Auditory and visual attention assessed with PET.

Brain mechanisms involved in the maintenance of attention to auditory and visual stimuli at different spatial locations were assessed using positron emission tomography with [15O]water to measure regional cerebral blood flow (rCBF) changes in 13 normal volunteers. Simultaneous auditory [dichotically presented consonant-vowel-consonants (CVCs)] and visual stimuli (vertically oriented, CVCs presented to the left and right of fixation) were presented on every trial. In different conditions subjects attended for targets in a specified stimulus channel (left or right ears or left or right visual fields) while maintaining fixation on a central x. Attending left or right for auditory stimuli increased rCBF in primary auditory cortex in Heschl's gyrus and in temporal lobe auditory association cortices in both hemispheres. Attending left or right for visual stimuli did not change rCBF in primary visual cortex, and only attention to the right significantly increased rCBF in contralateral occipital cortex. Visual attention caused significant rCBF changes in a widespread network that included frontal, parietal, and temporal cortical regions as well as the cerebellum, whereas rCBF changes due to auditory attention were largely localized in the temporal lobes. The results suggest that spatially directed attention is mediated by different mechanisms in the auditory and visual modalities.

Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder.

OBJECTIVE: In the treatment of attention-deficit hyperactivity disorder (ADHD), the efficacy of the tricyclic antidepressants and monoamine oxidase inhibitor antidepressants has been compared with that of both placebo and the stimulants (methylphenidate and/or dextroamphetamine). However, the effectiveness of bupropion has been contrasted only with placebo. The primary aim of this study was to contrast the efficacy of bupropion with that of methylphenidate in the treatment of ADHD. METHOD: A double-blind, crossover design was used in this study. After a 14-day medication washout period, 15 ADHD subjects (7 to 17 years old) were randomized to either methylphenidate or bupropion for 6 weeks, washed out for an additional 2 weeks, and then "crossed over" to the other drug. Methylphenidate was titrated to the maximum effective dose of 0.4 to 1.3 mg/kg per day (mean 0.7 mg/kg per day) and bupropion was titrated to an effective dose ranging from 1.4 to 5.7 mg/kg per day (mean 3.3 mg/kg per day). RESULTS: Both methylphenidate and bupropion produced significantly greater (p < .001) and equivalent improvement on the Iowa-Conners Teacher's Rating Scale according to both the subjects' parents and teachers. The same pattern of improvement was also noted for improvement on the Clinical Global Impression Scale, Kagan's Matching Familiar Figures Test, Continuous Performance Test, Children's Depression Inventory, Children's Manifest Anxiety Scale, and Rey Auditory-Verbal Learning Test. CONCLUSIONS: In this double-blind, crossover trial, bupropion and methylphenidate were both effective and did not differ in their overall efficacy as treatments for ADHD.

Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia.

OBJECTIVE: Structural neuroimaging and neuropathological studies have demonstrated a variety of aspects of brain morphology that appear to distinguish schizophrenic patients from comparison subjects (diagnostic effects), a predominance of left-sided pathology (laterality effects), and a greater likelihood of brain abnormality among males (gender effects). However, findings have been inconsistent across studies, perhaps reflecting limited power due to small study group sizes. The goal of this study was to examine diagnostic, laterality, and gender effects of brain morphology as assessed by magnetic resonance imaging in a large, carefully evaluated group of schizophrenic and comparison subjects. METHOD: One hundred two patients with schizophrenia (DSM-III-R) (70 men and 32 women) and 87 normal comparison subjects, chosen to be equivalent to the patients in terms of familial socioeconomic background, underwent magnetic resonance imaging with a 1.5-tesla scanner. All regions of interest were outlined manually by an experienced technician on all slices in which they were visualized. Region of interest volumes were compared across groups, and age, sex, and stature were controlled. RESULTS: Schizophrenic patients were found to have larger lateral and third ventricles and smaller thalamic, hippocampal, and superior temporal volumes than comparison subjects. No significant differences were demonstrated for intracranial, cerebral, cerebellar, temporal lobe, caudate nuclei, or temporal horn volumes. There were no significant Laterality by Diagnosis effects and no significant Gender by Diagnosis effects for any of the regions of interest. CONCLUSIONS: Many, but not all, of the hypotheses informed by earlier studies regarding diagnostic effects were confirmed, while hypotheses regarding gender and laterality interactions with diagnosis were not supported.

Influence of major depression on 1-year outcome in patients with traumatic brain injury.

The authors examine those factors that contributed to deterioration in social functioning, activities of daily living, or intellectual functioning during a 1-year period after traumatic brain injury (TBI). Fifty-two patients suffering an acute TBI were evaluated for existence and severity of mood disorders and impairment during their hospital stays and at 3-, 6-, and 12-month follow-up examinations. Patients whose scores on intellectual function, social function, or daily activities deteriorated during the 1-year period after trauma were considered to have a poor outcome. Eleven of 52 patients had a poor outcome in social function, which was associated with race, right-hemisphere lesions, intellectual impairment, and prolonged major depression. Seven of 52 patients had a poor outcome in daily activities, which was associated with a major depression of more than 6 months' duration and severity of Hamilton Depression Rating Scale scores. Eleven of these patients had a poor outcome in cognitive function, which was associated with cognitive impairment immediately after TBI. A major depression lasting more than 6 months was associated with deterioration of social functioning and activities of daily living during the 1-year period after TBI.

Magnetic resonance imaging in familial versus sporadic cases of schizophrenia.

Magnetic resonance imaging findings were compared in 22 familial and 29 sporadic cases with DSM-III-R diagnoses of schizophrenia, schizoaffective, or schizophreniform disorders. Volumetric measurements were used to assess the size of brain structures, including the cranium, cerebrum, lateral ventricles, temporal horns, third ventricle, lenticular nuclei, amygdaloid-hippocampal complex, and cerebellum, as well as the asymmetry of the lateral ventricles. Increased volume of the lenticular nuclei and greater ventricular asymmetry (the left ventricle being larger) were found in familial cases compared with sporadic cases and normal control subjects. It is possible that increased lenticular nuclei volume and greater lateral ventricular asymmetry reflect the role of genetic factors in schizophrenia.

Secondary mania following traumatic brain injury.

OBJECTIVE: In this study patients were examined during the first year after traumatic brain injury to determine the presence of secondary mania. METHOD: A consecutive series of 66 patients with closed-head injury were evaluated in the hospital and at 3-, 6-, and 12-month follow-ups. The patients were examined with a semistructured psychiatric interview and scales for measurement of impairment in activities of daily living, intellectual function, and social functioning. Patients fulfilling the DSM-III-R criteria for mania were compared to patients with major depression and to patients without affective disturbances in regard to their background characteristics, impairment variables, and lesion locations. RESULTS: Six patients (9%) met the criteria for mania at some point during follow-up. The presence of temporal basal polar lesions was significantly associated with secondary mania even when the effect of other lesion locations was taken into account. Secondary mania was not found to be associated with the severity of brain injury, degree of physical or cognitive impairment, level of social functioning, or previous family or personal history of psychiatric disorder. The duration of mania, however, appeared to be brief, lasting approximately 2 months. CONCLUSIONS: The 9% frequency of secondary mania in these patients with traumatic brain injury is significantly greater than that seen in other brain-injured populations (e.g., patients with stroke). The major correlate was the presence of a temporal basal polar lesion.

Depression following traumatic brain injury: a 1 year longitudinal study.

A group of 66 patients hospitalized for the treatment of closed head injury, were assessed for the presence of mood disorders during their hospital admission and at 3, 6 and 12 months follow-up. A total 28 patients met DSM-III-R diagnostic criteria for major depression at some time during the study (17 in the acute stage, 11 during follow-up). The mean duration of major depression was 4.7 months. However, there appeared to be a group of transiently depressed patients (41%) who where depressed inhospital but were no longer depressed at 3 months follow-up. Throughout the follow-up period, major depression showed a strong relationship with poor social functioning. There was not, however, a consistent relationship between depression and quantitative measures of either physical or cognitive impairment. Location of the brain lesion was associated with the development of major depression only in the acute stage. Transient depressive syndromes were associated with left dorsolateral frontal and/or left basal ganglia lesions.

Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics.

Previous data suggest the possibility that haloperidol daily dosing requirements may be confounded by smoking and, at higher doses, capacity-limited metabolism. Forty hospitalized patients suffering from an acute exacerbation of schizophrenia were treated for 2 weeks with fixed oral doses of haloperidol ranging from 10 to 70 mg/day (0.13 to 0.95 mg/kg/day) that produced mean steady-state concentrations between 4.5 and 55.4 ng/ml. No significant differences between the smoking and nonsmoking groups were obvious for the factors of weight, age, sex, daily doses, steady-state clearance, and steady-state haloperidol concentrations in plasma at week 1, week 2, and their mean. The hypothesis that the relationship between haloperidol dose and steady-state haloperidol concentration in plasma was affected by patients' smoking status and metabolic capacity was tested by multiple linear regression analysis and initially rejected. The relationship of dose to haloperidol concentration was fitted as a linear function. To improve the curve fit, the haloperidol concentrations and doses were transformed to their natural logs and then the regression line was refitted. The multiple regression analysis was repeated with the data in their transformed state. It was found that, although smoking status and dose of the drug did not independently affect the average haloperidol concentration, together they interacted in such a way that individual haloperidol concentrations were dependent on the smoking status at specific doses. Thus, two haloperidol dosing equations were generated, one for smokers and one for nonsmokers.

Depression and anxiety following traumatic brain injury.

The frequency, course, and clinical correlates of generalized anxiety disorder (GAD) and its relationship to major depression were examined in 66 patients with traumatic brain injury (TBI). Of 66 TBI patients, 7 (11%) had both GAD and major depression; 10 (15%) had major depression without GAD. Median duration was 1.5 months for nonanxious depressions, 7.5 months for anxious depressions, and 1.5 months for concurrent GAD. Anxious depressions were also associated with right hemisphere lesions, whereas major depressions alone were associated with left anterior lesions. These findings suggest that anxious major depression and major depression following TBI may be two different disorders with different underlying etiological mechanisms and perhaps differential response to treatment.

Comparison between acute- and delayed-onset depression following traumatic brain injury.

Sixty-six patients admitted for the treatment of acute closed head injury were assessed for the presence of mood disorders during the in-hospital period and at 3-, 6-, and 12-month follow-ups. Diagnosis was made using a structured psychiatric interview and DSM-III criteria. A total of 28 patients had major depression at some time during the study: 17 had acute-onset depression and 11 had delayed-onset depression. Acute-onset depressions are related to lesion location and may have their etiology in biological responses of the injured brain, whereas delayed depressions may be mediated by psychosocial factors, suggesting psychological reaction as a possible mechanism.

Depression in patients with acute traumatic brain injury.

OBJECTIVE: This study was undertaken to examine patients with closed head injuries for the presence of depressive disorders. METHOD: A consecutive series of 66 patients with closed head injuries but no significant spinal cord or other organ system injury were examined by means of a semistructured psychiatric interview. The Hamilton Rating Scale for Depression as well as scales measuring impairment in activities of daily living, intellectual functioning, and social functioning were administered. The patients' CT scans were also examined. RESULTS: Seventeen patients had major depression and two had minor depression. The presence of left dorsolateral frontal lesions and/or left basal ganglia lesions and, to a lesser extent, parietal-occipital and right hemisphere lesions was associated with an increased probability of developing major depression. Compared to the nondepressed group, the group with major depression had a higher frequency of previous psychiatric disorder and showed evidence of poorer social functioning. CONCLUSIONS: Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations.

Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients.

OBJECTIVE: Clozapine, an atypical antipsychotic, has been estimated to be effective in 30% of treatment-refractory schizophrenic patients. The authors hypothesized that if a dose-response relationship was obvious for this drug, the response rate could be significantly amplified. METHOD: Following an 8-24-day dose titration phase, 29 inpatients with treatment-resistant schizophrenia diagnosed according to DSM-III-R were given a clozapine dose of approximately 400 mg/day for 4 weeks; blood samples were obtained weekly during this period. RESULTS: A receiver operator curve demonstrated that the threshold clozapine plasma concentration for therapeutic response was 350 ng/ml. Sixty-four percent of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only 22% of the patients with concentrations less than 350 ng/ml responded. CONCLUSIONS: Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%.

Pharmacokinetic protocol for predicting plasma haloperidol concentrations.

The accurate prediction of steady-state plasma haloperidol concentrations was successfully accomplished by obtaining two blood samples following a 20 mg test dose (kinetic method). Prediction of steady-state concentrations on the basis of a mg/kg/day dosage (dose method), although equally precise, generated significantly less information concerning the variance between observed and predicted haloperidol plasma concentrations. Both predictive methods were less precise when the daily doses exceeded 0.47 mg/kg/day. Fifty percent (6/12 patients) of the haloperidol plasma concentrations were underpredicted if this threshold was exceeded. This finding may suggest the possibility of dose-dependent pharmacokinetics with haloperidol in some patients.

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia.

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8-18 ng/ml or 25-35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Wee 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r = -0.43, P less than 0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol + reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (less than 25% improvement in BPRS from baseline and week 2 BPRS less than 55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.