Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale.

BACKGROUND: Nonlocalizing neurologic deficits detectable by clinical evaluation-"soft signs"-are a robust finding in patients diagnosed with schizophrenia, but their conceptual and neuroanatomical correlates remain unclear. The purpose of this study was to evaluate the organization of these deficits and their clinical correlates using the Neurological Evaluation Scale (NES). METHODS: Ninety-three male veterans with schizophrenia and schizoaffective disorder were evaluated using a detailed clinical assessment that included the NES, the Extrapyramidal Symptom Rating Scale, the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale, the Positive and Negative Syndrome Scale, the Wisconsin Card Sorting Test (WCST), the Schedule for the Deficit Syndrome (SDS), and the Digit Symbol Substitution Task (DSST). RESULTS: Four factors explained 73% of the variance and had distinct clinical and neuropsychological correlates. Factor 1 reflected deficits involved with memory and sensory integration, and was associated with lower PANSS positive and higher AIMS scores. Factor 2 reflected impairments in motor control, and was associated with lower intelligence, more cognitive deficits, and deficit-syndrome schizophrenia. Factor 3 was related to lower intelligence and more perseverative errors on the WCST. Factor 4 was related to increasing age, more extrapyramidal symptoms, more perseverative errors, and worse scores on the DSST. CONCLUSIONS: Neurologic deficits in schizophrenia have an intrinsic organization that appears to have clinical significance, highlighting the continued utility of the NES in studies of neurological deficits in schizophrenia patients. The theoretical underpinning of this organization remains unclear.

Psychiatric safety of ketamine in psychopharmacology research.

RATIONALE: A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies. OBJECTIVE: To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset. MATERIALS AND METHODS: Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. The safety of ketamine administration was monitored in these subjects. RESULTS: Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed. CONCLUSION: Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine.

RATIONALE: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. OBJECTIVES: The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. METHODS: Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. RESULTS: After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. CONCLUSIONS: The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.

Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms.

RATIONALE: Serotonin-2 (5-HT(2)) receptor antagonism has been hypothesized to have antipsychotic activity. However, there has been limited evidence directly linking 5-HT(2) receptor antagonism to symptom control in schizophrenic patients. OBJECTIVES: In order to test this hypothesis this study evaluated the capacity of pretreatment with the 5-HT(2) receptor antagonist ritanserin to attenuate the effects of the 5-HT agonist, m-chlorophenylpiperazine (mCPP). METHODS: Twenty-two male inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder completed 4 test days during which 10 mg ritanserin or matched placebo was administered orally 50 min prior to the intravenous infusion of 0.1 mg/kg mCPP or saline. The test days were conducted in a randomized order under double-blind conditions. RESULTS: mCPP mildly and transiently increased positive symptoms and behavioral activation but not negative symptoms, as assessed by the Brief Psychiatric Rating Scale. mCPP also raised plasma prolactin and cortisol levels. All of these effects were attenuated by ritanserin pretreatment. CONCLUSIONS: These data support a contribution of 5-HT(2) receptor stimulation to symptom exacerbation in schizophrenic patients and a role for 5-HT(2) receptor antagonism in the prevention of this effect.