Bexarotene as add-on to antipsychotic treatment in schizophrenia patients: a pilot open-label trial.

OBJECTIVES: Bexarotene is a synthetic retinoid used for treatment of neoplastic or dermatologic disorders. Based on the retinoid dysregulation hypothesis, it was hypothesized that bexarotene augmentation would have a beneficial effect in the antipsychotic treatment of schizophrenia patients. This study is the first to investigate the safety and efficacy of add-on oral bexarotene to ongoing antipsychotic treatment in chronic schizophrenia patients who were stabilized on regular antipsychotic treatment. METHODS: A 6-week open label trial was conducted in 2 mental health centers from October 2005 to October 2006. Twenty-five patients with chronic schizophrenia received a low dose of bexarotene (75 mg/d) augmentation. Mental condition and laboratory tests were assessed at baseline and after weeks 2, 4, and 6 of the study. The primary outcome measure was change from baseline in 4 symptom scales: the Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Scale. Blood cell count, liver and thyroid functions, cholesterol, and triglyceride rates were followed. RESULTS: Significant improvement from baseline to endpoint was observed on total Positive and Negative Symptom Scale score (P = 0.022), general psychopathology (P = 0.024), positive (P = 0.012), and the dysphoric mood (P = 0.028) factor scores. Furthermore, a trend to a diminishing Extrapyramidal Symptom Rating Scale score (P = 0.053) was found. Bexarotene was found to be a safe medication as measured by all laboratory parameters with the exception of increased total cholesterol serum level. CONCLUSIONS: This short-term pilot study supports bexarotene as a potential valuable adjunct in management of schizophrenia. Low doses of bexarotene were well tolerated. A double-blind controlled study should be performed to replicate these preliminary positive results.

Association of the gene encoding neurogranin with schizophrenia in males.

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.

Transthyretin: no association between serum levels or gene variants and schizophrenia.

It has been proposed that schizophrenia results from an environmental insult in genetically predisposed individuals. Environmental factors capable of modulating transcriptional activity and their carriers could link the genetic and environmental components of schizophrenia. Among these is transthyretin (TTR), a major carrier of thyroid hormones and retinol-binding protein (RBP). Retinoids and thyroid hormones regulate the expression of several genes, both during development and in the adult brain. Decreased TTR levels have been reported in the cerebrospinal fluid of patients with depression and Alzheimer's disease, and the absence of TTR influences behavior in mice. DNA variants capable of altering TTR ability to carry its ligands, either due to reduced transcription of the gene or to structural modifications of the protein, may influence development of the central nervous system and behavior. In the present study we searched for variants in the regulatory and coding regions of the TTR gene, and measured circulating levels of TTR and RBP. We found a novel single nucleotide polymorphism (SNP), ss46566417, 18 bp upstream of exon 4. Neither this SNP nor the previously described rs1800458 were found associated with schizophrenia. In addition, serum TTR and RBP levels did not differ between mentally healthy and schizophrenic individuals. In conclusion, our data does not support an involvement of the TTR gene in the pathophysiology of schizophrenia.

Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.

Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined.

Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia.

Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.

Evidence for defective retinoid transport and function in late onset Alzheimer's disease.

The hypothesis of this article is that late onset Alzheimer's disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary evidence is cited supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. These findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid plaque formation.