Variability of placebo response in anxiety disorders

S.10 Has placebo gone out

The co-occurence of depression and anxiety is associated with severity of the illness, overall poorer outcome and special risks such as suicidality. In a twelve month follow up of the WHO PPGHC study 54.5% of comorbid cases still fullfilled diagnostic criteria for one or the other disorder as opposed to 32.9% of pure anxiety and 36.5% of pure depression cases. Therapeutic Consequences: The clinical features as well as this obvious chronic&y of comorbid states pose special problems for treatment. In drug treatment almost all psychotropic agents can produce some relief for anxiety (Linden et al 1988). This is especially true for sedatives and minor tranquilizers. In spite of their immediate onset of action they arc not considered to be useful drugs in the longterm management of anxiety disorders and also not indicated for the treatment of depression. There is now broad evidence that antidepressant drugs are helpful not only in the treatment of depression but also in the treatment of pure anxiety disorders, be it pant disorder, agoraphobia, generalized anxiety or even social phobia. Therefore, they can also be considered to be the first therapeutic choice in comorbid cases. This is true for classic tricyclic antidepressants such as clomipramine, imipramine or the sedating amitriptyline but also for selective serotonine reuptake inhibitors and other new antidepressants some of which also have sedative properties. Sedation can be of special importance in comorbid cases as initial relief of apprehension, agitation, and sleep problems often is of great importance in the initial treatment phase and helps to avoid comedication with tranquilizers. In outpatient routine practice, this concept of antidepressant drug treatment for depression and anxiety is only partly realized. In the WHO PPGHC study 31.9% of comorbid cases, 29.7% of the pure depression cases and 23.6% of anxiety cases got some prescription for psychological disorders. The majority of these prescription were minor tranquilizers: In comorbid cases 17.3% got tranquilizers and 13.4% antidepressants. In pure depressive states 14.6% of patients received tranqulizers and 12.3% antidepressants Patients with pure generalized anxiety got in 15.4% tranquilizers and in 5.5% antidepressants. These data show that awareness of comorbidity between depression and anxiety and even more modem pharmacological treatment concepts need to be more disseminated into clinical practice. Studies on psychotherapy of comorbid anxiety and depression are not available, although cognitive behaviour therapists in routine care make in 52.8% of anxiety cases also a second diagnosis of depression. Treatment procedures are largely overlapping in the sense that changes in cognitive schemas, improvement in self-regulation, or social skill training are helpful in depressive as well as anxiety disorders (Linden & Pasatu 1998). References [I] Angst J: Depression and Anxiety: Implications for Nosology, Course, and Treatment. J Clin Psychiat 1997, 58, 3-5 [2] Helmchen H., Linden M. (eds) Die Differenzierung van Angst und Depression. Springer, Berlin 1986 [3] Linden M, Geisehnann B, Helmchen H: Anxiolytika und Sedativa. Aktueller Stand und neuere Enhvicklungen. Milnch. Med. Wschr. 130: 571-574 (1988) [4] Linden M, Maier W, Achmer M, Herr R, Helmchen H, Benkert 0: Psychisthe Erkrankungen und ihre Behandhmg in Allgemeinatztpraxen in Deutschland. Ergebnisse aus einer Studie der Weltgesundheitsorganisation (WHO). Der Nervenarzt 67: 205-215, (1996). 151 of Coanitive and Behavioral Interventions . > Linden M. Pasatu J: The Internation _ in Routine Behavior Therapy J Cognitive Psychother 1998, 12 (in press) [6] Sartorius N, ijstiin B, Lecrubier Y, Wittchen HU: Depression Comobid with Anxiety: Results from the WHO Study on Psychological Disorders in Primary Health Care. Brit. J. Psychiat. 1996, 168, 38-43

S.10 Has placebo gone out of control? -1

Vae/azHili

R. Buller. Quint&s,

of placebo

response

in anxiety

CNS Therapeutic Business Unit, Freiburg, Germany

Placebo controlled studies are considered ‘state-of-the-art’ methodology for assessing the efficacy of drugs in the treatment of anxiety disorders. The placebo condition serves as a control for factors such as improvement due to ‘regression to the mean’, spontaneous remission, chance

ofcontrol?

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and response to non-specific therapeutic elements during the trial, while randomization is used to control for differences in baseline variables and other prognostic factors which may influence the outcome of the study. The FDA and the European authorities continue to require randomized placebo-controlled studies for the demonstration of efficacy. Recently, this paradigm has been challenged from various sides. In general, there are increasing ethical concerns about the use of placebo in clinical studies (Rothman and Michels, 1994). Ethics committees have become more critical of placebo-controlled designs even in patients anxiety disorders and require information about the possibility of using a ‘standard treatment’ as an active control. Even the use of non-drug treatments (psychotherapy, behavior therapy) as comparator has been proposed. Clinicians who are mainly involved in treating patients but do not participate in clinical research have argued the relevance of a drug-placebo comparison for their daily practice. Initially placebo response was quite low in agoraphobia, panic disorder and obsessive-compulsive disorder and correspondingly the effect size for active compounds was large. Therefore, only small samples were required for adequately powered studies. This gave the placebocontrolled study a scientific as well as an ethical advantage over activecontrol studies, as well, as less subjects were exposed to a new chemicai entity. However, more recent trials have observed increasing placebo response rates with smaller effect sizes. This has made it more difficult to demonstrate efficacy. With shrinking effect sizes larger trials are now needed and regulatory authorities have started to question the clinical relevance of small although statistically significant drug placebo differences. In order to reduce the rate of placebo responders many trials have used placebo run-in periods which are meant to identify placebo responders before randomization. Patients who show significant improvement during this phase are excluded from the trial. However, the rationale behind this technique has been questioned for studies in depression by Reimherr et al. (1989) and by Trivedi and Rush (1994) and may actually be counterproductive. If the placebo response is in fact short-lived and if the trial is long enough, patients who have initially improved should show a worsening of their condition already during the course of the trial. Such a pattern of early response and consequent worsening in placebo patients could actually lead to a larger difference between the drug and the placebo group. In order to help with the discussion on the future value of placebo as control in pivotal trials in anxiety disorders data from three large trials in panic disorder and from one large study in social phobia with a total of more than 2000 patients have been reviewed. All four studies used a one week placebo run-in period intended to limit placebo response. However, placebo response rate was high. In the majority of placebo responders the improvement was not transient but lasted throughout the study. Placebo response was observed to a similar degree on variables which assessed the disorder specific symptoms, global impairment, clinicianrated improvement. There was also a high variability of the placebo response among the participating centers. Since it is extremely difficult to show a drug effect against a high placebo response, some centers were not able to show the efficacy of the compound. Baseline severity also had an influence on the placebo response rate. Although participation in the trials was limited to patients with at least a moderate severity of their disorder, it was mainly subjects with high levels of severity that responded significantly better to drug than to placebo. In trials with patients suffering from anxiety disorder differential drop-out has been observed, with the highest rate of premature discontinuations in the placebo group. In the four studies presented here, the proportion of patients who continued until the end of the trial was similar in all treatment groups. Therefore increasing placebo response may be associated with lower dropout rates. In summary, placebo response is not a fixed entity The variability depends on a number of factors such as severity, duration of the illness, and may differ among centers. In the context of large multinational clinical trials the concept of demonstration efficacy by simply subtracting placebo response from the response to test drug may have to be reconsidered. Possible strategies for the future could aim at reducing the influence of variables which contribute to a high placebo response. However, this may lead to samples which are not representative for the clinical population

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,910 Has placebo gone out of control?

for which the new treatment is intended. More radically, future trials with new compounds may be conducted without placebo control and with the clear aim to demonstrate their superiority over current treatments. Until now differential efficacy among psychotropic drugs in the treatment of anxiety disorders has not been established and it is doubtful if this will be possible among compounds with a similar mechanism of action. References [1] Reimherr, F. W., Ward, M. F., Bye&y, W.F., 1989. The Introductory Placebo Washout: A Retrospective Evaluation. Psychiatry Research 30, 191-199. [2] Rothman, K. J., Michels, K. B., 1994. The Continuing Unethical Use of Placebo Controls. New Engl. J. Med. 331, 394-397. [3] Trivedi, M. H., Rush, J., 1994. D oes a Placebo Run-In 01 a Placebo Treatment cell Affect the Efficacy of Antidepressant Medications? Neuropsychopharmacology 11, 33-43.

[s.10.021

Investigator influence on drug-placebo in depression

differences

results suggest that regulators should be open to analysis of multicentre studies on the basis that only those centres capable of distinguishing active reference antidepressants from placebo contribute to the final efficacy evaluation. Alternative strategies may include the use of active placebos, since there is emerging evidence of differences in efficacy in the more severely depressed patients between selective serotonin reuptake inhibitors (SSRIs) and dual action drugs such as tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors (SNRIs) and mirtazapine. References

[ 1]

Niklson IA, Rein& P-E, Sennef C (1997) Factors that influence the outcome of placebo-controlled antidepressant clinical trials. Psychopharmacol. Bull. 33, 41-51.

Is.10.031

Controlling depression

the placebo

response

rates in

C. Sennef, R.M. Pinder’, PE. Reimitz, IA. Niklson. Clinical Deuelopment Department and Medical Directorate, NV Organon. Oss. The Netherlands

W.Z. Potter, M.A. Demitrack, D.J. DeBrota, D. Faries, J. Herrera. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA

The impression has grown in recent years that the placebo response rate in clinical trials of antidepressants has become larger, rendering it more difficult to demonstrate a robust therapeutic effect. Achieving a clinically relevant effect size has been problematical for a number of promising new agents developed for the treatment of depression and many of them have not received regulatory approval. Various explanations have been offered for the growing placebo response including the type of patients and their manner of selection, previous and concomitant treatments, (non)maintenance of double-blind conditions, study logistics and other characteristics of the investigational site, and recent changes in healthcare systems. Effect sizes tend to be larger in active-controlled studies than in those where a placebo arm is included, for both experimental and approved antidepressants. As a consequence, sample sizes are now very large for three-way trials in which the new agent is compared to an active reference as well as to placebo, necessitating the involvement of multiple investigational sites and the potential for even greater variability. Selection of the sites and the investigators may be one of the most critical decision points in determining the outcome of placebo-controlled trials. Our own results are from two double-blind, 6-weeks, placebo- and imipramine-controlled, multicentre and multinational dose-finding studies with a new psychotropic compound (NPC) under investigation for the treatment of major depressive disorder. Statistical analysis based on the intent-to-treat group using the last observation carried forward (LOCF) approach revealed a meagre effect size for both imipramine (n = 141) and NPC (n = 139) compared to placebo (n = 106), either on the 17-item Hamilton Rating Scale for Depression (HAMD- 17) or the Montgomery Asberg Depression Rating Scale (MADRS). Post-hoc analyses focussing on patient characteristics did not largely improve discriminative power; even for severe cases the gain in effect size was only marginal for both imipramine and NPC. However, splitting the centres on the basis of which could (DC) or could not (NDC) detect a difference of at least two points between imipramine and placebo on the HAMD- 17 total score at 6 weeks in the LOCF analysis did reveal differences from placebo for the NPC. DCs comprised 8/22 (36%) centres and recruited about 45% of patients, who tended to have more recurrent illness with a previous good response to antidepressant therapy. DCs had fewer dropouts and more study completers for either drug treatment but not for placebo, which suggests that different treatment strategies were employed by different centres regarding the occurrence of adverse events with or without therapeutic effects. Placebo-controlled trials are required by most regulatory agencies for approval of new antidepressants. While many factors may play a role in determining the outcome of such studies, our results suggest that investigator selection could be an important influence. Our criterion of an effect size of two points on the HAMD-17 is arbitrary, and consensus is needed on what is an appropriate measure. However, the

High and/or variable placebo response rates have a large impact on detection of antidepressant (AD) effects. Despite more than three decades of experience with randomized placebo controlled AD trials, no comprehensive understanding of the relative importance of the multiple possible factors influencing placebo response has emerged. Two strategies to reduce placebo response have been: 1) enrichment, meaning specific entry criteria other than satisfying the diagnosis of a current depressive episode; and, 2) fixed and variable placebo “lead-ins” prior to randomization In some, but not all instances, enrichment by the diagnostic subgroup of endogenous/melancholic, by the biologic marker of REM latency, and even by the simple severity criteria of setting a higher entry depression rating score, has either lowered the placebo response rate and/or enhanced drug placebo differences. Current data argues against the value of fixed placebo lead in periods whereas variable ones appear to allow for the exclusion of many placebo responders. In attempts to better understand factors underlying these observations we have initiated both retrospective analyses of our large cumulative data base on trials in depression and prospective studies of some of the strategies outlined above. We have focused, to date, on issues related to subject selection at points of entry and randomization as well as on rater behavior. Of particular concern is the possibility that raters systematically adjust, in a biased manner, to features of the protocol designed to minimize placebo response. As part of these investigations the cumulative database has been searched to look for trends over time in placebo response either in terms of absolute change over a six-week period, of a 50% decrease from baseline or a final score of 7 or less on the HAM-D 17. An earlier analysis had indicated that placebo response was increasing over time, a trend which in recent years has appeared reversed (presumably as a result of efforts including enrichment strategies). Analyses are continuing to examine if the response to placebo of a patient can be predicted from information typically available prior to randomization. It is assumed that patients entered into current trials may represent a very different pool than those entered 20 years ago; therefore, the distribution of characteristics predictive of placebo response may have changed. Interestingly, there has been a gradual, but significant fall in the average HAM-D 17 score at randomization, despite no relaxation in, and sometimes increasingly strict requirements for a specified minimum score. Analyses of the distribution of ratings at entry and point of randomization across studies provide evidence that strict minimum criteria are associated with a clustering of values just above the specified HAM-D value, consistent with the possibility that ratings are biased to be at or just above the criterion. This could explain the often-observed rapid fall in depression ratings on both active drug and placebo at the 1” week post randomization. Our findings from a recent study in which point of randomization was blinded and all entered patients were continued revealed a much more