Simvastatin Addition for Patients With Recent-onset Schizophrenia

NCT01999309 | Completed Phase 3 DMC

• 1 other identifier: 43806
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder; Psychosis NOS

Keywords

Schizophrenia spectrum disorders

Outcome Measures

Primary Outcomes (1)

• Total symptom severity

  Change in Positive And Negative Syndrome Scale (PANSS) total score

  0, 1, 3, 6, 9 and 12 months

Secondary Outcomes (6)

• Change in positive, negative and general symptom severity

  0, 1, 3, 6, 9 and 12 months

• Global functioning

  0, 1, 3, 6, 9, and 12 months

• Change in cognitive functioning

  0 and 12 months

• Presence and severity of metabolic syndrome

  0, 1, 6 and 12 months

• Change in presence and severity of movement disorders

  0, 6 and 12 months

Other Outcomes (3)

• Change in immunological parameters

  0, 1 and 12 months

• Change in depressive symptoms

  0, 6 and 12 months

• Number of participants with Adverse Events as a measure of safety and tolerability

  0 and 12 months

Study Arms (2)

Simvastatin

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.

Drug: Placebo

Interventions

Simvastatin DRUG

The lipid-lowering drug simvastatin is added to normal antipsychotic treatment. One 40 mg simvastatin tablet daily for the treatment period of one year.

Also known as: Zocor

Simvastatin

Placebo DRUG

Placebo is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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
• In case of familial risk for muscular disorders or previously experienced muscle toxicity when taking medication similar to simvastatin, creatine kinase (CK) levels will 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) and creatinine will be checked when a history of alcohol abuse, liver or kidney disorders is reported.
• 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)
• Ferrous objects in or around the body (e.g. braces, glasses, pacemaker, metal fragments)
• Claustrophobia

Sponsors & Collaborators

• Iris Sommer: lead
• Stanley Medical Research Institute: collaborator

Study Sites (2)

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Related Publications (3)

• Zaki JK, Lago SG, Spadaro B, Rustogi N, Gangadin SS, Benacek J, Drexhage HA, de Witte LD, Kahn RS, Sommer IEC, Bahn S, Tomasik J. Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia. Schizophr Res. 2024 Apr;266:66-74. doi: 10.1016/j.schres.2024.02.011. Epub 2024 Feb 19.

  PMID: 38377869 DERIVED

• Begemann MJH, Schutte MJL, van Dellen E, Abramovic L, Boks MP, van Haren NEM, Mandl RCW, Vinkers CH, Bohlken MM, Sommer IEC. Childhood trauma is associated with reduced frontal gray matter volume: a large transdiagnostic structural MRI study. Psychol Med. 2023 Feb;53(3):741-749. doi: 10.1017/S0033291721002087. Epub 2021 Jun 3.

  PMID: 34078485 DERIVED

• Begemann MJ, Schutte MJ, Slot MI, Doorduin J, Bakker PR, van Haren NE, Sommer IE. Simvastatin augmentation for recent-onset psychotic disorder: A study protocol. BBA Clin. 2015 Jul 3;4:52-58. doi: 10.1016/j.bbacli.2015.06.007. eCollection 2015 Dec.

  PMID: 26674520 DERIVED

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; Mental Disorders

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Iris EC Sommer, Prof. dr.

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: November 14, 2013
• First Posted: December 3, 2013
• Study Start: October 1, 2013
• Primary Completion: December 19, 2019
• Study Completion: December 19, 2019
• Last Updated: October 19, 2020

Record last verified: 2020-10

Locations

NL (2)