Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.

Does ketamine-mediated N-methyl-D-aspartate receptor antagonism cause schizophrenia-like oculomotor abnormalities?

Evidence from histological and pharmacological challenge studies indicates that N-methyl-D-aspartate (NMDA) receptor hypofunction may play an important role in the pathophysiology of schizophrenia. Our goal was to characterize effects of NMDA hypofunction further, as related to schizophrenia-associated neuropsychological impairment. We administered progressively higher doses of ketamine (target plasma concentrations of 50, 100, 150, and 200 ng/ml) to 10 psychiatrically healthy young men in a randomized, single-blind, placebo-controlled design and assessed oculomotor, cognitive, and symptomatic changes. Mean ketamine plasma concentrations approximated target plasma concentrations at each infusion step. Verbal recall, recognition memory, verbal fluency, pursuit tracking, visually guided saccades, and fixation all deteriorated significantly during ketamine infusion; lateral gaze nystagmus explained some, but not all, of the smooth pursuit abnormalities. We concluded that ketamine induces changes in recall and recognition memory and verbal fluency reminiscent of schizophreniform psychosis. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities characteristic of schizophrenia. These findings help delineate the similarities and differences between schizophreniform and NMDA-blockade-induced cognitive and oculomotor abnormalities.

Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations.

BACKGROUND: Ketamine has been associated with a unique spectrum of subjective "psychedelic" effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady-state plasma concentrations. METHODS: Ketamine or saline was administered in a single-blinded crossover protocol to 10 psychiatrically healthy volunteers using computer-assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed. RESULTS: The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose-related psychedelic effects. The relation between steady-state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug. CONCLUSIONS: Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady-state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.

Relationships between neuropsychological and oculomotor measures in schizophrenia patients and normal controls.

Establishing the relationship between oculomotor and neuropsychological impairments might facilitate a more coherent description of schizophrenia-associated neurocognitive deficits. Therefore, we assessed several aspects of neuropsychological and oculomotor function in 25 medicated schizophrenia patients and 24 age-matched controls. Neuropsychological tasks included the Wisconsin Cart Sort Test (WCST), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test, and finger tapping speed. Oculomotor functions assessed included smooth pursuit, initiation of smooth pursuit, predictive pursuit, fixation, visually guided saccades, remembered saccades, and antisaccades. Among the schizophrenia patients, predictive pursuit performance correlated significantly with finger tapping (dominant hand), TMT (both parts), and one WCST measure (categories completed). The only other significant correlation among the schizophrenia patients was between antisaccade performance and part A of the TMT. Perseverative errors during the WCST and antisaccade performance were the only measures significantly correlated among the normals. Closely related neurocognitive deficits may be responsible for impairments in TMT, WCST, predictive pursuit, and antisaccade performance in schizophrenia.

Saccadic eye movements in normal children from 8 to 15 years of age: a developmental study of visuospatial attention.

This cross-sectional study used saccadic eye movements, as measured by infrared occulography, to assess several aspects of visuospatial attention in normal children ages 8-15 years. Saccadic latency (a global measure of the ability to shift visuospatial attention), the ability to suppress extraneous saccades during fixation, and the ability to inhibit task-provoked anticipatory saccades all improve with age. However, the pattern of development differs for different tasks; saccadic latency shortens at a linear rate across the age range 8-15 years, while the capacity to inhibit anticipatory saccades matures by 12-13 years of age, and the ability to suppress saccades matures by 10 years of age. Analyses of age-related changes in oculomotor measures of attention may provide a novel approach in the study of children with attentional difficulties.

A developmental study of smooth pursuit eye movements in normal children from 7 to 15 years of age.

OBJECTIVE: To examine age-related changes in smooth pursuit tracking. METHOD: Using infrared occulography, smooth pursuit eye movements are examined in 53 normal 7- to 15-year-old children during 6 degrees and 12 degrees/second visual pursuit. In addition to smooth pursuit gain and saccadic frequency, measures of mean amplitude per second are introduced to facilitate comparison across age and target speed. RESULTS: The 6 degrees/second task is found to be easier than the 12 degrees/second task. Age is correlated with smooth pursuit system performance but not saccadic system performance during 12 degrees/second pursuit. No measure correlates with age during 6 degrees/second pursuit. CONCLUSIONS: Eye movements improve as children age. The future use of smooth pursuit eye movements to study children and adolescents with and at risk for schizophrenia must control for developmental changes.

A quantitative analysis of saccades and smooth pursuit during visual pursuit tracking. A comparison of schizophrenics with normals and substance abusing controls.

The eye movements of schizophrenic patients are characterized by decreased smooth pursuit gain and an increased frequency of saccades. However, the nature of these saccades and their function during smooth pursuit has not been clearly defined. To address this issue we examined the eye movements of 22 schizophrenic patients, 20 substance abusing patients (primarily alcohol; some with concomitant cocaine and/or cannabis abuse), and 17 normal controls during a visual pursuit task using infra-red oculography. A computerized pattern recognition algorithm divided pursuit eye movements into two basic components: smooth pursuit and saccadic eye movements. The algorithm also determined eye position error and velocity error before and after each saccade. Schizophrenic patients had lower smooth pursuit gain (p less than 0.02) and made more saccades during smooth pursuit (p less than 0.02) than either comparison group. When saccades were assigned to subcategories based on direction and position error, only the frequency of 'catch-up' saccades differentiated schizophrenic patients from the comparison groups (p less than 0.05). Smooth pursuit gain was negatively correlated with saccadic frequency among all three subject groups. Eye velocity preceding saccades was significantly lower among the schizophrenic patients, but pre or post saccadic position error did not differ among the three groups. Discrete analysis of the fine structure of visual pursuit tracking may lead to a better understanding of eye movement abnormalities in schizophrenia.

Smooth pursuit and saccadic eye movements and neurological soft signs in obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) demonstrate an increased number of neurological soft signs as well as neuroanatomic abnormalities detected with modern imaging techniques. Quantitative analysis of eye movements has proved fruitful in investigations of other neuropsychiatric disorders with similar findings. Therefore, we studied the smooth pursuit and saccadic eye movements of 8 OCD patients and 12 normal controls using infrared oculography and computerized pattern recognition software. We also measured neurologic soft signs using a standardized rating instrument. Despite having an increased number of neurological soft signs, OCD patients' performance on a variety of measures of eye movement was not significantly impaired. Neither the severity of obsessions or compulsions nor the number of neurologic soft signs correlated with any of the parameters of eye movement function. We conclude that OCD patients do not have prominent oculomotor dysfunction and that eye movement dysfunction and neurologic soft signs are not inextricably linked.