Simvastatin Addition for Patients With Recent-onset Schizophrenia

Schizophrenia Clinical Trial

Official title: Simvastatin Addition for Patients With Recent-onset Schizophrenia

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Disease
• Mental Disorders
• Psychosis NOS
• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia
• Schizophreniform Disorder

• NCT number: NCT01999309
• Study type: Interventional
• Source: UMC Utrecht
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Completion date: December 19, 2019