Simvastatin Addition for Patients With Recent-onset Schizophrenia
关键词
抽象
描述
Rationale: Different lines of evidence now suggest that low grade inflammation in the central nervous system is involved in the pathogenesis of schizophrenia. These include the altered risk of schizophrenia patients and their relatives for specific auto-immune diseases, clinical similarities between the course of schizophrenia and auto-immune disease and decreased prevalence of schizophrenia in men who have used Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or glucocorticosteroids for somatic disorders. Furthermore, an infectious cause or trigger is suggested by the observed association between schizophrenia and pre- and perinatal infections, as well as by seroconversion to certain pathogens in patients with schizophrenia. On a cellular level, inflammation of the central nervous system is suggested by an increased number of activated microglia cells in the brains of patients with schizophrenia as visualized by positron electron tomography. In an activated state, microglia cells can produce free radicals, pro-inflammatory components and other neurotoxic substances, causing cell death in their proximity. The activation of microglia cells provides a possible route by which an increased pro-inflammatory state in the brain could cause increased gray matter loss and more severe negative and cognitive symptoms. Although Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have been shown to be able to reduce symptoms in these patients, these drugs either have unfavourable cardiovascular side effects or are otherwise not well tolerated. Moreover, patients with schizophrenia already tend to have an increased cardiovascular risk. The combination of well-established vascular protection and reduction of inflammation by simvastatin offers a highly attractive potential to further improve the treatment of schizophrenia and related disorders.
Hypotheses: Daily treatment with 40mg simvastatin in addition to antipsychotic treatment reduces psychotic symptoms, improves cognition, attenuates brain volume loss, and decreases the risk for metabolic syndrome as well as for movement disorders, when compared to placebo.
Objective: The primary objective of this trial is to investigate the proposed beneficial effect of simvastatin as compared to placebo when given for one year in addition to antipsychotic medication to patients with psychotic disorder. We expect lower symptom severity as measured with the Positive And Negative Symptom Scale (PANSS) and less cognitive decline as measured with the Brief Assessment of Cognition in Schizophrenia (BACS).Secondary objectives are assessment of general functioning using the General Assessment of Functioning (GAF), presence and severity of metabolic syndrome, as defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLB), presence and severity of movement disorders using validated scales, and assessments of brain volume through magnetic resonance imaging (MRI). Lastly, we examine various immunological parameters in serum and peripheral blood mononuclear cells and the experience of childhood trauma using the Childhood Trauma Questionnaire Short Form (CTQ-SF).
Study design: Randomized placebo-controlled double-blind trial.
Study population: 150 men and women, between 18 and 50 years of age, diagnosed with schizophrenia, schizoaffective or schizophreniform disorder (DSM-IV 295.*) or psychosis NOS (not otherwise specified) (298.9). Duration of disease should be no more than three years.
Intervention: Patients will be randomized 1:1 to either 40 mg simvastatin or placebo daily, in the form of identical tablets.
Main study parameters/endpoints: Primary outcome is change in total symptom severity (PANSS score) from baseline to end of treatment. Secondary outcomes will be the changes in GAF scores, cognitive functioning, presence and severity of metabolic syndrome and movement disorders and assessment of brain volume change, in addition to the measurement of various immunological biomarkers, childhood trauma. and depression symptoms.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Use of simvastatin implies that there is a risk of side effects, as all lipid-lowering drugs carry the risk of negative effects. The number of patient visits will be limited and mainly requires time investment for a few physical examinations, questionnaires and two cognitive testing sessions (around 10 hours per year in total).
Blood will be drawn at four occasions with negligible and known risks (e.g. irritation). The burden and risks are acceptable while the benefits are expected to be considerable.
日期
最后验证: | 11/30/2017 |
首次提交: | 11/13/2013 |
提交的预估入学人数: | 11/24/2013 |
首次发布: | 12/02/2013 |
上次提交的更新: | 12/10/2017 |
最近更新发布: | 12/12/2017 |
实际学习开始日期: | 09/30/2013 |
预计主要完成日期: | 03/31/2019 |
预计完成日期: | 03/31/2019 |
状况或疾病
干预/治疗
Drug: Simvastatin
Drug: Placebo
相
手臂组
臂 | 干预/治疗 |
---|---|
Experimental: Simvastatin The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year. | Drug: Simvastatin The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year. |
Placebo Comparator: Placebo Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year. | Drug: Placebo Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year. |
资格标准
有资格学习的年龄 | 18 Years 至 18 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | Inclusion Criteria: - A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or schizoaffective disorder) or 298.9 (psychosis NOS) - Onset of first psychosis no longer than 3 years ago. - Age between 18 and 50 years - Written informed consent is obtained Exclusion Criteria: - Fulfilment of criteria for statin prescription; according to the Dutch Heart Foundation, statin treatment is indicated when the total cholesterol level is > 8 mmol/l (www.hartstichting.nl) - Presence of any of the contra-indications or warnings for the use of simvastatin as reported in the SPC (Summary of Product Characteristics) - Chronic use of glucocorticosteroids (temporary use is permitted, if stopped at least 1 month before start of treatment trial) - Chronic use of non-steroidal anti-inflammatory drugs (temporary use is permitted, if stopped at least 1 month before start of treatment trial) - Current use of statins or other lipid-lowering drugs - Pregnancy or breast-feeding - Active liver, kidney or muscle disease as defined by alanine aminotransferase (ALAT), creatinine or creatine kinase (CK) levels more than two times the upper boundary of normal levels - Use of comedication that either inhibits or induces the live enzyme CYP3A4 which is responsible for the degradation of simvastatin. Inhibitors of CYP3A4 include itraconazole, ketoconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, telaprevir, boceprevir, imatinib, ticagrelor, voriconazole; inducers of CYP3A4 include carbamazepin, efavirenz, nevirapine, etravirine (can be washed out before start of trial) - Use of comedication that may increase the risk for myalgia, rhabdomyolysis and myopathy, including colchicine, bosentan, phenobarbital, phenytoin, hypericum, rifabutin, rifampicin, fibrates (e.g. gemfibrozil), fusidic acid, carbamazepin (can be washed out before start of trial) For patients, the MRI scan requires addition exclusion criteria to be eligible to participate in this part of the study (if these additional criteria are not met, patients can participate in the study but not in the MRI component): - Ferrous objects in or around the body (e.g. braces, glasses, pacemaker, metal fragments) - Claustrophobia |
结果
主要结果指标
1. Total symptom severity [0, 1, 3, 6, 9 and 12 months]
次要成果指标
1. Change in positive, negative and general symptom severity [0, 1, 3, 6, 9 and 12 months]
2. Global functioning [0, 1, 3, 6, 9, and 12 months]
3. Change in cognitive functioning [0 and 12 months]
4. Presence and severity of metabolic syndrome [0, 1, 6 and 12 months]
5. Change in presence and severity of movement disorders using validated scales [0, 6 and 12 months]
6. Change in brain volume [1 and 12 months]
其他成果措施
1. Change in immunological parameters [0, 1 and 12 months]
2. Change in Calgary Depression Scale for Schizophrenia (CDSS) total score [0, 6 and 12 months]
3. Number of participants with Adverse Events as a measure of safety and tolerability [0 and 12 months]