Neuroendocrine studies in schizophrenia - An approach to pathophysiological mechanisms

Schizophrenia is a chronic and disabling disorder with marked resource implications for health care services. The nature of the underlying disease process(es) remains obscure. The hypotheses that a neurochemical abnormality underlies some of the manifestations of schizophrenia is plausible: the most likely candidate is an increase in dopaminergic neurotransmission. There are also indications of organic changes in schizophrenic brain which may underlie some of the features of chronic schizophrenia. The present series of studies investigate these putative pathophysiological mechanisms by examining the secretion of anterior pituitary hormones in unmedicated patients with accurately diagnosed acute and chronic schizophrenia. The reasons for employing a neuroendocrine strategy are threefold. Firstly there is good evidence that hypothalamic neurotransmitters play a crucial role in the modulation of pituitary secretion: changes in these hormones may thus provide information on central neurotransmitter function. Neuroendocrine changes have been found in several neuropsychiatric diseases which are of potential clinical relevance. Finally there are several indications that a degree of hypogonadism is present in schizophrenic patients (pathological changes in the gonads reduced fertility, menstrual disorders and reductions in gonadotrophin secretion). Several neuroendocrine studies are reported in this thesis. Firstly the basal levels of several pituitary, thyroid and gonadal hormones have been investigated in acute and chronic schizophrenics and compared with controls. The rhythms of gonadotrophin, prolactin and growth hormone secretion have also been investigated (together with examination of the reproducibility of some of these measures). The hormonal response to synthetic hypothalamic releasing hormones has been studied in patients with chronic schizophrenia. In view of the interest in dopamine neurotransmission in schizophrenia the clinical and hormonal effects of dopamine antagonists and agonists in acute and chronic schizophrenics have been investigated. Pineal function in schizophrenia has also been examined and a paper discussing this bound into the thesis. Clinical associations have been examined and are emphasised throughout. The results demonstrate selective reductions in gonadotrophin secretion in a subgroup of chronic schizophrenics which are associated with a reduction in the frequency but not amplitude of LH secretory episodes. While this pattern of abnormal secretion appeared to be reproducible within individual patients, the administration of acute or chronic dopamine antagonists was associated with a return towards normal levels. This suggests that dopamine overactivity may be implicated in the genesis of these abnormalities and this cozitention is supported by the finding that gonadotrophin abnormalities were associated with low prolactin secretion. These patients exhibiting these abnormalities had the longest length of illness and the more frequent positive symptoms of schizophrenia (e.g. delusions and hallucinations). The growth hormone response to a dopamine agonist was reduced in chronic schizophrenic patients as a group and markedly so in a subgroup of patients, particularly those with negative symptoms which are characteristic of chronic schizophrenia and which are thought to have an organic basis. By contrast basal levels and rhythms of putitary hormones were normal in acute schizophrenia. Nevertheless several important relationships were established in this group e.g. between prolactin secretion and 1) the positive symptoms of schizophrenia and 2) the dose and blood level of DA antagonists These findings indicate that abnormalities of gonadotrophin secretion are unlikely to be of aetiopathological significance in schizophrenia but point to important relations between dopamine neurotransmission, clinical symptoms and anterior pituitary hormone secretion. In addition, several clinical observations of the effects of dopamine agonists on schizophrenic patients were made which, although effectively negative results, have important theoretical implications for schizophrenia research. The specificity, selectivity and significance of these results to the study of schizophrenia is extensively discussed in the text and possible areas of clinical relevance highlighted. The results strengthen the notion that there may be separate pathophysiological processes underlying different aspects of the schizophrenia syndrome and indicate that these hormonal changes may be useful markers of these processes. There are strong indications that there are abnormalities of peptide/dopamine interaction in the hypothalamus in schizophrenia. Some lines of future enquiry, based on these researches, are discussed which may help elucidate this complex and disabling disease

The impact of target frequency on intra-individual variability in euthymic bipolar disorder: a comparison of two sustained attention tasks.

Greater intra-individual variability (IIV) in reaction time (RT) on a sustained attention task has been reported in patients with bipolar disorder (BD) compared with healthy controls. However, it is unclear whether IIV is task specific, or whether it represents general crosstask impairment in BD. This study aimed to investigate whether IIV occurs in sustained attention tasks with different parameters. Twenty-two patients with BD (currently euthymic) and 17 controls completed two sustained attention tasks on different occasions: a low target frequency (~20%) Vigil continuous performance test (CPT) and a high target frequency (~70%) CPT version A-X (CPT-AX). Variability measures (individual standard deviation and coefficient of variation) were calculated per participant, and ex-Gaussian modeling was also applied. This was supplemented by Vincentile analysis to characterize RT distributions. Results indicated that participants (patients and controls) were generally slower and more variable when completing the Vigil CPT compared with CPT-AX. Significant group differences were also observed in the Vigil CPT, with euthymic BD patients being more variable than controls. This result suggests that IIV in BD demonstrates some degree of task specificity. Further research should incorporate analysis of additional RT distributional models (drift diffusion and fast Fourier transform) to fully characterize the pattern of IIV in BD, as well as its relationship to cognitive processes

The language profile of formal thought disorder

Formal thought disorder (FTD) is clinically manifested as disorganized speech, but there have been only few investigations of its linguistic properties. We examined how disturbance of thought may relate to the referential function of language as expressed in the use of noun phrases (NPs) and the complexity of sentence structures. We used a comic strip description task to elicit language samples from 30 participants with schizophrenia (SZ), 15 with moderate or severe FTD (SZ + FTD), and 15 minimal or no FTD (SZ−FTD), as well as 15 first-degree relatives of people with SZ (FDRs) and 15 neurotypical controls (NC). We predicted that anomalies in the normal referential use of NPs, sub-divided into definite and indefinite NPs, would identify FTD; and also that FTD would also be linked to reduced linguistic complexity as specifically measured by the number of embedded clauses and of grammatical dependents. Participants with SZ + FTD produced more referential anomalies than NC and produced the fewest definite NPs, while FDRs produced the most and thus also differed from NC. When referential anomalies were classed according to the NP type in which they occurred, the SZ + FTD group produced more anomalies in definite NPs than NC. Syntactic errors did not distinguish groups, but the SZ + FTD group exhibited significantly less syntactic complexity than non-SZ groups. Exploratory regression analyses suggested that production of definite NPs distinguished the two SZ groups. These results demonstrate that FTD can be identified in specific grammatical patterns which provide new targets for detection, intervention, and neurobiological studies

Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia

Context: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. Objectives: To determine whether large (>100 000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. Design: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. Setting: The Wellcome Trust Case Control Consortium. Participants: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. Main Outcome Measures: Overall load of CNVs and presence of rare CNVs. Results: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. Conclusions: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder

Associations between childhood maltreatment and inflammatory markers.

BACKGROUND:Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.AimsTo determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis. METHOD:We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum. RESULTS:Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD. CONCLUSIONS:Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.Declaration of interestD.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group