A pilot study of loading versus titration of valproate in the treatment of acute mania.

OBJECTIVE: This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania. METHOD: Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n = 5; mean age = 33.4) or slower titration dose (10 mg/kg/day, n = 6. mean age = 30.6) of valproate for 7 days without other psychotropic agents. with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale. RESULTS: The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines. CONCLUSION: This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.

Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase.

RATIONALE: Phencyclidine (PCP) is widely used as an animal model of schizophrenia, because in humans it can induce positive and negative symptoms associated with schizophrenia. PCP is an antagonist of N-methyl-D-aspartate receptors, which are associated with the nitric oxide (NO) system. OBJECTIVE AND METHODS: The primary objective was to determine whether neuronal NO synthase (nNOS) is involved in PCP-induced behaviours and neuronal activation, as measured by the expression of c-Fos. After characterizing a PCP mouse model (dose-response study, Experiment 1), we measured PCP-induced effects in mice treated with nNOS antisense oligodeoxynucleotides (AS-ODNs) (Experiment 2), and in nNOS knockout (nNOS-/-) mice (Experiment 3). RESULTS: PCP 5 mg/kg induced the maximum behavioural effects of all doses tested, consisting of hyperlocomotion, stereotyped turning behaviour, without the presence of ataxia. PCP also induced an increase in Fos-like immunoreactivity (Fos-LIR) in the frontal cortex, as well as in the midline limbic (thalamic and hypothalamic nuclei) areas. In the AS-ODN-treated mice, PCP induced less behaviour when compared to water-treated controls. In the nNOS-/- mice, PCP induced less behaviour and a decrease in Fos-LIR in the frontal cortex and midline limbic areas, when compared to wild-type littermate controls. CONCLUSIONS: Our findings suggest that the frontal cortex and midline thalamic brain regions are involved in PCP-induced effects in mice. Furthermore, we show that an intact nNOS system is necessary to obtain PCP-induced effects. This may implicate nNOS as a viable drug target in the treatment of schizophrenia.

Blockade of phencyclidine-induced effects by a nitric oxide donor.

1. Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. 2. The effects of the NO donor, sodium nitroprusside (SNP), were studied in PCP-treated rats. Following drug administration, behavioural changes and the expression of c-fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored. 3. Acute PCP (5 mg kg(-1), i. p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 - 6 mg kg(-1), i.p.) by itself produced no effect on any behaviour studied but completely abolished PCP-induced behaviour in a dose- and time-dependent manner. 4. PCP had differential regional effects on c-fos expression in rat brain, suggesting regionally different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre-treatment with SNP blocked PCP-induced c-fos expression at doses similar to those that suppress PCP-induced behavioural effects. 5. These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished effects of PCP suggests that drugs targeting the glutamate-NO system may represent a novel approach to the treatment of PCP-induced psychosis and schizophrenia.

Olanzapine for patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study.

OBJECTIVE: This prospective, consecutive case-series outcome investigation evaluates the effectiveness of olanzapine in 16 patients with treatment-resistant schizophrenia. METHOD: Treatment resistance was defined as nonresponsiveness to at least 3 antipsychotic drugs from at least 2 different chemical classes. A minimum baseline score on the Brief Psychiatric Rating Scale (BPRS) of 45 was required for enrolment. Outcome evaluation measures included the BPRS, Global Assessment Scale (GAS), and Abnormal Involuntary Movement Scale (AIMS). RESULTS: Subjects (n = 16) has a mean age of 40 years and mean duration of illness of 16 years. Olanzapine treatment was initiated at 5 mg daily and was increased based on clinical judgement up to a maximum of 40 mg daily. Significant decreases in mean BPRS (P < 0.001) and GAS (P < 0.01) scores were observed at weeks 4, 8, 12, and 16, compared with baseline. Eight of 16 patients responded to olanzapine, as defined by a 20% decrease in BPRS score by week 16. Dyskinetic movements significantly increased at week 4 (P < 0.01) but did not differ from baseline at weeks 8 and 16. CONCLUSION: These results suggest that olanzapine at moderate to high doses may offer an effective treatment for a significant proportion of patients with schizophrenia nonresponsive to multiple trials of conventional antipsychotics. A randomized controlled trial is encouraged to validate these findings, and comparative trials are required to determine when clinicians should consider this approach.

Rural models for integrating primary care and mental health services.

This paper presents findings from a study designed to identify and describe models for integrating primary care and mental health services in rural communities. Data were obtained from telephone interviews with staff at rural primary care sites around the country. Findings are based on the responses of 53 primary care organizations in 22 states. The authors identify four integration models--diversification, linkage, referral and enhancement--which appear to exist in combination, rather than as pure types. The proposed analytic framework outlines aspects of integration that are readily amenable to study.

Bibliography database managers. A comparative review.

Bibliography database managers (BDMs) are used to manage information resources: specifically, to maintain a database of references and create bibliographies and reference lists for written works. This comparative review provides an overview of BDMs and capsule reviews of five programs: EndNote Plus 2.0; Library Master 3.0; Papyrus 7.0.11; Pro-Cite 2.2.1; and Reference Manager 6.02.

Development and loss of tolerance to the effects of ethanol on DRL performance of rats.

Six male Sprague-Dawley rats were trained on a DRL-20 operant schedule for food presentation. When stable performance was established, they were exposed to an escalating regimen of daily ethanol administration (1.125-3.75 g/kg, IP). This dosing regimen continued until the maximally tolerable dose for each subject was reached. Tolerance loss then was monitored for approximately 6 months by periodic ethanol challenge doses (1.5 g/kg). Dose-effect curves (DECs) were obtained prior to (DEC-1), immediately after (DEC-2), and 6 months following termination of (DEC-3) the ethanol exposure. Rate-increasing effects (DEC-1) were noted at low doses (0.75 and 1.125 g/kg), with a higher dose (2.25 g/kg) resulting in a decreased rate of responding. Tolerance, following chronic ethanol exposure, developed to both the rate-increasing and rate-decreasing effects of ethanol (DEC-2). While some tolerance was lost within the 6 months following the daily ethanol exposure (DEC-3), a significant degree of tolerance was still indicated by most of the response measures. This duration of tolerance was considerably longer than that generally reported, and is probably attributable to persistent learned compensatory behavior and/or intermittent ethanol challenge tests.

Tolerance to ethanol's disruptive effects on operant behavior in rats.

The effects of pre-session and post-session daily ethanol injections on the development and loss of tolerance to ethanol's effects on fixed ratio operant performance in rats was assessed using a cumulative dosing procedure. Daily pre-session ethanol administration produced a greater decrease in ethanol sensitivity than did daily post-session ethanol. Both tolerance effects persisted for at least 1 month after the chronic injection phase. No changes in ethanol sensitivity were apparent in the saline control group and no changes in estimated blood ethanol levels were found after the chronic treatments. The post-session ethanol groups displayed a performance decrement during the initial segment of the chronic injection period, but improved significantly across the chronic phase. These data suggest that some delayed effect of ethanol initially impaired performance but that tolerance to this ethanol effect also occurred and probably contributed to the decline in ethanol sensitivity seen in these groups. Compensatory learning as the mechanism for tolerance development in the pre-session and post-session ethanol groups was supported by the finding of no change in ethanol sensitivity in rats exposed to comparable daily ethanol without any concurrent operant task on which the direct, immediate, or indirect, delayed ethanol effects could operate.

Behavioral factors in development of tolerance to ethanol's effects.

Dose-effect analyses were used to monitor the development of tolerance for ethanol's effects on FR30 operant performance in rats under different conditions of chronic ethanol exposure: (a) pre-session ethanol injections (PRE) vs. post-session ethanol injections (POST) in Experiment 1; and (b) an ethanol liquid diet (ED) vs. a control diet (CD) in Experiment 2. The PRE and ED groups developed tolerance at the conclusion of the chronic regimens, which declined by six months but not to baseline levels. These data suggest that tolerance results from learned compensatory adjustments (through intoxicated practice) to ethanol's disruptive effects. The POST, but not the CD, group developed a progressively increasing degree of tolerance after several ethanol challenge tests. These results suggest that some threshold level of passive ethanol exposure in the POST group interacted with their limited intoxicated practice. Finally, the tolerance developed under intoxicated practice conditions did not appear to reflect a generalized tolerance to rate-reducing properties of drugs, changes in ethanol kinetics, or age-related changes.

Interactions between stimulants: effects on DRL performance and lethality in rats.

The Controlled Substances Act of 1970 drastically reduced the supply of amphetamines available to the public. It also inadvertently prompted the emergence of a new drug industry, namely the marketing of caffeine/phenylethylamine combinations packaged to look like many of the previously available amphetamine preparations. The findings of one recent experimental study corroborate anecdotal evidence that the interoceptive "high" produced by these look-alike stimulants mimics that produced by amphetamine. The present study was designed to further characterize the behavioral effects of caffeine/phenylethylamine combinations. The present findings suggest that adding ephedrine and phenylpropanolamine to caffeine markedly enhances the disruption of DRL performance, as well as the lethality of the drug. In addition, different patterns of interactions were obtained between amphetamine and caffeine versus the caffeine/ephedrine/phenylpropanolamine combination.

Schedule-controlled behavior as an index of the development and loss of ethanol tolerance in the rat.

Twelve male Sprague-Dawley rats, following training on one of two food-motivated operant schedules (Fixed-Ratio 30 or Variable Interval 30 s), were exposed to an escalating regimen of daily ethanol (1.125-3.0 g/kg, IP) administration. This increasing dose regimen continued until the maximally tolerable dose for each subject was reached. Tolerance was then monitored for approximately 6 months by periodic ethanol challenge doses (1.5 g/kg). Dose-effect curves (DECs) were obtained prior to chronic ethanol (DEC1), immediately after ethanol tolerance development (DEC2), and 6 months (DEC3) following termination of ethanol exposure. At DEC1, ethanol produced dose-dependent decreases in rate on both schedules with no significant schedule differences in ED50 (the dose effective at reducing the maximal response rate by one-half) values. Maximal tolerance was achieved in means of 46 and 55 days on the VI and FR schedules, respectively. Differences in rate of tolerance acquisition on the initial dose of the chronic regimen (1.125 g/kg) account for most of the difference in the overall rate of acquisition. Comparison of the ED50 data from DECs 1 and 2 indicated that daily ethanol exposure resulted in a 2-fold decrease in ethanol sensitivity (i.e., tolerance) on both operant schedules. The ED50 data from DECs 1 and 3 demonstrated a 1.7-fold decrease in ethanol potency on DEC3. This duration of tolerance was considerably longer than that generally reported, and possibly related to the extended ethanol exposure and the sensitivity of operant schedules to drug effects.

Periodic availability: factors affecting alcohol selection in rats.

The joint influence of alcohol availability conditions and alcohol concentration on the acquisition and maintenance of alcohol selection was examined in non-alcohol preferring Sprague-Dawley rats. Relative alcohol selection increased gradually in rats given periodic access to 10% alcohol but was immediately apparent in rats given periodic access to 5% alcohol. Rats given continuous access to alcohol (either forced or choice) did not show similar increases in alcohol selection until switched to the periodic schedule. The increases were not sustained in any group when alcohol became continuously available. Comparable increases in alcohol selection were evident in rats given periodic access to alcohol on various fixed schedules or on a random schedule. Several factors appear to influence the degree of alcohol selection under conditions of periodic availability: alcohol concentration, nature of prior experience with alcohol, the frequency of access to alcohol, the regularity of the periodic access to alcohol, and differences in individual responsivity to the schedule variable.

Effects of cortical, hypothalamic, and hippocampal lesions on chronic alcohol intake and preference in rats.

The effects of cortical, hippocampal, and suprachiasmatic (hypothalamic) lesions on forced alcohol consumption, alcohol preference and the distribution of alcohol intake throughout the day were examined in rats. Controls included by hypothalamic sham-operated and unoperated groups. Baseline water intake during light and dark and initial alcohol preference (10% alcohol versus water) were determined. All animals then were placed on a forced alcohol consumption regimen consisting of ad lib lab-chow and 10% ethanol in water. On the sixth day of each week during the alcoholization regimen, light and dark phase alcohol intake was assessed and on the seventh day of each week, a 24-hr, two-bottle alcohol preference test (10% ethanol) was given. After nine weeks on the forced alcohol regimen, all animals were given a seven day "withdrawal" period consisting of access to plain water and to 10% alcohol in water. Throughout both the forced alcoholization and withdrawal periods, the lesioned groups, especially the cortically lesioned group, displayed a significantly greater preference for the 10% alcohol solution than any of the control groups. Control and lesion groups did not differ significantly in their preference for a 5% alcohol solution or for a quinine solution, suggesting that simple taste threshold changes probably would not account for these data. The results are discussed in terms of the possibility that the brain lesions may have rendered the animals more sensitive to the "addictive" and/or reinforcing properties of ethanol.

Effect on bone growth of daily versus alternate-day corticosteroid administration: an experimental study.

Young rabbits that received large doses of corticosteroids on an alternate-day basis grew normally and showed muscle and bone turnover patterns indistinguishable from those of untreated animals. In contrast, the daily administration of corticosteroids profoundly affected the skeletal system: growth ceased, and there were marked narrowing and premature closure of the epiphyseal plates. Osteoporotic changes were present at 1 week and progressed during the next 9 weeks. Muscle atrophy occurred early in the course of treatment and was associated with increased muscle fat deposition. Thus, in this study, alternate-day administration of corticosteroids clearly lessened the corticosteroid side effects of growth retardation, osteoporosis, and muscle wasting.