Placebo-Controlled Trials in Schizophrenia J Clin Med Res • 2009;1(3):132-136 is based on the results of placebo-controlled trials [15]. The European authority parallel to the FDA approves drugs based on trials where the new preparation is compared to placebo and/or treatment with standard medication. Positive response to placebo in schizophrenia has been shown to range from 3 to 26% in various studies [16]. Dif- ferent patients respond differently to placebo, including those who apparently respond better to placebo, and it is probably not worthwhile to include those patients, if it is possible to identify them ahead of time [17]. Difficulties regarding placebo control in schizophrenia and possible solutions The main argument against placebo use is associated with the inherent difficulty of the physician to refrain from giving the patient effective treatment. This issue is difficult for every physician/investigator and especially for physi- cians who treat the mentally ill. Absence of active treatment may cause long and short- term risk or harm. Early diagnosis and treatment has been shown to achieve the best possible results in reducing nega- tive symptoms [18] or improving the chance for a longer re- mission [19]. Although some studies showed that even if the patients suffered exacerbation of illness after stopping active treatment, they returned to their basic state within a number of days or weeks with no long-term harm [20], however not all patients enter remission following episodes of exacerba- tion. Thus, we believe that first episode patients should not be recruited to clinical drug trials unless the study focuses on treatment specific to this population. The emotional state of the patients and the possibility of cognitive impairment raise questions regarding their capac- ity to provide informed consent for participation in research. This can be avoided by routinely using questionnaires that specifically examine the patient’s competency to par- ticipate in clinical trials [11]. In order to eliminate staff in- fluence, the research staff should be distinguished from the caregiving staff, and an external physician may participate in the recruitment stages of the investigation. Patients receiving involuntary treatment either in the hospital or in the community require special consideration regarding recruitment to placebo-controlled trials. It is ques- tionable whether a patient who does not consent to hospital- ization can voluntarily consent to participation in a pharma- ceutical trial. Alternatively, there is the view that though a patient may oppose treatment and hospitalization, if medi- cation is compulsory, he/she may prefer one treatment over another, or may agree to a specific treatment [2]. The authors believe that these patients should not be included in clinical trials, due to the sensitivity of the issue. Other opinions suggest that patients recruited to pla- cebo studies are not necessarily representative of the general patient population. They may be older, with a longer dura- tion of illness and more willing to participate in clinical trials because a cure has not yet been found for their illness. In addition, Placebo-controlled trials have a higher dropout rate [21]. A significant problem in commercial studies is the fi- nancial aspect: Today, most clinical trials for new drug ap- plications are designed and sponsored by pharmaceutical companies. Commercial companies are interested in place- bo-controlled trials and the direct financial relationship be- tween the company and the investigator may be problematic [22], and should be avoided. The investigator must assure beneficence, a favorable balance between the potential benefit and harm of participa- tion. Discussion There is no known pharmacological cure for schizo- phrenia. Treatment provided by physicians is in accord with the current knowledge of the illness, and is dispensed to al- leviate the symptoms and to improve the patient’s ability to function, and quality of life. Physicians will always hesitate to expose a patient to an unfamiliar agent when a known medication is obtainable. On the other hand, without medi- cal research and clinical trials, we would not have the effec- tive medications that we have today, which pending ongoing medical research, may indeed be replaced by more effective preparations in the future. The increasing rift surrounding the use of placebo in trials for the development of new psychiatric medications, involves scientific, clinical and ethical issues. It seems that there is no single all encompassing approach either for or against placebo-controlled trials. Placebo use is problem- atic in medicine. Administering treatment which in fact may be a placebo alters the physician-patient relationship, espe- cially when dealing with mental health patients suffering from schizophrenia. However, since there is no known cure for the disease, research is essential in this population, so it may be justifiable to encourage patient participation in clini- cal trials to advance medical knowledge in the field. In most cases the use of an active control in schizophrenia research is ethically and scientifically preferable [23]. This is not always possible. It is the investigator’s responsibility to ensure that clini- cal trials are designed and conducted according to appropri- ate clinical and ethical principles and that each proposed trial is based on solid hypothesis according to which the new treatment will be more effective and/or have less side-effects than existing treatment. In a clinically justified trial, when including a placebo control group, the size of the placebo group and duration of administration of placebo should be as limited as possible and the duration of the medication washout period should be 134 Articles © The authors, Journal compilation © J Clin Med Res and Elmer Press™, www.jocmr.org