Placebo-controlled study designs

The parallel-group, double-blind, placebo-controlled study design represents the golden standard of acute treatment trials of depression, mania and anxiety disorders. This design is intended to limit bias, in particular selection and measurement bias. Trials based on this design are expected to provide information about the effect size of a new compound and its side-effect profile. 

Another meta-analysis of placebo-controlled trials in depression published between 1980 and 2000 showed an increase in the response rates in the placebo arms of trials with a variety of antidepressants (Walsh et al.y 2002). Responses to placebo increased significantly in recent years, as shown by the high positive correlation with the year of publication. The association between response rate and year of publication was more statistically robust for placebo than for active medication. The change in placebo response rate did not appear to be explained directly by changes in study characteristics such as patient age, placebo lead-in or minimum required Hamilton Rating Scale for Depression score. A potential explanation could be the changing awareness of patients and the fact that many patients in recent clinical trials had been exposed to several previous treatments and thus expected to improve (see Box 5.4). 

Another important factor that may favor placebo responses in clinical studies is probably the patient recruitment strategy, as suggested by the following observation two almost identically designed studies with fluoxetine vs. placebo in the treatment of post-traumatic stress disorder (PTSD) were performed, but only one of them resulted in a significant difference between 

In contrast to experience with depression, placebo response rates of trials in social phobia show a rather constant pattern during the past decade between 9 and 29% of patients were characterized as placebo responders as measured by the Liebowitz Social Anxiety Scale (Kobak et al., 2002). 

Depending on the purpose of a study there are several subtypes of placebo-controlled trials (see Fig. 5.3). One design makes use of a single-blind placebo lead-in period. The purposes of this pretrial period of up to 4 weeks are  

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Given the ethical concerns about placebo-controlled study designs, several alternative procedures to reduce bias in clinical trials have been proposed ... 

Sandler, 2005) and illustrates once again the necessity of placebo-controlled study designs for evaluating ASD pharmacotherapies. Notably, the results from this study are at variance with previous open-label studies that reported benefits for citalo-pram in ASD (reviewed by Posey et ah, 2006). In addition, adverse events were significantly more frequent overall with citalopram than with placebo, with significant increases in energy level, impulsiveness, impaired attention and concentration, hyperactivity, stereotypy, and insomnia. 

Appropriate study design should be selected to achieve the desired outcome. A description of the type/design of frial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design. 

The effects of tamoxifen in women with and without CHD have been analyzed in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT). This randomized, placebo-controlled study included 13,388 women at increased risk for breast cancer. The conclusions of the trial are somewhat limited by the fact that it was designed to investigate the effect of tamoxifen as a chemopreventive for breast cancer, and not its effect on CVD risk. There was no indication that tamoxifen would modify the risk of CHD in women with or without heart disease (Reis et al. 2001). 

Methodological controls. Some published studies on the effectiveness of hypericum have experimental design flaws, but there are several that are methodologically controlled, employing double-blind, randomization, and placebo controls. Randomized, placebo-controlled studies were summarized and evaluated in a meta-analysis by Linde and colleagues (1996). The combined subject pool was 1,757 outpatients with mild to... 

Geller, B., Cooper, T.B., Graham, D.L., Fetner, H.H., Marsteller, F.A., and Wells, J.M. (1992) Pharmacokinetically designed doubleblind placebo-controlled study of nottriptyline in 6- to 12-yeat-olds with major depressive disorder. / Am Acad Child Adolesc Psychiatry 31 34—44. 

Several controlled studies of IMI involved less homogeneous samples of anxious children. Neither IMI nor alprazolam (a BZ) was superior to placebo in an 8-week study of 24 children (ages 7-18 years) with school refusal, which included subjects with anxiety and depression (Bernstein et ah, 1990). A more recent placebo-controlled study of IMI -I- CBT for 47 adolescents (ages 12-18 years) with school refusal, anxiety, and/or depression was designed to address the limitations of previous studies of TCA treatment for pediatric anxiety disorders (Bernstein et ah, 2000). Accordingly, sample size was based on proposed power analysis IMI dose and serum level were monitored to ensure adequate exposure (mean IMI dose 180 mg/day mean serum IMI180 pg/L and mean IMI -I- DMI 250 pg/L at week 3 and week 8) and CBT was manual based and closely monitored. Fifty-four percent of subjects treated with IMI -I- CBT met remission criteria (defined as > 75% school attendance at the end of the study), compared to 17% of subjects treated with placebo -I- CBT. No between-group differences were noted... 

Antihistamines such as diphenhydramine, a mainstay of OTC sleep preparations, are also used widely by parents for their children at doses of 1 mg/kg. Most of the reports of the use of clonidine for sleep disorders are clinical and anecdotal case reports of use in children with ADFFD (Wilens et ah, 1994 Prince et ah, 1996). There are some safety concerns about using clonidine once a day at bedtime, especially in patients who take a daytime stimulant. Melatonin was studied using a double-blind, placebo-controlled, crossover design (Jan et ah, 1994) on a mixed group of 15 children with sleep disturbances, with some improvement reported. However, caution is warranted in using this agent because melatonin is unregulated, and there are concerns about the purity and safety of some commercially available preparations (Werry and Aman, 1999). 

This option assumes a comparable or even standard placebo response rate for historical data and the current trial. The historical improvement rate (on placebo or without any treatment) is then used for purposes of comparison with results of subsequent non-placebo-controlled studies involving the same investigator and protocol design but different drugs. For historical placebo response data it is recommended that a small placebo treatment arm is used for safety data purposes and to avoid observer bias although this proposal may resolve or diminish some ethical concerns, it raises a number of scientific problems ... 

CBZ s spectrum of efficacy appears similar to that of lithium however, as noted earlier, it may be superior to lithium in mixed or dysphoric mania, rapid cyclers, and more severe episodes (e.g., fulminant, aggressive, psychotic) (202). The number of patients treated with CBZ for acute mania in some form of placebo-control design is very limited. In fact, we are not aware of any double-blind, placebo-controlled, parallel design studies addressing this question (i.e., class I design). 

As noted earlier, in the only double-blind, placebo-controlled, parallel design study of clonidine, Janicak et al. ( 264) studied a group of acutely ill, hospitalized manic patients, many with associated psychotic features. After a washout period averaging 1 week, patients were randomly assigned to receive either clonidine or placebo for a 2-week trial. The intent was to ascertain whether clonidine alone had any inherent antimanic properties, and therefore, no other concomitant psychotropics were allowed. Unfortunately, improvement in either group was minimal and did not differ, with some patients on clonidine developing problems with rash and hypotension. Doses of clonidine were comparable with those reported in prior positive studies, averaging 0.5 mg/day. 

Geller B, Cooper TB, Graham DL, et al. Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6 to 12 year-olds with major depressive disorder. J Am Acad Child Adolesc Psychiatry 1992 31 34-44. 

Inflammation is an important factor in the development of cardiovascular disease. Most clinical studies involving inflammation parameters have been relatively small. The Nurses Health Study involving 727 women was the largest study designed to determine the effects of n-3 fatty acids on biomarkers of inflammation and endothelium activation (Lopez-Garcia et al., 2004). They found an inverse association between ALA intake and plasma concentrations of C-reactive protein (a marker for inflammation), Interlukin-6, and E-selectin. Bemelmans et al. (2004) also found an inverse association between C-reactive protein and ALA intake in a randomized, double-blind placebo-controlled study involving 103 hypercholesterolemic subjects. 

Another meta-analysis has been conducted on 19 clinical trials with vitamin E supplementation and follow-up of a duration of more than one year. Nine trials were using vitamin E only without any other supplement and six of them were double-blind/placebo-controlled studies (28), The outcome of the analysis was that high dosages (>400 ILJ/d) may increase all-cause mortality and, therefore, should be avoided. Since in many studies other supplements were used concomitantly to vitamin E the authors concluded, the use of any high-dose supplement should be discouraged until evidence of efficacy is documented from appropriately designed clinical trials. ... 

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