk 15% did not complete the study
Selective reporting (reporting bias) Low risk Well reported
Other bias Low risk None identified