Response patterns derived from dichotomized (0/1) weekly CGI ratings conducted in antidepressant drug trials (Quitkin et al, 1984) were compared with those found in the pooled data from several randomized double-blind trials comparing the relative efficacy and tolerability low-dose flupenthixol im with that of three trieyclics (amitriptyline sr, imipramine, doxepine). Using the configurational frequency analysis (Krauth and Lienert, 1973), the postulated patterns could be rediscovered in our data apart from “early onset persistent patterns” which were less frequent in Quitkin et al's (1984) drug data. However, apart from this finding no “typical” patterns in terms of drug- or placebo-dependent response patterns could be detected in either the flupenthixol or Quitkin et al's (1984) data. It is concluded that there is little empirical evidence for the assumption of placebo- or drug related change- or response patterns. Moreover, theoretical aspects do not support the usefulness of such concepts.

A review of the literature on placebo-controlled studies in schizophrenia reveals, that the percentage of placebo responders in short-term trials amounts to 0–40%; on active treatment the response rate is 40–60%. In relapse prevention studies 18–100% of patients on placebo relapsed as compared to 0–40% on active treatment. Factors of importance for the variability between studies are discussed. Desirable designs of explanatory and pivotal studies, the importance of placebo controlled relapse prevention studies, and more rigorous assessment methods, eg video-taped and structured interviews for diagnostic and symptom rating purposes, are proposed as a means to improve the quality of the clinical documentation of new drugs.

A short review of placebo response in double-blind placebo-controlled therapeutic panic disorder studies published since 1985 is given. The main result is that the inefficacy-related drop-out rate of the placebo group of almost all clinical studies grows to more than 30% after 4-5 weeks of treatment and that often the results of placebo responders do not widely differ from that of the treatment groups. Except in some studies with very large sample sizes, the described response of the placebo group will not lead to significant differences between placebo and drug in completer analysis, making last observation carried forward (LOCF) analysis necessary. However, the large drop-out rates may lead to invalid efficacy results in later stages of the studies. As it can be shown that the inefficacy-related drop-out rates between placebo and target drug groups are as good an efficacy characteristic as any other, more conventional efficacy parameters, it is proposed to use the inefficacy related drop-out rate as the main efficacy parameter in placebo-controlled panic disorder studies of more than 4-5 weeks.

Meta-analysis of several double-blind, placebo-controlled studies, including 1277 patients, has been performed in order to compare the efficacy of moclobemide, a new reversible and selective MAO-A inhibitor (RIMA) and imipramine. The main interest of the analysis was to test the time course of improvement and the impact of the pre-defined outcome criteria (50% reduction of total HAMD score) on the response to treatment, if initial severity of depression and drop-outs due to inefficacy are taken into consideration. In order to analyze the interdependence of the severity of the disease and outcome, patient sample was subdivided into three HAMD (17 items) baseline score groups: low- (score ≤ 21), medium- (22-27) and high (≥ 28) scorers. We found that reliable assessment of the point in time at which a drug begins to show therapeutic effect in each individual is a critical factor in the determination of the time course of improvement. We defined therefore the onset of improvement as the time point of a significant decrease (20%) of HAMD baseline score without subsequent deterioration. The threshold for the distinction between a significant change and spontaneous fluctuations, or error variations due to instrument or observer, was the natural variability of the HAMD score during the first two observation days. The results of the analysis replicated our earlier findings and confirmed that in treatment responders the time course of improvement is identical under placebo and antidepressants. Neither the time-points of the onset of effect, nor the time-points at which a 50% decrease of HAMD was reached, differed between the groups. In particular, no treatment- Specific time lag showed up in the onset of action. The difference in efficacy between antidepressants and placebo was evident only in the total number of responders and non-responders. Moreover, onset of improvement within the first 10 days of treatment, which was observed in 40-50% of patients, was highly predictive of the final response to treatment. The rate of correctly predicted responders in our sample was 70% for all three treatment modalities. With respect to the severity of the disease, a slight shift towards earlier onset of improvement was found for more severe cases. This finding was true for placebo and drug responders hut there was no clear-cut other interdependence with the treatment outcome. Drop-out rales due to inefficacy were in this study similar under all treatments (20-24%) anil occurred mostly during the first two weeks of the trial (64-71%.).

Today it appears that a general consensus exists concerning the methodological principles to be used in establishing the efficacy profile of a new drug in anxiety disorders, ie a double-blind, parallel group design testing different doses of the new drug versus placebo (Angst et al, 1993; Rickels, 1990), however there is also growing concern about increasingly high placebo response rates and important differences between countries in these trials. This seems to be true despite the fact that in recent years, selection criteria for diagnosis and severity of the disorders have become more clearly defined and more restrictive than in the past.

This situation increases the risk of false negative results in otherwise well designed clinical trials with new anxiolytic drugs and can incite pharmaceutical companies to abandon the further development of efficacious compounds even if they have potential advantages in terms of safety over the available products.

To approve a drug means to release it for use in a specific patient population which should be characterized as clearly as possible in the labelled indications in the Summary of Product Characteristics (eg patients with major depression according to DSM III-R).

Ideally, the patient samples in various clinical trials should be representative of this specific patient population, and the crucial question is whether the study data allow an extrapolation to the wider patient population which we intend to treat.

Basically, what is valid for preclinical data and animal exposure, should also be valid for humans: more or less all regulatory authorities agree that they should accept valid data and information from all regions and all clinical studies available in order to minimize unnecessary human exposures and needless duplication. This is especially important in therapeutic fields where there is an urgent need for treatment due to the lack of suitable alternatives.

Already at the end of the 19th century, Hughlings-Jackson suggested that positive symptoms such as hallucinations and delusions should be kept apart from negative symptoms such as anhedonia and reduced energy in all psychoses. Both Kreapelin and Bleuler regarded the negative symptoms as fundamental in schizophrenia while the positive symptoms were regarded as being accessory, accompanying the disorder. This view was maintained for 60 years (table 1) until Schneider (1959) introduced the “first rank symptoms”, all of them positive. Schneider never advocated that these symptoms should be a sufficient basis for a diagnosis of schizophrenia. In any case, the “first rank Symptoms” have been included in most later diagnostic systems (table 1).

For many of the conditions with which psychiatry is concerned, there is still no anatomical or physiological abnormality that is reliably found in those affected with the conditions and not in other people. Some evidence exists that, for instance, severe and chronical psychopathological symptoms such as persistent auditory hallucinations, may be linked to structural brain abnormalities in certain subgroups of schizophrenic patients. However, such associations are not well-established as yet and the research in this field does not have practical implications for psychiatric assessment so far.

Because objective (physical) indices for measuring (the severity of) psychopathological states have hardly been available up to now, the rating scale is an essential instrument in clinical (psychopharmacological) research.

Large multinational, multicenter trials are increasingly being performed during Phase III of the clinical development of a psychotropic drug to demonstrate the efficacy of the new therapeutic agent in the shortest possible time. The testing of the new drug therapy under a common protocol, foreseeing the combination of clinical data collected across countries for a joint evaluation, is becoming more frequent in drug development. Usually, Sponsors use the services of Contract Research Organisations (CROs) to undertake and manage such large multinational, multicenter trials.

The Sponsor who is setting up large definitive CRO-managed studies with psychotropics may anticipate to encounter issues along the following lines: Psychiatric Practice, Organization and Logistics, Data Integration and Manpower.