Mary Ann Richardson

Treatment patterns of young chronic schizophrenic patients in the era of deinstitutionalization

A retrospective longitudinal treatment utilization study of 56 young chronic schizophrenic patients who began their treatment careers during the deinstitutionalization era was carried out covering all psychiatric services provided to each patient since first treatment. The group was primarily male and was characterized by histories of drug abuse and violence. Treatment utilization was heavy, discontinuous, and episodic with these patterns intensified for patients with histories of drug abuse. The majority of the group became “long-stay” hospital residents. The clinical and mental health policy implications of these findings are discussed and further research is suggested.

Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

Tetrahydrobiopterin (BH4) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly). These BH4 properties and their potential relevance to schizophrenia led us to investigate the hypothesis of a study group (healthy controls, n = 37; schizophrenics, n = 154) effect on fasting plasma total biopterin levels (a measure of BH4). Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds of gender, age, ethnicity, neuroleptic use history and dose of current use, 24-hour dietary phenylalanine/protein ratio (a dietary variable relevant to BH4 synthesis), and plasma phenylalanine (which stimulates BH4 synthesis). A mean decrement of 34% in plasma total biopterins for schizophrenics from control values supports clinical relevance for the finding. In a subsample (21 controls and 23 schizophrenics), sequence analysis was done of the GTP cyclohydrolase I feedback regulatory gene and no mutations were found in the coding region of the gene. A deficiency of BH4 could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology. Further, evidence has been accumulating which implicates the critical interdependence of these neurotransmitter systems in schizophrenia; this concept, along with the present study finding of a biopterin deficit, suggests that further study of the BH4 system in schizophrenia is warranted and desirable.

Branched chain amino acids decrease tardive dyskinesia symptoms.

Rationale: Prior studies had suggested (a) that a lessened ability to clear ingested forms of the large neutral amino acid (LNAA), phenylalanine (Phe), was associated with having tardive dyskinesia (TD), and (b) that greater availability of a group of LNAA, the branched chain amino acids (BCAA), concomitant with the lower availability of Phe to the brain are associated with a decrease in TD symptoms. The present study was then conducted to test whether increasing the daily intake of the BCAA would decrease the symptoms of TD. Methods: A 2-week trial of a BCAA medical food administered three times a day was conducted in nine men with long neuroleptic treatment histories. Frequency counts of TD movements were collected by videotape throughout the trial and these tapes were analyzed in blind random sequence for both patient and time for TD symptom level changes subsequent to completion of the trial. Plasma levels of the LNAA were also collected throughout the trial. Results: A statistically significant decrease in the level of TD symptoms was observed for the sample. The symptom changes were also clinically significant in that six of the nine subjects had symptom decreases of at least 58%, with all subjects having a decrease of at least 38%. BCAA administration increased plasma BCAA concentrations and BCAA/LNAA ratios and decreased plasma Phe concentrations and the Phe/LNAA ratio. Analyses indicated a strong significant correlation between the percent increase in the plasma BCAA values at the first administration and the percent improvement in TD over the trial in eight of the nine subjects. Conclusions: The BCAA show promise as a treatment for TD. The decrease in TD symptoms seen in the trial may have been modulated by the BCAA treatment-induced increased availability of the BCAA and decreased availability of Phe to the brain.

Intra-patient variability in the measurement of tardive dyskinesia

Intra-patient variability in the movements of tardive dyskinesia was examined through the analyses of 8-min frequency counts collected over a period of 11 weeks for six chronic schizophrenic patients. Weekly observation segments of 8 min, 4 min, 2 min, 1 min and 30 s showed considerable variation both across weeks and within sessions. Variations were of sufficient magnitude to contribute to the possibility of false negative tardive dyskinesia assessments and false positive treatment outcome designations. Measurement procedures taking this variability into account are urged for the study of tardive dyskinesia. Additionally, independently obtained rating scale scores showed no association to the collected frequency count data, suggesting fundamental differences between these two assessment procedures.

Phenylalanine hydroxylase gene in psychiatric patients: screening and functional assay of mutations

BACKGROUND Reports relating phenylalanine kinetics and metabolism to psychiatric disorders led us to undertake the comprehensive screening of the phenylalanine hydroxylase (PAH) coding region and functional testing of discovered mutations in a sample of psychiatric patients and healthy control subjects. METHODS Genomic DNA from psychiatric patients and control subjects was assayed for sequence variants in all PAH coding regions and splice junctions. In vivo functional analysis of mutations was conducted by assessing the kinetics and conversion to tyrosine of a standardized phenylalanine dose and by measuring fasting pterin levels. RESULTS A known missense mutation was observed in a schizoaffective subject, and a novel missense mutation was discovered in four subjects with schizophrenia and one normal subject. The schizoaffective patient heterozygous for the known A403V mutation showed the lowest rate of phenylalanine kinetics and lowest conversion to tyrosine in the patient sample. The four schizophrenic patients heterozygous for the novel K274E mutation showed significantly decreased phenylalanine kinetics, reduced conversion to tyrosine, and increased synthesis of the PAH cofactor tetrahydrobiopterin compared with schizophrenic subjects without the mutation. CONCLUSIONS The study findings suggest that larger scale studies are warranted to test the relationship of the PAH genotype with a psychiatric phenotype.

Phenylalanine kinetics are associated with tardive dyskinesia in men but not in women.

Rationale: An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neutral amino acid (LNAA), phenylalanine (Phe) was defined in a group of mentally retarded patients. Subsequently, an altered kinetics of Phe was associated with TD in men with schizophrenia based on plasma analyses subsequent to the ingestion of a protein meal. Methods: In the present study, a standardized oral challenge of pure Phe (100 mg/kg in 170 ml orange juice) was administered to psychiatric patients of both sexes (n = 312), with and without TD after an overnight fast. Plasma LNAA levels were assayed both fasting and 2 h subsequent to the ingestion of the challenge. The extent of the increase in plasma Phe levels 2 h following a standardized challenge is determined by the sum of the kinetic processes of plasma absorption, tissue distribution, metabolism and elimination. Results: The study hypothesis, that TD would be associated with significantly higher post-challenge plasma Phe indices of an absolute plasma Phe level and plasma Phe/LNAA ratio (a brain availability measure), was verified for the study men (n = 209), but not for the study women (n = 103). Conclusions: The demonstrated altered kinetics of Phe in men with TD indicates a greater availability of Phe to the brain in these men. We suggest that the disorder may be related to the effects of this greater availability. Such effects could be the direct neurotoxic effects of Phe and its metabolites and/or the modulating effects of these compounds on the synthesis of the monoamine neurotransmitters. The fact that TD (Yes/No) group differences in post-challenge plasma Phe indices were not seen for the study women suggests the possibility of a sex difference in the biology of TD that we propose may be reflective of the young age of the study sample.

Investigation of the phenylalanine hydroxylase gene and tardive dyskinesia.

Phenylketonuria (PKU), an inborn error of phenylalanine metabolism, has been shown to be a risk factor for tardive dyskinesia (TD). In male psychiatric patients there was a significant relationship between TD and measures of plasma phenylalanine following ingestion of a standardized phenylalanine dose that was indicative of higher brain availability of phenylalanine in patients with TD. In addition, a medical food formulation consisting of branched chain amino acids, which compete with phenylalanine for transport across the blood–brain barrier, has been demonstrated to be an efficacious treatment for TD. Cumulatively these findings suggested that TD was related to phenylalanine metabolism and thus that sequence variants in the gene for phenylalanine hydroxylase (PAH), the rate‐limiting enzyme in the catabolism of phenylalanine, could be associated with TD susceptibility. Genetic screening of PAH in a group of 123 psychiatric patients revealed ten sequence polymorphisms and two mutations, but none appeared to be a significant risk factor for TD.

The current systems assessment and the clinical care process: A tool for clinical supervision and the design of clinical information systems

A side benefit of a current systems assessment carried out prior to automation was the development of a systematic picture of the clinical care system as captured in the system flow chart. The results of this assessment provided clinical administrators with ablueprint identifying the current systems strengths and weaknesses, which could be used both to introduce improvements and to measure the effect of such changes totally apart from the initial question of automation.

Lack of platelet monoamine oxidase activity in cebus monkeys (Cebus albifrons)

1. Recent evidence suggests that monoamine oxidase (MAO) plays an important role modulating the extrapyramidal syndromes produced by neuroleptic drugs in both human and nonhuman primates. 2. To evaluate the possibility of using peripheral blood platelet MAO-B levels as indices of central nervous system MAO-B effects, we measured platelet MAO-B levels in Cebus monkeys that were previously tested with neuroleptics (N = 36) or drug naive (N = 6). 3. No platelet MAO-B was consistently detectable in these blood samples. 4. Thus platelet measures of MAO-B do not reliably reflect brain MAO-B function in nonhuman primates and do not offer a useful model for studying blood-brain MAO-B relationships.

A Simulation Study Of Automated Treatment Planning In A Mental Hospital

A simulation study of automated treatment planning in a state mental hospital revealed that automation, per se, was of little direct benefit to clinicians and had virtually no impact on the clinical process. However, supervisory and quality assurance staff found considerable utility in the ability to generate reports previously unavailable. The implications for planning automated clinical systems are discussed.