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.

Dose-tapering trajectories in patients with remitted psychosis undergoing guided antipsychotic reduction to reach minimum effective dose.

BACKGROUND: Patients with remitted psychosis wish to reduce antipsychotic doses yet facing increased risks of relapse. Examining dose-tapering processes may provide insights to re-evaluate the risk-to-benefit balance. We aimed to depict and subgroup tapering trajectories, and explore factors associated with different dose-reduction patterns. METHODS: A 2-year open-label randomized prospective comparative trial from August 2017 to September 2022 in Taiwan. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomizing a proportion to conduct guided dose reduction. We depicted the trajectories of individual patients and named subgroups based on dose-tapering patterns. Predictors of baseline characteristics for designated subgroups were examined by logistic regression analysis; changes in outcomes were compared by paired t-test. RESULTS: Fifty-one patients undergoing guided dose reduction, 18 (35.3%) reduced 4 steps consecutively (sequential reducers, SR), 14 (27.5%) reduced 1 to 3 steps (modest reducers, MR), 3 (5.9%) re-escalated to previous level (alert reducers, AR), 7 (13.7%) returned to baseline level (baseline returners, BR), 6 (11.7%) relapsed (failed reducers, FR) and 3 (5.9%) withdrew without relapse (early exits, EE). Patients with a history of relapse assumed a conservative dose-tapering pace; only the SR subgroup exhibited significant improvements in functioning and quality of life while failing to identify variables for predicting who would become SR or FR. CONCLUSIONS: Guided dose reduction comprises dynamic processes with differences between individual trajectories. The proposed naming of dose-tapering patterns/subgroups provides a framework depicting patients undergoing dose-tapering. Longer-term observation and more flexible tapering approaches are anticipated to reveal favorable outcomes.

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.

Hemispheric lateralization of semantic processing before and after aripiprazole treatment in first-episode psychosis or ultra-high risk state.

Whether aberrant language-related lateralization can be improved after antipsychotic treatment in drug-free patients with first-episode psychosis or ultra-high risk state is little known. We aimed to investigate the improvement in lateralization of semantic processing after antipsychotic treatment and associated clinical and cognitive changes. Twenty-one drug-free patients with first-episode psychosis or ultra-high risk state underwent functional magnetic resonance imaging with a semantic task, neuropsychological testing, and clinical assessments with the Positive and Negative Syndrome Scale before and after 6 weeks of aripiprazole treatment. A lateralization index of the region of interest, i.e., inferior frontal gyrus, was calculated and correlated with the behavioral indices of the semantic task, Positive and Negative Syndrome Scale scores, and language-related neuropsychological test scores. After treatment, the lateralization index of the inferior frontal gyrus was significantly increased, which was related to reduced activation of the right inferior frontal gyrus. The increase in the lateralization index was significantly associated with the increase in verbal fluency score. A higher baseline accuracy of the semantic task was associated with a higher post-treatment lateralization index of the inferior frontal gyrus and greater improvement of the total score and positive subscore of the Positive and Negative Syndrome Scale. Our findings indicated aripiprazole treatment significantly increased semantic processing-related lateralization in the inferior frontal gyrus in drug-free patients with first-episode psychosis or ultra-high risk state. A higher baseline accuracy might predict a higher post-treatment lateralization index and greater symptom improvement.

The plasma level of complement component 4A decreases with aripiprazole treatment in patients with early psychosis.

The complement component 4 (C4) gene has been reported to be significantly associated with schizophrenia, and C4A RNA expression was found to increase in postmortem brains of schizophrenia patients. This study aimed to examine the plasma levels of C4A and C4B proteins in patients with early psychosis and their changes following aripiprazole treatment. We recruited 45 patients, including 17 patients with ultra-high-risk and 28 patients with first-episode psychosis, and 45 age-matched and sex-matched controls. All patients received aripiprazole treatment for 4 weeks. Each patient received symptom evaluation before and after the treatment period. We measured the plasma levels of C4A and C4B in the pretreatment and posttreatment stages of patients and controls using an enzyme-linked immunosorbent assay. We found no significant differences in C4A and C4B levels between patients and controls, but the C4A level decreased significantly with aripiprazole treatment. Multivariate analysis showed that the decrease rate of C4A was significantly associated with the treatment response of the positive symptom dimension. In summary, we found that the plasma level of C4A decreased with aripiprazole treatment, and the decrease rate was associated with the treatment response of the positive dimension in patients with early psychosis. This mechanism deserves further clarification.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship.

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

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.

Detection of advanced brain aging in schizophrenia and its structural underpinning by using normative brain age metrics.

Conceptualizing mental disorders as deviations from normative functioning provides a statistical perspective for understanding the individual heterogeneity underlying psychiatric disorders. To broaden the understanding of the idiosyncrasy of brain aging in schizophrenia, we introduced an imaging-derived brain age paradigm combined with normative modeling as novel brain age metrics. We constructed brain age models based on GM, WM, and their combination (multimodality) features of 482 normal participants. The normalized predicted age difference (nPAD) was estimated in 147 individuals with schizophrenia and their 130 demographically matched controls through normative models of brain age metrics and compared between the groups. Regression analyses were also performed to investigate the associations of nPAD with illness duration, onset age, symptom severity, and intelligence quotient. Finally, regional contributions to advanced brain aging in schizophrenia were investigated. The results showed that the individuals exhibited significantly higher nPAD (P < 0.001), indicating advanced normative brain age than the normal controls in GM, WM, and multimodality models. The nPAD measure based on WM was positively associated with the negative symptom score (P = 0.009), and negatively associated with the intelligence quotient (P = 0.039) and onset age (P = 0.006). The imaging features that contributed to nPAD mostly involved the prefrontal, temporal, and parietal lobes, especially the precuneus and uncinate fasciculus. This study demonstrates that normative brain age metrics could detect advanced brain aging and associated clinical and neuroanatomical features in schizophrenia. The proposed nPAD measures may be useful to investigate aberrant brain aging in mental disorders and their brain-phenotype relationships.

A Multi-Center Study for the Development of the Taiwan Cognition Questionnaire (TCQ) in Major Depressive Disorder.

Cognitive dysfunction is associated with functional impairment of patients with Major Depressive Disorder (MDD). The goals were to explore the associated factors of cognitive impairment in MDD and to develop and validate a brief and culture-relevant questionnaire, the Taiwan Cognition Questionnaire (TCQ), among patients with MDD. This was a cross-sectional, multi-center observational study of MDD patients in Taiwan. Participants of Group 1 from 10 centers contributed to the validation of the TCQ by their response and sociodemographics. The participants of Group 2 from one center received an objective cognitive assessment for clarification of the relationship between the TCQ score and its associated factors. In Group 1, 493 participants were recruited. As for Group 2, an extra 100 participants were recruited. The global Cronbach's alpha for the TCQ was 0.908. According to the coordinates of the ROC curve, 9/10 was the ideal cut-off point. With the criteria, the sensitivity/specificity of the TCQ was 0.610/0.689. The TCQ score was positively associated with a history of being admitted to acute psychiatric care and the severity of depression and negatively associated with objective cognitive measures. The TCQ provides a reliable, valid, and convenient measure of subjective cognitive dysfunction in patients with MDD.

Discontinuing Antipsychotic Medication After Remission from First-Episode Psychosis: A Survey of Psychiatrists' Attitudes in Taiwan.

Background: Patients in remission after first-episode psychosis are inclined to discontinue antipsychotic treatment, which may lead to higher risk of relapse and unfavorable outcomes. Paradoxically, also there are evidences suggesting that certain patients may stay well in drug-free condition. Psychiatrists' views towards this dilemma might affect their approaches to these patients, and discrepant attitudes are noted between Western and Asian clinicians. This study aimed to examine psychiatrists' attitudes about discontinuing antipsychotic medications after remission from first-episode psychosis. Methods: Psychiatrists were recruited for this study using convenience sampling. A cross-sectional survey was conducted using a set of questionnaires comprising nine items for attitudes toward medication discontinuation, six vignettes for probing psychiatrists' practice in designated clinical scenarios, and a list of criteria that may affect their responses. Results: Responses were provided by 118 psychiatrists, two-thirds men, mean age 39.8 ± 10.1 years and mean experience 12.7 ± 9.7 years. Half of the participants endorsed that fewer than 20% of the remitted patients should stop medication completely; the majority advised that an observation period of 1 year or longer is necessary while discontinuing medication. The majority would not initiate discussion with patients about discontinuing medication. Responding to two case vignettes, those who endorsed that more patients could stop antipsychotics were also more inclined to discuss it with patients, but not consistently in response to the other four case vignettes. Taiwan psychiatrists expressed a wide range of decision-making considerations for discontinuing antipsychotics. Conclusion: The majority of Taiwan psychiatrists thought it was not feasible to stop medications completely but were willing to consider this option. Once being presented with actual clinical scenarios, many participants hesitated to discontinue antipsychotic medications for various reasons. The proactive attitude of psychiatrists towards conducting clinical trials to test the feasibility of medication discontinuation may help to provide better reference for this clinical dilemma.

Identifying dopamine supersensitivity through a randomized controlled study of switching to aripiprazole from other antipsychotic agents in patients with schizophrenia.

BACKGROUND: Aripiprazole has been reported to worsen psychotic symptoms when switching from other antipsychotics, possibly due to dopamine supersensitivity psychosis. OBJECTIVE: This study aimed to explore the predictors and possible underlying mechanisms of aripiprazole-related psychotic exacerbation. METHODS: We conducted an 8-week, open-label, randomized controlled study from October 2007 to September 2009, assigning patients with a primary diagnosis of schizophrenia or schizoaffective disorder to switch from other antipsychotics to aripiprazole with 2-week dual administration, and then to taper off the original agents in fast (n = 38, within 1 week) or slow (n = 41, within 4 weeks) strategies. Positive and Negative Syndrome Scale (PANSS) was examined at day 0, 7, 14, 28, 56. Aripiprazole-related exacerbation (ARE) was defined positive as a 2-point increase in delusion/hallucination dimension score within 28 days compared with baseline. Baseline demographic, clinical and intervention-related variables were compared between the ARE+ and ARE- groups. RESULTS: Of the 79 randomized patients, 21 fulfilled the criteria of ARE+ , and 46 were classified as ARE-. Fourteen patients in the ARE+ group had worsening psychotic symptoms in the first and second weeks. Compared with the ARE- group, the ARE+ group had a higher baseline chlorpromazine equivalent dose (405.8 ± 225.8 mg vs 268.1 ± 165.4 mg, p = 0.007) and was associated with prescription of first-generation antipsychotics (p = 0.038). CONCLUSIONS: A higher dose of original antipsychotics and prescription of first-generation antipsychotics may be associated with a higher risk of ARE. The underlying mechanism might be covert dopamine supersensitivity psychosis. These findings may help to identify high-risk patients and guide appropriate treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT00545467.

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.

A quarter of century after: The changing ecology of psychiatric emergency services.

INTRODUCTION: Previous studies demonstrated a trend of increasing common mental disorders among the Emergency Department (ED) visitors in Western countries. Little is known about the current conditions of the emergency psychiatric services in Asian countries. This study aims to survey the current epidemiology and the changing ecology of emergency psychiatry services in Taiwan. METHODS: A total of 804 psychiatry consultations were initiated at the ED during the 1-year period from July 1, 2014 to June 30, 2015 in a medical center in northern Taiwan. Clinical data of gender, age, chief complaints, tentative diagnoses, dispositions, and ED staying hours were compared to a previous report in the same hospital in 1988. RESULTS: Psychiatry consultation was initiated in 0.72% of all ED visits (804/111,923). Among these visits, females were 1.73 times of the males. The most common chief complaints were psychosis/mania (33.5%) and suicide/self-harm (33.2%), followed by homicide/violence (12.8%) and anxiety/depression (10.3%). Top tentative diagnoses were schizophrenia spectrum and other psychotic disorders (31.3%), trauma- and stressor-related disorders (17.5%), bipolar disorders (15.9%), and depressive disorders (14.2%). Compared to 1988, there are three major changes: (1) over-representation of female patients, (2) an increase of "neurosis" patients, and (3) an increase of suicide/self-harm as chief problem. DISCUSSION: This study portrays the current epidemiology and changing ecology of psychiatric emergency in Taiwan. The increase of neurotic and suicide/self-harm patients requires more services and clinical training in managing common mental disorders and suicide in the ED.

Protocol of guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis based on pragmatic design.

AIMS: Patients with psychosis intend to discontinue antipsychotic treatment for various reasons. As antipsychotic discontinuation involves a high risk of relapse, maintenance treatment is recommended by mainstream opinion even when remission is attained. To optimize the risk-to-benefit ratio of long-term antipsychotic treatment, we proposed an operationalized guided dose-reduction algorithm to serve as an intermediate approach as to achieve the lowest effective antipsychotic dose and better functioning for patients with remitted psychosis. METHODS: Outpatients with a history of schizophrenia-related psychotic disorders currently under stable medications and symptoms are eligible to register in this protocol. Patients intending for dose reduction are randomized into 2:1, guided dose reduction group (GDR) versus maintenance treatment group (MTG1). Eligible patients who do not intend to reduce antipsychotics serve as naturalistic maintenance controls (MTG2). The GDR patients reduce no more than 25% of their baseline antipsychotic dose, with at least a 6-month stabilization period before reducing another 25% of their last dose. The timing of the next dose reduction will be determined by shared decision-making with the patient. Following a dose reduction, the patients will receive three consecutive monthly monitoring; otherwise, they receive treatment as usual. DISCUSSION: By employing this pragmatic-based protocol, patients are empowered to evaluate their readiness for next dose reduction attempt. We would like to test in real-world situations if stable patients can reduce antipsychotics not at the expense of an increased risk of relapse, so as to optimize the balance between risk-to-benefit ratios of long-term antipsychotic treatment.

Challenging the Minimum Effective Antipsychotic Dose During Maintenance: Implications From 10-Year Follow-Up of First Episode Psychosis.

Background: Contradictory messages regarding the necessity of long-term antipsychotic treatment after first episode psychosis arouse deliberations in clinical practice. We explored if there is an alternative beyond the dichotomy of maintenance treatment and discontinuation of medications. Methods: We conducted a retrospective observational study by reviewing medical records at the study hospital of a cohort of patients since their participation in an early psychosis study starting from 2006, with special interests in patients able to maintain good functioning under treatment with a low antipsychotic dose. Results: Of the 81 patients with first-episode psychosis, 55 patients (67.9%) had follow-up information for longer than 5 years. The majority (n = 46, 83.6%) had non-affective psychosis, 20 patients (36.4%) had full-time employment/education by the time of their latest visit; among them, 15 patients received dosage of antipsychotics no more than the minimum effective dose [chlorpromazine equivalent (CPZE) dose, 200 mg/day]. Besides, 10 of 55 patients (18.2%) only received very low dose antipsychotics (CPZE < 50 mg/day) during maintenance, which was significantly correlated to good functioning. Being male, having a history of hospitalization, and being on clozapine therapy were correlated to poorer functioning. Antipsychotic-free status was achieved only in two non-psychotic patients. Conclusions: A substantial proportion of patients could achieve good functioning under low-dose antipsychotic maintenance after first-episode psychosis, even if they could not completely withdraw antipsychotics in the long term. Optimizing the balance between preventing relapse and preserving functioning by fine-tuning antipsychotic dosage during maintenance is a challenge warranting more clinical attention.

The Association Between the Use of Cholinesterase Inhibitors and Cardiovascular Events Among Older Patients With Alzheimer Disease.

OBJECTIVE: To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD). PATIENTS AND METHODS: This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005-2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs. RESULTS: The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96). CONCLUSION: The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.

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.

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.