Patients with first-episode psychosis in northern Taiwan: neurocognitive performance and niacin response profile in comparison with schizophrenia patients of different familial loadings and relationship with clinical features.

BACKGROUND: Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. METHODS: Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients' impairment on the CPT, WCST, and NRA. RESULTS: Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: -1.24 for NRA, - 1.06 for undegraded d', - 0.70 for degraded d', - 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. CONCLUSIONS: This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

Guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis: a 2-year randomized controlled trial with a naturalistic cohort.

BACKGROUND: Patients with remitted psychosis face a dilemma between the wish to discontinue antipsychotics and the risk of relapse. We test if an operationalized guided-dose-reduction algorithm can help reach a lower effective dose without increased risks of relapse. METHODS: A 2-year open-label randomized prospective comparative cohort trial from Aug 2017 to Sep 2022. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomized 2:1 into guided dose reduction group (GDR) v. maintenance treatment group (MT1), together with a group of naturalistic maintenance controls (MT2). We observed if the relapse rates would be different between 3 groups, to what extent the dose could be reduced, and if GDR patients could have improved functioning and quality of life. RESULTS: A total of 96 patients, comprised 51, 24, and 21 patients in GDR, MT1, and MT2 groups, respectively. During follow-up, 14 patients (14.6%) relapsed, including 6, 4, and 4 from GDR, MT1, and MT2, statistically no difference between groups. In total, 74.5% of GDR patients could stay well under a lower dose, including 18 patients (35.3%) conducting 4 consecutive dose-tapering and staying well after reducing 58.5% of their baseline dose. The GDR group exhibited improved clinical outcomes and endorsed better quality of life. CONCLUSIONS: GDR is a feasible approach as the majority of patients had a chance to taper antipsychotics to certain extents. Still, 25.5% of GDR patients could not successfully decrease any dose, including 11.8% experienced relapse, a risk comparable to their maintenance counterparts.

Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD.

The neurodevelopmental model of schizophrenia is supported by multi-level impairments shared among schizophrenia and neurodevelopmental disorders. Despite schizophrenia and typical neurodevelopmental disorders, i.e., autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as disorders of brain dysconnectivity, no study has ever elucidated whether whole-brain white matter (WM) tracts integrity alterations overlap or diverge between these three disorders. Moreover, whether the linked dimensions of cognition and brain metrics per the Research Domain Criteria framework cut across diagnostic boundaries remains unknown. We aimed to map deviations from normative ranges of whole-brain major WM tracts for individual patients to investigate the similarity and differences among schizophrenia (281 patients subgrouped into the first-episode, subchronic and chronic phases), ASD (175 patients), and ADHD (279 patients). Sex-specific WM tract normative development was modeled from diffusion spectrum imaging of 626 typically developing controls (5-40 years). There were three significant findings. First, the patterns of deviation and idiosyncrasy of WM tracts were similar between schizophrenia and ADHD alongside ASD, particularly at the earlier stages of schizophrenia relative to chronic stages. Second, using the WM deviation patterns as features, schizophrenia cannot be separated from neurodevelopmental disorders in the unsupervised machine learning algorithm. Lastly, the canonical correlation analysis showed schizophrenia, ADHD, and ASD shared linked cognitive dimensions driven by WM deviations. Together, our results provide new insights into the neurodevelopmental facet of schizophrenia and its brain basis. Individual's WM deviations may contribute to diverse arrays of cognitive function along a continuum with phenotypic expressions from typical neurodevelopmental disorders to schizophrenia.

Follow-up of subjects labelled with putative pre-psychotic states: Viewed from a transdiagnostic clinical high-at-risk mental state (CHARMS) paradigm.

BACKGROUND: Follow-up of subjects with putative pre-psychotic states is essential to clarify the transition process to psychosis, while "non-converters" also deserve clinical attention as many may evolve into other psychiatric disorders with diverse outcomes. This study aimed to examine help-seeking individuals who have been labelled at clinical high-risk state but not converting to full-blown psychosis during first two years of follow-up. METHODS: A retrospective observational cohort study of help-seeking subjects was conducted by reviewing medical records of participants in a previous early psychosis study at the study hospital between 2006 and 2020. We portrayed those who developed first episode psychosis after first 2-year follow-up in detail, and provided sketches of clinical macrophenotypes other than psychosis emerging from subjects among different risk groups. RESULTS: Among 132 eligible subjects, data of 98 (74.2%) were available for detailed evaluation. Of these, 15 transitioned to first-episode psychosis (11.4%) with time to psychosis from 2 to 11 years, 11 had anxiety spectrum (8.3%), 11 had depressive spectrum (8.3%), 10 had obsessive compulsive (7.6%), 5 had bipolar spectrum disorders (3.8%), 13 had predominantly schizotypal (9.8%) and 4 had other personality traits (3%), and 13 had problems attributable to adjustment or developmental issues (9.8%). CONCLUSION: Various diagnoses, either full- or sub-threshold, appropriately describe the diverse clinical phenomenology of a cohort presenting with non-specific and/or subthreshold psychotic symptoms. The clinical high-at-risk mental state (CHARMS) paradigm provides a reasonable transdiagnostic approach for orienting clinicians' attention toward young subjects seeking mental health help at an early stage of illness to potentially pluripotent trajectories.

Risk of Intracranial Hemorrhage With Concomitant Use of Antidepressants and Nonsteroidal Anti-inflammatory Drugs: A Nested Case-Control Study.

BACKGROUND: Whereas previous studies found that concomitant antidepressant and nonsteroidal anti-inflammatory drug (NSAIDs) use may increase the risk of gastrointestinal bleeding, either drug alone increases the risk of intracranial hemorrhage (ICH). OBJECTIVE: To assess the risk for ICH in patients on concomitant treatment with antidepressants and NSAIDs. METHODS: This was a nested case-control study using national insurance claims data in Taiwan between 2005 and 2013. Drug exposure was measured and compared during 3 time windows: 1 to 30, 31 to 60, and 61 to 90 days before the index date, which is the date of the ICH event. Both traditional and newer-generation antidepressants were considered in this study. RESULTS: Patients exposed to both antidepressants and NSAIDs 1 to 30 days before the index date presented a 50% increased odds of developing ICH (OR: 1.53; 95% CI: 1.31-1.80) compared with patients receiving antidepressants alone. Specifically, the concomitant use of nonselective NSAIDs and antidepressants increased these odds compared with antidepressants alone (OR: 1.56; 95% CI: 1.31-1.84), but using a selective cyclooxygenase-2 inhibitor with antidepressant did not alter ICH risk. Regarding antidepressant class, newer-generation antidepressants generally increase the odds of developing ICH by 60% when used concomitantly with NSAIDs. CONCLUSION AND RELEVANCE: Our results suggested that the concomitant use of antidepressants and NSAIDs was associated with an increased odds of developing ICH. NSAIDs, especially nonselective NSAIDs, and serotonergic antidepressants played an important role in this risk. Given the prevalent use of these 2 classes of drugs, this potential drug interaction deserves more attention.

Generalization of diffusion magnetic resonance imaging-based brain age prediction model through transfer learning.

Brain age prediction models using diffusion magnetic resonance imaging (dMRI) and machine learning techniques enable individual assessment of brain aging status in healthy people and patients with brain disorders. However, dMRI data are notorious for high intersite variability, prohibiting direct application of a model to the datasets obtained from other sites. In this study, we generalized the dMRI-based brain age model to different dMRI datasets acquired under different imaging conditions. Specifically, we adopted a transfer learning approach to achieve domain adaptation. To evaluate the performance of transferred models, brain age prediction models were constructed using a large dMRI dataset as the source domain, and the models were transferred to three target domains with distinct acquisition scenarios. The experiments were performed to investigate (1) the tuning data size needed to achieve satisfactory performance for brain age prediction, (2) the feature types suitable for different dMRI acquisition scenarios, and (3) performance of the transfer learning approach compared with the statistical covariate approach. By tuning the models with relatively small data size and certain feature types, optimal transferred models were obtained with significantly improved prediction performance in all three target cohorts (p â€‹< â€‹0.001). The mean absolute error of the predicted age was reduced from 13.89 to 4.78 years in Cohort 1, 8.34 to 5.35 years in Cohort 2, and 8.74 to 5.64 years in Cohort 3. The test-retest reliability of the transferred model was verified using dMRI data acquired at two timepoints (intraclass correlation coefficient â€‹= â€‹0.950). Clinical sensitivity of the brain age prediction model was investigated by estimating the brain age in patients with schizophrenia. The prediction made by the transferred model was not significantly different from that made by the reference model. Both models predicted significant brain aging in patients with schizophrenia as compared with healthy controls (p â€‹< â€‹0.001); the predicted age difference of the transferred model was 4.63 and 0.26 years for patients and controls, respectively, and that of the reference model was 4.39 and -0.09 years, respectively. In conclusion, transfer learning approach is an efficient way to generalize the dMRI-based brain age prediction model. Appropriate transfer learning approach and suitable tuning data size should be chosen according to different dMRI acquisition scenarios.

Criteria for Psychosis in Major and Mild Neurocognitive Disorders: International Psychogeriatric Association (IPA) Consensus Clinical and Research Definition.

Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders.

Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: a biomarker for rebound in psychotic symptoms?

BACKGROUND: Switching to aripiprazole from other antipsychotics can avoid antipsychotic-induced hyperprolactinemia but may result in an abnormally low prolactin level. This study aimed to assess whether the aripiprazole-induced abnormally low prolactin level was a biomarker for subsequent rebound of positive symptoms in schizophrenia patients. METHODS: Participants were 63 patients in an 8-week trial of switching to aripiprazole, in which preswitching antipsychotics were maintained for the first 2 weeks and aripiprazole was fixed at 15 mg orally throughout the trial. A prolactin level of < 3.7 ng/ml was defined as abnormally low, and an increase of two or more points in the positive subscore of the Positive and Negative Syndrome Scale at two adjacent ratings was defined as a psychotic rebound. RESULTS: Among 63 patients, 25 (39.7%) had an abnormally low prolactin level and 21 (33.3%) had a psychotic rebound after switching to aripiprazole. In patients with abnormally low prolactin levels, 48.0% of them had a rebound in psychotic symptoms, whereas in those without abnormally low prolactin levels 23.7% did so. Multivariable logistic regression analysis with adjustment for sex, early age at onset, and preswitching medications revealed that abnormally low prolactin levels were associated with psychotic rebound (adjusted odds ratio = 3.55, 95% confidence interval = 1.02, 12.5). Furthermore, there was concurrency between the trend of the cumulative proportion of patients having an abnormally low prolactin level and that of the cumulative proportion of patients having a rebound in psychotic symptoms. CONCLUSIONS: An abnormally low prolactin level after switching to aripiprazole in schizophrenia patients was a potential warning sign of a psychotic rebound. Hence, monitoring of prolactin levels after switching to aripiprazole may help avoid such rebound in schizophrenia. TRIAL REGISTRATION: NCT00545467 ; Date of registration: 17/10/2007.

Social cognition in schizophrenia: A network-based approach to a Taiwanese version of the Reading the Mind in the Eyes test.

BACKGROUND: This study aimed to examine social-cognitive impairments in patients with schizophrenia using the Eyes test. In contrast to previous methods using the correct answers, we developed the Taiwanese version of the Eyes test and constructed the response network to explore impairments in the emotional aspects of theory of mind in patients with schizophrenia. METHODS: Eighteen patients with schizophrenia and 18 healthy controls were recruited to examine their performance of the Eyes test. To explore the internal structures of mental states, we used network analysis to construct the networks of choice patterns (i.e. participants' answers) by using two network indicators, including density (an index of structure diversity of a network) and centrality (an index of the choice patterns within a network). Moreover, we divided all the choices into negative, positive, and neutral item groups based on emotion polarity. RESULTS: The patient group was slower and less accurate than the control group. Moreover, there was a negative correlation between accuracy and blunted affect, and there were positive correlations between reaction time and emotional withdrawal and apathetic social withdrawal. As compared to healthy controls, patients with schizophrenia showed larger density in the network structure and higher centrality than controls. Also, patients showed poorer performance on negative words than healthy controls. CONCLUSION: Our results demonstrated more diversity to recognize negative emotions from patients' choice patterns as compared to those in the control group. These findings suggest that deficits on recognizing negative emotions might be associated with the dysfunctions of mental states in schizophrenia.

Genetic associations and expression of extra-short isoforms of disrupted-in-schizophrenia 1 in a neurocognitive subgroup of schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.

Individualized prediction of schizophrenia based on the whole-brain pattern of altered white matter tract integrity.

BACKGROUND: A schizophrenia diagnosis relies on characteristic symptoms identified by trained physicians, and is thus prone to subjectivity. This study developed a procedure for the individualized prediction of schizophrenia based on whole-brain patterns of altered white matter tract integrity. METHODS: The study comprised training (108 patients and 144 controls) and testing (60 patients and 60 controls) groups. Male and female participants were comparable in each group and were analyzed separately. All participants underwent diffusion spectrum imaging of the head, and the data were analyzed using the tract-based automatic analysis method to generate a standardized two-dimensional array of white matter tract integrity, called the connectogram. Unique patterns in the connectogram that most accurately identified schizophrenia were systematically reviewed in the training group. Then, the diagnostic performance of the patterns was individually verified in the testing group by using receiver-operating characteristic curve analysis. RESULTS: The performance was high in men (accuracy = 0.85) and satisfactory in women (accuracy = 0.75). In men, the pattern was located in discrete fiber tracts, as has been consistently reported in the literature; by contrast, the pattern was widespread over all tracts in women. These distinct patterns suggest that there is a higher variability in the microstructural alterations in female patients than in male patients. CONCLUSIONS: The individualized prediction of schizophrenia is feasible based on the different whole-brain patterns of tract integrity. The optimal masks and their corresponding regions in the fiber tracts could serve as potential imaging biomarkers for schizophrenia. Hum Brain Mapp 39:575-587, 2018. © 2017 Wiley Periodicals, Inc.

Shared and distinct alterations of white matter tracts in remitted and nonremitted patients with schizophrenia.

Patients with schizophrenia do not usually achieve remission state even after adequate antipsychotics treatment. Previous studies found significant difference in white matter integrity between patients with good outcomes and those with poor outcomes, but difference is still unclear at individual tract level. This study aimed to use a systematic approach to identify the tracts that were associated with remission state in patients with schizophrenia. We evaluated 91 patients with schizophrenia (remitted, 50; nonremitted, 41) and 50 healthy controls through diffusion spectrum imaging. White matter tract integrity was assessed through an automatic tract-specific analysis method to determine the mean generalized fractional anisotropy (GFA) values of the 76 white matter tract bundles in each participant. Analysis of covariance among the 3 groups revealed 12 tracts that were significantly different in GFA values. Post-hoc analysis showed that compared with the healthy controls, the nonremission group had reduced integrity in all 12 tracts, whereas the remission group had reduced integrity in only 4 tracts. Comparison between the remission and nonremission groups revealed 4 tracts with significant difference (i.e., the right fornix, bilateral uncinate fasciculi, and callosal fibers connecting the temporal poles) even after adjusting age, sex, education year, illness duration, and medication dose. Furthermore, all the 4 tracts were correlated with negative symptoms scores of the positive and negative syndrome scale. In conclusion, our study identified the tracts that were associated with remission state of schizophrenia. These tracts might be a potential prognostic marker for the symptomatic remission in patients with schizophrenia.

Prevalence and clinical correlates of flunitrazepam-related complex sleep behaviors.

AIM: Complex sleep behaviors (CSB) are often associated with the use of hypnotic drugs. This study investigated the prevalence and correlates of CSB among psychiatric patients who were given flunitrazepam. METHODS: From June 2011 to May 2012, a total of 268 psychiatric outpatients who had received flunitrazepam for at least 3 months were enrolled. Data on occurrence of CSB, demographic characteristics, flunitrazepam dosage and duration of use, psychiatric diagnoses, physical illnesses, and alcohol use were collected. Logistic regression analysis was used to examine the clinical correlates of CSB. RESULTS: Sixty-six participants (24.6%) reported experiencing CSB. Logistic regression analysis showed that a high dosage (>2 mg/day) of flunitrazepam (odds ratio [OR] = 1.941, 95% confidence interval [CI] = 1.090-3.455, P = 0.024) and alcohol use (OR = 1.948, 95%CI = 1.023-3.709, P = 0.042) were significantly associated with the occurrence of CSB. Sex, age, duration of flunitrazepam use, psychiatric diagnoses, and physical illnesses were not significantly associated with the occurrence of CSB. CONCLUSION: CSB among flunitrazepam users should be monitored routinely, especially among those receiving a high dosage who also consume alcohol.

Altered integrity of the right arcuate fasciculus as a trait marker of schizophrenia: a sibling study using tractography-based analysis of the whole brain.

Trait markers of schizophrenia aid the dissection of the heterogeneous phenotypes into distinct subtypes and facilitate the genetic underpinning of the disease. The microstructural integrity of the white matter tracts could serve as a trait marker of schizophrenia, and tractography-based analysis (TBA) is the current method of choice. Manual tractography is time-consuming and limits the analysis to preselected fiber tracts. Here, we sought to identify a trait marker of schizophrenia from among 74 fiber tracts across the whole brain using a novel automatic TBA method. Thirty-one patients with schizophrenia, 31 unaffected siblings and 31 healthy controls were recruited to undergo diffusion spectrum magnetic resonance imaging at 3T. Generalized fractional anisotropy (GFA), an index reflecting tract integrity, was computed for each tract and compared among the three groups. Ten tracts were found to exhibit significant differences between the groups with a linear, stepwise order from controls to siblings to patients; they included the right arcuate fasciculus, bilateral fornices, bilateral auditory tracts, left optic radiation, the genu of the corpus callosum, and the corpus callosum to the bilateral dorsolateral prefrontal cortices, bilateral temporal poles, and bilateral hippocampi. Posthoc between-group analyses revealed that the GFA of the right arcuate fasciculus was significantly decreased in both the patients and unaffected siblings compared to the controls. Furthermore, the GFA of the right arcuate fasciculus exhibited a trend toward positive symptom scores. In conclusion, the right arcuate fasciculus may be a candidate trait marker and deserves further study to verify any genetic association.

Automatic whole brain tract-based analysis using predefined tracts in a diffusion spectrum imaging template and an accurate registration strategy.

Automated tract-based analysis of diffusion MRI is an important tool for investigating tract integrity of the cerebral white matter. Current template-based automatic analyses still lack a comprehensive list of tract atlas and an accurate registration method. In this study, tract-based automatic analysis (TBAA) was developed to meet the demands. Seventy-six major white matter tracts were reconstructed on a high-quality diffusion spectrum imaging (DSI) template, and an advanced two-step registration strategy was proposed by incorporating anatomical information of the gray matter from T1-weighted images in addition to microstructural information of the white matter from diffusion-weighted images. The automatic analysis was achieved by establishing a transformation between the DSI template and DSI dataset of the subject derived from the registration strategy. The tract coordinates in the template were transformed to native space in the individual's DSI dataset, and the microstructural properties of major tract bundles were sampled stepwise along the tract coordinates of the subject's DSI dataset. In a validation study of eight well-known tracts, our results showed that TBAA had high geometric agreement with manual tracts in both deep and superficial parts but significantly smaller measurement variability than manual method in functional difference. Additionally, the feasibility of the method was demonstrated by showing tracts with altered microstructural properties in patients with schizophrenia. Fifteen major tract bundles were found to have significant differences after controlling the family-wise error rate. In conclusion, the proposed TBAA method is potentially useful in brain-wise investigations of white matter tracts, particularly for a large cohort study.

Use of high-conductivity sample solution with sweeping-micellar electrokinetic capillary chromatography for trace-level quantification of paliperidone in human plasma.

Paliperidone is a new antipsychotic drug with a relatively low therapeutic concentration of 20-60 ng/mL. We established an accurate and sensitive CE method for the determination of paliperidone concentrations in human plasma in this study. To minimize matrix effect caused by quantification errors, paliperidone was extracted from human plasma using Oasis HLB SPE cartridges with three-step washing procedure. To achieve sensitive quantification of paliperidone in human plasma, a high-conductivity sample solution with sweeping-MEKC method was applied for analysis. The separation is performed in a BGE composed of 75 mM phosphoric acid, 100 mM SDS, 12% acetonitrile, and 15% tetrahydrofuran. Sample solution consisted of 10% methanol in 250 mM phosphoric acid and the conductivity ratio between sample matrix and BGE was 2.0 (γ, sample/BGE). The results showed it able to detect paliperidone in plasma samples at concentration as low as 10 ng/mL (S/N = 3) with a linear range between 20 and 200 ng/mL. Compared to the conventional MEKC method, the sensitivity enhancement factor of the developed sweeping-MEKC method was 100. Intra- and interday precision of peak area ratios were less than 6.03%; the method accuracy was between 93.4 and 97.9%. This method was successfully applied to the analysis of plasma samples of patients undergoing paliperidone treatment.

Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics.

This study aimed to compare strategies differing in the speed of switching schizophrenic patients to aripiprazole from other antipsychotic agents, with dual administration for 2 weeks and then tapering off the current antipsychotic in fast (within 1 week) versus slow (within 4 weeks) strategies. This 8-week, open-label, randomized, parallel study assigned patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder to either the fast-switching (n = 38) or slow-switching (n = 41) group. Efficacy assessments at 5 time points included Positive and Negative Syndrome Scale and Clinical Global Impression scale. Safety assessments included extrapyramidal symptoms, metabolic profile, serum prolactin level, QTc interval, and adverse events. Drug concentrations and cytochrome P450 CYP2D6 and CYP3A4 genotypes were also measured. The fast- and slow-switching groups were comparable in demographical and clinical features at baseline and dropout rate. In the intention-to-treat analysis using mixed-effects models, there were significant within-group decreases over time in the Positive and Negative Syndrome Scale total scores (P = 0.03) and its subscores except for positive subscores, whereas no between-group differences were found. A reduction in body weight (P = 0.01) and lower levels of total cholesterol (P = 0.03), triglycerides (P = 0.03), and prolactin (P = 0.01) were noted in both groups but no increase in extrapyramidal symptoms or prolongation of QTc. The blood concentrations of aripiprazole in all patients were in a therapeutic range at day 56, with CYP2D6*10 polymorphisms being associated with aripiprazole concentrations. In conclusion, there is no significant difference between the fast- and slow-switching strategy in terms of improvements in clinical symptoms and metabolic profile in this 8-week study.