Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

The Effect of Pharmacist-led Psychiatric Pharmacotherapy Conferences on the Appropriate Use of Antipsychotics.

The Hakodate Watanabe Hospital has held pharmacist-led multidisciplinary psychiatric pharmacotherapy conferences since September 2013 in order to optimize pharmacotherapy. The effects of holding regular conferences on the correction of high-dose antipsychotic polypharmacy, prevention and reduction of adverse reactions to antipsychotics, and reduction of the drug costs were investigated in psychiatric inpatients prescribed 4 or more antipsychotics. The results revealed that the number of antipsychotics and number of all drugs were significantly reduced by 1, the chlorpromazine (CP)-equivalent dose was significantly reduced by approximately 350 mg, and the drug costs were significantly reduced by 176.5 yen/d. In regard to the effects on the laboratory test data, the blood glucose and hemoglobin A1c (HbA1c) levels were significantly reduced. In addition, 84.8% of the patients were assessed as "unchanged" using the Clinical Global Impression of Change (CGI-C), indicating the absence of any significant changes in the severity of the clinical psychiatric symptoms. The results confirm that psychiatric pharmacotherapy conferences are effective for promoting appropriate use of antipsychotics, reducing the incidence of metabolic adverse reactions, such as elevation of the blood glucose, and also reducing the drug costs. The above results suggest that psychiatric pharmacotherapy conferences encourage psychiatric medical teams to adjust prescriptions while sharing information, and are effective for optimizing pharmacotherapy.

Theory of mind in adolescents with early-onset schizophrenia: correlations with clinical assessment and executive functions.

OBJECTIVE: We examined Theory of Mind (ToM) abilities in adolescents with early-onset schizophrenia (EOS) and their correlation with clinical findings and Executive Functions (EF). METHODS: The ToM abilities of 12 adolescents with EOS were compared with those of healthy participants matched in age and educational level. The Moving Shapes Paradigm was used to explore ToM abilities in three modalities: random movement, goal-directed movement and ToM - scored on the dimensions of intentionality, appropriateness and length of each answer. EF was tested using Davidson's Battery and the clinical psychopathology with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Adolescents with EOS were significantly more impaired than controls in the three dimensions evaluated for the goal-directed and ToM modalities. Regarding the random movement modality, the only difference was in appropriateness (p<0.01). No correlation with age or level of education was evident for ToM skills. Total PANSS score was negatively correlated with appropriateness score for the goal-directed (p=0.02) and ToM modalities (p=0.01). No correlation existed between performance in the ToM Animated Tasks and positive, negative or disorganisation PANSS subscores. No correlations were found among the three scores in the Moving Shapes Paradigm and any measures of the accuracy of the three tasks assessing EF. CONCLUSION: Our results confirm previous findings of ToM deficits in adult individuals with schizophrenia and attest the severity of these deficits in patients with EOS.

Use of L-929 cell line for phototoxicity assessment.

L-929 is an adherent type of mouse fibroblast cell line was known as an alternate test system for toxicity assessment. Its photosensitivity towards ultraviolet radiation (UVR) was studied under the exposure to various intensities of UVA, UVB and sunlight. MTT assay was used for cell viability under UVR alone or in combination with chlorpromazine. UVB intensity below 0.6mW/cm2 did not show phototoxicity till 150min (min) exposure. UVA intensity up to 1.5mW/cm2 for 180min exposure did not alter the cell viability, but at 2.0 and 3.0mW/cm2 showed reduced cell viability beyond 90 and 60min, respectively. Sunlight exposure showed a loss in cell viability beyond 60min. Chlorpromazine showed a dose dependent phototoxic response under UVA, UVB and sunlight exposure. The study suggests the suitability of L-929, as an in vitro test system for the phototoxicity, which was compared with NIH-3T3 cell line. Therefore, L-929 cell line may also be used for phototoxicity assessment. The system provides information regarding the lethality of higher intensities of UVR and its importance in view of increasing UV intensities on the earth's surface due to ozone depletion. Our results suggest that a small change in UVR intensity (especially UVB) in sunlight may increase the risk of phototoxicity.

An optimised methodology for the neurobehavioural assessment in rodents.

INTRODUCTION: The most widely used test to identify undesired effects of drugs on the central and the peripheral nervous system is the neurobehavioural observation battery adapted from that first described by Irwin in mice. As a neurobehavioural assessment is based on observations; thus, all factors involved need to be controlled and standardised to make the data collected objective, reproducible, reliable and predictive of safety liabilities. METHODS: An observation battery comprising 58 signs with assigned full details of numerical scores was defined, and a standard design with associated recording, presenting and analysing data system was established. Validation studies were conducted with chlorpromazine, amphetamine, diazepam or clonidine given orally to rats or mice, in order to assess if this methodology could clearly differentiate the profile of effects produced by these compounds. The analysis of data from 80 control rats allowed for the assessment of the normal behaviour in order to characterise the inter-individual, daytime-related variability and the habituation of animals to the procedure. RESULTS: The reference compounds induced their typical and expected transient effects on neurobehaviour, observed both in the home cage and open-arena, and on body temperature. In particular, amphetamine induced a stimulation of the nervous system activities and marked hyperthermia. Chlorpromazine, diazepam and clonidine induced depressive, anxiolytic or sedative effects associated with hypothermia. The analysis of data collected in control animals allowed for the identification of 6 signs which scored differently from the assigned normality at the first handling occasion due to the characteristic fear reactions to the unknown, and 9 signs at 8 h post-dose due to the animal's habituation to experimental conditions and handling. DISCUSSION: The neurobehavioural changes expected by reference compounds administration were detected. These results confirm that by using this methodology the normal behaviour of the rat and the mouse, the daytime-related variability and the habituation of animals can be characterised, allowing a refined, reliable and reproducible neurobehavioural assessment of test substances in rodents.

Antipsychotic dosing and concurrent psychotropic treatments for Medicaid-insured individuals with schizophrenia.

Antipsychotic medications have been first line treatment for schizophrenia for half a century, yet few studies have assessed outpatient maintenance treatment in large populations. This article describes oral antipsychotic dosing patterns and psychotropic treatments using computerized Medicaid claims data for individuals who were diagnosed with schizophrenia and received treatment on an outpatient basis during 1991. The findings show that the mean daily oral antipsychotic dose was 729 +/- 586 chlorpromazine equivalents (CPZ-EQ) for high-potency agents and 304 +/- 328 CPZ-EQ for low-potency agents. Males, younger individuals, and African-Americans received larger mean daily doses of high-potency agents, ranging from 747 to 800 CPZ-EQ. Antiparkinsonian agents were prescribed for over 90 percent of the outpatient antipsychotic treatment exposure. In summary, young adults, males, and African-Americans were given high-potency antipsychotic medications at outpatient maintenance doses that exceeded the maximum recommended levels, despite well-established evidence that high-dose treatment offers no additional benefit. Likewise, concurrent antiparkinsonian treatment exceeded the 1990 World Health Organization recommendations.

Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy.

Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored. We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls). Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity). Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients. Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity. High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients. This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia.

A decision analysis approach to neuroleptic dosing: insights from a mathematical model.

BACKGROUND: Although several published studies suggest that little benefit accrues from raising doses of conventional antipsychotic drugs above 500-800 chlorpromazine equivalents per day (CPZeq/day), institutionalized patients with schizophrenia often receive larger doses. Decision analysis could alter this practice by helping clinicians select doses through use of quantitative models that incorporate the consequences of each dose, the likelihood of those consequences, and explicit risk/benefit weightings. METHOD: This study uses representative published data to develop equations and graphs that describe dose-associated likelihoods of treatment response, side effects, and balances between benefits and incidence of side effects. RESULTS: Response rates fit a sigmoid curve that flattens at 500 CPZeq/day; a hyperbolic curve describing side effects reaches a plateau at much higher doses. Combining these curves shows that higher drug doses yield ever diminishing returns, because as the dose increases, the number of side effects per benefited patient also increases. A table and graphs show clinicians how to use these results to critique their current practices and make explicit risk/benefit judgments about dosages. CONCLUSION: Mathematical expressions for dose-related side effect and response rates are potentially useful tools for evaluating low-, intermediate-, or high-dosage neuroleptic treatment regimens.

Race, quality of care, and antipsychotic prescribing practices in psychiatric emergency services.

OBJECTIVE: The study examined whether the prescription practices of clinicians in psychiatric emergency services differed for African-American patients. Prescription of antipsychotic medications and its relation to quality of care was a particular focus. METHODS: Data from 442 independently observed evaluations of patients in psychiatric emergency services were examined using multivariate analyses. The observations were made during a five-year period at four urban general hospitals in California. RESULTS: Clinicians in the four emergency services, most of whom were Caucasian, prescribed more psychiatric medications to African Americans than to other patients and devoted significantly less time to their evaluations. African Americans received more oral doses and more injections of antipsychotic medications, and the mean 24-hour dosage of antipsychotics (1,321 milligrams) was significantly higher than for other patients (825 milligrams). The tendency to overmedicate African-American patients was lower when clinicians' efforts to engage the patients in treatment were rated higher. CONCLUSIONS: The results highlight the importance of efforts to engage African Americans in the treatment process and the need for clinical skills and training to help bridge cultural distances.

Clinical pharmacology and the prescription of psychotropic medication.

There are many reasons why once a day oral dosage may be advantageous in administration of psychotropic drugs to mental patients, such as convenience for the patient, avoided side effects, ease of remembering, all of which contribute to reliable dosage as well as cost savings. This paper illustrates cost data, pharmacokinetics of psychotropic drugs, and suggests a basis for determining adequate pill size for unit dosage. On a cost per milligram basis, there is economic savings if medication is prescribed in the largest size the patient can conveniently take. Pharmacological data support a rationale for higher unit dosage. They indicate a dose response relationship between dose and therapeutic effectiveness and probably a blood level relationship. The long half-life indicates that once-a-day medication is a reasonable dosage schedule. The most important evidence for once-a-day medication, however, is the empirical evidence that it works, and is safe. Dosage information from double blind investigations provides a basis for determining adequacy of pill size for antipsychotic therapy.

Comparative survey of psychiatrists' prescription preferences: New York and Texas.

The present survey compares the treatment preferences of New York and Texas psychiatrists using a questionnaire report of a single psychiatric case. The characteristics of this approach enable the investigator to hold and symptoms and syndromes of the patient constant. All clinicians respond to identical stimuli. What varies naturally, then, is the judgment of the clinician in developing his treatment procedure, thereby enabling estimation of the degree of standardization in treatment preferences. Three hundred twelve psychiatrists from New York and 133 from Texas provided data for comparative purposes. On the first admission 41% of the New York respondents and 24% of the Texas psychiatrists preferred a regimen that included more than one drug. When a combination of drugs was selected, chlorpromazine-trifluoperazine was preferred. But ten other specific combinations also were selected. Most were of potent neuroleptics, but some included antidepressant-neuroleptic combinations. None of the variables included in the study provided tangible systematic variance for these treatment preferences. A year and a half after first admission, followed by treatment in and out of hospital, the patient's clinical course continued to deteriorate. At this point more than 50% of the respondents in each state selected a regimen that included a minimum of two drugs. As many as 24 different combinations were selected for this single case. Nineteen percent of the New York respondents and 13% of the Texas respondents selected a regimen that included three or more psychoactive medications. The existence of these treatment preferences requires a more basic understanding of treatment preferences, for these seems to be no basis for them.