This was a 6 week, parallel group, placebo controlled trial undertaken in Roozbeh Psychiatric Hospital, Tehran, Iran during January 2002-January 2003.

Eligible participations were 45 in patient, age between 21–43 years old and met DSM-IV criteria for a current manic episode, on the basis of a clinical interview by an academician psychiatrist. In addition, a score of at least 20 points on the Young Mania rating Scale 19 was required representing at least a moderate to severe mania. Mental retardation, neurological or other medical impairment, the need for ongoing treatment with other psychoactive medications, and/or current substance dependence, seizure disorder requiring medication, participation in an investigational drug trial within 30 days before the start of the trial, known sensitivity to haloperidol, lithium or ritanserin, use of clozapine within 1 month before study entry; use of depot neuroleptics within one cycle before study entry, laboratory values outside the normal range, women of childbearing potential who were without adequate contraception were exclusionary criteria. The trial was performed in accordance with the Declaration of Helsinki and subsequent revisions and approved by ethics committee at Tehran University of Medical Sciences. Written informed consents were obtained before entering into the study.

All patients entered the hospital untreated with any medications. Patients were randomly allocated 23 to lithium + haloperidol+ ritanserin (Group A) or lithium + haloperidol + placebo (Group B) for a 6-week, double-blind, placebo-controlled study. Two patients from group A and one from group B dropped out from the study leaving 42 patients who met the DSM-IV criteria for manic episode. Rapid titration of lithium to therapeutic level 1–1.2 mEq/L was facilitated by the use of the pharmacokinetic method of predicting a therapeutic dose. Weekly lithium levels were obtained for compliance monitoring. Adjunctive antipsychotic medication that was haloperidol and was started simultaneously with lithium. The dose of haloperidol was titrated up to 10 mg/day. A fixed dose of ritanserin 10 mg/day was used throughout the study. Concomitant lorazepam use was restricted to a maximum dose of 2 mg/day for the first 4 days of treatment and thereafter by up to 1 mg/day for the next 6 days. Lorazepam was not permitted beyond the initial 10 days and was not allowed within 8 hours of the administration of mania rating scale. Biperiden was permitted to treat extrapyramidal symptoms up to a maximum of 6 mg/day throughout the course of the study. Biperiden was not allowed as prophylaxis for extrapyramidal symptoms. Patients were assessed by a third year resident of psychiatry at baseline and after 3, 7, 14, 21, 28 and 42 days after the medication started. Patients were hospitalized throughout the study.

The principal measure of the outcome was the Young Mania Rating Scale. The rater used standardized instructions in the use of Young Mania Rating Scale. The mean decrease in Young Mania Rating Scale score from baseline was used as the main outcome measure of response of mania to treatment. The extrapyramidal symptoms were assessed using the Extrapyramidal Symptoms Rating Scale (ESRS) 20. Patients were randomized to receive ritanserin or placebo in a 1: 1 ratio using a computer generated code. The assignments were kept in sealed, opaque envelopes until the point of allocation.

Side effects were systematically recorded throughout the study and were assessed using a checklist administered by a resident of psychiatry on day 3, 7, 14, 21, 28 and 42 (Table 3).

A two-way repeated measures analysis of variance (time-treatment interaction) was used. The two groups as a between-subjects factor (group) and the seven measurements during treatment as the within-subjects factor (time) were considered. This was done for Young Mania Rating Scale scores. In addition, a one-way repeated measures analysis of variance with a two-tailed post-hoc Tukey mean comparison tests were performed on the change Mania Rating Scale scores from baseline. To compare the reduction of score of Young Mania Rating Scale at week 6 compared to baseline and ESRS score in different days an unpaired two-sided Student's t-test was used. Results are presented as mean ± SD differences and were considered significant with P = 0.05. To compare the baseline data and frequency of side effects between the protocols, Fisher's exact test was performed. A traditional "observed cases" (OC, the patients who completed the trial) analysis in 42 days was the primary efficacy analysis. In addition, intention to treat (ITT) analysis with last observation carried forward (LOCF) procedure was also performed. All results discussed are based on OC analysis unless otherwise stated.

The mean ± SD scores of two groups of patients are shown in Figure 2. There were no significant differences between the two groups in day 0 (baseline) on the Young Mania rating Scale (t = 0.81, d.f. = 43, P = 0.81). The difference between the two protocols was significant as indicated by the effect of group, the between-subjects factor (F = 5.02, d.f. = 1, P = 0.03; F = 5.11, d.f. = 1, P = 0.029 for OC and LOCF respectively). The behavior of the two treatments was homogeneous across the time (groups-by-time interaction, Greenhouse-Geisser correction; F = 1.71, d.f. = 2.85, P = 0.17). In addition, a one-way repeated measures analysis of variance showed a significant effect of both protocols on the Young Mania rating Scale (P < 0.0001). In both groups post-hoc comparisons showed a significant change from day 3 on the Young Mania rating Scale. The difference between the two protocols was significant at the endpoint (day 42) (t = 3.56, d.f. = 40, P < 0.001). The changes at the endpoint compared to baseline were: -22 ± 4.47 (mean ± SD) (the baseline score was 25.38 ± 3.17) and -19.33 ± 5.06 (the baseline score was 26 ± 3.58) for group A and B respectively. A significant difference was observed on the change of scores of the Young Mania rating Scale in day 42 compared to baseline in the two groups in (t = 2.09, d.f. = 40, P < 0.042).

The means ESRS for the placebo group were higher than the ritanserin group and the difference was significant in day 42. (Table 2). A not quite significant difference was observed between the overall mean biperiden dosage in the two groups. (106 ± 46.89 and 143 ± 56.18 for group A and B respectively (mean ± SD) (P = 0.06).

Seventeen side effects were observed over the trial. The difference between the two groups in the frequency of side effects was not significant (Table 3).