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BackgroundNeurodevelopmental deficits resulting from prenatal stress are associated with neurological disorders that include deficits of social behavior, such as schizophrenia1 and autism2–7. Studies of human brain and animal models indicate that an epitranscriptomic process known as ‘RNA editing’ contributes to the pathophysiology of these disorders, which occur more frequently in males than in females8–20. RNA editing plays an important role in brain development through its modification of excitatory and inhibitory neurotransmission21.MethodsWe exposed pregnant mice to restraint stress three times daily during gestational weeks 2 and 3. We treated the adult male offspring with haloperidol (1mg/kg), clozapine (5mg/kg) or saline twice daily for 5 days. Subsequently we measured social interaction behavior (SI) and locomotor activity, followed by next-generation sequencing analyses of hippocampal RNA editing.ResultsMice exposed to PRS exhibited reduced SI, which correlated with hippocampal RNA editing of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA2, GluA3 and GluA4, the potassium channel Kv1.1, the calcium channel subunit Cav1.3, calcium-dependent secretion activator (CAPS-1) and the calcium-dependent cell adhesion protein, cadherin 22 (CDH22). Treatment with clozapine, but not haloperidol, normalized SI behavior, and selectively reduced the deficits in GluA2 RNA editing in PRS mice.ConclusionsRNA editing may contribute to impaired hippocampal function after exposure to PRS. The efficacy of clozapine in improving SI behavior may include indirect stimulation of GluA2 RNA editing in the hippocampus. Although these data are from male mice and not humans, the results suggest a new molecular pathway by which PRS leads to life-long impairments of hippocampal function.

Background Accumulating evidence indicates that reduced activity within the monoamine systems contributes to the pathophysiology of major depressive disorder (MDD) and suicide. In this study, we have tested the hypothesis that monoaminergic gene transcription is abnormally regulated in MDD and suicide. Methods The transcription of specific monoaminergic genes was quantified by qPCR in the dorsolateral prefrontal cortex (DLPFC) of postmortem MDD subjects (n = 80) and non-psychiatric controls (CTRL, n = 32). We measured transcripts encoding monoaminergic transporters (the serotonin transporter (SERT), norepinephrine transporter (NET), dopamine transporter (DAT), plasma monoamine transporter (PMAT), vesicular monoamine transporter (VMAT)) in addition to the tryptophan hydroxylase (TPH) enzymes, TPH1 and TPH2. We tested for transcriptional differences between diagnostic groups and tested for differences in the depressed suicides. Results Multivariate analysis of monoaminergic gene transcription revealed a sex by diagnosis interaction (F8,99 = 2.87, p = 0.007). We report lower VMAT1 and PMAT expression in depressed males, and conversely higher VMAT2, TPH2 and NET expression in depressed females, relative to controls of the same sex (p Limitations Gene expression measures were not associated with the presence of antidepressant medication. Nevertheless, to minimize the impact of medication status and other potential confounding variables, these were included as covariates in our analyses. Conclusions We report sex differences in the transcription of monoaminergic genes in the DLPFC in MDD. Therefore abnormalities of monoaminergic gene expression may contribute to altered DLPFC activity exhibited in major depression.

Background Accumulating evidence indicates that the glutamate system contributes to the pathophysiology of major depressive disorder (MDD) and suicide. We previously reported higher mRNA expression of glutamate receptors in the dorsolateral prefrontal cortex (DLPFC) of females with MDD. Methods In the current study, we measured the expression of mRNAs encoding glutamate transporters in the DLPFC of MDD subjects who died by suicide (MDD-S, n = 51), MDD non-suicide subjects (MDD-NS, n = 28), and individuals who did not have a history of neurological illness (CTRL, n = 32). Results Females but not males with MDD showed higher expression of EAATs and VGLUTs relative to CTRLs. VGLUT expression was significantly higher in the female MDD-S group, relative to the other groups. EAAT expression was lower in the male violent suicides. Limitations This study has limitations common to most human studies, including medication history and demographic differences between the diagnostic groups. We mitigated the effects of confounders by including them as covariates in our analyses. Conclusions We report sex differences in the expression of glutamate transporter genes in the DLPFC in MDD. Increased neuronal glutamate transporter expression may increase synaptic glutamate, leading to neuronal and glial loss in the DLPFC in MDD. These deficits may lower DLPFC activity, impair problem solving and impair executive function in depression, perhaps increasing vulnerability to suicidal behavior. These data add to accumulating support for the hypothesis that glutamatergic transmission is dysregulated in MDD and suicide. Glutamate transporters may be novel targets for the development of rapidly acting antidepressant therapies.

Accumulating evidence indicates that the glutamate and monoamine systems contribute to the pathophysiology of major depressive disorder (MDD) and suicide. We have tested the expression of genes encoding glutamate transporters and monoaminergic proteins in the dorsolateral prefrontal cortex (DLPFC) of MDD subjects who died by suicide (MDD-S, n=51), MDD non-suicide subjects (MDD-NS, n=28), and non-psychiatric controls (CTRL, n=32). We analyzed glutamate transporters (EAAT1, EAAT2, VGLUT1, and VGLUT2) and monoaminergic genes (SERT, NET, DAT, PMAT, VMAT, TPH1 and TPH2). Females but not males with MDD showed higher expression of all glutamate transporters relative to CTRLs (P

Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.

BACKGROUND: Tumor necrosis factor (TNF)-alpha inhibitors and other biologic response modifiers (BRMs) are frequently used to treat a variety of inflammatory diseases. Use of these agents may increase risk of serious infections, malignancies, and other complications such as worsening symptoms of heart failure or demyelinating disease. Because of these risks, a baseline assessment and routine monitoring have been recommended, but standardized guidelines for monitoring have yet to be established. OBJECTIVE: To measure the compliance with the recommended safety monitoring in the Clinical Care Guidelines for BRMs at the University of Illinois Hospitals and Health Sciences System (UI Health). METHODS: The Clinical Care Guidelines for BRMs was developed by a committee of pharmacists, nurses, and physicians based on an assessment of published literature and medication labeling. The guidelines included recommendations for safety monitoring prior to BRM therapy, such as the tuberculosis (TB) test, Hepatitis B surface Antigen (HBsAg) test, liver function test (LFT), complete blood count (CBC), up-to-date vaccinations, risk assessment for cancer, pregnancy testing, monitoring for contraindications with concomitant medications, concomitant disease state risk assessment, and patient education. The guidelines were introduced to UI Health in February 2012 by a systemwide email and by in-services given by the health system’s Specialty Pharmacy Service. In-services were given in the clinics known to generate large numbers of BRM orders (e.g., gastroenterology and rheumatology) and at the outpatient center for infused therapies. The purpose of the in-services was to introduce providers to the guidelines and encourage their compliance. To ensure that guideline requirements were met when BRMs were ordered, a process was established to identify BRM orders, assess the orders for compliance with 4 of the safety monitoring tests from the guidelines (TB, HBsAg, LFT, and CBC), and make interventions. When necessary, Specialty Pharmacy Services coordinated with the pharmacists and other providers in the clinic to order lab tests and ensure they were completed prior to the start of therapy. Feedback was provided during the study to proactively improve compliance with the guidelines. After completion of the study, a report containing outpatient prescription orders for BRMs (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, and tocilizumab) from August 2011 through July 2012 was generated from the electronic medical record. Retrospective analyses of completion of safety monitoring were conducted for patients administered BRM treatment. Completion rates were compared before and after implementation of guidelines in February 2012. Completion was considered to have occurred when all 4 safety monitoring tests had been conducted —TB (unless known to be positive from a previous test), HBsAg, LFT, and CBC. Completion data from August 2011 through January 2012 were before the guidelines were implemented, and data from February 2012 through July 2012 were after the guidelines. Chi square analyses were performed on completion frequencies in the patients before and after the guidelines were implemented. RESULTS: Of the 320 unique patient BRM orders evaluated in this study, 195 (61%) were generated in the Rheumatology clinic, 99 (31%) in the Gastroenterology clinic, 21 (6.5%) in the Dermatology clinic, and 5 (1.5%) in the Transplant clinic. Before the guidelines were implemented, 54 ( 31%) of 173 patient orders complied with the safety monitoring by having all 4 clinical tests performed at the appropriate time points. After guideline implementation, 88 (60%) of 147 patient orders were compliant and had all 4 clinical tests conducted, which represents a statistically significant improvement in the rate of compliance (Pearson chi square = 26.43

Background Impairment of glutamate neurons that relay sensory and cognitive information from the medial dorsal thalamus to the dorsolateral prefrontal cortex and other cortical regions may contribute to the pathophysiology of schizophrenia. In this study, we have assessed the cell-specific expression of glutamatergic transcripts in the medial dorsal thalamus. Methods We used laser capture microdissection to harvest two populations of medial dorsal thalamic cells, one enriched with glutamatergic relay neurons and the other with gamma-aminobutyric acidergic neurons and astroglia, from postmortem brains of subjects with schizophrenia ( n = 14) and a comparison group ( n = 20). Quantitative polymerase chain reaction of extracted RNA was used to assay gene expression in the different cell populations. Results The transcripts encoding the ionotropic glutamate receptor subunits NR2D, GluR3, GluR6, GluR7, and the intracellular proteins GRIP1 and SynGAP1 were significantly decreased in relay neurons but not in the mixed glial and interneuron population in schizophrenia. Conclusions Our data suggest that reduced ionotropic glutamatergic expression occurs selectively in neurons, which give rise to the cortical projections of the medial dorsal thalamus in schizophrenia, rather than in thalamic cells that function locally. Our findings indicate that glutamatergic innervation is dysfunctional in the circuitry between the medial dorsal thalamus and cortex.

RNA editing is a posttranscriptional process which critically modulates the function of several neurotransmitter receptors regulating mood, anxiety, learning, and memory. Data from several postmortem studies have shown increased 5-hydroxytryptamine-2C receptor RNA editing in mood disorders and suicide, and therefore the 5-hydroxytryptamine-2C receptor might be expected to have reduced signal transduction in these patients. In this study, we have tested the hypothesis that the expression levels of the enzymes which catalyze RNA editing, adenosine deaminase acting on RNA 1 (ADAR1) and ADAR2, are also abnormal in suicide. Gene expression was measured in the dorsolateral prefrontal cortex of individuals from the Stanley Consortium Brain series, which includes patients with schizophrenia (n=15), major depression (n=15), bipolar disorder (n=15), and a comparison group (n=14). Of the psychiatric patients, 20 were suicide victims. ADAR1 expression was found to be significantly increased in major depressive suicide victims compared with patients who did not commit suicide. Neither ADAR1 nor ADAR2 expression was altered in any of the other diagnostic groups. These data indicate that ADAR1 could play a role in the pathophysiology of suicide in patients with major depression.

Schizophrenia is a severe psychiatric disorder which influences around 1 % of the worldwide population. Differences between male and female patients with schizophrenia have been noted. There is an earlier age of onset in males compared with females with this diagnosis, and in addition, there are differences in symptom profiles between the sexes. The underlying molecular mechanism of sex difference remains unclear. Here we present a comprehensive analysis to reveal the sex differences in gene expression in schizophrenia with stringent statistics criteria. We compiled a data set consisting of 89 male controls, 90 male schizophrenia patients, 35 female controls and 32 female schizophrenia patients from six independent studies of the prefrontal cortex (PFC) in postmortem brain. When we tested for a sex by diagnosis interaction on gene expression, 23 genes were up-regulated and 23 genes were down-regulated in the male group (q-value

Post-transcriptional RNA editing of the G-protein coupled 5-hydroxytryptamine-2C (5-HT 2C ) receptor predicts an array of 24 receptor isoforms, some of which are characterized by reduced constitutive activity and potency to initiate intracellular signaling. The amygdala is integral to anxiety, fear, and related psychiatric diseases. Activation of 5-HT 2C receptors within the amygdala is anxiogenic. Here, we describe the RNA editing profiles from amygdala of two inbred mouse strains (BALB/cJ and DBA/2J) known to be more anxious than a third (C57BL/6J). We confirmed the strain anxiety differences using light ↔ dark exploration, and we discovered that BALB/cJ and DBA/2J are each characterized by a higher functioning RNA editing profile than C57BL/6J. BALB/cJ and DBA/2J exhibit a roughly two-fold reduction in C site editing, and a corresponding two-fold reduction in the edited isoform VSV. C57BL/6J is characterized by a relative decrease in the unedited highly functional isoform INI. We estimated the heritability of editing at the C site to be approximately 40%. By sequencing genomic DNA, we found complete conservation between C57BL/6J, BALB/cJ, DBA/2J and 37 other inbred strains for the RNA edited region of Htr 2 c , suggesting Htr 2 c DNA sequence does not influence variation in Htr 2 c RNA editing between inbred strains of mice. We did, however, discover that serotonin turnover is reduced in BALB/cJ and DBA/2J, consistent with emerging evidence that synaptic serotonin levels regulate RNA editing. These results encourage further study of the causes and consequences of 5-HT 2C receptor RNA editing in the amygdala of mice.

article GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n = 21) and a comparison group of individuals without a history of psychiatric ill- ness (n = 18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Ae. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression ofGABA-Aα1-3,GABA-Aβ2,GABA-Aγ2,andGAD67inthemedicatedgroupcomparedtotheunmedicatedgroup. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication.

Objectives We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. Methods This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). Results BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). Conclusions The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.

Despite decades of research, the aetiology of schizophrenia remains elusive. However, the recent success of atypical antipsychotic drugs such as clozapine and risperidone has broken a 30 year trend during which pharmaceutical companies focused solely on D2 receptor antagonism in their quest for new drug treatments for schizophrenia. In the next few years, at least four other new atypical antipsychotics, olanzapine, sertindole, seroquel and ziprasidone, will be introduced throughout the developed world. It is likely that atypical compounds such as these will largely displace the typical neuroleptics, which provide only limited efficacy and produce unpleasant side-effects. The majority of the patents taken out in recent years remain focussed on the traditional notions of dopamine blockade, but there is an increasing trend in industry to select D1, D3 and D4 receptors as targets for potential drugs, rather than the D2 subtype. Greater emphasis is now being placed on the serotonergic hypothesis of schizophren...

The genetic basis of psychiatric illness is relatively undisputed, but inconsistencies such as reduced penetrance in families and the rates of discordance in identical twins indicate that the role of environmental factors requires investigation. Recent discoveries show that environmental stressors during critical periods of brain development alter epigenetic processing, leading to lifelong changes in gene expression, which are associated with adult psychiatric illness. The chemistry of epigenetics involves the modification of chromatin, often through DNA methylation and histone deacetylation. These processes can be altered by drugs, some of which are being tested as potential treatments for psychiatric illness. If these drugs are found to be efficacious due to the modulation of epigenetic processes, then pharmacoepigenetic predictors of treatment response could be developed. Epigenetic alterations of genes regulating the pharmacokinetics of drugs, such as the genes encoding the cytochrome P450 enzymes and drug transporters, are strong candidates for investigation. Further studies are required in this field, but pharmacoepigenetics has the potential to provide clinically useful biomarkers for psychotropic treatment response. The challenges in the development of pharmacoepigenetic biomarkers are discussed.

A cysteine to serine substitution at amino acid 23 in the 5-HT 2C receptor gene alters the pharmacological properties of the protein. We investigated this polymorphism in subjects with schizophrenia resistant to conventional neuroleptic drugs, and analysed our data for allelic association between the disease state or clinical response to the atypical antipsychotic drug, clozapine. Ninety percent of subjects who had one or more 5-HT 2C ser alleles (19/21) were classified as clozapine responders compared with 59% (84/141) without this allele (χ 2 = 7.7, p = 0.005), suggesting that this mutation is a predictor of good response to clozapine. There was no association between schizophrenia and the 5-HT 2C ser allele, but our results indicate that the 5-HT 2C receptor may contain the major site of action through which clozapine mediates its antipsychotic effects.

Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where 'nature' is considered to be inherited or genetic vulnerability to schizophrenia, and 'nurture' is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia.

Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.

The role of the serotonergic system in the neuroplastic events that create, repair, and degenerate the brain has been explored. Synaptic plasticity occurs throughout life and is critical during brain development. Evidence from biochemical, pharmacological, and clinical studies demonstrates the huge importance of an intact serotonergic system for normal central nervous system (CNS)function. Serotonin acts as a growth factor during embryogenesis, and serotonin receptor activity forms a crucial part of the cascade of events leading to changes in brain structure. The serotonergic system interacts with brain-derived neurotrophic factor (BDNF), S100beta, and other chemical messengers, in addition to ts cross talk with the GABAergic, glutamatergic, and dopaminergic neurotransmitter systems. Disruption of these processes may contribute to CNS disorders that have been associated with impaired development. Furthermore, many psychiatric drugs alter serotonergic activity and have been shown to create changes in brain structure with long-term treatment. However, the mechanisms for their therapeutic efficacy are still unclear. Treatments for psychiatric illness are usually chronic and alleviate psychiatric symptoms, rather than cure these diseases. Therefore, greater exploration of the serotonin system during brain development and growth could lead to real progress in the discovery of treatments for mental disorders.

Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizo- phrenia, bipolar disorder, major depression, and normal controls (n 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/ Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral pre- frontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions. Synapse 51:112-118, 2004. © 2003 Wiley-Liss, Inc.

5-HT(2C) receptor (5HT(2C)R, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT(2C)R RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT(2C)R gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT(2C-MNI) and 5-HT(2C-VDI). Screening of the 5-HT(2C)R gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT(2C-INI) is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT(2C)R-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.

The aim of this study was to investigate the possible involvement of genetic variation in serotonin receptors in the aetiology of bipolar affective disorder. The 5-HT2A receptor gene was systematically screened for genetic variants by single strand conformation polymorphism (SSCP) methods in subjects with bipolar affective disorder. Four polymorphisms (two structural changes, Thr25Asn and His4 M52Tyr, and two silent polymorphisms, 102-T/C and 516-C/T) which had previously been found in patients with schizophrenia and control subjects were detected. No novel polymorphisms were found in patients with bipolar affective disorder. These polymorphisms were genotyped in a sample of 129 patients and 252 controls of German origin and 176 patients and 182 controls of British origin. No strong associations were found between any of these polymorphisms and bipolar affective disorder. Genetic variation at the 5-HT2A receptor gene does not play a major role in the pathogenesis of the disorder.

We report allelic association between a polymorphism (T102C) within the coding region of the 5-HT2A gene (HTR2A, 13q14-21) and response to clozapine in schizophrenic patients. Homozygosity for the C102 allele was more frequent (30/57, 53%) among patients who did not respond to clozapine than in those who responded (23/92, 25%). This finding is evidence that allelic variation of genes which encode neurotransmitter receptors can influence clinical response to antipsychotic drugs.

Clozapine is an atypical antipsychotic with affinity for a broad range of receptors, including serotonin (5-HT) and dopamine receptors. It is successful in treating about 60% of patients refractory to other antipsychotic drugs. Since genetic variation in clozapine's neurotransmitter receptor targets may affect clinical response through altering drug binding or receptor expression, we have studied a His452Tyr polymorphism in the 5-HT2A receptor (HTR2A) in a sample of 153 schizophrenic patients undergoing clozapine treatment and 178 normal controls. An association was found between the allele Tyr452 and poor clinical response.

We did association studies in multiple candidate genes to find the combination of polymorphisms that give the best predictive value of response to clozapine in schizophrenic patients. A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76.7% success in the prediction of clozapine response (p=0.0001) and a sensitivity of 95% (+/- 0.04) for satisfactory response. These results will form the basis for a simple test to enhance the usefulness of clozapine in psychiatric treatment.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.