Bowden 2005.

Methods	Study design: randomised, placebo‐controlled study
Participants	Diagnosis: bipolar I disorder, current episode manic Method of diagnosis: according to the DSM‐IV Age: for lithium, median = 38.0 years (SD = not given); for quetiapine, median = 41.3 years (SD = not given); for placebo, median = 38.8 years (SD = not given) range = 18 ‐ 73 years Sex: for lithium 40.8% women; 59.2% men, for quetiapine 43.9% women; 56.1% men, placebo 42.1% women; 57.9% men. Location: 24 centres in Europe and Asia Co‐morbidities: not described Adjunctive therapy: not described Adjunctive medication: "The following sedatives/hypnotics were permitted during the study for insomnia, providing the maximum doses were not exceeded and only 1 was used on any study day: zolpidem tartrate (maximum dose = 10 mg/day), chloral hydrate (maximum dose = 2 g/day from days 1 to 7 and 1 g/day from days 8 to 84), zopiclone (maximum dose = 7.5 mg/day), and zaleplon (maximum dose = 20 mg/day). Use of concomitant anti‐ cholinergic medications was not allowed after randomisation unless in relation to an adverse event of extrapyramidal symptoms (EPS). Lorazepam treatment for agitation (but not insomnia) was allowed as follows: up to 6 mg/day from screening to day 4, up to 4 mg/day from days 5 to 7, up to 2 mg/day from days 8 to 10, and up to 1 mg/day from days 11 to 14. Lorazepam was withheld for 6 hours before psychiatric assessments were conducted and was not permitted by the protocol after day 14. Within these guidelines, treatment was at the discretion of the physician, and if a participant experienced insomnia and agitation concurrently, lorazepam plus one of the permitted sedatives/hypnotics could be co‐administered".
Interventions	Participants were randomly assigned to either: Experimental arm ‐ lithium N=67 Duration: 12 weeks Treatment protocol: all medication was administered twice daily in a double‐blind fashion. Double‐blinding was maintained throughout the study. Lithium dosing was initiated on day 1 at a dose of 900 mg/day. Dose adjustment between days 5 and 84 was at the discretion of the investigator in order to optimise efficacy and tolerability. The target trough serum lithium concentration was between 0.6 and 1.4 mEq/L and was monitored throughout the study by an investigator inde‐ pendent of the dosing investigator. Study blinding was maintained by collecting blood samples from all participants at least 12 hours after administration of the previous dose of study medication, and serum lithium concentrations were determined on days 4, 7, 14, 21, 28, 42, 56, 70, and 84 (or final visit). Additional tests were conducted as needed, at the discretion of the investigator, to assess lithium toxicity. The mean serum lithium concentrations in lithium‐treated participants were within the target range of 0.6 to 1.4 mEq/L at all assessments from day 4 onward. The median serum lithium concentration was 0.73 mEq/L at day 14, 0.80 mEq/L at day 21, and 0.80 mEq/L at day 84". Therapist/face‐to‐face contact: not described Comparator arm ‐ quetiapine N = 72 Duration: 12 weeks Treatment protocol: all medication was administered twice daily in a double‐blind fashion. Double‐blinding was maintained throughout the study. Quetiapine was flexibly dosed and initiated at target doses of 100 mg on day 1, 200 mg on day 2, 300 mg on day 3, and 400 mg on day 4. Quetiapine dose could be adjusted up to 600 mg/day on day 5 and up to 800 mg/day thereafter (days 6 to 84). At day 21, 90% of participants who responded to quetiapine were taking doses between 400 and 800 mg/day. At day 84, 91% of responders were taking doses in this range. The mean quetiapine dose for responders was 586 mg/day in the last week of treatment prior to day 21 and 618 mg/day prior to day 84 (mean doses calculated by averaging the median dose for responders in the last week of treatment).
Outcomes	Timepoints for assessment: days 1 (baseline), 4, 7, 14, 21, 28, 42, 56, 70, and 84. Primary outcome: Change from baseline in YMRS score at day 21. Secondary outcome: Withdrawal Completion Additional medications used The YMRS response rate (a 50% or greater reduction in YMRS score from baseline) at day 21 The YMRS response rate (a 50% or greater reduction in YMRS score from baseline) at day 84 The proportion of participants experiencing YMRS remission (YMRS score ≤ 12) at day 21 The proportion of participants experiencing YMRS remission (YMRS score ≤ 12) at day 84 Adverse events Change from baseline YMRS at day 7 Change from baseline YMRS at day 84 Change from baseline in CGI severity of Illness score at day 21 Change from baseline in CGI severity of Illness score at day 84 Montgomery‐Asberg Depression Rating Scale day 84 Mean weight gain (kg) day 84
Notes	Date of study: April 2001‐May 2002 Funding source: this study was supported by AstraZeneca Pharmaceuticals, Wilmington, Del. Declarations of interest among the primary researchers: AstraZeneca Pharmaceuticals, Wilmington, Del. (Drs. Mullen and Brecher and Mr. Jones); and AstraZeneca Pharmaceuticals, Södertälje, Sweden (Dr. Paulsson, Mr. Vågerö, and Ms. Svensson).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"On day 1, participants were randomly assigned to treat‐ ment with quetiapine or lithium or their matching placebos".
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias) All outcomes	Low risk	"Study blinding was maintained by collecting blood samples from all participants. In addition, all investigators and individuals who administered psychiatric rating scales remained blinded to treatment for the duration of the study".
Incomplete outcome data (attrition bias) All outcomes	Low risk	More participants treated with quetiapine (67.3%) or lithium (68.4%) completed the study at day 84 compared with those treated with placebo (36.1%).
Selective reporting (reporting bias)	Low risk	Comprehensively reported
Other bias	Low risk	None identified