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Introduction:Mental disorders are increasingly common among adults in both the developed and developing world and are predicted by the WHO to be the leading cause of disease burden by 2030. Many common physical conditions are more common among people who also have a common mental disorder. This scoping review aims to examine the current literature about the prevention, identification and treatment of physical problems among people with pre-existing mental health disorders in primary care in Europe.Methods:The scoping review framework comprised a five-stage process developed by Arksey & O’Malley (2005). The search process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Both quantitative and qualitative studies were included, with no restriction on study design.Results:The initial search identified 299 studies, with a further 28 added from the hand-search (total n = 327) of which 19 were considered relevant to the review research question and included for full analysis. Depression was the mental health condition most commonly studied (nine studies), followed by depression and anxiety (seven studies), with three studies examining any mental disorder. Eleven studies examined the effects of various interventions to address physical and mental comorbidity, with the most commonly studied intervention being collaborative care.Conclusions:With just 19 studies meeting our criteria for inclusion, there is clearly a paucity of research in this area. Further research is essential in order to understand the pathophysiological mechanisms underlying the association between mental disorders and chronic conditions.

Background The onset of mental disorders typically occurs between the ages of 12 and 25, and the burden of mental health problems is the most consequential for this group. Indicated prevention interventions to target individuals with subclinical symptoms to prevent the transition to clinical levels of disorders, even leading to suicide, have shown to be effective. However, the threshold to seek help appears to be high. Digital interventions could offer a solution, especially during the Covid-19 pandemic. This implementation study will investigate the digital indicated prevention intervention ENgage YOung people Early (ENYOY), the Dutch version of the original Moderated Online Social Therapy Platform (MOST+) from Australia. In addition, the relationship between stress biomarkers, symptoms and outcome measures of youth using the platform will be investigated in this study. Methods The MOST+ platform will be adapted, translated and developed for the situation in the Netherlands in collaboration with a Youth Panel. A prospective cohort of 125 young people (16–25 years) with beginning mental health complaints will be on the platform and followed for a year, of which 10 participants will have an additional smart watch and 10 participants will be asked to provide feedback about the platform. Data will be collected at baseline and after 3, 6 and 12 months. Outcome measures are Psychological Distress assessed with the Kessler Psychological Distress Scale (K10), Social and occupational functioning (measures by the SOFAS), positive mental health indicators measured by the Positive Health Instrument, stress biomarkers with a smart-watch, website journeys of visitors, and feedback of youth about the platform. It will be a mixed-method study design, containing qualitative and quantitative measures. Discussion This trial will specifically address young people with emerging mental health complaints, and offers a new approach for treatment in the Netherlands. Considering the waiting lists in (child and adolescent)-psychiatry and the increase in suicides among youth, early low-threshold and non-stigmatizing help to support young people with emerging psychiatric symptoms is of crucial importance. Moreover, this project aims to bridge the gap between child and adolescent and adult psychiatry. Trial registration Netherlands Trial Register ID NL8966, retrospectively registered on the 19th of October 2020.

BackgroundPhenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis.MethodsWe therefore assessedin vivostriatal dopamine D2/3receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available.ResultsMean D2/3R availability was significantly higher (13%;p= 0.032) in the PKU group (n= 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p< 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p< 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p= 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r= 0.72,p= 0.003) and the error rate during a cognitive flexibility task (r= 0.59,p= 0.020).ConclusionsThese findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

BackgroundThe majority of people with psychosis suffer from cognitive problems. These cognitive problems are among the most disabling features of the illness and have a negative effect on clinical outcome. Research has demonstrated that acetylcholine including muscarinic receptors play an important role in cognitive function. A post-mortem study in chronic patients with schizophrenia demonstrated a decrease of 75% of muscarinic M1 receptors.AimThe aim of this study was to investigate the role of M1 receptors in-vivo in brain and cognitive function in psychosis.MethodsThirty medication free patients with psychosis and 30 healthy controls matched for age, gender and IQ were included for 1) 1x IDEX Spect scan to determine M1 binding potential; 2) 2x fMRI scan using a visual memory task; 3) 2x MRS to determine choline concentrations; 2x CANTAB cognitive battery. Except for SPECT all subjects were tested twice, once with placebo and once with biperiden M1 antagonist.ResultatenPatients demonstrated a significant negative correlation between M1 binding potential and cognitive impairments and negative symptom scores on PANSS. Following biperiden challenge, performance on verbal learning and memory was worse. Hippocampal activity was larger during a visual memory task in patients.ConclusieThese results support a role for the M1 receptor in cognitive function in psychosis.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Background 22q11 deletion syndrome (22q11DS) is associated with mild or borderline intellectual disability (ID). There are hardly any reports on subjects with 22q11DS with moderate or severe ID, and therefore its behavioural and psychiatric characteristics are unknown. Method We describe behavioural and psychiatric characteristics of 33 adults with 22q11DS and a Full-Scale IQ (FSIQ) below 55. Participants were divided into two groups: one group having a FSIQ ≤ 55 caused by intellectual decline (n = 21) and one group with a FSIQ ≤ 55 who had always functioned at this level (n = 12). Results High scores on psychopathology sub-scales were found for both subgroups. 22q11DS patients with intellectual decline showed higher rates of co-morbid psychopathology, particularly psychosis. Furthermore, psychosis and intellectual decline were positive correlated. Conclusion This is the first report addressing adult patients with 22q11DS and moderate to severe ID. Overall we found high levels of psychopathology with higher scores of psychopathology in the intellectual decline group. Life time psychosis seems to be related to deterioration.

Background22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for psychosis. A dysfunctional motivational reward system is thought to be one of the salient features in psychosis caused by abnormal dopamine functioning. It is unknown whether patients with 22q11DS have a dysfunctional reward system.MethodsThis study aims to investigate reward learning in 22q11DS. The study included 10 adults with 22q11DS (age: 33.1 years, 60% female) and 10 age-gender-matched healthy controls (HC, age: 39.7 years, 60% female). A single infusion 18F-fallypride PET scan was acquired during which all subjects performed a version of the learning phase of the Probabilistic Stimulus Selection Task for reward learning (RL), modified to deliver social feedback.ResultsIQ-scores were significantly lower in the 22q11DS group (P < .001) compared to HC. The 22q11DS group both earned significantly less money (P < .05) and performed worse during the RL-task (P < .05) than HC. However, the learning curve for the RL-task was the same for both groups. IQ-scores were a significant positive predictor for earnings (P < .05) and performance (P < .05), but not for the learning curve.ConclusionsThese preliminary results indicate that people with 22q11DS are capable of learning at the same speed as HC, however they are less susceptible for reward than HC because their overall performance during RL is worse than HC. This lower reward sensitivity could be a result of haplo-insufficiency of COMT in 22q11DS and consequently abnormal prefrontal dopamine functioning.Disclosure of interestThe authors have not supplied their declaration of competing interest.

It has been hypothesised that in subjects with 22q11 deletion syndrome (22q11DS) disturbances of the dopamine (DA) system contribute to their increased risk for cognitive deficits and psychiatric problems. However, central DAergic neurotransmission in 22q11DS has not been investigated. We measured striatal D2 receptor binding potential (D2R BPND) using (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide-single photon emission computed tomography ([123I]IBZM SPECT) in 12 adults with 22q11DS and 12 matched controls. Correlations between D2R BPND and plasma prolactin (pPRL) levels were also determined. 22q11DS subjects and controls had similar D2R BP ND. There was a positive correlation between D2R BP ND and pPRL values in controls, but no such relation was found in 22q11DS subjects. This study suggests that a 22q11 deletion does not affect striatal DAergic neurotransmission in the living human brain. However, the disturbed relationship between D2R BPND and pPRL values suggests DAergic dysfunction at a different level. Further studies on DAergic function in extra-striatal brain regions and under challenged conditions are needed.

Purpose To study striatal dopamine D-2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D).Methods Fifteen DYT11 mutation carriers ( 11 clinically affected) and 15 age- and sex-matched controls were studied using I-123-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas.Results Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects.Conclusions Our findings are consistent with the theory of reduced dopamine D-2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.

Alpha-methyl-para-tyrosine (AMPT) temporarily inhibits tyrosine hydroxylase, the rate limiting step in the dopamine biosynthesis cascade. AMPT has been approved for clinical use in phaeochromocytoma in 1979. Recently however, AMPT has been increasingly employed as a pharmacological challenge in acute dopamine depletion studies including neuroimaging studies. The use of this exciting challenge technique allows us to increase our understanding of dopaminergic neurotransmission in the brain. In addition, there have been clinical reports that AMPT may be useful to treat movement disorders like dystonia, dyskinesia and Huntingtons chorea, psychiatric disorders like mania, psychosis, obsessive compulsive disorder and substance abuse as well as behavioral problems in 22q11 deletion syndrome. In this review we will discuss the effects of AMPT in challenge studies that have been reported in humans. Furthermore we will review all studies reporting therapeutic effects of AMPT in neuropsychiatric disorders and adverse effects associated with AMPT use reported in both challenge and therapeutic research.

Velo-cardio-facial syndrome (VCFS) is associated with deletions on the long arm of chromosome 22, mild intellectual disability, poor social interaction and a high prevalence of psychosis. However, to date there have been no studies investigating the neuropsychological functioning of adults with VCFS. We compared 19 adults with VCFS with 19 age, gender and IQ matched controls using a comprehensive neuropsychological battery. Compared to controls, adults with VCFS had significant impairments in visuoperceptual ability (Visual Object and Space Perception Battery), problem solving and planning (Tower of London) and abstract and social thinking (Comprehension WAIS-R). It is likely that haploinsufficiency (reduced gene dosage) of a neurodevelopmental gene or genes mapping to chromosome 22q11 underlies the cognitive deficits observed in individuals with VCFS.

This presentation reports on the outcomes of a practice-based and science-based enterprise in the Netherlands to develop a comprehensive national prevention program focused on children of parents with a mental illness. An outline of the multicomponent program is presented which includes a wide set of interventions that address evidence-based risk factors and protective factors in multiple domains, including children in different age groups, parents and families, social networks, professionals and the community as a whole.The 20-year history of this program illustrates the importance of long-term collaborative investments that are required of practitioners, policymakers and scientists to develop and implement a nationwide, comprehensive approach for addressing the prevalent transmission of psychiatric problems from parent to child. The results of recently undertaken controlled efficacy studies of various preventive interventions are presented, as well as findings from process evaluations. Also, strengths and weaknesses of the current program are discussed and recommendations will be offered for the main challenges ahead in terms of program innovation, implementation and research.Disclosure of interestThe author has not supplied his declaration of competing interest.

Estrogen replacement therapy (ERT) may preserve cognitive function in postmenopausal women, but the mechanism is unknown. Thus, the authors studied aging of parietal lobe and hippocampus using proton MR spectroscopy. ERT naïve postmenopausal women had a significant increase in choline-containing compounds (Cho) compared to long-term ERT users and young women. Cho reflects increased neuronal/glial membrane turnover. Thus, ERT's "neuroprotective" effect may include modulating the effects of age on neural integrity in brain regions involved in cognitive function.

BackgroundVelo-cardio-facial syndrome (VCFS) is associated with deletions in the q11 band of chromosome 22, learning disability and psychosis, but the neurobiological basis is poorly understood.AimsTo investigate brain anatomy in adults with VCFS.MethodMagnetic resonance imaging was used to study 10 patients with VCFS and 13 matched controls. We carried out three analyses: qualitative; traced regional brain volume; and measurement of grey and white matter volume.ResultsThe subjects with VCFS had: a high prevalence of white matter hyperintensities and abnormalities of the septum pellucidum; a significantly smaller volume of cerebellum; and widespread differences in white matter bilaterally and regional specific differences in grey matter in the left cerebellum, insula, and frontal and right temporal lobes.ConclusionsDeletion at chromosome 22q11 is associated with brain abnormalities that are most likely neurodevelopmental and may partially explain the high prevalence of learning disability and psychiatric disorder in VCFS.

The processing of changing nonverbal social signals such as facial expressions is poorly understood, and it is unknown if different pathways are activated during effortful (explicit), compared to implicit, processing of facial expressions. Thus we used fMRI to determine which brain areas subserve processing of high‐valence expressions and if distinct brain areas are activated when facial expressions are processed explicitly or implicitly. Nine healthy volunteers were scanned (1.5T GE Signa with ANMR, TE/TR 40/3,000 ms) during two similar experiments in which blocks of mixed happy and angry facial expressions (“on” condition) were alternated with blocks of neutral faces (control “off” condition). Experiment 1 examined explicit processing of expressions by requiring subjects to attend to, and judge, facial expression. Experiment 2 examined implicit processing of expressions by requiring subjects to attend to, and judge, facial gender, which was counterbalanced in both experimental conditions. Processing of facial expressions significantly increased regional blood oxygenation level‐dependent (BOLD) activity in fusiform and middle temporal gyri, hippocampus, amygdalohippocampal junction, and pulvinar nucleus. Explicit processing evoked significantly more activity in temporal lobe cortex than implicit processing, whereas implicit processing evoked significantly greater activity in amygdala region. Mixed high‐valence facial expressions are processed within temporal lobe visual cortex, thalamus, and amygdalohippocampal complex. Also, neural substrates for explicit and implicit processing of facial expressions are dissociable: explicit processing activates temporal lobe cortex, whereas implicit processing activates amygdala region. Our findings confirm a neuroanatomical dissociation between conscious and unconscious processing of emotional information. Hum. Brain Mapping 9:93–105, 2000. © 2000 Wiley‐Liss, Inc.

This study examines the effects of angiotensin II on hypertrophy and proliferation of aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats and the receptor subtypes mediating these effects. In quiescent confluent cells, angiotensin II induced a dose-dependent increase in thymidine and leucine incorporation without stimulating cell proliferation. In nonconfluent cells, angiotensin II stimulated cell proliferation only in combination with a submaximal concentration of fetal calf serum. These effects were enhanced in cells from spontaneously hypertensive rats compared with Wistar-Kyoto rats. The effects of angiotensin II could be blocked by the AT1 receptor antagonist DuP 753 but not by the AT2 receptor ligand PD 123177. In receptor binding studies with cells derived from both rat strains, AT1-typical binding was observed. These data show that the angiotensin II receptors present in vascular smooth muscle cells in culture from both rat strains are of the AT1 receptor subtype. This receptor subtype appears to mediate vascular smooth muscle cell hypertrophy and proliferation as well as vasoconstriction. Although no difference in the receptor profile was detectable between the two rat strains, the affinity for the ligands to the receptor and the receptor density tended to be greater in cells from spontaneously hypertensive rats than in cells from Wistar-Kyoto rats. These results may partly explain the greater hypotensive response to angiotensin II receptor blockade in spontaneously hypertensive rats than in Wistar-Kyoto rats, although both rat strains have the same plasma concentrations of angiotensin II.

Objective: Prediction of transition to psychosis in the prodromal phase of schizophrenia has raised interest in intervention prior to the onset of frank psychosis. The aim of this review was to examine whether interventions in the prodromal phase have a favourable benefit/risk ratio. Method: A literature search in PubMed, EMBASE and PsycINFO was performed. Results: Three randomized clinical trials with antipsychotic medication and/or cognitive behavioural therapy as clinical intervention suggested a positive effect at the end of treatment, but no significant differences were found at the end of follow-up periods from 1 to 4 years. Naturalistic studies present a hypothesis about a possible preventive effect of antidepressive medication. The results of eight other studies are more difficult to interpret. Side-effects of antipsychotic medication and non-adherence with medication are essential problems. Conclusion: At the present time, the data concerning the benefits and risks do not justify prodromal intervention as standard clinical practice. © 2009 John Wiley & Sons A/S.

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.

Haploinsufficiency of 22q11 genes including catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel-based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia.

BackgroundVelo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS.MethodThe COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery.ResultsAfter corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found.ConclusionsCOMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.

Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinson's disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic system by sex hormones, as there is preliminary evidence that estrogen modulates treatment response in these disorders. Furthermore, sex differences in dopamine-mediated cognitive decline suggest estrogen may also play a role in healthy aging. However, the effects of estrogen on the dopaminergic system are poorly understood, and nobody has examined the effect of long-term estrogen therapy (ET) on this system. We compared dopaminergic responsivity (growth hormone (GH) response to apomorphine) in post-menopausal women on ET to women who were ET-naive. GH response to subcutaneous apomorphine (0.005 mg/kg) was measured in two groups of healthy post-menopausal women aged between 55 and 70 years: those taking ET (n = 13) and those who had never taken ET (n = 13). Neither group was taking any other medication. GH was measured at 15 min intervals from -30 min before administration of apomorphine to 90 min post-administration. GH response was measured in two ways: area under the curve (AUC) and maximum response over baseline (GH). There were no between-group differences in demographic or baseline variables. The ET treated women had a significantly greater (p = 0.03) AUC than ET naive women (mean +/- S.D.; 5.3 +/- 4.7 vs. 2.6 +/- 2.3). However, (GH) did not differ significantly between groups (6.1 mU/l +/- 6.2 vs. 2.7 mU/l +/- S.D. = 4.1). Also, analysis of GH response over time revealed a significant main effect of time (p < 0.0005), and a group by time interaction (p = 0.004) , but no significant main effect of group. Our results suggest that ET may enhance dopaminergic responsivity in post-menopausal women. Estrogen deficiency following menopause may partly explain age and gender differences in late-onset neuropsychiatric disorders.

There are significant gender differences in human brain disease. For example, females are significantly more likely to suffer from Alzheimer's disease (AD) than men (even after correcting for differences in life expectancy), and females on hormone replacement therapy (HRT) are significantly less likely to suffer from Alzheimer's disease than women who do not take HRT. However the neurobiological basis to these differences in clinical brain disease were unknown until relatively recently. In this review we will discuss results of studies that show; (i) gender differences in human brain disease are most likely to be explained by gender differences in brain development and ageing; (ii) sex steroids have a significant effect on the brain; (iii) sex steroids are crucial to the development and ageing of brain regions affected in age-related brain diseases (for example AD); (iv) sex steroids interact with neuronal networks and chemical systems at many different levels; (v) sex steroids affect cognitive function in elderly women. Thus, the current literature supports the hypothesis that sex steroids can modulate brain ageing, and this provides a neurobiological explanation for the significantly higher prevalence of AD in females who do not take HRT, and may lead to new treatment approaches for age-related brain disease including AD.

Although high-functioning individuals with autistic disorder (i.e. autism and Asperger syndrome) are of normal intelligence, they have life-long abnormalities in social communication and emotional behaviour. However, the biological basis of social difficulties in autism is poorly understood. Facial expressions help shape behaviour, and we investigated if high-functioning people with autistic disorder show neurobiological differences from controls when processing emotional facial expressions. We used functional MRI to investigate brain activity in nine adults with autistic disorder (mean age +/- standard deviation 37 +/- 7 years; IQ 102 +/- 15) and nine controls (27 +/- 7 years; IQ 116 +/- 10) when explicitly (consciously) and implicitly (unconsciously) processing emotional facial expressions. Subjects with autistic disorder differed significantly from controls in the activity of cerebellar, mesolimbic and temporal lobe cortical regions of the brain when processing facial expressions. Notably, they did not activate a cortical 'face area' when explicitly appraising expressions, or the left amygdala region and left cerebellum when implicitly processing emotional facial expressions. High-functioning people with autistic disorder have biological differences from controls when consciously and unconsciously processing facial emotions, and these differences are most likely to be neurodevelopmental in origin. This may account for some of the abnormalities in social behaviour associated with autism.

Hyponatremia, an electrolyte disturbance usually without clinical significance, may sometimes lead to serious complications when overlooked or not treated appropriately. One cause of hyponatremia, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been associated with some drugs, including carbamazepine (CBZ). Because of its antidiuretic effects, CBZ has been used successfully to treat diabetes insipidus centralis. Possible mechanisms for the antidiuretic effects of CBZ have been proposed. Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors appears likely, but an increased sensitivity of the renal tubules to circulating ADH cannot be excluded. CBZ has led to hyponatremia in patients with epilepsy, neuralgia, mental retardation, and psychiatric disorders with a frequency varying from 4.8 to 40%. Oxcarbazepine (OCBZ), which is structurally related to CBZ, has shown similar hyponatremic effects, but whether hyponatremia occurs more often than with CBZ is not yet clear. Experience with OCBZ is still limited, and there is no definite explanation for a possible difference in antidiuretic potency. Most patients with CBZ/OCBZ-induced hyponatremia are asymptomatic. In rare cases, water intoxication has been reported, necessitating treatment discontinuation.

Introduction:Schizophrenia and OCD have a high comorbidity. Structural brain abnormalities in patients with schizophrenia and OCD are common. Furthermore, in clinical practice, both disorders present with motor abnormalities, neurological soft signs and cognitive deficits stemming from possibly similar brain etiology. Our aim was to investigate whole brain grey and white matter abnormalities and total brain volume in patients with schizophrenia with and without comorbidity with OCD. Methods:Voxel-based and volumetric analysis of high resolution structural T1-weighted 3 Tesla MRI images was used in 10 male patients with schizophrenia and OCD and 15 age and education matched patients with schizophrenia without OCD symptoms. Results:Schizophrenic patients with OCD had significantly reduced white matter density of the cerebellum, bilaterally, compared to schizophrenic patients without OCD symptoms. Furthermore, reduced total white matter volume was found in schizophrenic patients with OCD, which correlated significantly with the Yale Brown Obsessive Compulsive Scale total score. Conclusions:Patients with schizophrenia and OCD had reduced cerebellar white matter and a smaller total mean white matter volume, compared to schizophrenic patients without OCD symptoms. Cerebellar white matter abnormalities could be the underlying pathology for neurological soft signs, motor deficits and cognitive difficulties found in the population of schizophrenic patients with OCD. References

We thank Eliez & Blasey ([2001][1]) for their kind comments about our paper ([van Amelsvoort et al , 2001][2]). However, we disagree that our paper implied that Eliez et al ([2000][3]) reported relatively smaller frontal lobe volumes and would like to draw their attention to the following. Normal