Treatment Response In First-episode Schizophrenia Research Articles

Baseline white matter function predicts short-term treatment response in first-episode schizophrenia.

The detection and characterization of functional activities in the gray matter of schizophrenia (SZ) have been widely explored. However, the relationship between resting-state functional signals in the white matter of first-episode SZ and short-term treatment response remains unclear. Thirty-six patients with first-episode SZ and 44 matched healthy controls were recruited in this study. Patients were classified as nonresponders and responders based on response to antipsychotic medication during a single hospitalization. The fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) of white matter were calculated. The relationships between functional changes and clinical features were analyzed. In addition, voxel-based morphometry was performed to analyze the white matter volume. One-way analysis of variance showed significant differences of fALFF and ReHo in the left posterior thalamic radiation and left cingulum (hippocampus) in the patient group, and the areas were regarded as seeds. The FC was calculated between seeds and other white matter networks. Compared with responders, nonresponders showed significantly increased FC between the left cingulum (hippocampus) and left posterior thalamic radiation, splenium of corpus callosum, and left tapetum, and were associated with the changes of clinical assessment. However, there was no difference in white matter volume between groups. Our work provides a novel insight that psycho-neuroimaging-based white matter function holds promise for influencing the clinical diagnosis and treatment of SZ.

Virtual histology of morphometric similarity network after risperidone monotherapy and imaging-epigenetic biomarkers for treatment response in first-episode schizophrenia.

Antipsychotic treatment has been conceived to alter brain connectivity, but it is unclear how the changes of network phenotypes relate to the underlying transcriptomics. Given DNA methylation (DNAm) may alter transcriptional levels, we further integrated an imaging-transcriptomic-epigenetic analysis to explore multi-omics treatment response biomarkers. Forty-two treatment-naive first-episode schizophrenia patients were scanned by TI weighted (T1W) imaging and DTI before and after 8-week risperidone monotherapy, and their peripheral blood genomic DNAm values were examined in parallel with MRI scanning. Morphometric similarity network (MSN) quantified with DTI and T1W data were used as a marker of treatment-related alterations in interareal cortical connectivity. We utilized partial least squares (PLS) to examine spatial associations between treatment-related MSN variations and cortical transcriptomic data obtained from the Allen Human Brain Atlas. Longitudinal MSN alterations were related to treatment response on cognitive function and general psychopathology symptoms, while DNAm values of 59 PLS1 genes were on negative and positive symptoms. Virtual-histology transcriptomic analysis linked the MSN alterations with the neurobiological, cellular and metabolic pathways or processes, and assigned MSN-related genes to multiple cell types, specifying neurons and glial cells as contributing most to the transcriptomic associations of longitudinal changes in MSN. We firstly reveal how brain-wide transcriptional levels and cell classes capture molecularly validated cortical connectivity alterations after antipsychotic treatment. Our findings represent a vital step towards the exploration of treatment response biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.

Developmental trajectories of premorbid functioning predict cognitive remediation treatment response in first-episode schizophrenia.

Cognitive development after schizophrenia onset can be shaped by interventions such as cognitive remediation, yet no study to date has investigated whether patterns of early behavioral development may predict later cognitive changes following intervention. We therefore investigated the extent to which premorbid adjustment trajectories predict cognitive remediation gains in schizophrenia. In a total sample of 215 participants (170 first-episode schizophrenia participants and 45 controls), we classified premorbid functioning trajectories from childhood through late adolescence using the Cannon-Spoor Premorbid Adjustment Scale. For the 62 schizophrenia participants who underwent 6 months of computer-assisted, bottom-up cognitive remediation interventions, we identified MATRICS Consensus Cognitive Battery scores for which participants demonstrated mean changes after intervention, then evaluated whether developmental trajectories predicted these changes. Growth mixture models supported three premorbid functioning trajectories: stable-good, deteriorating, and stable-poor adjustment. Schizophrenia participants demonstrated significant cognitive remediation gains in processing speed, verbal learning, and overall cognition. Notably, participants with stable-poor trajectories demonstrated significantly greater improvements in processing speed compared to participants with deteriorating trajectories. This is the first study to our knowledge to characterize the associations between premorbid functioning trajectories and cognitive remediation gains after schizophrenia onset, indicating that 6 months of bottom-up cognitive remediation appears to be sufficient to yield a full standard deviation gain in processing speed for individuals with early, enduring functioning difficulties. Our findings highlight the connection between trajectories of premorbid and postmorbid functioning in schizophrenia and emphasize the utility of considering the lifespan developmental course in personalizing therapeutic interventions.

White matter correlates of impulsivity in frontal lobe and their associations with treatment response in first-episode schizophrenia

BackgroundIt is known that increased impulsivity in schizophrenia patients causes poor treatment outcomes by increasing cost, stigma, hospitalization, treatment challenge, and physical harm. Dysfunction in the prefrontal cortex appears to be involved in the impulsivity associated with schizophrenia; nonetheless, there is a dearth of research on specific white matter alterations in the prefrontal cortex related to impulsivity. MethodsWe enrolled in the present study 119 first-episode schizophrenia patients. We measured their symptom severity at baseline and after eight weeks of treatment, using the positive and negative syndrome scale. We performed neuroimaging analysis using the Tract-Based Spatial Statistics program and by specifying the prefrontal white matter as a region of interest. ResultsIn voxel-wise correlational analysis, we observed white matter regions showing significant positive correlations with poor impulse control scores, in both the right dorsolateral prefrontal cortex and the right frontal pole region. The fractional anisotropy values of these areas correlated positively with symptom severity at baseline. Moreover, after eight weeks, treatment non responders showed significantly higher fractional anisotropy values in the same areas. ConclusionsThe results of the present study suggest that white matter tracts in the right dorsolateral prefrontal cortex and the right frontal pole may underlie dysfunctional impulse control and could be potential predictive markers for short-term treatment in patients with first-episode schizophrenia.

Dissecting the Heterogeneity of Treatment Response in First-Episode Schizophrenia.

The Mental Health Centers for Intervention Development and Applied Research (CIDAR) program prioritized research to provide an evidence base for biomarker development. At the Zucker Hillside Hospital (ZHH), our CIDAR grant supported research on a comprehensive investigation of treatment response and outcome in first episode schizophrenia. Results provide evidence that baseline neuroimaging, neurocognitive, and genetic measures are significantly associated with clinical response to treatment, and that our currently available interventions can effectively treat aspects of psychotic illness, as well as potentially reduce comorbidity associated with illness. Future research may include combining modalities to more robustly predict response and identify treatment targets, as well as to further develop more effective intervention strategies for these devastating and disabling disorders.

Treatment Response in First-episode Schizophrenia

First episode schizophrenia (FES) patients tend to be more responsive to treatment. An adequate response has been associated with a favourable long-term course in FES patients. Yet, despite the generally very favourable response profile around one quarter of the patients shows persisting symptoms of psychosis. To improve the outcome and course of psychosis great effort has emerged in identifying biological and clinical variables associated with non-response in order to identify non-responders as early as possible and adopt specific treatment strategies improving illness outcome. Different antipsychotic treatment regimens have been evaluated in terms of their efficacy in reducing symptoms of FES with psychological interventions gaining increasing importance in the treatment concept of patients suffering from their first illness episode. Therefore, aim of this review is to summarize current evidence on the response patterns, the most important predictors of response/non-response as well as on effective treatment interventions in FES patients.

Time to Treatment Response in First-Episode Schizophrenia

Response patterns may differ between patients with first-episode and multiepisode schizophrenia. This analysis explored trial duration with first-episode patients and asked whether early limited improvement predicts ultimate lack of treatment response with first-episode patients as it does with multiepisode patients. One hundred twelve subjects (mean age = 23.3 years, SD = 5.1 years) who presented between November 1998 and October 2004 with a first episode of psychosis and had a DSM-IV diagnosis of schizophrenia or schizophreniform or schizoaffective disorder were randomly assigned to treatment with olanzapine or risperidone for 16 weeks. Treatment response, the primary outcome measure, was defined as a rating of mild or better on all of the positive symptom items on the Schedule for Affective Disorders and Schizophrenia Change Version With Psychosis and Disorganization Items. Response rates were calculated for each study week. A logistic regression analysis examined the association between percentage reduction in symptom severity scores from baseline values at weeks 2, 4, or 8 and response by week 16. The study was conducted at The Zucker Hillside Hospital, Glen Oaks, New York and the Bronx-Lebanon Hospital Center, Bronx, New York. The estimated cumulative response rate was 39.59% (95% CI, 29.77%-49.41%) by week 8 and 65.19% (95% CI, 55.11%-75.27%) by week 16. The confidence intervals for estimated response at weeks 10, 12, 14, and 16 were not distinct. Response rates increased approximately 5 to 6 percentage points each 2-week interval between week 10 and 16. Percentage reduction in symptom severity score at week 4 (but not 2 or 8) was associated (χ²₁ = 3.96; P < .05) with responder status at week 16 (odds ratio = 1.03; 95% CI, 1.00-1.05). However, receiver operating characteristic curves did not suggest any level of percentage symptom reduction that would be clinically useful as a predictor of response by week 16. Many first-episode patients respond between weeks 8 and 16 of treatment with a single antipsychotic medication. Limited early symptom improvement does not identify those first-episode patients who will not improve with a full 16-week trial with enough accuracy to be clinically useful. clinicaltrials.gov Identifier: NCT00000374.

Magnetic Resonance Imaging Predictors of Treatment Response in First-Episode Schizophrenia

Identifying neurobiological predictors of response to antipsychotics in patients with schizophrenia is a critical goal of translational psychiatry. Few studies, however, have investigated the relationship between indices of brain structure and treatment response in the context of a controlled clinical trial. In this study, we sought to identify magnetic resonance (MR) imaging measures of the brain that predict treatment response in patients experiencing a first-episode of schizophrenia. Structural MR imaging scans were acquired in 39 patients experiencing a first-episode of schizophrenia with minimal or no prior exposure to antipsychotics participating in a double-blind 16-week clinical trial comparing the efficacy of risperidone vs olanzapine. Twenty-five patients were classified as responders by meeting operationally defined treatment response criteria on 2 consecutive study visits. Fourteen patients never responded to antipsychotic medication at any point during the clinical trial. MR imaging scans were also acquired in 45 age- and sex-matched healthy volunteers. Cortical pattern matching methods were used to compare cortical thickness and asymmetry measures among groups. Statistical mapping results, confirmed by permutation testing, indicated that responders had greater cortical thickness in occipital regions and greater frontal cortical asymmetry compared with nonresponders. Moreover, among responders, greater thickness in temporal regions was associated with less time to respond. Our findings are consistent with the hypothesis that plasticity and cortical thickness may be more preserved in responders and that MR imaging may assist in the prediction of antipsychotic drug response in patients experiencing a first-episode of schizophrenia.

Time Course for Antipsychotic Treatment Response in First-Episode Schizophrenia

The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia. Time to clinical response (>/=20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days. Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1-2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients. Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.

Time Course for Antipsychotic Treatment Response in First-Episode Schizophrenia

The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia. Time to clinical response (>/=20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days. Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1-2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients. Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.

Prolactin levels in risperidone treatment of first-episode schizophrenia

OBJECTS: To evaluate the risperidone effect on prolactin (PRL) levels and to analyse the relation between PRL change and treatment response in first-episode schizophrenia patients.METHOD: Patients with a first-episode of schizophrenia who were consecutively admitted for hospitalisation participated in a longitudinal follow-up study that included clinical evaluation (PANSS) and PRL assessment. All patients were treated under open conditions with risperidone.RESULTS: Risperidone in an average dose lower than 4 mg significantly improved both positive and negative symptoms. Co-operating responders undergoing maintenance therapy showed a mild trend towards further long-term improvement. At the end of acute treatment the average elevation of PRL levels almost doubled the baseline value. There was a trend among responders to return to their initial values during long-term therapy. Three-quarters of the subjects had hyperprolactinaemia at the end of acute treatment (44 days), and after 1 year about one-quarter had hyperprolactinaemia. No significant correlation between PRL change and PANSS score change was found.CONCLUSION: There is a considerable variation of PRL elevation among subjects. In some patients the development of tolerance of the PRL-elevating effect was observed. Risperidone-induced changes of PRL levels may not be associated with treatment response.

Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia

There is growing evidence for a relationship between the duration of untreated psychosis (DUP) and the prognosis in schizophrenia. The objective of this study is to evaluate whether DUP and premorbid level of social functioning are related to treatment response in acute treatment of first-episode schizophrenia. Seventy-nine first-episode schizophrenia patients were assessed with BPRS, SAPS, and SANS on admission and discharge during their first hospitalisation. Percentage of the difference between admission and discharge in total scores of all scales were taken as measures of absolute symptom reduction. The median DUP was 6 months (mean=8.6). DUP was correlated with reduction in BPRS and SAPS scores but not SANS scores. Patients with a short DUP ( n=41) also showed a higher reduction in BPRS, and SAPS scores than those with a long DUP. Premorbid Adjustment Scale (PAS) scores were inversely correlated with age at onset and positively correlated with BPRS scores at admission. We did not find any relationship between PAS scores and response to treatment. Our findings suggest that DUP may be an important predictor of response in acute treatment of first-episode schizophrenia and thus, attempts for early diagnosis may also have a positive effect on acute treatment response.

Predictors of antipsychotic treatment response in patients with first episode schizophrenia, schizoaffective, and schizophreniform disorders

Background Duration of untreated psychosis (DUP) may contribute to the observed heterogeneity of the treatment response in first-episode schizophrenia. Aims To examine the relationship of DUP and premorbid function with clinical outcomes following up to 2 years of antipsychotic treatment. Method For a subsample ( n =191) of subjects participating in a clinical trial, DUP and premorbid function were prospectively compared with clinical response to olanzapine or haloperidol. Results Shorter DUP and good premorbid function each independently are associated with better clinical response, including improvement in overall psychopathology and negative symptoms. Premorbid function also is associated with positive symptom, social and vocational outcomes. Conclusions Earlier antipsychotic treatment is associated with better outcomes in first-episode schizophrenia. Poor premorbid function could indicate an illness subtype less likely to respond to antipsychotic treatment regardless of when it is instituted.

Obstetric complications predict treatment response in first-episode schizophrenia.

Understanding the role of obstetric complications (OCs) in schizophrenia could potentially shed light on the heterogeneity in the aetiology and course of schizophrenia. Many investigators have reported an association between OCs and schizophrenia, but few have examined the association between OCs and treatment outcome. We investigated this question in a sample of patients studied during their first episode of schizophrenia, schizoaffective or schizophreniform disorder. OC histories were obtained for 59 patients participating in the Hillside First Episode Study. Cox proportional hazards regression analysis was used to estimate the effect of OCs on treatment response during the first episode of schizophrenia. Twelve of the 59 patients (20%) had positive histories of OCs. This group exhibited lower rates of treatment response than those with negative OC histories (hazard ratio controlling for sex = 0.28; 95% CI = 0.13, 0.62). The positive OC group also had significantly greater lateral ventricle volume, baseline disorganization and number of live births. The effect of OC history on treatment response held when these three variables were controlled for. A history of obstetric complications predicted poor response to treatment in the first episode of schizophrenia. This large effect was based on a small sample of 59 patients. Thus, replication is called for.

Time course and biologic correlates of treatment response in first-episode schizophrenia.

To examine the course and potential predictors of treatment response in the early phase of schizophrenia. Prospective study of an inception cohort. Psychiatric division of an academic medical center with a suburban metropolitan catchment area. Seventy first-episode patients who had undergone four biologic assessment procedures (brain magnetic resonance imaging, behavioral response to methylphenidate hydrochloride, growth hormone levels, eye tracking) were treated with a standardized antipsychotic drug protocol until recovery. Response was measured in terms of psychopathology and degree of remission. Using survival analysis, the proportion of patients remitting by 1 year was estimated at 83%. Mean and median times to remission were 35.7 weeks and 11 weeks, respectively. No baseline demographic or psychopathologic measure significantly predicted time to or level of remission. However, males tended to be nonresponders to treatment and have diagnoses of schizophrenia rather than schizoaffective disorder. Brain pathomorphology and abnormal basal growth hormone significantly predicted time to remission. These results indicate that the antipsychotic treatment response of first-episode schizophrenics is better than chronic multiepisode patients and suggest that specific pathobiologic markers reflect pathophysiologic processes that mediate antipsychotic treatment response.