Simvastatin Addition for Patients With Recent-onset Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder; Psychosis NOS
MeSH terms: Schizophrenia; Psychotic Disorders; Mental Disorders
Study type: Interventional
Phase: Phase 3

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.
    

Detailed 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.
    

Intervention name(s): Simvastatin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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 is added to normal antipsychotic treatment. One identical looking placebo tablet daily for the treatment period of one year.
Other intervention name(s): Zocor
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia spectrum disorders