The history of vitamin A goes back over one hundred years, but our realization of its importance for the brain and cognition is much more recent. The brain is more efficient than other target tissues at converting vitamin A to retinoic acid (RA), which activates retinoic acid receptors (RARs). RARs regulate transcription, but their function in the cytoplasm to control nongenomic actions is also crucial. Controlled synthesis of RA is essential for regulating synaptic plasticity in regions of the brain involved in learning and memory, such as the hippocampus. Vitamin A deficiency results in a deterioration of these functions, and failure of RA signaling is perhaps associated with normal cognitive decline with age as well as with Alzheimer's disease. Further, several psychiatric and developmental disorders that disrupt cognition are also linked with vitamin A and point to their possible treatment with vitamin A or RA.

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

Visual defects are documented in psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. One of the most consistent alterations in patients is a change in cone and rod electroretinographic (ERG) responses. We previously showed a reduced rod b-wave amplitude in a small sample of young offspring born to an affected parent. A confirmation of the patients ERG anomalies in young offspring at high genetic risk would offer a new approach to the neurodevelopmental investigation of the illness. We thus investigated cone and rod responses in a larger sample of young healthy high-risk offspring.

The ERG was recorded in 99 offspring of patients having DMS-IV schizophrenia, bipolar or major depressive disorder (mean age 16.03; SD 6.14) and in 223 healthy controls balanced for sex and age. The a- and b-wave latency and amplitude of cones and rods were recorded.

Cone b-wave latency was increased in offspring (ES = 0.31; P = 0.006) whereas rod b-wave amplitude was decreased (ES = -0.37; P = 0.001) and rod latency was increased (ES = 0.35; P = 0.002).

The ERG rod and cone abnormal response previously reported in adult patients having schizophrenia, bipolar disorder or major depressive disorder are detectable in genetically high-risk offspring as early as in childhood and adolescence. Moreover, a gradient of effect sizes among offspring and the three adult diagnoses was found in the cone response. This suggests that ERG waveform as a risk endophenotype might become part of the definition of a "childhood risk syndrome".

Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.

Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2-15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A, which is located in this region, and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e.g., autism and Rett syndromes). We have shown that E6AP also acts as a coactivator of the estrogen receptor (ER). ER is a ligand-induced transcription factor that exerts potent and wide-ranging effects on the developing brain. Furthermore, the expression pattern of ER in the brain overlaps with that of E6AP. Up till now, all the published studies have examined the role of the ubiquitin-protein ligase activity of E6AP in the development of AS, and it is not known what role the newly discovered coactivation functions of E6AP and ER plays in the pathology of AS. Here, we demonstrate that E6AP and ER co-immunoprecipitate and are in the same protein complex in neuronal cells (Neuro2a). In addition, both colocalize in nuclear and cytoplasmic compartments of the mouse hippocampal neurons and Neuro2a cells. Moreover, we identified a novel E6AP and ER direct transcriptional regulation of a gene Cyp26b1 known to be involved in learning and memory processes. This transcriptional regulation involves recruitment of E6AP and ER to a newly discovered functional estrogen response element (ERE) located at the Cyp26b1 gene promoter and is associated with transcription permissive epigenetic events leading to increase of active transcription of the gene in neurons upon estrogen treatment. This novel transcriptional regulation was also validated in the AS mouse model where E6AP expression is abrogated in the mouse brain. In fact, Cyp26b1 expression is decreased by 31% in AS mice versus age-matched control (Ctrl) mice hippocampi. Also, retinoic acid transcriptional signaling was shown to be amplified as evidenced by specific increased Rarβ and decreased Erbb4 mRNA expression in AS mice versus Ctrl mice hippocampi. These transcript level changes were also supported by the same trend of changes at the protein level. Collectively, our data present a proof of principle that the transcriptional coactivation function of E6AP may have a crucial role in the pathobiology of AS. This function, yet to be thoroughly investigated, reveals the possibility of harnessing the antagonistic estrogen-retinoic acid transcriptional signaling crosstalk and potentially other unknown effectors for the investigation of important possible targets as putative novel treatment modalities and venues for reversing neurological manifestations in AS and related syndromes like ASDs.

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies.

This review provides the rationale and reports on the progress to date regarding the targeting of retinoid receptors for the treatment of schizophrenia and schizoaffective disorder and the role of retinoic acid in functions of the normal brain, and in psychotic states. After a brief introduction, we describe the normal function of retinoic acid in the brain. We then examine the evidence regarding retinoid dysregulation in schizophrenia. Finally, findings from two add-on clinical trials with a retinoid (bexarotene) are discussed. The authors of this review suggest that targeting retinoid receptors may be a novel approach to treat schizophrenia and schizoaffective disorder. Further studies are warranted.

In this column we examine the recent literature regarding adjunctive antipsychotic treatment of schizophrenia. We provide a brief introduction outlining the urgent need for new therapeutics, particularly for the treatment of negative and cognitive symptoms of schizophrenia. We then address (by mechanism of action) the most extensively studied adjunctive antipsychotic treatments. We conclude that adjunctive treatments targeting glutamatergic modulation, as well as supplementation with certain vitamins, have the strongest evidence for use in the treatment of schizophrenia. Further, larger randomized, controlled trials are needed, focusing on certain subgroups of patients and specific antipsychotic medications.

Tissue plasminogen activator (tPA) mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms.

The prefrontal cortex shows structural and functional alterations in mood disorders. Retinoid signaling, brain-derived neurotrophic factor (BDNF), and its receptor TrkB are reported to be involved in depression. Here, we found that mRNA levels of key elements of retinoid signaling were significantly reduced in the postmortem dorsolateral prefrontal cortex/anterior cingulate cortex (ACC) from elderly depressed patients who did not die from suicide. Decreased mRNA levels of BDNF and TrkB isoforms were also found. Similar alterations were observed in rats subjected to chronic unpredictable mild stress. Along with neurons immunopositive for both retinoic acid receptor-α (RARα) and TrkB, a positive correlation between mRNA levels of the 2 receptors was found in the ACC of control subjects but not of depressed patients. In vitro studies showed that RARα was able to bind to and transactivate the TrkB promoter via a putative RA response element within the TrkB promoter. In conclusion, the retinoid and BDNF-TrkB signaling in the prefrontal cortex are compromised in mood disorders, and the transcriptional upregulation of TrkB by RARα provide a possible mechanism for their interaction. The retinoid signaling pathway that may activate TrkB expression will be an alternative novel target for BDNF-based antidepressant treatment.

Vitamin A (retinol), in the biologically active form of retinoic acid (RA), has been proposed as involved in the pathogenesis of schizophrenia. We hypothesized that genetic basis of genes encoding RA metabolism enzymes, which control the cellular RA level, might be associated with this disease. This cascade genetic association model, using markers in genes of synthesis and degradation enzymes within the retinoid cascade, would better fit the biological character of the retinoid hypothesis than the single gene strategy. In the present study we chose to investigate 7 genes involved in the synthesis, degradation and transportation of RA, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and Transthyretin (TTR), for their roles in the development of schizophrenia. We genotyped 18 single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of these 7 genes using LDR technology in the 617 Chinese Han subjects. Case-control analyses were performed to detect association of these 7 genes with schizophrenia. Association analyses using both allelic and genotypic single-locus tests revealed no significant association between the risk for each of investigated gene and schizophrenia. However, analyses of multiple-locus haplotypes indicated that the overall frequency of rs4646642-rs4646580 of ALDH1A2 gene showed significant difference between patients and control subjects (p=0.0055). We also employed multifactor dimensionality reduction method to detect multilocus effects. In summary, in this work we show multiple candidate genes involved in retinoid cascade in schizophrenics. In addition, our results suggest a positive association between ALDH1A2 and schizophrenics in the Chinese population and support the retinoid hypothesis of schizophrenia.

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system-owing to its strategic anatomic location-may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

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.

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.

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.

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.

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.

Retinoic acid signaling is important for patterning the central nervous system, paired appendages, digestive tract, and other organs. To begin to investigate retinoic acid signaling in zebrafish, we determined orthologies between zebrafish and tetrapod retinoic acid receptors (Rars) and examined the expression patterns of rar genes during embryonic development. Analysis of phylogenies and conserved syntenies showed that the three cloned zebrafish rar genes include raraa and rarab, which are co-orthologs of tetrapod Rara, and rarg, which is the zebrafish ortholog of tetrapod Rarg. We did not, however, find an ortholog of Rarb. RNA in situ hybridization experiments showed that rarab and rarg, are maternally expressed. Zygotic expression of raraa occurs predominantly in the hindbrain, lateral mesoderm, and tailbud. Zygotic expression of rarab largely overlaps that of raraa, except that in later stages rarab is expressed more broadly in the brain and in the pectoral fin bud and pharyngeal arches. Zygotic expression of zebrafish rarg also overlaps the other two genes, but it is expressed more strongly in the posterior hindbrain beginning in late somitogenesis as well as in neural crest cells in the pharyngeal arches. Thus, these three genes have largely overlapping expression patterns and a few gene-specific expression domains. Knowledge of these expression patterns will guide the interpretation of the roles these genes play in development.