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Superoxide Dismutase, BDNF, and Cognitive Improvement in Drug-Naive First-Episode Patients With Schizophrenia: A 12-Week Longitudinal Study.
Wu, Z, Liu, Q, Zhang, Y, Guan, X, Xiu, M, Zhang, X
The international journal of neuropsychopharmacology. 2022;(2):128-135
Abstract
OBJECTIVE Cognitive improvement after antipsychotic agents in patients with schizophrenia (SCZ) appears to involve redox regulation through neurotrophins such as brain derived neurotropic factor (BDNF). This study examined whether cognitive improvement was associated with the increase in superoxide dismutase (SOD) and whether higher levels of BDNF could have a permissive role in allowing SOD to improve cognition. METHODS We examined this hypothesis in 183 drug-naïve first-episode SCZ patients taking risperidone monotherapy for 12 weeks. We measured total copper-zinc SOD (CuZn-SOD), manganese SOD (Mn-SOD), and SOD activities and BDNF levels in these patients and compared their levels with 152 healthy controls. We assessed cognitive functioning and clinical symptoms at baseline and 12-week follow-up. RESULTS After treatment with risperidone, CuZn-SOD activity was significantly increased, and BDNF levels were slightly increased. Increased CuZn-SOD activity was associated with the cognitive effectiveness of risperidone monotherapy. The BDNF levels and SOD activities were correlated at baseline but not after 12-week treatment. Furthermore, baseline CuZn-SOD activity positively correlated with improvement on the delayed memory subscale of the Repeatable Battery for the Assessment of Neuropsychological Status only in the high BDNF subgroup. CONCLUSIONS Our longitudinal study suggests that risperidone can enhance SOD activity and that, in combination with higher baseline BDNF levels acting in a permissive role, can improve cognitive impairments in SCZ. Greater baseline CuZn-SOD activity also may have predictive value for cognitive improvement of delayed memory in SCZ patients receiving risperidone treatment.
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Association of Elements with Schizophrenia and Intervention of Selenium Supplements.
Li, Z, Liu, Y, Li, X, Ju, W, Wu, G, Yang, X, Fu, X, Gao, X
Biological trace element research. 2018;(1):16-21
Abstract
The purpose of this study is to explore more trace elements (zinc, potassium, copper, iron, boron, manganese, selenium, chromium and cadmium elements) in addition to calcium, magnesium, lead and arsenic in the sera of patients with schizophrenia and the general population in China and to determine the effect of selenium on schizophrenia patients. Participants were collected from the Pingyin County Mental Health Hospital and Pingyin County. A t test was used to analyse the differences between schizophrenia patients and healthy subjects, and element content differences in gender. Logistic multivariate regression analysis was applied to analyse the influence of elements to schizophrenia. Repeated measures analysis of variance was used to analyse differences in the elements after 1 and 3 months. Mn, Se, Cd, Pb, Ca, Cu and Fe were lower than those in the normal group, and B, Cr, As, K and Mg were higher than those in the control group. The odd ratios (ORs) of serum As and serum K were 2.624 and 1.035, respectively. The ORs of sera Cr, Mn, Se, Ca and Cu were all below one. After intervention of 'selenium weikang' about 1 and 3 months, the serum As was decreased and the serum selenium and copper were increased. Cr, Mn, Se, Ca and Cu might have beneficial, statistically significant effects on schizophrenia. Elements As and K might be harmful to schizophrenia with statistical significance. After selenium supplementation, the schizophrenia patients improved in some factors, like the appetite and memory, and the As element decreased.
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Effectiveness of integrated care including therapeutic assertive community treatment in severe schizophrenia-spectrum and bipolar I disorders: Four-year follow-up of the ACCESS II study.
Schöttle, D, Schimmelmann, BG, Ruppelt, F, Bussopulos, A, Frieling, M, Nika, E, Nawara, LA, Golks, D, Kerstan, A, Lange, M, et al
PloS one. 2018;(2):e0192929
Abstract
UNLABELLED The ACCESS-model offers integrated care including assertive community treatment to patients with psychotic disorders. ACCESS proved more effective compared to standard care (ACCESS-I study) and was successfully implemented into clinical routine (ACCESS-II study). In this article, we report the 4-year outcomes of the ACCESS-II study. Between May 2007 and December 2013, 115 patients received continuous ACCESS-care. We hypothesized that the low 2-year disengagement and hospitalization rates and significant improvements in psychopathology, functioning, and quality of life could be sustained over 4 years. Over 4 years, only 10 patients disengaged from ACCESS. Another 23 left for practical reasons and were successfully transferred to other services. Hospitalization rates remained low (13.0% in year 3; 9.1% in year 4). Involuntary admissions decreased from 35% in the 2 years prior to ACCESS to 8% over 4 years in ACCESS. Outpatient contacts remained stably high at 2.0-2.4 per week. We detected significant improvements in psychopathology (effect size d = 0.79), illness severity (d = 1.29), level of functioning (d = 0.77), quality of life (d = 0.47) and stably high client satisfaction (d = 0.02) over 4 years. Most positive effects were observed within the first 2 years with the exception of illness severity, which further improved from year 2 to 4. Within continuous intensive 4-year ACCESS-care, sustained improvements in psychopathology, functioning, quality of life, low service disengagement and re-hospitalization rates, as well as low rates of involuntary treatment, were observed in contrast to other studies, which reported a decline in these parameters once a specific treatment model was stopped. Yet, stronger evidence to prove these results is required. TRIAL REGISTRATION Clinical Trial Registration Number: NCT01888627.
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α-Lipoic Acid as Adjunctive Treatment for Schizophrenia: An Open-Label Trial.
Sanders, LLO, de Souza Menezes, CE, Chaves Filho, AJM, de Almeida Viana, G, Fechine, FV, Rodrigues de Queiroz, MG, Gonçalvez da Cruz Fonseca, S, Mendes Vasconcelos, SM, Amaral de Moraes, ME, Gama, CS, et al
Journal of clinical psychopharmacology. 2017;(6):697-701
Abstract
PURPOSE/BACKGROUND Accumulating evidence suggests an involvement of oxidative stress in the pathophysiology of schizophrenia. This offers a hypothesis-derived therapeutic approach to hinder oxidative damage and its clinical sequelae. α-Lipoic acid (ALA) is a powerful natural antioxidant indicated to treat diabetic neuropathy. METHODS/PROCEDURES In this pilot investigation, we administered ALA (100 mg/d) for 4 months, as an adjunct to antipsychotic medication, to 10 patients with schizophrenia. FINDINGS/RESULTS We found robust improvement in measures of psychopathology (63.9% reduction in Brief Psychiatric Rating Scale scores), neurocognitive parameters, extrapyramidal symptoms, and decreased lipid peroxidation. IMPLICATIONS/CONCLUSIONS If larger, double-blind, placebo-controlled studies confirm these preliminary findings, ALA could prove useful as adjunctive therapy for schizophrenia.
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ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial.
Lieberman, JA, Davis, RE, Correll, CU, Goff, DC, Kane, JM, Tamminga, CA, Mates, S, Vanover, KE
Biological psychiatry. 2016;(12):952-61
Abstract
BACKGROUND An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins. METHODS A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales. RESULTS ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone. CONCLUSIONS The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.
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N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms.
Rossell, SL, Francis, PS, Galletly, C, Harris, A, Siskind, D, Berk, M, Bozaoglu, K, Dark, F, Dean, O, Liu, D, et al
BMC psychiatry. 2016;(1):320
Abstract
BACKGROUND Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ. METHODS This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes. DISCUSSION This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.
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Safety, tolerability, and efficacy of quetiapine in youth with schizophrenia or bipolar I disorder: a 26-week, open-label, continuation study.
Findling, RL, Pathak, S, Earley, WR, Liu, S, DelBello, M
Journal of child and adolescent psychopharmacology. 2013;(7):490-501
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Abstract
OBJECTIVE The purpose of this study was to describe the safety, tolerability, and efficacy of quetiapine monotherapy continued for up to 26-weeks in youth with schizophrenia or bipolar I disorder. METHODS Medically healthy boys and girls with a baseline Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) diagnosis of schizophrenia (ages 13-17 years) or a manic episode of bipolar I disorder (ages 10-17 years) who participated in one of two acute, double-blind, placebo-controlled studies of immediate-release quetiapine were potentially eligible to enroll in a 26-week, open-label study. During the open-label study, quetiapine was flexibly dosed at 400-800 mg/day, with options to reduce dosing to 200 mg/day based on tolerability. Safety and tolerability outcomes assessed from open-label baseline to week 26 included adverse events (AEs), metabolic/laboratory parameters, extrapyramidal symptoms, suicidality, and vital signs. RESULTS Of 381 patients enrolled in the open-label study (n=176, schizophrenia; n=205, bipolar disorder diagnosis), 237 patients (62.2%) completed the 26-week study period (71.0%, schizophrenia; 54.6%, bipolar disorder). The most common AEs reported during the study included somnolence, headache, sedation, weight increase, and vomiting. A total of 14.9% of patients experienced a shift to potentially clinically significant low levels of high-density lipoprotein cholesterol and 10.2% of patients experienced a shift to potentially clinically significant high triglyceride levels. Weight gain ≥ 7% was reported in 35.6% of patients between open-label baseline and final visit. After adjustment for normal growth, 18.3% of study participants experienced clinically significant weight gain (i.e., increase in body mass index ≥ 0.5 standard deviations from baseline). CONCLUSIONS In this 26-week study, quetiapine flexibly dosed at 400-800 mg/day, with options to reduce dosing based on tolerability, was generally safe and well tolerated in youth. Clinicians should monitor lipid profiles and weight gain in youth with schizophrenia or bipolar disorder during treatment with quetiapine.
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia.
Adams, DH, Kinon, BJ, Baygani, S, Millen, BA, Velona, I, Kollack-Walker, S, Walling, DP
BMC psychiatry. 2013;:143
Abstract
BACKGROUND We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole). METHODS Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131). RESULTS There was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444). CONCLUSION These data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics. TRIALS REGISTRATION A Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR Schizophrenia.
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Selenium, zinc, and copper plasma levels in patients with schizophrenia: relationship with metabolic risk factors.
Vidović, B, Dorđević, B, Milovanović, S, Škrivanj, S, Pavlović, Z, Stefanović, A, Kotur-Stevuljević, J
Biological trace element research. 2013;(1-3):22-8
Abstract
The aim of this study was to determine the plasma selenium (Se), copper (Cu), and zinc (Zn) levels and to evaluate their possible association with metabolic syndrome (MetS) components in patients with schizophrenia. The study group consisted of 60 patients with schizophrenia and 60 sex- and age-matched healthy controls. Anthropometric measurements, blood pressure, and biochemical analysis of fasting blood were performed in all subjects. Patients with schizophrenia had significantly higher plasma Cu concentrations compared with controls (0.97 ± 0.31 vs. 0.77 ± 0.32 mg/L, p = 0.001). The plasma Cu concentration showed a positive correlation with plasma glucose and diastolic blood pressure in the patient groups (r s = 0.263, p < 0.05 and r s = 0.272, p < 0.05, respectively). The plasma Se level correlated positive with MetS score (r s = 0.385, p < 0.01), waist circumference (r s = 0.344, p < 0.05), plasma glucose (r s = 0.319, p < 0.05), and triglyceride concentrations (r s = 0.462, p < 0.001) in patients with schizophrenia. Plasma Zn did not correlate with any of the MetS components. These results suggest that alterations in plasma Cu and Se levels in medicated patients with schizophrenia could be associated with metabolic risk factors.
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An open, large, 6-month naturalistic study of outcome in schizophrenic outpatients, treated with olanzapine.
Krzystanek, M, Krupka-Matuszczyk, I
Human psychopharmacology. 2011;(1):81-5
Abstract
BACKGROUND In many countries of the industrialised world second generation ("atypical") antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of olanzapine differs from that of other second generation antipsychotics. OBJECTIVES To evaluate the effects of olanzapine compared to other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis. SEARCH STRATEGY 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. 2. Reference searching We inspected the reference of all identified studies for more trials. 3. Personal contact We contacted the first author of each included study for missing information. 4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data. SELECTION CRITERIA We included all randomised trials that used at least single-blind (rater-blind) design, comparing oral olanzapine with oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model. MAIN RESULTS The review currently includes 50 studies and 9476 participants which provided data for six comparisons (olanzapine compared to amisulpride, aripiprazole, clozapine, quetiapine, risperidone or ziprasidone). The overall attrition from the included studies was considerable (49.2%) leaving the interpretation of results problematic. Olanzapine improved the general mental state (PANSS total score) more than aripiprazole (2 RCTs, n = 794, WMD -4.96 CI -8.06 to -1.85), quetiapine (10 RCTs, n = 1449, WMD -3.66 CI -5.39 to -1.93), risperidone (15 RCTs, n = 2390, WMD -1.94 CI -3.31 to -0.58) and ziprasidone (4 RCTs, n = 1291, WMD -8.32 CI -10.99 to -5.64), but not more than amisulpride or clozapine. This somewhat better efficacy was confirmed by fewer participants in the olanzapine groups leaving the studies early due to inefficacy of treatment compared to quetiapine (8 RCTs, n = 1563, RR 0.56 CI 0.44 to 0.70, NNT 11 CI 6 to 50), risperidone (14 RCTs, n = 2744, RR 0.78 CI 0.62 to 0.98, NNT 50 CI 17 to 100) and ziprasidone (5 RCTs, n = 1937, RR 0.64 CI 0.51 to 0.79, NNT 17, CI 11 to 33).Fewer participants in the olanzapine group than in the quetiapine (2 RCTs, n = 876, RR 0.56 CI 0.41 to 0.77, NNT 11 CI 7 to 25) and ziprasidone (2 RCTs, n = 766, RR 0.65 CI 0.45 to 0.93, NNT 17 CI 9 to 100) treatment groups, but not in the clozapine group (1 RCT, n = 980, RR 1.28 CI 1.02 to 1.61, NNH not estimable), had to be re-hospitalised in the trials.Except for clozapine, all comparators induced less weight gain than olanzapine (olanzapine compared to amisulpride: 3 RCTs, n = 671, WMD 2.11 kg CI 1.29 kg to 2.94 kg; aripiprazole: 1 RCT, n = 90, WMD 5.60 kg CI 2.15 kg to 9.05 kg; quetiapine: 7 RCTs, n = 1173, WMD 2.68 kg CI 1.10 kg to 4.26 kg; risperidone: 13 RCTs, n = 2116, WMD 2.61 kg CI 1.48 kg to 3.74 kg; ziprasidone: 5 RCTs, n = 1659, WMD 3.82 kg CI 2.96 kg to 4.69 kg). Associated problems such as glucose and cholesterol increase were usually also more frequent in the olanzapine group. Other differences in adverse effects were less well documented. Nevertheless, olanzapine may be associated with slightly more extrapyramidal side effects than quetiapine (use of antiparkinson medication (6 RCTs, n = 1090, RR 2.05 CI 1.26 to 3.32, NNH 25 CI 14 to 100), but less than risperidone (use of antiparkinson medication 13 RCTs, n = 2599, RR 0.78 CI 0.65 to 0.95, NNH 17 CI 9 to 100) and ziprasidone (use of antiparkinson medication 4 RCTs, n = 1732, RR 0.70 CI 0.50 to 0.97, NNH not estimable). It may also increase prolactin somewhat more than aripiprazole, clozapine and quetiapine, but clearly less so than risperidone (6 RCTs, n = 1291, WMD -22.84 CI -27.98 to -17.69). AUTHORS' CONCLUSIONS Olanzapine may be a somewhat more efficacious drug than some other second generation antipsychotic drugs. This small superiority in efficacy needs to be weighed against a larger weight gain and associated metabolic problems than most other second generation antipsychotic drugs, except clozapine. These conclusions are tentative due to the large number of people leaving the studies early which possibly limits the validity of the findings. Further large, well-designed trials are necessary to establish the relative effects of different second generation antipsychotic drugs.