Coding of variables was reliable. There was over 90% agreement in all but the numbers completing the study (70%) and listing of outcome instruments; in about 10% of reports the principal rater (BT) failed to identify one of the scales, often among several used.
Over 95% (1954) of the 2000 trials were in people with schizophrenia, serious or chronic mental illness, psychosis, or movement disorders. Most of the 2275 reports were fully published in journals (1940, 85%), while the remainder were presented at conferences (253, 11%) or published as letters, in books, as chapters in books, or as product monographs (82, 4%). The BMJ and Lancet publish a few more schizophrenia trials than JAMA and the New England Journal of Medicine (21, 33, 6, 2 respectively), but all these widely read journals were limited sources of trials on this most serious, costly illness. Most trials were published in general psychiatric journals.
The number of trials relevant to schizophrenia rose steadily with time, from about 20 per year in the 1950s and 1960s to an average of nearly 75 per year in the past decade (β=1.9, r2=0.59, P<0.001, where β is the estimated yearly change and r2 the yearly data explained by a linear trend).
Most (2214, 97%) of the reports were published in English. Most (1238, 54%) were from North America, with 37% (849) from Europe and 8% (188) from the rest of the world. Trial output from North America increased at a faster rate than that from Europe and the rest of the world (0.9, 0.7, and 0.3 extra trials per year respectively).
The quality of reporting was poor. Only 4% (80) of the trials clearly described the methods of allocation. Explicit descriptions of blinding were adequate in only 22% (440) of trials, while some description of treatment withdrawals was given in 42% (840). One per cent (20) of the 2000 trials achieved a maximum quality score of 5. Just under two thirds (1280) scored 2 or less, which means that they barely, if at all, described any attempt to reduce the potential for introduction of bias at allocation or rating of outcome, placebo effects, or the fate of all participants. A score of 3 or more was predefined as better quality. Just 33% (354/1062) of North American trials achieved this, compared with 36% (262/724) of European trials and 43% (77/180) of those from the rest of the world (χ2=9.23, P<0.01). Studies from Canada (n=103) and a combined group of the Middle East and Asia (n=109) were particularly well reported (98, 46% scoring 3 or higher). We found little evidence that the quality of trial reporting improved with time. From 1950 to 1997 the mean quality score was consistently under 2.5.
The average number of trial participants was 65, with no discernible change over time (β=0.2, r2=0.7, P=0.4). Only 20 trials (1%) raised the issue of the statistical power of the study. The average size of schizophrenia trials was small. For an outcome such as clinically important improvement in mental state to show a 20% difference between groups a study would have to have 150 participants in each arm (α=0.05, power 85%). Only 3% (60) of studies were of this size or greater. More than 50% of trials had 50 or fewer participants (figure).
On average, just under 12% of participants left the studies early, although the trend was towards increasing loss to follow up (β=0.01, r2=0.6, P<0.001). Over half of the trials lasted six weeks or less (1082, 54%), and less than one fifth allowed more than six months to evaluate the treatments (382, 19%).
Only 272 (14%) of the total sample of trials were clearly community based, but the proportion increased (β=0.1, r2=0.92, P<0.01). Even in the 1990s, however, the proportion was still small (23%, 135/587).
Interventions were classed as drug treatment, psychotherapy (any treatment based on talking), physical treatment (electroconvulsive therapy, psychosurgery), policy or care packages (case management, team treatment), and other (table ). Overall, 1725 (86%) of the 2000 trials evaluated the effects of 437 different drugs. Haloperidol was an increasingly frequent comparator (β=0.5, r2=0.6, P<0.001). Overall, the proportion of drug trials declined somewhat over time (β=−0.002, r2=0.5, P=0.03), with studies of psychotherapy and policy or care packages increasing.
Interventions investigated in 2000 controlled trials of schizophrenia treatment
In all, 510 (25%) studies did not use rating scales to measure outcomes. The remaining 1490 trials used 640 different instruments. These were broadly classified; table lists the most popular. Overall, 369 scales were used only once. Most trials used between one and five instruments, but greater numbers were not uncommon, with one trial using 17 different outcome scales.
Outcome instruments used in 2000 controlled trials of schizophrenia treatment