Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia.

BACKGROUND: Agonists at the N-methyl-D-aspartate (NMDA)-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (N-methylglycine, or called sarcosine) both improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics. Previous studies, however, found no advantage of D-serine, glycine, or D-cycloserine added to clozapine. The present study aims to determine the effects of sarcosine adjuvant therapy for schizophrenic patients receiving clozapine treatment. METHODS: Twenty schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Measures of clinical efficacy and side-effects were determined every other week. RESULTS: Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effect was noted. CONCLUSIONS: Unlike patients treated with other antipsychotics, patients who received clozapine treatment exhibit no improvement by adding sarcosine or agonists at the NMDA-glycine site. Clozapine possesses particular efficacy, possibly related to potentiation of NMDA-mediated neurotransmission. This may contribute to the clozapine's unique clinical efficacy and refractoriness to the addition of NMDA-enhancing agents.     

D-alanine added to antipsychotics for the treatment of schizophrenia.

BACKGROUND: Hypofunction of the N-methyl-d-aspartate (NMDA) subtype glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine, glycine, endogenous full agonists of the glycine site of the NMDA receptor (NMDA-glycine site), D-cycloserine, a partial agonist, or sarcosine, a glycine transporter-1 inhibitor, improves the symptoms of schizophrenia. D-alanine is another endogenous agonist of the NMDA-glycine site that might have beneficial effects on schizophrenia. METHODS: Thirty-two schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-alanine (100 mg/kg/day), which was added to their stable antipsychotic regimens. Measures of clinical efficacy and side effects were determined every other week. RESULTS: Patint who received D-alanine treatment revealed significant reductions in their Clinical Global Impression Scale and Positive and Negative Syndrome Scale (PANSS) total scores. The Scale for the Assessment of Negative Symptoms and PANSS subscores of positive and cognitive symptoms were improved. D-alanine was well tolerated, and no significant side effect was noted. CONCLUSIONS: The significant improvement with the D-alanine further supports the hypothesis of hypofunction of NMDA neurotransmission in schizophrenia and strengthens the proof of the principle that NMDA-enhancing treatment is a promising approach for the pharmacotherapy of schizophrenia.     

Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia.

BACKGROUND: Lamotrigine, a novel anticonvulsant drug having modulatory effects on glutamatergic neurotransmission, improves mood and cognition parameters in bipolar disorder. Recent studies suggest that when added to clozapine, lamotrigine treatment may result in significant positive symptoms reductions in schizophrenia. Similar effects were not observed in an open trial in which lamotrigine was used as adjuvant to nonclozapine antipsychotics. METHODS: Thirty-eight treatment-resistant schizophrenia inpatients receiving conventional and atypical antipsychotics enrolled in a 10-week, double-blind, placebo-controlled study, in which they were randomized in a 2:1 ratio to receive adjuvant treatment with lamotrigine, gradually titrated to a 400 mg/day dose, or placebo. Of these, 31 completed the trial. Measures of clinical efficacy and side effects were determined every other week. Serum levels of amino acids were assessed at the beginning and end of the study. RESULTS: In primary last observation carried forward analysis, no statistically significant between-group differences were observed; however, the completers' analyses revealed that lamotrigine treatment resulted in significant (p < or = .05) reductions in positive and general psychopathology symptoms, as measured by the Positive and Negative Syndrome Scale. No significant differences in lamotrigine effects were noted between conventional versus atypical antipsychotics. Lamotrigine treatment was well tolerated, and glutamate serum levels remained stable throughout the study. CONCLUSIONS: These preliminary findings 1) support the hypothesis that lamotrigine adjuvant treatment may improve positive symptoms and general psychopathology in schizophrenia, 2) suggest that beneficial effects may be achieved when lamotrigine is added to both conventional and atypical antipsychotics, and 3) warrant additional, larger scale trials.     

Biological perspectives: the role of glutamate in schizophrenia and its treatment

Schizophrenia is a heartbreaking, debilitating, youth-stealing, lifetime disorder for most individuals afflicted with it. While the serendipitous discovery of chlorpromazine 60 plus years ago and the subsequent “discoveries” since have significantly reduced positive symptoms, the devastation of negative/cognitive symptoms continues to ruin lives. Given the cost in lives and dollars that schizophrenia drains out of our society, neuroscientists will continue to explore better approaches to fighting this disorder. The hypoglutamate model appears promising, yet there are miles to go before we sleep. As Nestler et al. (2009, p. 398) deftly acknowledge, “. . . it is important to point out that postulating a role for abnormal glutamatergic neurotransmission in schizophrenia is akin to proposing that the brain is involved in schizophrenia since every single neuron in the brain receives thousands of excitatory synapses that utilize glutamate as their neurotransmitter.”     

D-serine added to clozapine for the treatment of schizophrenia.

OBJECTIVE: D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed. METHOD: In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week. RESULTS: The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine. CONCLUSIONS: The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.     

Citalopram,a selective serotonin reuptake inhibitor,in the treatment of aggression in schizophrenia

The aim of this double-blind cross-over study was to investigate whether treatment with the selective serotonin reuptake inhibitor, citalopram reduces aggressiveness in chronically violent schizophrenic inpatients. Initially 19 patients were enrolled into this double-blind cross-over study in which the patients were treated for 24 weeks with placebo and 24 weeks with citalopram (20–60 mg/day) as a supplement to their previous neuroleptic medication. Fourteen patients completed the entire study, but sufficient data on 15 patients could be used in the end–point analysis of efficacy. Psychiatric assessments (Brief Psychiatric Rating Scale, Clinical Global Impression Scale for Severity of Illness, Social Dysfunction and Aggression Scale and the Global Aggression Scale) and side effects (UKU Side Effect Scale) were recorded at baseline and 4 times during both periods. Aggressive incidents (Staff Observation Aggression Scale) were recorded throughout the study. During citalopram treatment, the frequency of aggressive incidents was significantly lower and the mental state did not deteriorate. Patients either experienced no side effects or else side effects were equally mild during both periods.     

舒血宁合并抗精神病药物治疗慢性精神分裂症的双盲对照研究

目的 探讨舒血宁合并抗精神病药物治疗慢性精神分裂症的临床疗效。方法 采用双盲对照，随机分组进行研究。结果 表明舒血宁合并抗精神病药物的药效优于单独用抗精神病药物（Ｐ〈０．０５）；舒血宁还可减少抗精神病药物的锥体外系反应，而且对改善慢性精神分裂症的阴性症状有较为明显的效果，同时也无严重的副作用。结论 舒血宁治疗慢性精神分裂症是值得进一步探讨研究的。     

Religious beliefs in schizophrenia: their relevance for adherence to treatment

The study examined how religious beliefs and practices impact upon medication and illness representations in chronic schizophrenia. One hundred three stabilized patients were included in Geneva's outpatient public psychiatric facility in Switzerland. Interviews were conducted to investigate spiritual and religious beliefs and religious practices and religious coping. Medication adherence was assessed through questions to patients and to their psychiatrists and by a systematic blood drug monitoring. Thirty-two percent of patients were partially or totally nonadherent to oral medication. Fifty-eight percent of patients were Christians, 2% Jewish, 3% Muslim, 4% Buddhist, 14% belonged to various minority or syncretic religious movements, and 19% had no religious affiliation. Two thirds of the total sample considered spirituality as very important or even essential in everyday life. Fifty-seven percent of patients had a representation of their illness directly influenced by their spiritual beliefs (positively in 31% and negatively in 26%). Religious representations of illness were prominent in nonadherent patients. Thirty-one percent of nonadherent patients and 27% of partially adherent patients underlined an incompatibility or contradiction between their religion and taking medication, versus 8% of adherent patients. Religion and spirituality contribute to shaping representations of disease and attitudes toward medical treatment in patients with schizophrenia. This dimension should be on the agenda of psychiatrists working with patients with schizophrenia.     

联用帕罗西汀治疗精神分裂症阴性症状研究

目的:探讨抗精神病药联用帕罗西汀治疗精神分裂症阴性症状的疗效.方法:以阴性症状为主的住院慢性精神分裂症33例,在原用抗精神病药基础上,联用帕罗西汀,疗程12周.使用阳性 与阴性症状量表(PANSS)和副反应量表(TESS)评定,在治疗前和治疗4、8、12周末各评定1次.结果:联用帕罗西汀12周后,PANSS总分、阴性症状因子分及情感迟钝、情感退缩、情感交流障碍、被动/淡漠及社交退缩因子分均比治疗前显著降低.结论:以阴性症状为主的慢性精神分裂症,在使用抗精神病药物的同时联用帕罗西汀,对改善阴性症状有明显作用.     

改良电休克联合抗精神病药物治疗女性难治性精神分裂症的疗效对比观察

目的探讨改良电休克（MECT）联合抗精神病药物治疗女性难治性精神分裂症的临床疗效和安全性。方法40例女性难治性精神分裂症患者白药物治疗第2周起联合MECT治疗8周。采用阳性与阴性症状量表（PANSS）和治疗时出现的症状量表（TESS）评定疗效和不良反应,采用韦氏记忆量表（WMS）评定MECT对记忆的影响。结果MECT治疗后第2、4、8周末PANSS评分明显降低。WMS评分在治疗结束后1d明显降低,1周及2周时恢复。第8周末总有效率为85％。结论MECT联合抗精神病药物治疗女性难治性精神分裂症的疗效显著,不良反应少,虽对记忆力有一定影响,但是短暂的,可逆的。     

Long-acting injectable risperidone and oral antipsychotics in patients with schizophrenia: results from a prospective, 1-year,non-interventional study (InORS)

Objective. To explore differences in outcomes for patients with schizophrenia treated with risperidone long-acting treatment (RLAT) or oral antipsychotics (oAP). Methods. The International Observational Registry on Schizophrenia (InORS) explored flexible doses of newly initiated RLAT and oAPs for adults with schizophrenia, exploring 6-month retrospective hospitalization data and 12-month prospective medication use, outcomes, and tolerability. Efficacy outcomes included hospitalizations, the Clinical Global Impression of Schizophrenia (CGI-SCH), and the Global Assessment of Functioning (GAF). Medication switch patterns were also analysed. Results. Data were analysed from 1083 patients (561 RLAT, 522 oAP). At baseline, RLAT patients had higher symptom severity, greater functional impairment, and poorer compliance. Percentages of patients hospitalized were similar between groups, and median duration per hospitalization decreased after RLAT initiation and with oAP. The difference in duration of hospitalization between the retrospective and prospective period was significantly better with RLAT (P = 0.002). Mean CGI-SCH change from baseline was significantly better for RLAT vs. oAP patients for overall, positive, and negative symptom scores (P < 0.05). Mean functional improvement from baseline was significantly higher with RLAT vs. oAP (P < 0.001). Conclusions. Hospitalizations and symptomatic and functional outcomes were better with RLAT vs. oAP; frequent medication switches were associated with less favourable outcomes.     

High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia.

BACKGROUND: Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine. In this study, we assessed whether high-dose glycine may also be therapeutically beneficial when added to olanzapine and risperidone treatment. METHODS: Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover treatment trial with.8 g/kg/day glycine added to their ongoing antipsychotic medication. Clinical assessments were performed biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored. RESULTS: Glycine treatment was well tolerated and resulted in a significant (p <.0001) 23% +/- 8% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. The negative symptoms improvement remained significant even following covariation for changes in other symptom clusters and extrapyramidal side effects. High posttreatment glycine serum levels significantly predicted (r =.60) clinical response. CONCLUSIONS: These findings indicate that the efficacy of olanzapine and risperidone may be augmented using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine.     

Lithium carbonate in chronic schizophrenia--a brief trial of lithium carbonate added to neuroleptics for treatment of resistant schizophrenic patients.

The value of lithium carbonate as an adjunctive treatment of resistant schizophrenia was tested in a 4-week clinical trial using a single-blind, randomized, consent design. Treatment and control groups were drawn from a population of detained patients in an English special (maximum security) hospital. The 2 groups were comparable in terms of age, sex, severity of symptoms, length of hospitalization and concurrent neuroleptic dosage. The addition of lithium carbonate to the treatment regimen did not result in symptomatic improvement in patients completing the treatment protocol. The ethical and practical difficulties raised by the trial are discussed.     

Benzodiazepines in the treatment of schizophrenia: an updated survey.

Reports on the effects of benzodiazepines in schizophrenia have appeared since the early 1960s. Conclusions drawn from these studies, most of which have been uncontrolled, have ranged from worse than placebo to better than neuroleptics. A critical appraisal of the literature seems to warrant the following main conclusions. Benzodiazepines alone, in conventional doses, have no convincing antipsychotic effect in schizophrenia, although they may reduce anxiety, tension and insomnia. However, very high doses of diazepam, and possibly other benzodiazepines, may have a symptomatic antipsychotic effect, especially in paranoid-hallucinatory schizophrenics, also when given alone. Benzodiazepines, in conventional doses, can enhance the antipsychotic effect of neuroleptics in schizophrenics who have not responded satisfactorily to neuroleptics alone. This effect may be most conspicuous against hallucinations, but improvement may also be obtained from delusions, thought disturbances, some negative symptoms, anxiety and tension. Some benzodiazepines may be more effective than others in schizophrenia, but this has been insufficiently elucidated.     

首发精神分裂症不同维持治疗时间的复发分析

目的:研究不同维持治疗时间对首发精神分裂症复发的影响。方法:对406例首发精神分裂症患者痊愈出院后5年内进行随访,分析维持治疗时间与复发的关系。结果:所有患者5年内累计复发率为63%,在病情稳定情况下按医嘱维持2年组5年内累计复发率为80%,3年组为60.7%,4年组为19.0%,这3组复发率差别有显著统计学意义。结论:首发精神分裂症患者5年累计复发率在下降,按医嘱维持治疗时间越长,复发率越低,为减少复发、减少致残,首发痊愈后应特别注意坚持抗精神病药物的治疗。     

Improved outcomes following a switch to olanzapine treatment from risperidone treatment in a 1-year naturalistic study of schizophrenia patients in Japan

Aims: This study assessed clinical and functional outcomes following a switch from risperidone to olanzapine in a 1‐year naturalistic study of schizophrenia patients in Japan. Methods: We used data from a large 1‐year prospective, multicenter, observational non‐interventional study of individuals who were initiated on olanzapine for the treatment of schizophrenia in Japan. Current analyses focused on patients who were switched at study entry from risperidone to olanzapine (n = 258). Repeated measures analysis was employed to assess outcomes on validated measures. Results: At study entry, 45% were inpatients and 55% outpatients. Participants were in their early 40s with mean illness duration of 14 years. Approximately half were male. Most were switched from risperidone to olanzapine due to poor medication efficacy (67.8%) rather than medication intolerability (29.1%). Most patients (67.8%) completed the 1‐year study. Patients experienced clinically and statistically significant (P < 0.05) improvements in global symptom severity, positive, negative, depressive, and cognitive symptoms, health‐related quality of life, and paid work rates. Most patients (59.2%) demonstrated treatment response to olanzapine and 43.4% experienced symptom remission. Mean weight gain was 2.19 kg, with one‐third of patients (33.3%) experiencing clinically significant weight gain (≥7%). Conclusions: In this 1‐year naturalistic study, inpatients and outpatients who were switched from risperidone to olanzapine experienced clinically and statistically significant improvements in their clinical and functional outcomes. One‐third of all patients experienced clinically significant weight gain. Current findings highlight the favorable benefit‐to‐risk profile of switching to olanzapine therapy following treatment failure on risperidone among patients with schizophrenia in Japan.     

High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance

Objectives. Recent schizophrenia (SCZ) research aims to establish biomarkers with high predictive value for the diagnosis, severity of illness or treatment resistance. SCZ is accompanied by activated immune-inflammatory pathways, including increased levels of cytokines and chemokines, but few studies tried to identify predictive properties of such measures. Methods. We included 54 medicated SCZ patients and 118 healthy controls and examined 15 cytokines and chemokines. Possible associations between these immune-inflammatory biomarkers and the diagnosis of SCZ, severity of illness and treatment resistance were investigated. Results. SCZ is associated with a specific cytokine – chemokine profile, i.e., increased CCL11, MIP-1α, sTNF-R1 and sTNF-R2 levels, and decreased levels of IP-10, TNF-α, IL-2 and IL-4. The combination of five biomarkers (sTNF-R1, sTNF-R2, CCL11, IP-10, IL-4) may predict the diagnosis of SCZ with a sensitivity of 70.0% and a specificity of 89.4%. There was a weak association between the negative symptoms and biomarkers, i.e., IL-2 (inversely) and CCL11 (positively). Patients with treatment resistance showed increased levels of sTNF-R1, sTNF-R2 and MCP-1. Conclusions. The findings of this study reinforce that SCZ is associated with a pro-inflammatory profile and suggest that some immune mediators may be used as reliable biomarkers for the diagnosis of SCZ and treatment resistance.     

Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment

Abstract

Objectives. The glutamatergic hypothesis of schizophrenia proposes alterations of excitatory amino acid transporters (solute carrier family, SLCs) expression and cerebellar dysfunctions. The influence of the neuregulin-1 (NRG1) risk genotype or effects of antipsychotics on expression of EAATs are unknown. Methods. We compared post-mortem samples from the cerebellar hemispheres and vermis of 10 schizophrenia patients with nine normal subjects by investigating gene expression of SLC1A3, SLC1A1 and SLC1A6 by in-situ hybridization. We further assessed the allelic composition regarding the polymorphism rs35753505 (SNP8NRG221533) near the NRG1 gene. To control for effects due to antipsychotic treatment, we chronically treated rats with the antipsychotics haloperidol or clozapine and assessed gene expression of SLCs. Results. Schizophrenia patients showed increased expression of SLC1A3 in the molecular layer of the vermis. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of SLC1A6 in the molecular layer of both hemispheres, compared to individuals homozygous for the T allele. The animal model revealed suppression of SLC1A6 by clozapine. Conclusions. Increased SLC1A3 expression indicates facilitated transport and may result in reduced glutamate neurotransmission. Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded.