Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation.

Medline search of relevant studies published between 1990 and 2008.

In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-Schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism.

This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses.

To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).

Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.

Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.

NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

The electroencephalogram (EEG) can be a useful tool in determining differences in general neural activity and specific waveforms in individuals with a number of psychiatric disorders. This paper aims to outline and discuss significant findings in EEG and event-related potential (ERP) research into bipolar disorder (BD).

A literature review was performed through searches of MedLine, EMBASE, CINAHL and PsycInfo medical research databases for papers published from 1985 onwards. References of selected articles were also examined for other relevant studies.

Differences in general EEG data were found in subjects with BD, namely increased theta and delta and decreased alpha wave bands. Changes in EEG were also found in euthymic BD subjects and those undergoing medication programmes. ERP studies commonly report prolonged latencies and reduced amplitudes in the P300 component. Hyperfunctioning of the right hemisphere in BD was also reported in some studies, although further confirmation of this finding is required. Finally, the effects of medication and the role that genetics plays in EEG still remain unclear.

The literature reviewed demonstrates supporting evidence for the presence of significant differences in EEG and ERP data in subjects with BD. However, methodological considerations such as varying mood states and medication status of the patients need to be followed more stringently for future research to bring about a robust model of the cognitive deficits of BD.

The present study investigated the attentional bias induced by drug-related stimuli in active abusers; abstinent abusers on opioid substitution therapy; and abstinent drug-dependent patients in recovery on a community-based non-pharmacological therapy programme. Drug-dependent groups included both cocaine and heroin abusers.

Classical and emotional Stroop tasks were used to test all drug-dependent patients and controls with no history of addiction. Response times were recorded. An interference effect was obtained by comparing the congruent and incongruent conditions in the classical Stroop version. An attentional bias towards drug cues was derived by comparing latencies in the neutral and emotional conditions of the emotional Stroop.

No between-group differences were found in the classical Stroop. In the emotional Stroop, active drug-dependent patients showed higher attentional bias (i.e. longer response times to drug-related words) than any of the other three groups.

The attentional bias induced by drug cues in patients with addiction disorder might change depending on the patients' clinical status. All treated patients, whether on opioid substitution therapy or on community therapy, showed less attentional bias towards drug-related stimuli than active drug users, although the observed smaller bias was most likely induced by therapy acting through different mechanisms. Although drug-cues response is influenced by other multiple variables, e.g. motivation, craving, classical conditioning and substance availability, these data lend support to the hypothesis that treatment might contribute to decrease the attentional bias towards drug cues, which seems to play a critical role in achieving a positive outcome in the treatment of addiction.

Major depressive disorder (MDD) is closely related to stress reactions and serotonin probably underpins the pathophysiology of MDD. Alterations of the hypothalamic-pituitary-adrenal axis at the gene level have reciprocal consequences on serotonin neurotransmission. Glucocorticoid receptor (GR) polymorphisms affect glucocorticoid sensitivity, which is associated with cortisol feedback effects. Therefore, we hypothesised that GR polymorphisms are associated with the susceptibility to MDD and predict the treatment response.

Ninety-six subjects with a minimum score of 17 on the 21-item Hamilton Depression Scale (HAMD) at baseline were enrolled into the present study. The genotypes of GR (N363S, ER22/23EK, Bcl1, and TthIII1 polymorphisms) were analysed. The HAMD score was again measured after 1, 2, 4 and 8 weeks of antidepressant treatment to detect whether the therapeutic effects differed with the GR genotype.

Our subjects carried no N363S or ER22/23EK genetic polymorphisms and three types of Bcl1 and TthIII1 genetic polymorphisms. The C/C genotype and C allele at Bcl1 polymorphism were more frequent in MDD patients than in normal controls (p < 0.01 and p = 0.01, respectively). The genotype distributions did not differ significantly between responders and non-responders.

These results suggest that GR polymorphism cannot predict the therapeutic response after antidepressant administration. However, GR polymorphism (Bcl1) might play a role in the pathophysiology of MDD. Future studies should check this finding in larger populations with different characteristics.

To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).

Participants were randomised to a 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using a Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.

Among the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumed caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared to placebo at week 2 of treatment but not at other study visits.

NAC appeared to have little effect on the participants who were using substances. A larger study on a substance-using population will be necessary to determine if NAC may be a useful treatment for substance use.

Olfactory identification deficits (OIDs) are seen in schizophrenia, but it is unclear whether they are state- or trait-related.

We examined the prevalence of OIDs, as assessed by the University of Pennsylvania Smell Identification Test (UPSIT), and their correlations with prodromal symptoms in young relatives at risk for schizophrenia or schizoaffective disorder (HR-S).

UPSIT scores were lower in HR- S than in healthy controls, but were non-significant after covarying the effects of age, gender and IQ. OID deficits in HR-S were correlated, after covarying out the effects of age and IQ, with prodromal disorganisation.

The potential value of OID deficits as markers of psychopathological vulnerability in young relatives at risk for schizophrenia deserves further investigation.

The aims of this study were to research the following issues in a Spanish population of patients with schizophrenia. (a) The sensitivity and reliability of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to detect cognitive impairment in schizophrenia. (b) The convergent validity of RBANS on a larger battery of neuropsychological tests sensitive to the cognition disorders typically observed in schizophrenia. (c) The correlates of poor performance in RBANS with clinical features and illness severity.

Thirty schizophrenia patients, 30 non-psychotic patients and 30 healthy participants were assessed using RBANS (form A). We administered a battery of neuropsychological tests and four scales to evaluate patient’s clinical status.

Schizophrenia patients and non-psychotic patients performed significantly worse than healthy controls on RBANS, and schizophrenia patients performed slightly worse than non-psychiatric controls, but this difference was not significant. Good inter-test reliability and concurrent validity were found. Only a moderate correlation between RBANS performance and illness severity was observed.

RBANS revealed coherence in identifying cognitive impairment in schizophrenia patients of a different cultural background, and it is shown to be a sensitive, valid and easy-to-perform tool for the neuropsychological assessment of Spanish patients with schizophrenia.

Studies exploring relation of visual memory to white matter are extensively lacking. The Rey Visual Design Learning Test (RVDLT) is an elementary motion, colour and word independent visual memory test. It avoids a significant contribution from as many additional higher order visual brain functions as possible to visual performance, such as three-dimensional, colour, motion or word-dependent brain operations. Based on previous results, we hypothesised that test performance would be related with white matter of dorsal hippocampal commissure, corpus callosum, posterior cingulate, superior longitudinal fascicle and internal capsule.

In 14 healthy subjects, we measured intervoxel coherence (IC) by diffusion tensor imaging as an indication of connectivity and visual memory performance measured by the RVDLT. IC considers the orientation of the adjacent voxels and has a better signal-to-noise ratio than the commonly used fractional anisotropy index.

Using voxelwise linear regression analyses of the IC values, we found a significant and direct relationship between 11 clusters and visual memory test performance. The fact that memory performance correlated with white matter structure in left and right dorsal hippocampal commissure, left and right posterior cingulate, right callosal splenium, left and right superior longitudinal fascicle, right medial orbitofrontal region, left anterior cingulate, and left and right anterior limb of internal capsule emphasises our hypothesis.

Our observations in healthy subjects suggest that individual differences in brain function related to the performance of a task of higher cognitive demands might partially be associated with structural variation of white matter regions.

The FATIMA study (FAst TItration of quetiapine fumarate in bipolar I MAnia) evaluated the safety, tolerability and efficacy of a rapid dose escalation of quetiapine in acutely ill bipolar I patients experiencing a manic episode.

In an open-label, phase II pilot study, 29 patients aged 18 years or older, hospitalised with a bipolar I manic episode, received quetiapine twice daily for 21 days. Quetiapine was administered at 200, 400, 600, then 800 mg/day on the first 4 days, with flexible dosing (400–800 mg/day) subsequently. The primary endpoint was the proportion of patient dropouts because of adverse drug reactions during the first 7 days. Secondary safety assessments included incidences of adverse drug reactions and significant changes in vital signs. Efficacy assessments included Young Mania Rating Scale (YMRS) and Clinical Global Impressions Severity of Illness (CGI-S) score changes from day 1 to day 21.

Twenty patients (69%) completed the study. No patients withdrew as a result of drug-related adverse events (AEs) during the first 7 days. Twenty-three patients reported 58 adverse events, and most of the adverse events were mild or moderate. No clinically relevant abnormalities in vital signs were reported. Mean YMRS and CGI-S scores decreased significantly from baseline to day 21 (p < 0.001). Response and remission rates were 78 and 70%, respectively, at the end of the study.

Rapid dose escalation of quetiapine to 800 mg/day over 4 days was well tolerated and effective in reducing symptoms within 5 days in acutely ill bipolar I patients with a manic episode.

Impairment in emotion perception represents a fundamental feature of schizophrenia with important consequences in social functioning. A fundamental unresolved issue is the relationship between emotion perception and face perception. The aim of the present study was to examine whether facial identity recognition (Identity Discrimination) is a factor predicting facial emotion recognition in the context of the other factors, known as contributing to emotion perception, such as cognitive functions and symptoms.

We enrolled 58 stable schizophrenic out-patients and 47 healthy subjects. Facial identity recognition and emotion perception were assessed with the Comprehensive Affect Testing System. Different multiple regression models with backward elimination were performed in order to discover the relation of each significant variable with emotion perception.

In a regression including the six significant variables (age, positive symptomatology, Identity Discrimination, attentive functions, verbal memory-learning, executive functions) versus emotion processing, only attentive functions (standardised β = 0.264, p = 0.038) and Identity Discrimination (standardised β = 0.279, p = 0.029) reached a significant level. Two partial regressions were performed including five variables, one excluding attentive functions and the other excluding Identity Discrimination. When we excluded attentive functions, the only significant variable was Identity Discrimination (standardised β = 0.278, p = 0.032). When we excluded Identity Discrimination, both verbal memory-learning (standardised β = 0.261, p = 0.042) and executive functions (standardised β = 0.253, p = 0.048) were significant.

Our results emphasised the role of face perception and attentional abilities on affect perception in schizophrenia. We additionally found a role of verbal memory-learning and executive functions on emotion perception. The relationship between those above-mentioned variables and emotion processing could have implications for cognitive rehabilitation.

Among potential endophenotypes proposed for bipolar affective disorder focusing on circadian abnormalities associated with the illness has particularly high face validity. Melatonin sensitivity to light is one circadian endophenotype proposed as useful in bipolar disorder. The aim of this study was to investigate melatonin sensitivity to light over a range of light intensities in order to compare and contrast responses in bipolar I patients with those of healthy adult volunteers.

The study included seven patients (4 females, 3 males) with bipolar I disorder and 34 control participants (22 females, 12 males) with no personal or family history of affective illness. Melatonin sensitivity to light was determined in all patients and participants across a range of light intensities (0, 200, 500 and 1000 lux).

The results indicated that patients showed melatonin super-sensitivity to light in comparison with controls, a response that was consistent across the entire light intensity range investigated.

The study provides further evidence for a super sensitive response in bipolar I patients and suggests that its potential usefulness as an endophenotypic marker of the illness is deserving of further research.

Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has been suggested to be associated with major depressive disorder (MDD). There were a few reports of the relationship between the variant and late-onset depression (LOD) in Chinese Han population.

To investigate the relationship among BDNF Val66Met gene variants, BDNF plasma level and LOD.

Chinese Han patients with LOD (n = 99) and control subjects (n = 110) were assessed for BDNF Val66Met gene polymorphism. BDNF plasma level was tested only in LOD.

There were no significant differences in genotypes and allele frequencies between cases and controls (p = 0.744 and p = 0.845, respectively). Plasma BDNF level also did not show significant differences in three genotypes in LOD (p = 0.860).

The Val66Met polymorphism in BDNF gene may not confer susceptibility to LOD in Chinese Han population.

To investigate scanpath abnormalities during the encoding of static stimuli in schizophrenia and their interaction with visuospatial working memory (VSWM) dysfunction.

Outpatients with schizophrenia and control subjects were asked to encode a static pattern for subsequent recognition after a short delay. We measured the number of correct and incorrect choices. We also assessed the number and the distribution of fixations, the scanning time in specific regions of interest (ROIs) and the head movements during the encoding of the stimuli. The distributions of fixations and scanning time in definite ROIs during the discrimination of the correct pattern from the foils were also measured.

Patients recognised fewer correct patterns than controls. Correct trials in patients were characterised by a specific exploration of the central part of the stimulus during its presentation, whereas this feature was absent in incorrect trials. However, the scanning time and the numbers of fixations and head movements during encoding were similar in both groups and unrelated to recognition accuracy. In both groups, correct trials were associated with a selective exploration of the correct pattern amongst the six possibilities during recognition. Furthermore, patients gave more attention to incorrect patterns with a leftmost element identical to that of the correct response and also those approximating its global structure.

Patients showed a VSWM deficit independent of oculomotor dysfunctions and head movements during encoding. Patients’ correct trials were related to specific scanning during encoding and discrimination phases. Analysis of these patterns suggests that patients try to compensate for reduced VSWM ability by using specific encoding strategies.

The purpose of this study was to investigate whether the effects of quetiapine on abnormalities of early auditory processing in patients with schizophrenia were reflected by mismatch negativity (MMN).

Subjects were 23 patients with schizophrenia and 23 controls. Psychopathology was rated in patients with the Positive and Negative Syndrome Scale (PANSS) at baseline and after 4-week and after 8-week treatments with quetiapine. Auditory stimuli for event-related potentials consisted of 100 ms/1000 Hz standards, intermixed with 100 ms/1500 Hz frequency deviants and 250 ms/ 1000 Hz duration deviants. A stimulus onset asynchrony of each was 300 ms. Electroencephalograph was recorded at Fz. BESA 5.1.8 was used to perform data analysis. MMN waveforms were obtained by subtracting waveforms elicited by standards from those elicited by frequency- or duration-deviant stimuli.

Quetiapine decreased all PANSS scores. Patients showed smaller mean amplitudes of frequency and duration MMN at baseline than did controls. A repeated measure analysis of variance with sessions (i.e. baseline and 4- and 8-week treatments) and MMN type (frequency versus duration) as within-subject factors revealed no significant MMN type or MMN type × session main effect for MMN amplitudes (for MMN type: F = 0.704, df = 1, p = 0.403; for MMN type × session: F = 0.299, df = 2, p = 0.796). Session main effect was significant (F = 3.576, df = 2, p = 0.031). Least square difference tests showed significant differences between MMN amplitudes at 8 weeks and those at both baseline (p = 0.025) and 4 weeks (p = 0.020). MMN amplitudes at 8 weeks were higher than those at baseline.

Quetiapine improved the amplitudes of MMN after the 8-week treatment. MMN offers objective evidence that treatment with the quetiapine may ameliorate preattentive deficits in schizophrenia.

Recent studies have proposed the existence of three distinct subgroups of bipolar 1 disorder based on age at onset (AAO). The present study aims to investigate potential clinical and functional differences between these subgroups in an Australian sample.

Participants (n = 239) were enrolled in the Bipolar Comprehensive Outcomes Study (BCOS), a 2-year longitudinal, observational, cross-sectional study. Assessment measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD21), Clinical Global Impressions Scale (CGI-BP), SF-36, SLICE/Life Scale, and the EuroQol (EQ-5D). Participants were also asked about their age at the first major affective episode.

Three AAO groups were compared: early (AAO < 20, mean = 15.5 ± 2.72; 44.4% of the participants); intermediate (AAO 20–39, mean = 26.1 ± 4.8; 48.14% of the participants) and late (AAO > 40, mean = 50.6 ± 9.04; 7.4% of the participants). Higher rates of depression, suicidal ideation and binge drinking were reported by the early AAO group. This group also reported poorer quality of life in a number of areas. The early AAO group had a predominant depressive initial polarity and the intermediate group had a manic predominance.

Early AAO is associated with an adverse outcome.

The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI.

To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study.

Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks.

There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression.

C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.

Recent cross-sectional studies suggest that brain changes in schizophrenia are progressive during the course of the disorder. However, it remains unknown whether this is a global process or whether some brain areas are affected to a greater degree. The aim of this study was to examine the longitudinal brain changes in patients with chronic older schizophrenia by magnetic resonance imaging (MRI).

Three-dimensional (3D) T1-weighted and diffusion tensor (DT) MRI were performed twice on each of 16 chronic older schizophrenia patients (mean age = 58.1 ± 6.7 years ) with an interval of 1 year between imaging sessions. To clarify the longitudinal morphological and white matter changes, volume data and normalised diffusion tensor imaging (DTI) metrics were compared between the first and follow-up studies using a paired t-test.

Focal cortical volume loss was observed in the left prefrontal lobe and anterior cingulate on volumetric study. In addition, DTI metrics changed significantly at the bilateral posterior superior temporal lobes, left insula, genu of the corpus callosum and anterior cingulate.

There are ongoing changes in the brains of schizophrenic patients during the course of the illness. Discrepancies between volume data and DTI metrics may indicate that the pattern of progressive brain changes varies according to brain region.