Andrea Polari

Genetic Dysregulation of Glutathione Synthesis Predicts Alteration of Plasma Thiol Redox Status in Schizophrenia

Genetic studies have shown an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls. As compared with patients with a low-risk GCLC GAG TNR genotype, patients with a high-risk genotype, having an impaired GSH synthesis, displayed a decrease of fibroblast GSH and plasma total cysteine levels, and an increase of the oxidized form of cysteine (cystine) content. Increased levels of plasma free serine, glutamine, citrulline, and arginine were also observed in the high-risk genotype. Taken together, the high-risk genotypes were associated with a subgroup of schizophrenia characterized by altered plasma thiols and free amino acid levels that reflect a dysregulation of redox control and an increased susceptibility to oxidative stress. This altered pattern potentially contributes to the development of a biomarker profile useful for early diagnosis and monitoring the effectiveness of novel drugs targeting redox dysregulation in schizophrenia.

Duration of untreated psychosis: a proposition regarding treatment definition

Aim: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first‐episode psychosis cohort to assess the impact of the choice of definition on DUP estimation.

A psychoeducation tool for patients with first‐episode psychosis

Psychoeducation interventions have been developed to explain illness and treatment to people with schizophrenia, in order to enable them to cope more effectively with their illness. Psychoeducational interventions are administrated in group, individual, family or multifamily group formats and address the illness from a multidimensional viewpoint, including biological, psychological and social perspectives. Participants are usually provided with information, emotional support and management strategies. Most often the intervention includes didactic materials such as leaflets, flyers, presentation slides, posters, movies and so on. In terms of efficacy, psychoeducational interventions seem to reduce the risk of relapse rate, hospital readmission and length of stay and promote medication compliance (1). It has been pinpointed that the optimal time for starting psychoeducation is still unknown, but it is suggested that psychoeducation should be offered as early as possible in order to be more effective (2). However, few studies have validly assessed the best timing for psychoeducation. Feldman et al. (2) found that psychoeducation in patients with either long (>7 years) or short (<5 years) illness duration did not influence 5-year rate of readmission, while it did so in those whose illness duration ranged from 5 to 7 years. The authors hypothesised that in participants with longer duration of illness, psychoeducation may actually reinforce a more fatalistic view of the illness, while it may fail to have any impact on participants with shorter duration of illness due to illness denial. This suggests that insight may play a more central role in this issue; in our experience, psychoeducation in itself may actually promote insight in the early phase of psychosis, provided content is properly adapted. However, most psychoeducational interventions are designed for patients suffering from well-established schizophrenia and their content may be inappropriate for first-episode psychosis (FEP) patients. There is therefore a need for new tools to address this issue in this patient population.

Pharmacogenetic study on risperidone long-acting injection: influence of cytochrome P450 2D6 and pregnane X receptor on risperidone exposure and drug-induced side-effects.

AbstractRisperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.

Duration of untreated psychosis: What are we talking about?

Duration of untreated psychosis (DUP) broadly refers to the time elapsing between onset of psychosis and treatment initiation. Its relationship with outcome has been intensely studied in the framework of the development of early intervention strategies for psychosis. Results of such research are however still a matter of controversy, some studies showing a negative impact of long DUP on outcome (1–4) while others do not (5–8). In a systematic literature review, Marshall (9) nevertheless concluded that there is a significant, albeit small to moderate, negative association between DUP and outcome, and most early intervention programmes rank reduction of DUP as a primary priority. From a clinical point of view, reduction of DUP emerges as a logical target when witnessing the collateral damage suffered by patients who experience long delays prior to onset of care (10). Additionally, recent imaging data have shown that the prodrome and the early phase of psychotic disorders are periods of active and progressive structural changes in key brain areas such as the hippocampus (11). If one assumes that there is an active process of neuroprogression underlying these changes, then the longer the DUP, the greater the time available for this potentially neurotoxic process to unfold (12). The nature of the pathogenic process remains to be fully elucidated; however, it probably includes reduction in neurotrophins, oxidative stress and inflammatory cytokines. Given the evidence that appropriate treatment is potentially neuroprotective (13), reduction in DUP could therefore be associated with reduction in potentially cumulative brain insult, and hence improvement in symptomatic and functional outcomes. In the last few years, assessment of psychosis onset has been the object of a considerable attention, and this interest has led to both a degree of consensus about its definition and the development of scales specifically designed to determine the date of its initial occurrence (14,15). A closer look at this literature reveals on the other hand that criteria applied to define the endpoint of DUP, in other words the time of treatment initiation, is much less consistent and vary greatly between studies. According to international guidelines, an adequate treatment of first episode psychosis should combine adapted medication (generally utilising low-dose strategy) and psychosocial intervention delivered in the context of easily accessible and specialised treatment teams (16–18). However, despite the availability of such guidelines, the concept of ‘treatment initiation’ usually refers to the commencement of very incomplete and often ill-defined interventions (Table 1). These include ‘initiation of medication’, ‘commencement of any form of treatment’, ‘initiation of adequate treatment’, ‘time of first effective treatment’, as well as ‘hospitalisation’ or ‘entry to a specialised programme’. In addition, adherence to treatment is in the vast majority of cases not assessed when in fact clinical experience reveals that enrollment in a specialised service or prescription of medication does not necessarily equate with the person being fully engaged with the service, receiving sufficient psychosocial support, or taking medication as prescribed. In the studies mentioned above, it is therefore highly likely that many patients for whom DUP was defined as having concluded actually remained untreated or partially treated. Only two studies defined treatment initiation on the basis of adherence to or observed response to medication treatment (14,30). However, by focusing on this aspect of treatment, they neglect the importance of psychosocial intervention in the recovery process (31), while recent randomised controlled trials have now clearly proven that integrated early intervention programmes that include specialised psychosocial treatment lead first episode psychosis patients to a better outcome than generic mental health programmes (32,33). This lack of consistency in definition is concerning, considering that an absence of consensus on what ‘treatment initiation’ actually comprises could very well be one of the critical factors that so far

Impaired mismatch negativity to frequency deviants in individuals at ultra-high risk for psychosis, and preliminary evidence for further impairment with transition to psychosis

BACKGROUND There is evidence to suggest that people with established psychotic disorders show impairments in the mismatch negativity induced by a frequency-deviant sound (fMMN), and that these impairments worsen with the deterioration of psychotic symptoms. This study aimed to test whether individuals at ultra-high risk (UHR) for psychosis show pre-morbid impairments in fMMN, and if so, whether fMMN continues to deteriorate with transition to psychosis. METHOD fMMN was recorded in a cohort of UHR individuals (n=42) and compared to healthy controls (n=29). Of the 27 UHR participants who returned for a second EEG session, six participants had transitioned to psychosis by 12-month follow-up (UHR-T) and were compared to the 21 participants who did not transition (UHR-NT). RESULTS fMMN amplitude was significantly reduced, relative to healthy controls, in the UHR cohort. Furthermore, UHR-T individuals showed a significant decrease in fMMN amplitude over the period from baseline to post-transition; this reduction was not observed in UHR-NT. CONCLUSIONS These results suggest that fMMN is abnormal in UHR individuals, as has repeatedly been found previously in people with established psychotic disorders. The finding that fMMN impairment worsens with transition to psychosis is consistent with the staging model of psychosis; however, caution must be taken in interpreting these findings, given the extremely small sample size of the UHR-T group.

Dynamic Prediction of Transition to Psychosis Using Joint Modelling

Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n = 304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.

Clinical trajectories in the ultra-high risk for psychosis population

BACKGROUND Traditionally, research in the ultra-high risk (UHR) for psychosis population has focused on the treatment of existing symptomatology and prevention of transition to psychosis. Recently, there has been an increase in focus on outcomes in individuals who do not transition to psychosis. However, there is a lack of standardised definitions of remission, recovery, recurrence and relapse in UHR, resulting in the inability to generalise and replicate outcomes. METHOD The aims of the current study were to develop definitions for remission, recovery, recurrence and relapse, and apply them to a UHR cohort allowing the identification of longitudinal clinical trajectories. Further stratification in broader categories of favourable and unfavourable outcomes was applied. The predictive value of various baseline factors on specific clinical trajectories was also assessed. RESULTS 17 different trajectories were identified in a cohort of 202 individuals within a 12-month period and classified according to the suggested definitions for recovery (35.7%), remission (7.5%), any recurrence (20%), no remission (17.3%), relapse (4.0%) and transition to psychosis (15.8%). Favourable and unfavourable trajectories represented 43.2% and 57.1% respectively. Long duration of untreated symptoms and high depression scores were associated with unfavourable outcomes. DISCUSSION It is possible to apply clear definitions of remission, recovery, recurrence, relapse and transition to psychosis to a UHR cohort to evaluate longitudinal clinical trajectories. Acceptance and use of these definitions will help to facilitate comparisons between trials and to improve clinical clarity across the range of available therapeutic options in UHR individuals.

Does reason for referral to an ultra-high risk clinic predict transition to psychosis?

To examine reasons for referral to a specialist ultra‐high risk (UHR) for psychosis clinic and whether these reasons are associated with risk for subsequent transition to psychosis.

The construct validity of the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE) as a measure of minimal self-disturbance: Preliminary data

AIM The Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE) is a self-report measure of minimal self-disturbance. The aim of the current report was to assess the construct validity of the scale by examining its convergent validity with the gold-standard measure of minimal self-disturbance, the Examination of Anomalous Self-Experience (EASE), and its discriminant validity. METHOD The sample consisted of 46 participants (21 ultra-high risk for psychosis patients, 14 first episode psychosis patients, 11 healthy controls). Correlations between the clinical instruments were examined. RESULTS The IPASE correlated strongly with general psychopathology and positive psychotic symptoms, moderately with negative symptoms, and weakly with manic symptoms. The strongest correlation (r = 0.92) was apparent between IPASE and EASE total scores. CONCLUSION These preliminary data indicate construct validity of the IPASE, demonstrating both convergent and discriminant validity. The IPASE may be suitable as a screener measure for minimal self-disturbance, but should not be used as a replacement to measure the construct of minimal self-disturbance, which requires considerable psychopathological sophistication.