[show abstract][hide abstract] ABSTRACT: There are currently no biological tests that differentiate patients with bipolar disorder (BPD) from healthy controls. While there is evidence that peripheral gene expression differences between patients and controls can be utilized as biomarkers for psychiatric illness, it is unclear whether current use or residual effects of antipsychotic and mood stabilizer medication drives much of the differential transcription. We therefore tested whether expression changes in first-episode, never-medicated BPD patients, can contribute to a biological classifier that is less influenced by medication and could potentially form a practicable biomarker assay for BPD. We employed microarray technology to measure global leukocyte gene expression in first-episode (n=3) and currently medicated BPD patients (n=26), and matched healthy controls (n=25). Following an initial feature selection of the microarray data, we developed a cross-validated 10-gene model that was able to correctly predict the diagnostic group of the training sample (26 medicated patients and 12 controls), with 89% sensitivity and 75% specificity (p<0.001). The 10-gene predictor was further explored via testing on an independent cohort consisting of three pairs of monozygotic twins discordant for BPD, plus the original enrichment sample cohort (the three never-medicated BPD patients and 13 matched control subjects), and a sample of experimental replicates (n=34). 83% of the independent test sample was correctly predicted, with a sensitivity of 67% and specificity of 100% (although this result did not reach statistical significance). Additionally, 88% of sample diagnostic classes were classified correctly for both the enrichment (p=0.015) and the replicate samples (p<0.001). We have developed a peripheral gene expression biomarker profile, that can classify healthy controls from patients with BPD receiving antipsychotic or mood stabilizing medication, which has both high sensitivity and specificity. Moreover, assay of three first-episode patients who had never received such medications, to first enrich the expression dataset for disease-related genes independent of medication effects, and then to test the 10-gene predictor, validates the peripheral biomarker approach for BPD.
PLoS ONE 01/2013; 8(6):e69082. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.
Schizophrenia Research 06/2011; 131(1-3):139-45. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in cellular posttranscriptional regulation. In this
review, we describe some key features of miRNA-mediated gene regulation in the central nervous system, and the recent evidence
suggesting a role for miRNA dysregulation in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease,
Parkinson’s disease and Huntington’s disease. Finally, we comment on the potential for miRNA-based therapeutic strategies
for treatment of these disorders.
KeywordsmiRNA-Posttranscriptional regulation-Neurodegenerative disorders-Synapse-Molecular genetics
[show abstract][hide abstract] ABSTRACT: Tetrahydrobiopterin (BH4) is an essential cofactor for amine neurotransmitter synthesis. BH4 also stimulates and modulates the glutamatergic system, and regulates the synthesis of nitric oxide by nitric oxide synthases. A connection between BH4 deficiencies and psychiatric disorders has been previously reported; major depression and obsessive-compulsive disorder have been found in subjects with a BH4 deficiency disorder and more recently we have observed a robust plasma deficit of biopterin (a measure of BH4), in a large group of schizophrenic patients compared to control subjects. To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders. A significant difference in biopterin was seen among the diagnostic groups (P < 0.0001). Post hoc analyses indicated significant biopterin deficits relative to the normal control group for the schizoaffective group, who had biopterin levels comparable to the schizophrenic group. Bipolar disorder subjects had plasma biopterin levels that were higher that the schizoaffective disorder group and significantly higher than the schizophrenic group. The demonstrated significant biopterin deficit in both schizophrenia and schizoaffective disorder, may suggest an etiological role of a BH4 deficit in these two disorders, via dysregulation of neurotransmitter systems.
Neurochemical Research 01/2007; 32(1):107-13. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2006; 141B(2):195-7. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tetrahydrobiopterin (BH(4)) 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 BH(4) 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 BH(4)). 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 BH(4) synthesis), and plasma phenylalanine (which stimulates BH(4) 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 BH(4) 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 BH(4) system in schizophrenia is warranted and desirable.
[show abstract][hide abstract] ABSTRACT: A series of studies had demonstrated that deficient clearance of the large neutral amino acid phenylalanine was associated with tardive dyskinesia (TD), that the administration of the branched chain amino acids (BCAA) significantly decreased TD symptoms over placebo, and that the observed TD symptom reduction was significantly correlated with a diminished availability of phenylalanine to the brain of adult men with psychosis. As part of an initiative by the National Institute of Mental Health to expand the testing of treatments that were successful in adults to children and adolescents, the present pilot study was undertaken to test whether the BCAA would also reduce TD symptoms in children and adolescents. A 2-week trial of the BCAA was thus conducted in 6 children and adolescents (age range, 10.5-16.5 years) for the treatment of TD symptoms.
A clinical diagnosis of TD was made in all subjects on the basis of a global score derived from the Simpson Abbreviated Dyskinesia Rating Scale. Subjects were videotaped for TD evaluation at baseline and after 1 and 2 weeks of BCAA treatment given in the form of a drink administered 3 times daily. TD symptom change over the trial period was evaluated by researchers blinded to the treatment status of the evaluation.
TD symptom decreases were substantial in 5 of the 6 participants, ranging from 40% to 65%. Two of the subjects received an additional course of treatment, and further reductions in TD symptoms over those seen in the 2-week trial were observed.
The substantial symptom decrease and tolerability observed suggest the use of the BCAA formulation for the treatment of TD in children and adolescents and warrant further large-scale studies.
The Journal of Clinical Psychiatry 02/2004; 65(1):92-6. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: The efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men with psychiatric disorders was tested.
Public-sector psychiatric patients with long histories of antipsychotic treatment and presumably long-standing tardive dyskinesia were randomly assigned to receive branched-chain amino acids or placebo. Treatment frequency was three times a day, 7 days a week for 3 weeks. The efficacy measure was a frequency count of videotaped tardive dyskinesia movements.
A robust and highly significant difference was observed between patients who received high-dose branched-chain amino acids (222 mg/kg of body weight t.i.d.) (N=18) and those who received placebo (N=18) in the percent change in tardive dyskinesia symptoms from baseline to the end of the 3-week trial. Significant and marked differences were seen between the two groups at the >/=30% and >/=60% levels of decrease in tardive dyskinesia symptoms. No clinically significant differences were seen between the pre- and posttrial results of physical examinations and laboratory screening tests. Minimal gastrointestinal symptoms occurred during the trial. The reduction in tardive dyskinesia symptoms in the amino acids group was not related to changes in antipsychotic and glucose plasma levels. A mechanism of response related to decreased amine neurotransmitter synthesis was suggested by the significant positive correlations observed between decreases in tardive dyskinesia symptoms and decreases in aromatic amino acid plasma concentrations over the course of the trial.
Branched-chain amino acids constitute a novel, safe treatment for tardive dyskinesia, with a strong potential for providing significant improvement in the diseased physiognomy of the afflicted person.
American Journal of Psychiatry 06/2003; 160(6):1117-24. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
The study findings suggest that larger scale studies are warranted to test the relationship of the PAH genotype with a psychiatric phenotype.