Simvastatin Addition for Patients With Recent-onset Schizophrenia

Last updated: October 14, 2020
Sponsor: Iris Sommer
Overall Status: Completed

Phase

3

Condition

Schizophrenia And Schizoaffective Disorders (Pediatric)

Schizotypal Personality Disorder (Spd)

Tourette's Syndrome

Treatment

N/A

Clinical Study ID

NCT01999309
43806
  • Ages 18-50
  • All Genders

Study Summary

Rationale: There is ample evidence that inflammatory processes play a role in the pathophysiology of schizophrenia. 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 PANSS (Positive and Negative Syndrome Scale) and less cognitive decline as measured with the BACS (Brief Assessment of Cognition in Schizophrenia).Secondary objectives are assessment of general functioning, presence and severity of metabolic syndrome and degree of movement disorders, and assessments of brain volume. Lastly, we examine various immunological parameters in serum and peripheral blood mononuclear cells and the experience of childhood trauma.

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). Onset of first psychosis no longer than 3 years ago.

Intervention: Patients will be randomized 1:1 to either 40 mg simvastatin or placebo daily, in the form of identical tablets.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, orschizoaffective 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

  • Female patients of childbearing potential need to utilize a proper method ofcontraception (the pill, vaginal ring, hormonal patch, intrauterine device, cervicalcape, condom, contraceptive injection, diaphragm) in case of sexual intercourse duringthe study.

Exclusion

Exclusion Criteria:

  • Fulfilment of criteria for statin prescription; according to the Dutch HeartFoundation, statin treatment is indicated when the total cholesterol level is > 8mmol/l (www.hartstichting.nl)

  • Presence of any of the contra-indications or warnings for the use of simvastatin asreported in the SPC (Summary of Product Characteristics)

  • Chronic use of glucocorticosteroids (temporary use is permitted, if stopped at least 1month before start of treatment trial)

  • Chronic use of non-steroidal anti-inflammatory drugs (temporary use is permitted, ifstopped 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 ofnormal levels

  • In case of familial risk for muscular disorders or previously experienced muscletoxicity when taking medication similar to simvastatin, creatine kinase (CK) levelswill also be checked (as recommended by the Dutch Farmacotherapeutisch Kompas,www.farmacotherapeutischkompas.nl/). In addition, levels of aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gammaglutamyltranspeptidase (γ-GT) andcreatinine will be checked when a history of alcohol abuse, liver or kidney disordersis reported.

  • Use of comedication that either inhibits or induces the live enzyme CYP3A4 which isresponsible for the degradation of simvastatin. Inhibitors of CYP3A4 includeitraconazole, 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 andmyopathy, including colchicine, bosentan, phenobarbital, phenytoin, hypericum,rifabutin, rifampicin, fibrates (e.g. gemfibrozil), fusidic acid, carbamazepin (can bewashed out before start of trial) For patients, the MRI scan requires addition exclusion criteria to be eligible toparticipate in this part of the study (if these additional criteria are not met, patientscan participate in the study but not in the MRI component):

  • Ferrous objects in or around the body (e.g. braces, glasses, pacemaker, metalfragments)

  • Claustrophobia

Study Design

Total Participants: 121
Study Start date:
October 01, 2013
Estimated Completion Date:
December 19, 2019

Study Description

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.

Connect with a study center

  • University Medical Center Groningen

    Groningen, 9700 RB
    Netherlands

    Site Not Available

  • University Medical Center Utrecht

    Utrecht, 3584 CX
    Netherlands

    Site Not Available

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