Long-term estrogen therapy and 5-HT(2A) receptor binding in postmenopausal women; a single photon emission tomography (SPET) study.

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT(2A) receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT(2A) receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT(2A) receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT(2A) receptor ligand (123)I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT(2A) receptor availability. Never-users had significantly higher 5-HT(2A) receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p=0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT(2A) receptor availability correlated negatively with verbal and general memory and delayed recall (r=-0.45, p=0.01; r=-0.40, p=0.02; r=-0.36, p=0.04). Right superior temporal 5-HT(2A) receptor availability correlated negatively with verbal memory (r=-0.36, p=0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory (r=-0.70, p=0.002; r=-0.69, p=0.002); and in never-users, receptor availability negatively correlated with attention and concentration (r=-0.54, p=0.02). Long-term ET may be associated with lower 5-HT(2A) receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT(2A) receptor in hippocampus is associated with poorer memory function.

Choline acetyltransferase variants and their influence in schizophrenia and olanzapine response.

Choline acetyltransferase (ChAt) is extensively distributed throughout the CNS where, by catalyzing acetylcholine synthesis, it participates in modulating wide-ranging cholinergic-dependent functions including cognitive performance, sleep, arousal, movement, and visual information processing. Recently, compelling evidence has mounted implicating ChAt in schizophrenia. In particular, studies have identified significant reductions in ChAt activity in the nucleus accumbens and pontine tegmentum of such patients, which furthermore correlate significantly with measures of cognitive performance in the disorder. Similarly, elevated levels of choline, the acetylcholine precursor, have been identified among patients, implicating altered ChAt activity in these individuals. We sought to investigate the potential contribution of three ChAt gene polymorphisms in schizophrenia, and uncovered evidence for significant association between one of these, rs1880676G/A, and disease susceptibility among Basque individuals (genotypewise chi(2) = 20.7, P = 0.00003; allelewise chi(2) = 10.1, P = 0.002). A similar trend for association with susceptibility was observed for a second SNP, rs3810950G/A, (genotypwise chi(2) = 6.4, P = 0.05; allelewise chi(2) = 3.75, P = 0.05). Evidence was also uncovered for a potential influence of these polymorphisms on olanzapine treatment outcome among Spanish patients (F-statistic = 5.02, P = 0.03; F-statistic = 6.53, P = 0.02 respectively), and on improvements in positive symptoms in the case of rs3810950 (F-statistic = 5.3, P = 0.03) and general psychopathology in the case of rs1880676 and rs3810950 (F-statistic = 5.24, P = 0.03; F-statistic = 5.31, P = 0.03 respectively) during therapy. While more comprehensive studies are warranted to determine the precise contribution of ChAt mediated mechanisms in schizophrenia, our findings tentatively implicate a genetic influence of ChAt in the disorder's susceptibility and treatment.

No association between ADRA2A polymorphisms and schizophrenia.

There is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.

Heat stroke in schizophrenia during clozapine treatment: rapid recognition and management.

A case of heatstroke is reported in a 32-year-old man diagnosed with schizophrenia and on clozapine monotherapy. The importance of the need to avoid misdiagnosing heat stroke as neuroleptic malignant syndrome is reviewed.

Serotonergic polymorphisms and psychotic disorders in populations from North Spain.

There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P < or = 0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

Pharmacogenomics--can genetics help in the care of psychiatric patients?

Psychiatric patients demonstrate varied responses to treatment. Consequently, treatment strategies are trial-and-error, which has a negative effect on prognosis and compliance. The aim of pharmacogenomic research is to enable customised drug treatment by identifying variations within multiple candidate genes (those encoding drug-targeted neurotransmitter receptors, transporters and metabolic enzymes) that are likely to confer the inter-individual differences in drug response and development of drug-induced side effects. Pharmacogenetic and pharmacogenomic research to date has identified genetic polymorphisms of dopamine (DA) and serotonin (5-HT) receptor subtypes, the serotonin transporter (5-HTT) and metabolic enzymes (cytochrome P450 [CYP] family) as important contributors to the variability in response to psychiatric drugs and the development of drug-induced side effects such as tardive dyskinesia and weight gain. It is anticipated that technological and methodological advances will provide further candidate genes and refine association analyses of existing candidates, enabling pharmacogenomic research to move towards future treatment regimes that are catered to the individual.

Advances in the pharmacogenetic prediction of antipsychotic response.

Pharmacogenetics (investigation of a limited number of genes) and pharmacogenomic (investigation of large number of genes and their expression) strategies are being used for the identification of genetic factors contributing to response variability. Whereas pharmacogenomic investigation is producing a wealth of information that will take several years to analyse and translate into clinical advantages, pharmacogenetic research has already produced some interesting results such as the identification of metabolic polymorphisms that may be important for therapeutic doses and side-effects, and the identification of response-related mutations in drug targets. Preliminary studies have also shown that pharmacogenetic information can be used for the pre-treatment prediction of treatment response. It is expected that over the next decade these advances are introduced into clinical practice and will help to tailor psychiatric treatment to the patient's individual needs.

GABAergic inhibitory mechanisms for repetition-adaptivity in large-scale brain systems.

Molecular mechanisms for systems level adaptivity of brain activation are largely unknown but a key role for active inhibition by gamma-aminobutyric acid (GABA) is plausible. We used functional magnetic resonance imaging to contrast the modulatory effects on brain adaptivity to task repetition and task difficulty of two GABAergic drugs, lorazepam and flumazenil. In a working memory paradigm, occipitotemporal regions clearly demonstrated attenuation of activation as a function of within-session task repetition or practice in data acquired following placebo, but this spatiotemporal pattern of repetition adaptivity was abolished by both lorazepam and flumazenil. However, in other brain systems flumazenil enhanced repetition adaptivity compared to placebo: in frontal cortex, flumzenil induced attenuation of signal related to task repetition and in hippocampus it exaggerated normal enhancement of signal with repetition. In contrast, there were no significant effects of either flumazenil or lorazepam on areas of frontal cortex which normally demonstrated significant neurocognitive load response or adaptivity to task difficulty. We argue that repetition adaptivity of large-scale brain systems is regulated by GABAergic inhibitory mechanisms and that expression of repetition adaptivity in a given brain system may show an "inverted-U" form of relationship with pharmacologically manipulable levels of GABAergic inhibitory tone.

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

An RT-PCR study of 5-HT(6) and 5-HT(7) receptor mRNAs in the hippocampal formation and prefrontal cortex in schizophrenia.

5-Hydroxytryptamine (5-HT; serotonin) 5-HT(6) receptors (5-HT(6)R) and 5-HT(7) receptors (5-HT(7)R) have been implicated in schizophrenia and as targets of atypical antipsychotic drugs. We have studied the expression of these receptors in the hippocampal formation and dorsolateral prefrontal cortex (DLPFC) of 17 subjects with schizophrenia and 17 controls using reverse transcription-polymerase chain reaction (RT-PCR) with cyclophilin co-amplification. In schizophrenia, 5-HT(6)R mRNA was decreased in the hippocampal formation, and 5-HT(7)R mRNA was decreased in the dorsolateral prefrontal cortex. The mRNAs were unchanged in rats treated for 2 weeks with haloperidol, chlorpromazine, risperidone, olanzapine or clozapine. Regional decreases in 5-HT(6)R and 5-HT(7)R expression in schizophrenia may contribute to the overall serotonergic alterations which occur in the disorder, in part through their interactions with other neurotransmitter systems including glutamate and acetylcholine.

IQ in childhood psychiatric attendees predicts outcome of later schizophrenia at 21 year follow-up.

OBJECTIVE: Preschizophrenic children who merit psychiatric referral are claimed to have a particularly malevolent illness when the psychosis develops later. The 21 years outcome of a sample of such children was investigated. METHOD: Fifty-one children who attended psychiatric services, and were later diagnosed as having schizophrenia, were followed up a mean of 21 years later. Baseline childhood demographic, clinical and putative aetiological characteristics were identified from the case notes. Follow-up assessment evaluated clinical symptoms, social functioning and service utilization. The predictive value of baseline factors on outcome was examined. RESULTS: Outcome was poor, and seven (14%) of the subjects were deceased. Childhood IQ was strongly predictive of social outcome (F=5.1, P=0.01) and service utilization (F=5.2, P=0.01), but not clinical symptoms. No other factors predicted outcome. CONCLUSION: Low childhood IQ had an unfavourable impact on social outcome and service utilization once schizophrenia developed.

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.

1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action.

RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia.

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.

Applications of pharmacogenetics in psychiatry: personalisation of treatment.

In spite of the lack of epidemiological information, pharmacogenetic research has produced evidence of the relationship between genes and treatment response. Genetic variants of metabolic enzymes are related to toxic reactions; polymorphisms in genes coding for drug-targeted neurotransmitter receptors influence therapeutic efficacy. Also, recent studies have shown that response to antipsychotic drugs can be predicted by looking at the individual's pharmacogenetic profile. In addition to providing the first evidence that treatment response can be predicted by looking at a core of key genes, these studies illustrate the feasibility of individualisation of psychiatric treatment.

Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia.

A dysfunctional glutamatergic system has been implicated in the pathophysiology of schizophrenia. The group III metabotropic glutamate receptor (mGluR) types 7 and 8 presynaptically inhibit glutamate release, thereby modulating glutamatergic transmission in the brain. We conducted association studies to investigate the novel Tyr433Phe (mGluR7) variant and the 2846-C/T (mGluR8) polymorphism in schizophrenia. Both variants, present at high frequencies, failed to demonstrate any significant association with schizophrenia (mGluR7 [Tyr433Phe] allele: P=0.33; genotype: P=0.63; mGluR8 [2846-C/T] allele: P=0.72; genotype: P=0.63).

Neurotransmitter receptor variants and their influence on antipsychotic treatment (Review)).

Psychiatric treatment requires the use of drugs which are in many cases associated with severe side effects and inadequate response. In the past decade extensive research has investigated the link between gene alterations and treatment response and several strong associations have been reported. The identification of genes influencing treatment outcome will facilitate the pre-treatment selection of the most beneficial drug according to an individual's pharmacogenetic profile. Recent advances indicate that this goal is achievable in the near future. The scope of this communication is to review all the recent findings in psychopharmacogenetics leading to the individualization of treatment.

Genetic strategies for the personalization of antipsychotic treatment.

Pharmacogenetic research into complex traits, such as response to antipsychotic treatment has proved a difficult task. Nevertheless, investigation of drug metabolic enzymes has revealed polymorphisms in specific cytochrome P450 genes responsible for treatment-induced toxic reactions. However, the picture becomes more complicated when drug target sites are investigated in search of genetic influence. Most antipsychotic drugs are multitarget, denoting a complex mechanism of action. Although individual genes have been reported to influence antipsychotic response, no single gene can account for the variability observed in treatment response. Current investigations focus on single gene variants that may be associated with particular side effects or symptoms as well as contributing to general response. The scope of this article is to review recent advances of pharmacogenetic research on antipsychotic drugs and the strategies under development for the individualization of treatment.