The challenge study controversy

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Oral Session X V I I I What do Challenge Studies Tell U s and are They Ethical? CANNABINOIDS & PSYCHOSIS: EVIDENCE FROM STUDIES WITH I.V THC IN SCHIZOPHRENIC PATIENTS AND CONTROLS D.C. D ' S o u z a , W. Abi-Saab, S. M a d o n i c k , Y. Wray, K. Forselius, L. M a c D o u g a l l , L. Brush, K. Cassello, J. Krystal

Yale UniversiO~School of Medicine, Psychiatry Service l16A, VA Connecticut Healthcare, 950 Campbell Ave., West-Haven, CT06516 Introduction: Several lines of evidence suggest an association between cannabis and psychosis. Advances in the molecular pharmacology of cannabinoids have renewed interest in the potential role that brain cannabinoid receptors play in the pathophysiology of psychosis. Most of the data associating cannabis and psychosis is based on retrospective reports or naturalistic studies. Aims:: (1) Do cannabinoids exacerbate psychosis in schizophrenic patients, (2) Can cannabinoids 'model' psychosis in controls? (3) Is there evidence for altered cannabinoid sensitivity in schizophrenia? (4) Are there clues to why schizophrenic patients use cannabis? Methods: In an ongoing study, neuroleptic-treated schizophrenics and controls previously exposed to cannabis underwent 3 days of testing with 0, 2.5 and 5mg intravenous THC in a randomized, double-blind, counterbalanced design. Psychosis, anxiety, perceptual alterations and frontal and temporal cortical function were assessed. Results and Conclusions: THC exacerbated positive symptoms in schizophrenics and induced positive symptoms in controls. THC also increased negative symptoms and induced perceptual alterations in both groups. THC impaired performance on an immediate and delayed recall task, a working memory task, verbal fluency and a task of selective attention. Dose-related differences between groups, differences in the magnitude and quality of THC effects suggest altered cannabinoid sensitivity in schizophrenia and raise the intriguing possibility brain cannabinoid receptor dysfunction may contribute to the pathophysiology of schizophrenia.

ATTENUATION OF KETAMINE EFFECTS IN HEALTHY HUMANS BY LAMOTRIGINE, A DRUG THAT REDUCES GLUTAMATE RELEASE A. A n a n d , R. Berman, D.S. Charney, J.H. Krystal

Department of Psychiatry, Yale University School of Medicine, Psychiatry Service (116-A), VA Connecticut Healthcare System, 950 Campbell Ave., West Haven, CT06516, USA The study of ketamine effects in healthy human subjects has been of interest to the field of schizophrenia research, in part, because of its capacity to generate novel hypotheses regarding the neurobiology and treatment of schizophrenia. Recent studies in animals suggests that NMDA glutamate receptor antagonists, such as ketamine, may stimulate the release of glutamate in the cortex and limbic system. The purpose of this study was to test the hypothesis that reductions in glutamate release, achieved via lamotrigine administration, might attenuate ketamine effects. Lamotrigine is an antagonist of P- and N-calcium channels and voltage-dependent sodium channels. Methods: Healthy human subjects (n= 17) completed four test days involving pretreatment with lamotrigine 300mg or placebo 2 hours prior to the administration of ketamine ( bolus: 0.23 mg/kg over 1 min followed by 0.58 mg/kg over I hr) or placebo. Cognitive and behavioral testing was performed. Results: Lamotrigine pretreatment did not reduce plasma ketamine levels. However, lamotrigine attenuated the positive and negative symptoms (PANSS), perceptual alterations (Clinician-administered dissociative states scale) and amnestic effects of ketamine in healthy human subjects. Implications: This study suggests that a component of the cognitive and behavioral effects of ketamine is mediated by the stimulation of glutamate release. It also supports the evaluation of this and other strategies for attenuating glutamate release, such as a group 2 metabotropic glutamate receptor agonist, in the treatment of schizophrenia.

THE CHALLENGE STUDY CONTROVERSY W.T. Carpenter, M. Avila, R. Conley

University of Maryland School of Medicine, Department of Psychiatry, Maryland Psychiatric Research Center, PO Box 21247, Baltimore, Maryland. 21228, USA Challenge studies yield data on pathophysiology by a transitory perturbation of symptoms. Application in psychiatry includes exploration of serotonin in depression, dopamine and glutamate in schizophrenia, and endorphins in panic. Critics assert that adverse effects constitute unjustified harm, that subjects are recruited from vulnerable populations without valid informed consent, that scientific merit is low, and that intent to harm is unethical. The ketamine challenge in schizophrenia subjects is central to the current ethics debate. Data from all schizophrenia subjects in ketamine challenge studies in the US will be presented. Group data on 56 patients suggest that the psychosis reaction is modest, that anxiety is minimal, and that the

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experience is brief with no lasting adverse effects. Qualitative analysis of the 'worse case episodes' and follow-up data suggest no lasting adverse effect. The authors conclude that scientific merit is high and risks are reasonable. Guidelines for the ethical conduct of challenge studies are suggested. The view that such studies should be subjected to unique restrictions is not supported by the data.

The ethical conduct of challenge studies meets a social and moral obligation to the mentally ill citizen of the future through the creative acquisition of new knowledge.

Reference Carpenter, W.T., Jr. The schizophrenia ketamine challenge study debate. Biological Psychiatry, in press.