Neurocognitive subgroups among newly diagnosed patients with schizophrenia spectrum or bipolar disorders: A hierarchical cluster analysis.

Studies across schizophrenia (SZ) and bipolar disorder (BD) indicate common transdiagnostic neurocognitive subgroups. However, existing studies of patients with long-term illness precludes insight into whether impairments result from effects of chronic illness, medication or other factors. This study aimed to investigate whether neurocognitive subgroups across SZ and BD can be demonstrated during early illness stages. Data from overlapping neuropsychological tests were pooled from cohort studies of antipsychotic-naïve patients with first-episode SZ spectrum disorders (n = 150), recently diagnosed BD (n = 189) or healthy controls (HC) (n = 280). Hierarchical cluster analysis was conducted to examine if transdiagnostic subgroups could be identified based on the neurocognitive profile. Patterns of cognitive impairments and patient characteristics across subgroups were examined. Patients could be clustered into two, three and four subgroups, of which the three-cluster solution (with 83% accuracy) was selected for posthoc analyses. This solution revealed a subgroup covering 39% of patients (predominantly BD) who were cognitively relatively intact, a subgroup of 33% of patients (more equal distributions of SZ and BD) displaying selective deficits, particularly in working memory and processing speed, and a subgroup of 28% (mainly SZ) with global impairments. The globally impaired group exhibited lower estimated premorbid intelligence than the other subgroups. Globally impaired BD patients also showed more functional disability than cognitively relatively intact patients. No differences were observed across subgroups in symptoms or medications. Neurocognitive results can be understood by clustering analysis with similar clustering solutions occurring across diagnoses. The subgroups were not explained by clinical symptoms or medication, suggesting neurodevelopmental origins.

Macroscale EEG characteristics in antipsychotic-naïve patients with first-episode psychosis and healthy controls.

Electroencephalography in patients with a first episode of psychosis (FEP) may contribute to the diagnosis and treatment response prediction. Findings in the literature vary due to small sample sizes, medication effects, and variable illness duration. We studied macroscale resting-state EEG characteristics of antipsychotic naïve patients with FEP. We tested (1) for differences between FEP patients and controls, (2) if EEG could be used to classify patients as FEP, and (3) if EEG could be used to predict treatment response to antipsychotic medication. In total, we studied EEG recordings of 62 antipsychotic-naïve patients with FEP and 106 healthy controls. Spectral power, phase-based and amplitude-based functional connectivity, and macroscale network characteristics were analyzed, resulting in 60 EEG variables across four frequency bands. Positive and Negative Symptom Scale (PANSS) were assessed at baseline and 4-6 weeks follow-up after treatment with amisulpride or aripiprazole. Mann-Whitney U tests, a random forest (RF) classifier and RF regression were used for statistical analysis. Our study found that at baseline, FEP patients did not differ from controls in any of the EEG characteristics. A random forest classifier showed chance-level discrimination between patients and controls. The random forest regression explained 23% variance in positive symptom reduction after treatment in the patient group. In conclusion, in this largest antipsychotic- naïve EEG sample to date in FEP patients, we found no differences in macroscale EEG characteristics between patients with FEP and healthy controls. However, these EEG characteristics did show predictive value for positive symptom reduction following treatment with antipsychotic medication.

Phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients (from the OPTiMiSE cohort).

OBJECTIVE: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients. METHOD: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes. RESULTS: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (ß = 0.94, P = 0.016), younger age (ß = -0.07, P = 0.031) and absence of current comorbid major depression disorder (ß = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG. CONCLUSIONS: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies.

White matter maturation during 12 months in individuals at ultra-high-risk for psychosis.

OBJECTIVE: The neurodevelopmental hypothesis of psychosis suggests that disrupted white matter (WM) maturation underlies disease onset. In this longitudinal study, we investigated WM connectivity and compared WM changes between individuals at ultra-high-risk for psychosis (UHR) and healthy controls (HCs). METHOD: Thirty UHR individuals and 23 HCs underwent MR diffusion tensor imaging before and after 12 months of non-manualized standard care. Positive and negative symptoms and level of functioning were assessed. Tract-based spatial statistics were employed. RESULTS: During 12 months, none of the UHR individuals transitioned to psychosis. Both UHR individuals and HCs increased significantly in fractional anisotropy (FA). UHR individuals showed significant FA increases predominantly in the left superior longitudinal fasciculus (SLF) (P = 0.01), and HCs showed significant FA increases in the left uncinate fasciculus (P = 0.03). Within UHR individuals, a significant positive correlation between FA change and age was observed predominantly in the left SLF (P = 0.02). Within HCs, no significant correlation between FA change and age was observed. No significant correlations between baseline FA and clinical outcomes were observed; however, FA changes were significantly positively correlated to changes in negative symptoms (P = 0.04). CONCLUSION: As normal brain maturation occurs in a posterior to frontal direction, our findings could suggest disturbed WM maturation in UHR individuals.

Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study.

OBJECTIVE: Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation. METHOD: Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted. RESULTS: Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%. CONCLUSION: Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.

Patterns of white matter microstructure in individuals at ultra-high-risk for psychosis: associations to level of functioning and clinical symptoms.

BACKGROUND: Individuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals. METHODS: Forty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method. RESULTS: PLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD. CONCLUSIONS: UHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

Selective attention and mismatch negativity in antipsychotic-naïve, first-episode schizophrenia patients before and after 6 months of antipsychotic monotherapy.

BACKGROUND: Attention deficits have been frequently reported in schizophrenia. It has been suggested that treatment with second-generation antipsychotics can ameliorate these deficits. In this study, the influence of 6 months treatment with quetiapine, a compound with less affinity for dopamine D2 receptors than for serotonergic 5-HT2A receptors, on electrophysiological parameters of attention was investigated in a group of antipsychotic-naïve, first-episode schizophrenia patients compared with a group of age- and gender-matched healthy controls. METHOD: A total of 34 first-episode, antipsychotic-naïve patients with schizophrenia and an equal number of healthy controls were tested in a selective attention and a typical mismatch negativity (MMN) paradigm at baseline and after 6 months. The patients were treated with quetiapine according to their clinical needs during the period between baseline and follow-up, whereas controls received no treatment. RESULTS: Patients showed lower MMN and P200 amplitude than healthy controls in the selective attention paradigm at baseline, while this was not the case for MMN of the typical MMN paradigm. Interestingly, after 6 months treatment, this MMN deficit was only ameliorated in patients treated with above median dosages of quetiapine. Patients had lower P3B amplitude, yet showed similar levels of processing negativity and N100 amplitude compared with healthy controls, both at baseline and follow-up. CONCLUSIONS: The results indicate that deficits in MMN, P200 and P3B amplitude are present at early stages of schizophrenia, although depending on the paradigm used. Furthermore, the results indicate that 6 months quetiapine treatment ameliorates MMN but not P3B deficits, and only in those subjects on higher dosages.

Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology.

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.

OBJECTIVE: Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. METHOD: Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. RESULTS: Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found. CONCLUSION: The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.

The influence of impaired processing speed on cognition in first-episode antipsychotic-naïve schizophrenic patients.

BACKGROUND: Impaired cognition is a prominent feature of schizophrenia. To what extent the heterogeneous cognitive impairments can be accounted for by considering only a single underlying impairment or a small number of core impairments remains elusive. This study examined whether cognitive impairments in antipsychotic-naïve, first-episode schizophrenia patients may be determined by a relative slower speed of information processing. METHOD: Forty-eight antipsychotic-naïve patients with first-episode schizophrenia and 48 matched healthy controls were administered a comprehensive battery of neuropsychological tests to assess domains of cognitive impairments in schizophrenia. Composite scores were calculated, grouping tests into cognitive domains. RESULTS: There were significant differences between patients and healthy controls on global cognition and all cognitive domains, including verbal intelligence, processing speed, sustained attention, working memory, reasoning and problem solving, verbal learning and memory, visual learning and memory, and reaction time. All these significant differences, except for verbal intelligence and global cognition, disappeared when processing speed was included as a covariate. CONCLUSION: At the first stage of illness, antipsychotic-naïve patients with schizophrenia display moderate/severe impairments in all the cognitive domains assessed. The results support the contention of a global cognitive dysfunction in schizophrenia that to some extent may be determined by impaired processing speed.

Volumetric changes in the basal ganglia after antipsychotic monotherapy: a systematic review.

INTRODUCTION: Exposure to antipsychotic medication has been extensively associated with structural brain changes in the basal ganglia (BG). Traditionally antipsychotics have been divided into first and second generation antipsychotics (FGAs and SGAs) however, the validity of this classification has become increasingly controversial. To address if specific antipsychotics induce differential effects on BG volumes or whether volumetric effects are explained by FGA or SGA classification, we reviewed longitudinal structural magnetic resonance imaging (MRI) studies investigating effects of antipsychotic monotherapy. MATERIAL AND METHODS: We systematically searched PubMed for longitudinal MRI studies of patients with schizophrenia or non-affective psychosis who had undergone a period of antipsychotic monotherapy. We used specific, predefined search terms and extracted studies were hand searched for additional studies. RESULTS: We identified 13 studies published in the period from 1996 to 2011. Overall six compounds (two classified as FGAs and four as SGAs) have been investigated: haloperidol, zuclophentixol, risperidone, olanzapine, clozapine, and quetiapine. The follow-up period ranged from 3-24 months. Unexpectedly, no studies found that specific FGAs induce significant BG volume increases. Conversely, both volumetric increases and decreases in the BG have been associated with SGA monotherapy. DISCUSSION: Induction of striatal volume increases is not a specific feature of FGAs. Except for clozapine treatment in chronic patients, volume reductions are not restricted to specific SGAs. The current review adds brain structural support to the notion that antipsychotics should no longer be classified as either FGAs or SGAs. Future clinical MRI studies should strive to elucidate effects of specific antipsychotic drugs.