Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

The Vitamins in Psychosis Study: A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Vitamins B12, B6, and Folic Acid on Symptoms and Neurocognition in First-Episode Psychosis.

BACKGROUND: Elevated homocysteine is observed in schizophrenia and associated with illness severity. The aim of this study was to determine whether vitamins B12, B6, and folic acid lower homocysteine and improve symptomatology and neurocognition in first-episode psychosis. Whether baseline homocysteine, genetic variation, sex, and diagnosis interact with B-vitamin treatment on outcomes was also examined. METHODS: A randomized, double-blind, placebo-controlled trial was used. A total of 120 patients with first-episode psychosis were randomized to an adjunctive B-vitamin supplement (containing folic acid [5 mg], B12 [0.4 mg], and B6 [50 mg]) or placebo, taken once daily for 12 weeks. Coprimary outcomes were change in total symptomatology (Positive and Negative Syndrome Scale) and composite neurocognition. Secondary outcomes included additional measures of symptoms, neurocognition, functioning, tolerability, and safety. RESULTS: B-vitamin supplementation reduced homocysteine levels (p = .003, effect size = -0.65). B-vitamin supplementation had no significant effects on Positive and Negative Syndrome Scale total (p = .749) or composite neurocognition (p = .785). There were no significant group differences in secondary symptom domains. A significant group difference in the attention/vigilance domain (p = .024, effect size = 0.49) showed that the B-vitamin group remained stable and the placebo group declined in performance. In addition, 14% of the sample had elevated baseline homocysteine levels, which was associated with greater improvements in one measure of attention/vigilance following B-vitamin supplementation. Being female and having affective psychosis was associated with improved neurocognition in select domains following B-vitamin supplementation. Genetic variation did not influence B-vitamin treatment response. CONCLUSIONS: While 12-week B-vitamin supplementation might not improve overall psychopathology and global neurocognition, it may have specific neuroprotective properties in attention/vigilance, particularly in patients with elevated homocysteine levels, patients with affective psychosis, and female patients. Results support a personalized medicine approach to vitamin supplementation in first-episode psychosis.

Individual placement and support for vocational recovery in first-episode psychosis: randomised controlled trial.

BACKGROUND: High unemployment is a hallmark of psychotic illness. Individual placement and support (IPS) may be effective at assisting the vocational recoveries of young people with first-episode psychosis (FEP).AimsTo examine the effectiveness of IPS at assisting young people with FEP to gain employment (Australian and Clinical Trials Registry ACTRN12608000094370). METHOD: Young people with FEP (n = 146) who were interested in vocational recovery were randomised using computer-generated random permuted blocks on a 1:1 ratio to: (a) 6 months of IPS in addition to treatment as usual (TAU) or (b) TAU alone. Assessments were conducted at baseline, 6 months (end of intervention), 12 months and 18 months post-baseline by research assistants who were masked to the treatment allocations. RESULTS: At the end of the intervention the IPS group had a significantly higher rate of having been employed (71.2%) than the TAU group (48.0%), odds ratio 3.40 (95% CI 1.17-9.91, z = 2.25, P = 0.025). However, this difference was not seen at 12- and 18-month follow-up points. There was no difference at any time point on educational outcomes. CONCLUSIONS: This is the largest trial to our knowledge on the effectiveness of IPS in FEP. The IPS group achieved a very high employment rate during the 6 months of the intervention. However, the advantage of IPS was not maintained in the long term. This seems to be related more to an unusually high rate of employment being achieved in the control group rather than a gross reduction in employment among the IPS group.Declaration of interestNone.

Reasons for referral and findings of clinical neuropsychological assessment in youth with mental illness: A clinical file audit.

Study aims were to 1) determine the characteristics and reasons for referral for Clinical Neuropsychological Assessment (CNA) and 2) characterize the findings and recommendations contained in the CNA reports, of clients attending a youth mental health service. File audit of all CNA reports (N = 140) of youth attending a mental health service. Cognitive performances on neuropsychological tests that were administered to >50% of clients were examined. Referral reasons, findings, and recommendations for future treatment were coded and described from neuropsychological files. Age of clients referred for CNA ranged from 13-29, the majority were male (62.5%), referred primarily from the early psychosis clinic (63.2%), and had a mean number of 3.5 presenting problems. Cognitive performances ranged from extremely low to very superior. Mean number of reasons for referral was 2, with treatment recommendation (55%) and diagnostic clarification (50.7%) being the most common. Mean number of findings from CNA was 5.8; most commonly, a diagnosis of clinically meaningful cognitive impairment (85%), followed by a recommendations for additional services/investigations (77.1%). CNA provides diagnostic clarification and treatment recommendations for youth receiving mental health treatment. Future studies should examine the cost-effectiveness, implementation, and objective impact of CNA in clinical practice.

Stress hormones and verbal memory in young people over the first 12 weeks of treatment for psychosis.

AIMS: Memory impairment in psychosis may be mediated through detrimental effects of hypothalamic-pituitary-adrenal (HPA) axis function. This study prospectively investigated the relationship between cortisol, sulphate dehydroepiandrosterone (DHEA(S) and cortisol: DHEA(S) ratio and memory in 35 first-episode psychosis (FEP) patients during the first 12 weeks of treatment and 23 healthy controls (HC). METHODS: Morning blood sampling and tests of attention, working memory and verbal memory occurred at baseline and 12-week follow-up. RESULTS: FEP and HC groups did not significantly differ in levels of cortisol, DHEA(S) or their ratio at baseline or over 12-weeks. The FEP group performed significantly below HC on all cognitive measures at baseline and over 12-weeks. Cortisol levels were unrelated to cognition in both groups. At baseline, DHEA(S) was positively associated with attention in HCs, but negatively associated with attention in FEP participants. Change in DHEA(S) was negatively associated with change in memory over 12-weeks in both groups. At 12-weeks, there was a negative correlation between the cortisol: DHEA(S) ratio and attention in both groups. CONCLUSIONS: These findings are mostly in contrast to findings in chronic schizophrenia. Investigation at different illness phases and over longer-follow-up periods is required to determine the complex relationship between HPA-axis and memory functioning in psychosis.

Adjunctive Taurine in First-Episode Psychosis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study.

OBJECTIVE: Taurine is an inhibitory neuromodulatory amino acid in the central nervous system that activates the GABA- and glycine-insensitive chloride channel and inhibits the N-methyl-D-aspartate receptor. It also functions as a neuroprotective agent and has a role in neural development and neurogenesis. The aim of this study was to determine the efficacy of adjunctive taurine in improving symptomatology and cognition among patients with a DSM-IV first-episode psychotic disorder. METHODS: 121 patients with first-episode psychosis, aged 18-25 years, attending early intervention services consented to participate in this randomized, double-blind, placebo-controlled trial conducted from January 2007 to May 2009. Patients taking low-dose antipsychotic medication were randomly assigned to receive once-daily taurine 4 g or placebo for 12 weeks. The coprimary outcomes were change in symptomatology (measured by the Brief Psychiatric Rating Scale [BPRS] total score) and change in cognition (measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia [MATRICS] Consensus Cognitive Battery composite score) at 12 weeks. Secondary outcomes included tolerability and safety and additional clinical and functioning measures. RESULTS: 86 participants (n = 47 taurine; n = 39 placebo) were included in the final analysis. Taurine significantly improved symptomatology measured by the BPRS total score (95% CI, 1.8-8.5; P = .004) and psychotic subscale (95% CI, 0.1-1.5; P = .026) compared to placebo. Additionally, improvements were observed in the Calgary Depression Scale for Schizophrenia (95% CI, 0.1-3.0; P = .047) and Global Assessment of Functioning (95% CI, 0.3-8.8; P = .04) scores. There was no group difference in composite cognitive score (95% CI, -1.7 to 1.0; P = .582). A significant group difference was found on one safety and tolerability item (psychic item 2, asthenia/lassitude/increased fatigability) of the Udvalg for Kliniske Undersogelser, with the taurine group showing a more favorable outcome (P = .006). CONCLUSIONS: Adjunctive taurine did not improve cognition, but it appears to improve psychopathology in patients with first-episode psychosis. The use of taurine warrants further investigation in larger randomized studies, particularly early in the course of psychosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00420823.

The impact of neuropsychological functioning and coping style on perceived stress in individuals with first-episode psychosis and healthy controls.

Stress is implicated in the development and course of psychotic illness, but the factors that influence stress levels are not well understood. The aim of this study was to examine the impact of neuropsychological functioning and coping styles on perceived stress in people with first-episode psychosis (FEP) and healthy controls (HC). Thirty-four minimally treated FEP patients from the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, and 26 HC participants from a similar demographic area participated in the study. Participants completed a comprehensive neuropsychological test battery as well as the Coping Inventory for Stressful Situations (task-, emotion- and avoidance-focussed coping styles) and Perceived Stress Scale (PSS). Linear regressions were used to determine the contribution of neuropsychological functioning and coping style to perceived stress in the two groups. In the FEP group, higher levels of emotion-focussed and lower levels of task-focussed coping were associated with elevated stress. Higher premorbid IQ and working memory were also associated with higher subjective stress. In the HC group, higher levels of emotion-focussed coping, and contrary to the FEP group, lower premorbid IQ, working memory and executive functioning, were associated with increased stress. Lower intellectual functioning may provide some protection against perceived stress in FEP.

Vascular endothelial growth factor and brain-derived neurotrophic factor in quetiapine treated first-episode psychosis.

Objective. It has been suggested that atypical antipsychotics confer their effects via brain-derived neurotrophic factor (BDNF). We investigated the effect of quetiapine on serum levels of BDNF and vascular endothelial growth factor (VEGF) in drug-naive first-episode psychosis subjects. Methods. Fifteen patients drawn from a larger study received quetiapine treatment for twelve weeks. Baseline levels of serum BDNF and VEGF were compared to age- and sex-matched healthy controls and to levels following treatment. Linear regression analyses were performed to determine the relationship of BDNF and VEGF levels with outcome measures at baseline and week 12. Results. The mean serum BDNF level was significantly higher at week 12 compared to baseline and correlated with reductions in Brief Psychiatric Rating Scale (BPRS) and general psychopathology scores. Changes in serum VEGF levels also correlated significantly with a reduction in BPRS scores, a significant improvement in PANNS positive symptoms scores, and displayed a positive relationship with changes in BDNF levels. Conclusions. Our findings suggest that BDNF and VEGF are potential biomarkers for gauging improvement of psychotic symptoms. This suggests a novel neurotrophic-based mechanism of the drug effects of quetiapine on psychosis. This is the first report of VEGF perturbation in psychosis.

The relative contribution of neurocognition and social cognition to 6-month vocational outcomes following Individual Placement and Support in first-episode psychosis.

AIMS: To examine whether baseline neurocognition and social cognition predict vocational outcomes over 6 months in patients with first-episode psychosis (FEP) enrolled in a randomised controlled trial of Individual Placement and Support (IPS) versus treatment as usual (TAU). METHODS: 135 FEP participants (IPS n=69; TAU n=66) completed a comprehensive neurocognitive and social cognitive battery. Principal axis factor analysis using PROMAX rotation was used to determine the underlying cognitive structure of the battery. Setwise (hierarchical) logistic and multivariate linear regressions were used to examine predictors of: (a) enrolment in education and employment; and (b) hours of employment over 6 months. Neurocognition and social cognition factors were entered into the models after accounting for premorbid IQ, baseline functioning and treatment group. RESULTS: Six cognitive factors were extracted: (i) social cognition; (ii) information processing speed; (iii) verbal learning and memory; (iv) attention and working memory; (v) visual organisation and memory; and (vi) verbal comprehension. Enrolment in education over 6 months was predicted by enrolment in education at baseline (p=.002) and poorer visual organisation and memory (p=.024). Employment over 6 months was predicted by employment at baseline (p=.041) and receiving IPS (p=.020). Better visual organisation and memory predicted total hours of paid work over 6 months (p<.001). CONCLUSIONS: Visual organisation and memory predicted the enrolment in education and duration of employment, after accounting for premorbid IQ, baseline functioning and treatment. Social cognition did not contribute to the prediction of vocational outcomes. Neurocognitive interventions may enhance employment duration in FEP.

A randomized controlled trial of vocational intervention for young people with first-episode psychosis: method.

AIM: Young people who are experiencing first-episode psychosis (FEP) are at increased risk of being unemployed compared to either their same age peers in the general population, or those with other mental illnesses. Significant research has been conducted examining employment interventions for those with chronic psychotic illness. This has yielded strong results in favour of an intervention called individual placement and support (IPS). However, significantly less work has examined the benefit of this approach to those in FEP when the potential for vocational rehabilitation is perhaps greater. This study adds to the knowledge of vocational intervention in first-episode psychotic illness. Additionally, it expands this work into the areas of cognition, social cognition, social inclusion and economics. METHODS: The study is a single-blind, randomized controlled trial comparing receiving high-quality FEP treatment as usual plus IPS (IPS + TAU) to a FEP treatment as usual (TAU) intervention alone within a specialized FEP service. RESULTS: The study recruited 146 people attending a first-episode psychosis service over 2 years. They were assessed at baseline, 6 months (end of intervention) 12 and 18 months with a battery covering psychopathology, economic, demographic, social cognitive, cognitive and diagnostic variables. CONCLUSIONS: This paper describes the methodology for the largest attempted study of IPS in FEP. This study has the capacity to answer questions about the benefits on illness and economic impacts of vocational recovery in FEP. Further, it has the capacity to extend knowledge about the contribution of cognitive and social cognitive factors to recovery in this domain.

Clinical neuropsychology within adolescent and young-adult psychiatry: conceptualizing theory and practice.

Historically, clinical neuropsychology has made significant contributions to the understanding of brain-behavior relationships, particularly in neurological conditions. During the past several decades, neuropsychology has also become established as an important discipline in psychiatric settings. Cognition is increasingly recognized as being core to psychiatric illnesses and predictive of functional outcomes, augmenting theories regarding symptomatology and illness progression. Adult-type psychiatric disorders (including schizophrenia and other psychotic, mood, anxiety, eating, substance-related, and personality disorders) typically emerge during adolescence or young adulthood, a critical neurodevelopmental period. Clinical neuropsychological assessment in adolescent psychiatric patients is particularly valuable in informing clinical formulation and intervention and can be therapeutic across a number of levels. This article articulates the theoretical considerations and practical challenges and applications of clinical neuropsychology within adolescent and young-adult psychiatry. The importance of considering the neurodevelopmental context and its relationship to current theoretical models underpinning clinical practice are discussed.

Phospholipase A2 activity in first episode schizophrenia: associations with symptom severity and outcome at week 12.

OBJECTIVES: Intracellular phospholipases A2 (inPLA2) are activated during monoaminergic neurotranismision and act as key enzymes in cell membrane repair and remodelling, neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes and neuroinflammation. Several independent studies found increased inPLA2 activity in drug-naïve first episode and chronic schizophrenia. This study investigates if inPLA2 activity is associated with symptoms severity and treatment response in first episode schizophrenia (FES). METHODS: InPLA2 activity was measured in serum of 35 young FES patients (mean age: 19.36 ± 3.32, mean duration of illness: 7.53 ± 6.28 months, 16 neuroleptic-naïve) before and after 12 weeks of treatment with second-generation antipsychotic medications (olanzapine, quetiapine or risperidone), as well as in 22 healthy controls matched for age. Psychopathology and social functioning were assessed at the same time points. RESULTS: Baseline inPLA2 activity was significantly increased in drug-naïve and treated FES patients compared to healthy controls. Baseline inPLA2 activity was also associated with severity of negative symptoms and lower functioning at baseline. Furthermore, baseline inPLA2 activity was associated with improvement in negative symptoms and functioning within the first 12 weeks of treatment. CONCLUSIONS: Intracellular PLA2 activity is increased in first episode schizophrenia and associated with symptom severity and outcome after 12 weeks of treatment. Future studies should investigate the implications of inPLA2 activity as a potential predictor of treatment response for different antipsychotic agents.

Cognition at illness onset as a predictor of later functional outcome in early psychosis: systematic review and methodological critique.

BACKGROUND: Cognitive deficits occur early in the course of psychosis, are mostly stable, and have been identified as potential functional prognostic markers. Previous reviews of chronic schizophrenia have concluded that specific cognitive deficits are strongly associated with poorer functional outcomes. However, results of schizophrenia studies may be influenced by the effects of long-term illness or treatment or be biased toward individuals with poorer outcomes and may not be relevant to early psychosis (EP). This review aimed to systematically examine the evidence regarding general and social cognitive predictors of later functional outcome in EP and critique the methodology of the studies reviewed. A final aim was to conduct a meta-analysis of the studies reviewed, but methodological reasons precluded this. METHOD: A comprehensive search of PsycINFO and MEDLINE databases identified 15 relevant articles and 7 further articles following a reference list search, totaling 22 included articles. RESULTS: Most studies found at least one cognitive domain predicted functional outcome, but examination of separate cognitive domains revealed there were more null than significant associations between cognition and functional outcome across every cognitive domain. No study examined social cognition as a predictor of outcome. The frequency with which different cognitive domains predicted outcome varied depending on study methodology and this was most noticeable when studies with short-term follow-up were compared with longer-term follow-up studies. CONCLUSIONS: Due to the methodological variability and limitations of the studies reviewed, firm conclusions regarding the relationship between cognition and functional outcomes in EP cannot be made. Tentatively, cognition may be prognostic in EP, especially for longer-term outcomes. However, further research that addresses the methodological issues identified, including examination of social cognition and other non-cognitive predictors, is needed.

Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: a longitudinal T2 relaxometry pilot study.

We used magnetic resonance imaging to examine the effect of ethyl-eicosapentaenoic acid (E-EPA) on hippocampal T(2) relaxation time in first episode psychosis patients at baseline and after 12 weeks of follow-up. There was an increase in T(2) in the placebo group but not in the E-EPA group, suggesting a neuroprotective effect of E-EPA treatment. In addition, the smaller the increase in T(2), the greater the improvement in negative symptoms.

The effect of atypical antipsychotics on pituitary gland volume in patients with first-episode psychosis: a longitudinal MRI study.

BACKGROUND: Pituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations. AIMS: To determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population. METHOD: Pituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naïve, at baseline and after 3months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication. RESULTS: There was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naïve and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r=-0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses. CONCLUSIONS: Atypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.

Grey and white matter abnormalities are associated with impaired spatial working memory ability in first-episode schizophrenia.

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

Medial temporal lobe glutathione concentration in first episode psychosis: a 1H-MRS investigation.

Glutathione (GSH) is implicated in the pathophysiology of schizophrenia. Previous brain spectroscopy studies, however, have been inconsistent, and there is little data available from first episode psychosis patients. This study compared brain GSH in a first episode cohort (n=30) to controls (n=18), using magnetic resonance spectroscopy (MRS), examining a temporal lobe voxel. Short-echo (TE 30 ms) acquisition proton MRS was performed on a 3T clinical magnetic resonance scanner. Comparison of the first-episode and control groups' GSH concentrations revealed a significant main effect of group (F(1,46)=4.7, p=0.035), but no main effect of hemisphere (F(1,46)=2.3, p=0.137) or group-by-side interactions (F(1,46)=0.4, p=0.513). Medial temporal lobe GSH concentrations in the first episode group were 22% higher than those in the control group. This study provides further evidence of significant perturbations in brain GSH in first episode psychosis, and supports a broader involvement of GSH in the pathophysiology of schizophrenia.

Dosing quetiapine in drug-naive first-episode psychosis: a controlled, double-blind, randomized, single-center study investigating efficacy, tolerability, and safety of 200 mg/day vs. 400 mg/day of quetiapine fumarate in 141 patients aged 15 to 25 years.

OBJECTIVE: To assess dosing, efficacy, and tolerability of quetiapine fumarate in drug-naive first-episode psychosis. METHOD: We present a prospective, randomized, controlled, single-center, double-blind, fixed-dose, 4-week comparison study of 200 mg/day versus 400 mg/day of quetiapine in 141 drug-naive acutely ill first-episode psychosis patients (diagnosed according to DSM-IV) aged 15 to 25 years. The double-blind 4-week trial (Part 1) was followed by a single-blind, naturalistic, flexible-dose 8-week period (Part 2). The main outcome measures were symptomatic change, functioning, and tolerability. Data were collected from July 2003 until January 2006. RESULTS: The estimated time trends of the linear mixed-effects modeling indicated that efficacy between the 2 treatment groups in Part 1 was similar for most outcome measures except for 5 measures: the Scale for the Assessment of Negative Symptoms (SANS) anhedonia-asociality subscale (p = .011), the Social and Occupational Functioning Assessment Scale (p = .020), the Global Assessment of Functioning scale (p = .070), the SANS affective flattening or blunting subscale (p = .051), and the Udvalg for Kliniske Undersogelser total (p = .056), suggesting that the 200-mg group improved more for the SANS anhedonia-asociality subscale, whereas the 400-mg group showed a slight deterioration. Social and global functioning also improved more in the 200-mg group than in the 400-mg group. Part 2 of the study revealed that, independent of the initial target dose, when clinicians were able to adjust the dose flexibly, the dose at 12 weeks was similar between groups and averaged 268 mg/day. CONCLUSION: Our study in acutely ill drug-naive first-episode psychosis patients suggests that quetiapine is a safe and well-tolerated antipsychotic medication. In contrast to multiepisode patients, dosing should be more conservative in untreated new-onset cases. An initial dose of 250 to 300 mg/day of quetiapine is proposed as a primary target dose in drug-naive first-episode psychosis patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449397.

Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial.

OBJECTIVE: To investigate if ethyl-eicosapentaenoic acid (E-EPA) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis (FEP). METHOD: We performed a 12-week, randomized, double-blind, placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients. Sixty-nine patients were eligible for analysis; a post hoc analysis was computed for a subgroup of nonaffective FEP patients (N = 53). The first participant was included in November 2000 and the last participant completed the trial in August 2003. Primary outcome measures were symptom change scores and time to first response, while tolerability measures and cumulative antipsychotic dose were secondary outcome measures. RESULTS: Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores. Cox regression analysis revealed a significant treatment by diagnosis interaction (p = .024) for time to first response favoring E-EPA in nonaffective psychosis. Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 (42.9% [15/35] vs. 17.6% [6/34] for all participants, p = .036; 54.2% [13/24] vs. 17.2% [5/29] for the nonaffective psychosis subset, p = .008); however, the difference at week 12 was no longer significant. Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20% less antipsychotic medication between weeks 4 through 6 (p = .03), had less extrapyramidal side effects in the initial 9 weeks (p < .05 for all participants and for all timepoints), and reported less constipation (p = .011) and fewer sexual side effects (p = .016) than those treated with antipsychotic medication alone. CONCLUSION: The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications. However, it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis, possibly due to a ceiling effect, since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone. Further controlled trials in nonaffective early psychosis seem warranted. TRIAL REGISTRATION: Australian Clinical Trials Registry identifier 12605000267651 (http://actr.org.au).

Moyamoya disease in a patient with schizophrenia.

We present the case of a 23-year-old Vietnamese male with a 2-year history of a psychotic illness marked by prominent negative symptoms, fatuousness and disturbed behavior. Neuroimaging revealed a prominent vascular flow void affecting the middle and anterior cerebral arteries, with associated increased collateral supply to the frontal cortex, consistent with Moyamoya disease. Neurological examination was unremarkable; however, neuropsychological assessment revealed significant executive dysfunction, including stimulus-driven behavior. Whilst the diagnosis of schizophrenia and Moyamoya disease may be coincidental, an interaction between the 2 diseases may have led to some of the atypical features of this case, including prominent executive dysfunction and marked sensitivity to psychotropic medication. We discuss the nature of possible interactions between the 2 conditions. This case also highlights the importance of re-evaluating patients with atypical or treatment-resistant psychoses for cerebral pathology.