The history and current status of competence and informed consent in psychiatric research.

Informed consent to research has recently become a focus of public attention as questions have been raised about the adequacy of information disclosed to potential research subjects and about the competence of psychiatric research subjects to provide valid informed consent to participate in potentially high risk studies. Around the world, policies and position statements have been written to address these concerns and to offer suggestions to protect potentially vulnerable research subjects, such as persons with neuropsychiatric disorders. Relevant literature has demonstrated that a subset of persons with such disorders have significant competence-related deficits, and thus may require specific means of protection with regard to informed consent to research. Recent guidelines offered to improve the informed consent process include review of potential studies for scientific merit and potential risk, assessment of subject competence to consent to research, and the use of proxy decision-makers when subjects are deemed incompetent.

Novel antipsychotic agents and their implications for forensic psychiatry.

Recent developments in psychopharmacology have lead to the introduction of several novel antipsychotic agents into clinical practice. As these agents become more commonly encountered, it is essential that forensic psychiatrists have a working knowledge of their efficacy as well as the advantages of their use. This article reviews current literature regarding the clinical efficacy and mechanisms of action of clozapine, risperidone, olanzapine, quetiapine, sertindole, and ziprasidone, with a discussion of their use in forensic psychiatry. Specifically, studies show certain advantages of the novel agents in the treatment of violent patients. Use of these medications may also reduce the risk of civil litigation. The novel antipsychotic agents offer the potential of improved patient care within forensic settings by both expediting judicial processing while providing long-term cost savings. Forensic patients represent an underserved population but must have equal access to new medications as they become available. Familiarity with these issues and the medications themselves will facilitate their use in forensic settings.

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.

OBJECTIVE: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics.

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo-controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine. We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls. Schizophrenics experienced a brief-ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals. These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia. Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls.

Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers.

OBJECTIVE: Agents that antagonize the N-methyl-D-aspartic acid (NMDA) receptor, such as phencyclidine and ketamine, produce an acute psychotic state in normal individuals that resembles some symptoms of schizophrenia. The aim of this study was to determine which brain regions are involved in NMDA receptor-mediated psychosis. METHOD: Positron emission tomography with [18F]fluorodeoxyglucose was used to determine cerebral metabolic activity in 17 healthy volunteers while an acute psychotic state was induced simultaneously by the administration of subanesthetic doses of ketamine. RESULTS: Ketamine produced focal increases in metabolic activity in the prefrontal cortex and an acute psychotic state. A change in one psychotic symptom, conceptual disorganization, was significantly related to prefrontal activation. CONCLUSIONS: These data suggest that the prefrontal cortex may be involved in mediating NMDA receptor-induced psychosis.

Lack of gender differences in neuroleptic response in patients with schizophrenia.

OBJECTIVE: The authors sought to determine if there were gender differences in neuroleptic response in male and female patients with schizophrenia who were matched for clinical and demographic variables and participated in a double-blind trial of traditional antipsychotic drugs. METHODS: 24 males (m) and 20 females (f) with schizophrenia or schizoaffective disorder who did not differ in clinical characteristics (age of onset, course of illness, prior hospitalizations, premorbid functioning) participated in an extended drug-free period followed by a neuroleptic trial under double-blind, placebo-controlled conditions. RESULTS: Males and females showed significant improvement in total, positive and negative BPRS symptoms during neuroleptic treatment. However, there were no significant differences in treatment response between sexes. No sex differences were found in baseline drug-free symptomatology, neuroleptic dose or dosage by weight. CONCLUSIONS: There were no significant sex differences in neuroleptic treatment response in male and female patients well-matched for clinical, treatment and demographic characteristics. Methodological issues which distinguish this study from prior studies reporting gender differences in neuroleptic response are examined.

NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers.

A rapidly growing body of preclinical data has implicated the glutamatergic N-methyl-d-aspartate (NMDA) receptor in memory and other cognitive processes. There is comparatively less information about this receptor system in human cognition. We examined the effects of subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, on two forms of memory, free recall and recognition, as well as attention and behavior in a double-blind, placebo-controlled, 1-hour infusion in 15 healthy volunteers. Ketamine produced decrements in free recall, recognition memory, and attention. In addition, ketamine induced a brief psychosis in our healthy volunteers marked by thought disorder and withdrawal-retardation. Ketamine-induced memory impairments were not accounted for by changes in subject's attention and were not significantly related to psychosis ratings. These data suggest that the NMDA receptor plays a direct role in two types of explicit memory. The implications of these data for the pathophysiology of schizophrenia are discussed.