Arsime Demjaha

Specific and Generalized Neuropsychological Deficits: A Comparison of Patients With Various First-Episode Psychosis Presentations

OBJECTIVE Overwhelming evidence suggests that compromised neuropsychological function is frequently observed in schizophrenia. Neurocognitive dysfunction has often been reported in other psychotic disorders, although there are inconsistencies in the literature. In the context of four distinct diagnostic groups, the authors compared neuropsychological performance among patients experiencing their first psychotic episode. METHOD Data were derived from a population-based, case-control study of patients with first-episode psychosis. A neuropsychological test battery was administered to patients with a diagnosis of schizophrenia (N=65), bipolar disorder or mania (N=37), depressive psychosis (N=39), or other psychotic disorders (N=46) following index presentation, as well as to healthy comparison subjects (N=177). The presence of specific and generalized cognitive deficits was examined. RESULTS The schizophrenia group presented widespread neuropsychological impairments and performed significantly worse than healthy comparison subjects on most neuropsychological measures. Patients with other psychotic disorders and depressive psychosis also demonstrated widespread impairments. Deficits in patients with bipolar disorder or mania were less pervasive but evident in performance scores on verbal memory and fluency tests. Differences between the four patient groups and healthy comparison subjects and among the patient groups were attenuated after controlling for differences in general cognitive ability (IQ). CONCLUSIONS Early in their course, cognitive deficits are present in all psychotic disorders but are most severe and pervasive in schizophrenia and least pervasive in bipolar disorder and mania.

How Genes and Environmental Factors Determine the Different Neurodevelopmental Trajectories of Schizophrenia and Bipolar Disorder

The debate endures as to whether schizophrenia and bipolar disorder are separate entities or different manifestations of a single underlying pathological process. Here, we argue that this sterile argument obscures the fact that the truth lies somewhere in between. Thus, recent studies support a model whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and/or environmental factors that impair neurodevelopment; for example, copy number variants and obstetric complications are associated with schizophrenia but not with bipolar disorder. As a result, children destined to develop schizophrenia show an excess of neuromotor delays and cognitive difficulties while those who later develop bipolar disorder perform at least as well as the general population. In keeping with this model, cognitive impairments and brain structural abnormalities are present at first onset of schizophrenia but not in the early stages of bipolar disorder. However, with repeated episodes of illness, cognitive and brain structural abnormalities accumulate in both schizophrenia and bipolar disorder, thus clouding the picture.

Disorganization/Cognitive and Negative Symptom Dimensions in the At-Risk Mental State Predict Subsequent Transition to Psychosis

OBJECTIVE The at-risk mental state (ARMS) is associated with a very high risk of psychosis, but it is difficult to predict which individuals will later develop psychosis on the basis of their presenting symptoms. We investigated psychopathological dimensions in subjects with an ARMS and examined whether particular symptom dimensions predicted subsequent transition to psychosis. METHOD The sample comprised 122 subjects (aged 16-35 years) meeting Personal Assessment and Crisis Evaluation clinic criteria for the ARMS recruited through Outreach and Support in South London, a clinical service for people with an ARMS. A principal axis factor analysis was performed on symptom scores, obtained at presentation from the Comprehensive Assessment of the At-Risk Mental State, using Varimax rotation. The relationship between dimension scores and transition to psychosis during the following 24 months was then examined employing Cox regression analysis. RESULTS Factor analysis gave rise to a 5-factor solution of negative, anxiety, disorganization/cognitive, self-harm, and manic symptom dimensions, accounting for 37% of the total variance. Scores on the negative and on the disorganization/cognitive dimensions were associated with transition to psychosis during the follow-up period (P = 0.044 and P = 0.005, respectively). CONCLUSION The symptoms of the ARMS have a dimensional structure similar to that evident in patients with schizophrenia except for the positive symptom dimension. The association between scores on the disorganization/cognitive and negative dimensions and later transition is consistent with independent evidence that formal thought disorder, subjective cognitive impairments, and negative symptoms are linked to the subsequent onset of psychosis.

Aggressive behaviour at first contact with services: findings from the AESOP First Episode Psychosis Study

BACKGROUND Aggressive behaviour is increased among those with schizophrenia but less is known about those with affective psychoses. Similarly, little is known about aggressive behaviour occurring at the onset of illness. METHOD The main reasons for presentation to services were examined among those recruited to a UK-based first episode psychosis study. The proportion of individuals presenting with aggressive behaviour was determined and these individuals were compared to those who were not aggressive on a range of variables including sociodemographic, clinical, criminal history, service contact, and symptom characteristics. Among the aggressive group, those who were physically violent were distinguished from those who were not violent but who were still perceived to present a risk of violence to others. RESULTS Almost 40% (n=194) of the sample were aggressive at first contact with services; approximately half of these were physically violent (n=103). Younger age, African-Caribbean ethnicity and a history of previous violent offending were independently associated with aggression. Aggressive behaviour was associated with a diagnosis of mania and individual manic symptoms were also associated with aggression both for the whole sample and for those with schizophrenia. Factors differentiating violent from non-violent aggressive patients included male gender, lower social class and past violent offending. CONCLUSIONS Aggressive behaviour is not an uncommon feature in those presenting with first episode psychosis. Sociodemographic and past offending factors are associated with aggression and further differentiate those presenting with more serious violence. A diagnosis of mania and the presence of manic symptoms are associated with aggression.

Self-harm in first-episode psychosis

BACKGROUND Little is known about self-harm occurring during the period of untreated first-episode psychosis. AIMS To establish the prevalence, nature, motivation and risk factors for self-harm occurring during the untreated phase of first-episode psychosis. METHOD As part of the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study, episodes of self-harm were identified among all incident cases of psychosis presenting to services in south-east London and Nottingham over a 2-year period. RESULTS Of the 496 participants, 56 (11.3%) had engaged in self-harm between the onset of psychotic symptoms and first presentation to services. The independent correlates of self-harm were: male gender, belonging to social class I/II, depression and a prolonged period of untreated psychosis. Increased insight was also associated with risk of self-harm. CONCLUSIONS Self-harm is common during the pre-treatment phase of first-episode psychosis. A unique set of fixed and malleable risk factors appear to operate in those with first-episode psychosis. Reducing treatment delay and modifying disease attitudes may be key targets for suicide prevention.

Combining dimensional and categorical representation of psychosis: the way forward for DSM-V and ICD-11?

BACKGROUND There is good evidence that psychotic symptoms segregate into symptom dimensions. However, it is still unclear how these dimensions are associated with risk indicators and other clinical variables, and whether they have advantages over categorical diagnosis in clinical practice. We investigated symptom dimensions in a first-onset psychosis sample and examined their associations with risk indicators and clinical variables. We then examined the relationship of categorical diagnoses to the same variables. METHOD We recruited 536 patients as part of a population-based, incidence study of psychosis. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A principal axis factor analysis was performed on symptom scores. The relationship of dimension scores with risk indicators and with clinical variables was then examined employing regression analyses. Finally, regression models were compared to assess the contribution of dimensions versus diagnosis in explaining these variables. RESULTS Factor analysis gave rise to a five-factor solution of manic, reality distortion, negative, depressive and disorganization symptom dimensions. The scores of identified dimensions were differentially associated with specific variables. The manic dimension had the highest number of significant associations; strong correlations were observed with shorter duration of untreated psychosis, acute mode of onset and compulsory admission. Adding dimensional scores to diagnostic categories significantly increased the amount of variability explained in predicting these variables; the reverse was also true but to a lesser extent. CONCLUSIONS Categorical and dimensional representations of psychosis are complementary. Using both appears to be a promising strategy in conceptualising psychotic illnesses.

Opposite Effects of Catechol-O-Methyltransferase Val158Met on Cortical Function in Healthy Subjects and Patients with Schizophrenia

BACKGROUND Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects. METHODS We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5. RESULTS In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group x genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ. CONCLUSIONS Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder.

Dopaminergic Function in the Psychosis Spectrum: An [18F]-DOPA Imaging Study in Healthy Individuals With Auditory Hallucinations

BACKGROUND The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. METHODS We compared dopamine synthesis capacity (using 6-[(18)F]fluoro-L-DOPA [[(18)F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. RESULTS There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. CONCLUSIONS Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.

The test-retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function.

Brain presynaptic dopaminergic function can be assessed using 18F-DOPA positron emission tomography (PET). Regional 18F-DOPA utilization may be used to index dopaminergic abnormalities over time or dopaminergic response to treatment in clinical populations. Such studies require prior knowledge of the stability of the 18F-DOPA signal in the brain regions of interest. Test-retest reliability was examined in eight healthy volunteers who each received two 18F-DOPA PET scans, approximately 2 years apart. 18F-DOPA utilization (k(i)(cer)) was determined using graphical analysis relative to a reference tissue input (Patlak and Blasberg, 1985). Reproducibility (measured as the within-subjects variation) and reliability (measured as intraclass correlation coefficients, ICCs) of 18F-DOPA k(i)(cer) were assessed in the structural and functional subdivisions of the striatum and select extrastriatal brain regions. Voxel-based median ICC maps were used to visualize the distribution of 18F-DOPA k(i)(cer) reliability across the brain. The caudate and putamen, and associative and sensorimotor, striatal subdivisions showed good reliability across the two scan sessions with bilateral ICCs ranging from 0.681 to 0.944. Reliability was generally lower in extrastriatal regions, with bilateral ICCs ranging from 0.235 in the amygdala to 0.894 in the thalamus. These data confirm the utility of 18F-DOPA PET in assessing dopaminergic function in the striatum and select extrastriatal areas but highlight the limitations in using this approach to measure dopaminergic function in low uptake extrastriatal brain areas. This information can be used to optimize the experimental design of future studies investigating changes in brain dopaminergic function with 18F-DOPA.

The effects of neuregulin1 on brain function in controls and patients with schizophrenia and bipolar disorder

Recent studies have identified neuregulin1 as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders. The present investigation examined the impact of neuregulin1 genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 115 subjects comprising 41 patients with schizophrenia, 29 patients with bipolar disorder and 45 healthy volunteers. We then used statistical parametric mapping to estimate the main effects of diagnostic group, the main effect of genotype and their interaction. We tested the hypothesis that the high-risk variant of neuregulin1 would be associated with altered prefrontal function. In all three diagnostic groups, the high-risk variant of neuregulin1 was associated with greater deactivation in the left precuneus. In addition, there was an interaction between diagnosis and genotype in two regions of the prefrontal cortex. The right inferior frontal gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with schizophrenia. Conversely, the right posterior orbital gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with bipolar disorder. Our results suggest that genetic variation in neuregulin1 has a measurable impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in different regions of the prefrontal cortex.