Differential benefits of olanzapine on executive function in schizophrenia patients: Preliminary findings.

OBJECTIVE: Schizophrenia patients show executive function (EF) impairments in voluntary orienting as measured by eye-movements. We tested 14 inpatients to investigate the effects of the antipsychotic olanzapine on EF, as measured by antisaccade eye-movement performance. METHODS: Patients were tested at baseline (before olanzapine), 3-5 days post-medication, and 12-14 days post-medication. Patients were also assessed on the Positive and Negative Syndrome Scale (PANSS) to measure the severity of schizophrenia-related symptoms, and administered the Stroop task, a test of EF. Nine matched controls were also tested on the antisaccade and Stroop. RESULTS: Both groups showed improvement on Stroop and antisaccade; however, the schizophrenia group improved significantly more on antisaccade, indicating an additional benefit of olanzapine on EF performance. Patients with poorer baseline antisaccade performance (High-Deficit) showed significantly greater improvement on the antisaccade task than patients with better baseline performance (Low-Deficit), suggesting that baseline EF impairment predicts the magnitude of cognitive improvement with olanzapine. These subgroups showed significant and equivalent improvement on PANSS scores, indicating that improvement on the antisaccade task with olanzapine was not a result of differences in magnitude of clinical improvement. CONCLUSIONS: This preliminary study provides evidence that olanzapine may be most advantageous for patients with greater baseline EF deficits.

Effects of adjunct valproic acid on clinical symptoms and saccadic eye movements in schizophrenia.

OBJECTIVE: Valproic acid (VPA) has been suggested as a potential adjunct therapy in schizophrenia for the treatment of clinical symptoms and cognitive deficits. Here, we investigate the effects of VPA on clinical symptoms and saccadic eye movements while controlling for multiple medication effects. METHODS: Remitted and first-episode schizophrenia patients taking haloperidol were given adjunct VPA for approximately 2 weeks and tested using a measure of clinical symptoms (Positive and Negative Syndrome Scale) and saccadic eye movement tasks over three testing periods. The effects of VPA were compared with schizophrenia patients medicated with equivalent doses of haloperidol alone (HAL group) and normal controls. RESULTS: Schizophrenia patients had higher error rates on the antisaccade task (AS task) compared with normal controls. Adjunct VPA did not affect AS task error rates but was associated with an increase in response times for both saccade and AS tasks, with a significantly greater and dose-dependent increase in response times for the AS task. There were no differences in clinical improvement between VPA and HAL schizophrenia patient groups when controlling for haloperidol medication state. CONCLUSIONS: These results suggest that adjuvant VPA therapy results in both sensorimotor and cognitive slowing but does not either help or further impair inhibitory control in schizophrenia, as measured by the elevated AS task errors.

Effects of haloperidol on cognition in schizophrenia patients depend on baseline performance: a saccadic eye movement study.

Schizophrenic patients are heterogeneous with respect to voluntary eye movement performance, with some showing impairment (e.g., high antisaccade error rates) and others having intact performance. To investigate how this heterogeneity may correlate with different cognitive outcomes after treatment, we used a prosaccade and antisaccade task to investigate the effects of haloperidol in schizophrenic subjects at three time points: baseline (before medication), 3-5 days post-medication, and 12-14 days post-medication. We also investigated changes on the Stroop Task and the Positive and Negative Syndrome Scale (PANSS) in these same subjects. Results were compared to matched controls. When considered as a single patient group, haloperidol had no effects across sessions on reflexive and voluntary saccadic eye movements of schizophrenic patients. In contrast, the performance of the Control group improved slightly but significantly across sessions on the voluntary eye movement task. When each subject was considered separately, interestingly, for schizophrenic patients change in voluntary eye movement performance across sessions depended on the baseline performance in a non-monotonic manner. That is, there was maximal worsening of voluntary eye movement performance at an intermediate level of baseline performance and the worsening decreased on either side of this intermediate baseline level. When patients were divided into categorical subgroups (nonimpaired and impaired), consistent with the non-monotonic relationship, haloperidol worsened voluntary eye movement performance in the nonimpaired patients and improved performance in the impaired patients. These results were only partially reflected in the Stroop Test. Both patient subgroups showed clinically significant improvement over time as measured by the PANSS. These findings suggest that haloperidol has different effects on cognitive performance in impaired and nonimpaired schizophrenic patients that are not evident in clinical ratings based on the PANSS. Given that good cognitive function is important for long-term prognosis and that there is heterogeneity in schizophrenia, these findings are critical for optimal evaluation and treatment of schizophrenic patients.

Who receives antidepressants and what impact do they have? An acute-care study.

The purpose of this study was to examine characteristics associated with prescribing antidepressants in major depression and the utility of such antidepressants in an acute-care, inpatient setting. Demographic and clinical (self-report and clinician-rated scales) were obtained for 111 inpatients diagnosed with major depression. Three comparison sets were made: (1) all patients prescribed antidepressants versus those who were not; (2) those in the top quartile for length of stay (LOS) versus those in the bottom quartile; and (3) patients discharged in less than one week who were prescribed versus not prescribed, antidepressants. Overall, minimal differences were found in the three comparison sets. Those prescribed antidepressants had higher admission BDI scores, longer LOS, more previous episodes, higher education levels, and were more likely to be admitted voluntarily. At admission, there were no clear predictors of LOS. Regardless of differences between groups at admission or discharge (antidepressant versus no antidepressant, short versus long LOS), no differences were found in the length of time before patients were readmitted. These findings suggest that the traditional practice of avoiding immediate medication at hospitalization appears to have some validity.

Ratings of early major depressive disorder symptom change during a brief psychiatric hospitalization.

Ratings of change in MDD severity during a brief psychiatric hospitalization were examined across informant sources to determine the extent of change from admission to discharge and if specific symptoms are especially likely to change. Study participants were 137 inpatients with a primary diagnosis of MDD. Symptom data were collected at admission and discharge from attending psychiatrists, nurses, and patients. Global ratings of MDD severity and specific MDD symptoms significantly decreased during the course of hospitalization. This effect held across informant sources. All symptoms were equally likely to change. Females were rated as more depressed at admission and discharge by psychiatrists, but no gender differences were seen in self-report or nurse ratings. Shorter length of stay and involuntary admission status were associated with greater reduction in MDD severity. The temporal course and magnitude of the symptom reduction may result in part from unique aspects of an inpatient setting or from an underreporting of symptoms. The association between a shorter length of stay and greater symptom reduction may reflect a distinction between treatment responders and nonresponders.

Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial involving 9,260 psychiatric admissions.

OBJECTIVE: The authors examined clinical differences between divalproex sodium and generic immediate-release valproic acid. METHOD: This 6-year prospective, quasi-experimental clinical trial compared the effectiveness and tolerability of divalproex and valproic acid. The dependent variables were length of hospital stay, rehospitalization rate, and adverse drug reactions in 9,260 psychiatric admissions. RESULTS: Inpatients who initially received divalproex sodium had a 32.7% longer hospital stay and 3.8% higher readmission rate than did patients who initially received valproic acid. Initial treatment with divalproex prolonged length of stay by 30.3% in patients treated with divalproex and valproic acid during different admissions. After other variables were controlled by multiway analysis of variance, the hospital stay of patients who continued the initial medication was 15.2% longer (2.0 days) for divalproex than valproic acid. Switching medications was more common for valproic acid, partly because of study design. Medication intolerance occurred in approximately 6.4% more patients taking valproic acid than divalproex. However, switching from valproic acid to divalproex did not significantly prolong length of stay, over that for continuous divalproex, or increase the rehospitalization rate. CONCLUSIONS: Lower peak valproate concentrations with divalproex sodium may have enhanced tolerability but may also explain the lower effectiveness. Extended-release divalproex could lower effectiveness further and require higher doses. Thus, inpatients are better served by beginning with generic valproic acid and by changing to delayed-release divalproex only if intolerance occurs. This would save up to one-third of inpatient costs and two-thirds of a billion dollars yearly in medication costs.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.