Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).

Disturbing the rhythm of thought: Speech pausing patterns in schizophrenia, with and without formal thought disorder.

Everyday speech is produced with an intricate timing pattern and rhythm. Speech units follow each other with short interleaving pauses, which can be either bridged by fillers (erm, ah) or empty. Through their syntactic positions, pauses connect to the thoughts expressed. We investigated whether disturbances of thought in schizophrenia are manifest in patterns at this level of linguistic organization, whether these are seen in first degree relatives (FDR) and how specific they are to formal thought disorder (FTD). Spontaneous speech from 15 participants without FTD (SZ-FTD), 15 with FTD (SZ+FTD), 15 FDRs and 15 neurotypical controls (NC) was obtained from a comic strip retelling task and rated for pauses subclassified by syntactic position and duration. SZ-FTD produced significantly more unfilled pauses than NC in utterance-initial positions and before embedded clauses. Unfilled pauses occurring within clausal units did not distinguish any groups. SZ-FTD also differed from SZ+FTD in producing significantly more pauses before embedded clauses. SZ+FTD differed from NC and FDR only in producing longer utterance-initial pauses. FDRs produced significantly fewer fillers than NC. Results reveal that the temporal organization of speech is an important window on disturbances of the thought process and how these relate to language.

Non-literal understanding and psychosis: Metaphor comprehension in individuals with a diagnosis of schizophrenia.

Previous studies suggest that understanding of non-literal expressions, and in particular metaphors, can be impaired in people with schizophrenia; although it is not clear why. We explored metaphor comprehension capacity using a novel picture selection paradigm; we compared task performance between people with schizophrenia and healthy comparator subjects and we further examined the relationships between the ability to interpret figurative expressions non-literally and performance on a number of other cognitive tasks. Eye-tracking was used to examine task strategy. We showed that even when IQ, years of education, and capacities for theory of mind and associative learning are factored in as covariates, patients are significantly more likely to interpret metaphorical expressions literally, despite eye-tracking findings suggesting that patients are following the same interpretation strategy as healthy controls. Inhibitory control deficits are likely to be one of multiple factors contributing to the poorer performance of our schizophrenia group on the metaphor trials of the picture selection task.

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.

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.

A bipolar II cohort (ABC): The association of functional disability with gender and rapid cycling.

BACKGROUND: Bipolar II disorder (BP II) is a chronic, frequently co-morbid, and complex disorder with similar rates of attempted suicide to BP I. However, case identification for BP II studies that is based on clinician diagnosis alone is prone to error. This paper reports on differences between clinical and research diagnoses and then describes the clinical characteristics of a carefully defined BP II cohort. METHODS: A cohort of rigorously defined BP II cases were recruited from a range of primary and secondary health services in the North of England to participate in a programme of cross-sectional and prospective studies. Case identification, and rapid cycling, comorbidities and functioning were examined. RESULTS: Of 355 probable clinical cases of BP II disorder, 176 (∼50%) met rigorous diagnostic criteria. The sample mean age was ∼44 years, with a mean duration of mood disorder of ∼18 years. Two thirds of the cohort were female (n=116), but only 40% were in paid employment. Current and past year functioning was more impaired in females and those with rapid cycling. LIMITATIONS: This paper describes only the preliminary assessments of the cohort, so it was not possible to examine additional factors that may contribute to the explained variance in functioning. CONCLUSIONS: This carefully ascertained cohort of BP II cases show few gender differences, except for levels of functional impairment. Interestingly, the most common problem identified with using case note diagnoses of BP II arose because of failure to record prior episodes of mania, not failure to identify hypomania.

A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects.

OBJECTIVE: This study determined whether cognitive impairments and structural brain changes in older depressed subjects, especially in the hippocampus, are related to hypercortisolemia. METHOD: Sixty-one depressed subjects over age 60 who met DSM-IV criteria for major depression and 40 healthy comparison subjects underwent structural magnetic resonance imaging, neuropsychological testing, apolipoprotein E (APOE) genotyping, and salivary cortisol assessment (over 3 days) with follow-up 6 months later. Hippocampal volume was measured by manual segmentation that was blind to diagnosis. Average area under the curve for salivary cortisol over the 3 days was calculated. Cognitive function was assessed by using a combined memory z score. RESULTS: Depressed subjects showed multiple impairments in attention, working memory, visual memory, verbal memory, new learning, and executive function in relation to comparison subjects. They had hypercortisolemia (53% increase in area under the curve) and a reduction in right hippocampal volume (6% decrease). Hippocampal volume reduction was not associated with increased cortisol levels but was significantly correlated with continuing memory deficits at 6 months. Persisting "mild cognitive impairment" was seen in 20 (41%) of 49 subjects at 6 months and was associated with reduced hippocampal volume but not severity of depression, cortisol levels, or APOE genotype. CONCLUSIONS: Older depressed subjects have persisting cognitive impairments associated with hippocampal volume reduction, but the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism. Neuropathological studies are required to investigate the basis for hippocampal changes, while follow-up will determine whether hippocampal atrophy is a risk factor for cognitive decline.

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x(2)=4.46, df 1, p =.04) and with DRD3 genotype (x(2)=6.62, df 2, p =.04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x(2)=5.02, df 1, p =.02 for gly allele carrier status; x(2) = 7.51, df 2, p =.002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p =.006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p =.02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients.

This study was undertaken to re-examine whether homozygosity for the Gly-9 variant (allele 2) of the dopamine D3 receptor gene (DRD3) is associated with increased risk for tardive dyskinesia (TD) in schizophrenic patients. Seventy-one antipsychotic-treated subjects with schizophrenia from Newcastle upon Tyne, UK, were genotyped for the presence of allele 1 (Ser-9) and allele 2 (Gly-9) of the dopamine D3 receptor (DRD3) Ser-9-Gly polymorphism. Among 32 patients with TD, 7 subjects (22 %) were homozygous for the Gly-9 variant (2-2 genotype), whereas 4 out of 39 patients (10 %) without TD had this genotype. The non-significant tendency in this sample towards an over-representation of allele 2 and the 2-2 genotype among schizophrenic patients with TD is in line with our initial report as well as recent studies by others, indicating that the Gly-9 allele of DRD3 may be a susceptibility factor for the development of TD in neuroleptic-treated individuals with schizophrenia. There are, however, some recent non-supportive reports, and since the trend in our present study failed to reach statistical significance, further studies on larger samples and future meta-analysis may be necessary to establish the role of the DRD3 in the pathogenesis of TD.

Tolerability of high-dose venlafaxine in depressed patients.

High doses of antidepressants are often used for treatment-resistant depression. Venlafaxine, a dual serotonin and noradrenaline reuptake inhibitor, has been shown to have a tolerable side-effect profile in previous studies using doses of up to 375 mg/day. We investigated the tolerability of higher than currently recommended doses of venlafaxine using the UKU side-effect rating scale. Seventy outpatients fulfilling DSM-IV criteria for major depressive disorder were recruited into two demographically matched groups according to their daily dosage of venlafaxine: high dose n = 35 (> or = 375 mg/day, range 375-600 mg, average 437 mg/day) or standard dose n = 35 (< 375 mg/day, range 75-300 mg, average 195 mg/day. Clinical characteristics were noted and the UKU side-effect rating scale was administered to a subsample of patients. The most frequently reported complaints in both groups were increased fatigue (48%), concentration difficulties (48%), sleepiness/sedation (37%), failing memory (44.4%) and weight gain (29.6%). Apart from weight gain, the complaints were found to be experienced significantly more severely by the high-dose group. Six patients discontinued venlafaxine due to intolerable side-effects but only two of these patients were on a high dose. There was a tendency for mildly raised blood pressure in 10% of patients on an average dose of 342 mg/day. However, no difference between the two groups was found. This preliminary open study demonstrates that venlafaxine is tolerated at higher than British National Formulary recommended doses (i.e. up to 600 mg daily). However, increased frequency and severity of reported side-effects in the high-dose group are not associated with increased rates of discontinuation.

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.

Wake-up call for British psychiatry.

The recent drive within the UK National Health Service to improve psychosocial care for people with mental illness is both understandable and welcome: evidence-based psychological and social interventions are extremely important in managing psychiatric illness. Nevertheless, the accompanying downgrading of medical aspects of care has resulted in services that often are better suited to offering non-specific psychosocial support, rather than thorough, broad-based diagnostic assessment leading to specific treatments to optimise well-being and functioning. In part, these changes have been politically driven, but they could not have occurred without the collusion, or at least the acquiescence, of psychiatrists. This creeping devaluation of medicine disadvantages patients and is very damaging to both the standing and the understanding of psychiatry in the minds of the public, fellow professionals and the medical students who will be responsible for the specialty's future. On the 200th birthday of psychiatry, it is fitting to reconsider the specialty's core values and renew efforts to use psychiatric skills for the maximum benefit of patients.

A volumetric study of MRI signal hyperintensities in late-life depression.

OBJECTIVE: An increase in white-matter lesions has been previously described in older subjects with depression. The authors investigated whether the regional location varied between depressed and normal subjects and determined the relationship of magnetic resonance (MR) signal hyperintensities to known clinical risk factors for vascular disease. METHODS: Authors used automated image-processing software to determine volumes of signal hyperintensities from MR brain scans of older people with depression (N=29; mean age: 76 years) and normal subjects of similar age (N=32). RESULTS: Overall, subjects with depression had a significantly greater frontal-lobe white-matter lesion volume than normal subjects (0.35% versus 0.22%). However, after excluding subjects with hypertension, diabetes, or ischemic heart disease (leaving 14 depressed and 15 normal subjects), we found even greater differences between groups, with a larger volume of MR signal hyperintensities in the frontal region of the depressed group, but no difference in the basal ganglia or parietal and occipital lobes. CONCLUSION: The results support the "vascular depression" hypothesis and suggest that those with depression but without traditional vascular risk factors may be much more susceptible to cerebrovascular disease than normal subjects. The mechanisms for this increased susceptibility remain to be determined.

Developing the BALANCE trail--the role of the pilot study and start-up phase.

OBJECTIVES: The initial design of the BALANCE (Bipolar Affective disorder: Lithium / ANtiConvulsant Comparative Evaluation) Trial of maintenance treatment for bipolar disorder was based on the experience of previous trials in bipolar disorder and psychiatry and on the methods developed for large randomized trials in other areas of medicine. This report describes the adaptations to the initial design and trial procedures following the initial phases of the study. The rationale for the trial and full protocol have been published elsewhere. METHODS: A pilot study and start-up phase were used to check the tolerability of the interventions, refine the trial design and develop trial procedures that are acceptable to both clinicians and patients. RESULTS: Changes to the procedures included: the dropping of masking of allocated treatment from clinicians and participants; introduction of the use of postal delivery to supply medication; and dispensing with the proposed schedule of regular follow up appointments. In addition, support was made available to participating psychiatrists who often had limited experience of participating in randomized trials. CONCLUSIONS: Pilot studies and start-up phases are essential to refine clinical trial design and allow development of procedures that are both methodologically rigorous and flexible and robust enough to promote recruitment and follow up. BALANCE is now actively recruiting in the UK and USA.