Schizophrenia
Conditions
Keywords
schizophrenia, anti-inflammatory, salsalate, statins, omega-3-fatty acids
Brief summary
Despite current antipsychotic treatment, the majority of people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. An alternative approach to the use of psychotropic agents for the treatment of persistent symptoms is the use of anti-inflammatory agents to reverse the pro-inflammatory state hypothesized to underlie the symptom and sign manifestations of the illness. The investigators primary hypothesis is that add-on anti-inflammatory combination therapy will have significant beneficial effects on persistent positive symptoms and cognitive impairments. The investigators secondary hypotheses are: 1. add-on anti-inflammatory combination therapy will be associated with improvements in depressive and negative symptoms and a reduction in pro-inflammatory cytokines 2. add-on anti-inflammatory combination therapy compared to placebo will not be associated with elevated adverse risk.
Detailed description
Schizophrenia has been hypothesized to be due, in part, to disruptions of normal immune system and inflammatory responses to viral or bacterial infections or other stimuli of these systems. Epidemiological and clinical studies have provided extensive evidence that perinatal exposure to infection contributes to the etiology of schizophrenia. The recent reports of associations between markers of single nucleotide polymorphisms located within the major histocompatibility complex on chromosome 6p22.1 and schizophrenia provide further support for etiological hypotheses of immune system dysfunction in schizophrenia. There are a large number of reports that suggest that people with schizophrenia have altered cytokine levels, with one or more studies reporting elevated levels of the pro-inflammatory cytokines: IL-1β, IL-6, IL-12, CRP, IFN-γ, and TNF-α; and reduced levels of the anti-inflammatory cytokine: IL-10. In this study we examine the use of combination anti-inflammatory therapy as an intervention in patients with schizophrenia. We will use 1. Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines; 2. Omega-3-fatty acids eicosapentaenoic (EPA; 2 gm/day) and docosahexaenoic (DHA; 2 gm/day). Omega-3-fatty acids exert their anti-inflammatory effects through their oxygenation into resolvins or protectins, which are potent anti-inflammatory agents; 3. Fluvastatin, 40 mgs/day. Fluvastatin is a lipid-lowering drugs, which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA). Fluvastatin may also exert anti-inflammatory effects independent of its lipid-lowering effects via a mechanism involving HMG-CoA inhibition and decreased NF-κB activation. We have chosen to use combination therapy with three different classes of anti-inflammatory agents to address the potential benefit of this therapeutic approach for persistent positive symptoms and cognitive impairments. The three agents have unique anti-inflammatory mechanisms of action, which we believe offers the most robust evaluation of this therapeutic approach and maximizes the likelihood of eliciting pronounced therapeutic effects.
Interventions
DRUGAnti-inflammatory Combination Therapy
1. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening 2. fluvastatin: target dose 40 mg/day, administered in a single evening dose 3. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
DRUGPlacebo
Non-medication pills; To be taken in morning and evening intervals.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Participants will meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder. * Participants will be required to meet the following symptom criteria: 1. BPRS total score of 45 or greater on the 18 item version (scale: 1-7) or a Clinical Global Impression (CGI) severity of illness item score of 4 (moderate) or greater. 2. BPRS positive symptom item total score of 8 or greater and a score of 4 or more on at least one individual item. * Participants will be clinically stable, be treated with the same antipsychotic for at least 60 days and a constant therapeutic dose for at least 30 days prior to study entry. * Participants must be judged competent to participate in the informed consent process and provide voluntary informed consent
Exclusion criteria
* Participants who meet DSM-IV-TR criteria for alcohol or substance dependence (except nicotine) within the last 6 months or DSM-IV-TR criteria for alcohol or substance abuse (except nicotine) within the last month will be excluded * Participants with a current infection or an organic brain disorder or medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol will be excluded. * Participants with a history of: aspirin allergy, pre-existing tinnitus, tuberculosis, HIV, or hepatitis C; or autoimmune disease. * Participants who are currently treated with a statin, warfarin, dipyridamole, or other anti-coagulants. * Participant is currently treated with an omega-3-fatty acid preparation and cannot discontinue their use of the preparation for the duration of the study. * Female participant who is sexually active and not using any form of birth control such as oral contraceptives or IUDs. * Female participant who is pregnant or breastfeeding. * Participant with current/active peptic ulcer disease or gastritis; anemia or thrombocytopenia (platelet count ≤120). * Participant who is currently treated with a medication that can increase the risk of myopathy and rhabdomyolysis such as Fluconazole, Ketoconazole, Colchicine, Daptomycin, Erythromycin, or immunosuppressants that alter statin levels.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Persistent Positive Symptoms | The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from 1=Not Present to 7=Very Severe. The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating. |
| Change in Neuropsychological Test Performance | The MCCB was administered at baseline and end-of-study (Week 12). | The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depressive Symptoms | The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. Total score calculated by adding scores for scales #1-#9. Each scale ranges from 0=Absent to 3=Severe. The minimum total CDS score is 0 and the maximum total CDS score is 27. A higher score indicates a more severe depression rating. |
| Change in Negative Symptoms | Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Median SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms. |
| Change in Pro-inflammatory Cytokines | A cytokine profile will be collected at baseline and at week 12 (end-of-study). | Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection. |
| Change in C-Reactive Protein (CRP) | A cytokine profile will be collected at baseline and at week 12 (end-of-study). | Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection. |
Countries
United States
Participant flow
Pre-assignment details
Signed a consent form: 52 (50 unique subjects: 2 withdrew then later re-enrolled, not counted in analysis); Ineligible prior to Evaluation Phase: 1 subject (1=clinically unstable); Entered Evaluation Phase: 49 subjects; Withdrawn prior to randomization: 10 (8=Did not meet BPRS criteria; 1=Did not meet age criteria; 1=On an excluded medication)
Participants by arm
| Arm | Count |
|---|---|
| Anti-inflammatory Combination Therapy Salsalate, statin and omega-3-fatty acid combination therapy
Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose | 19 |
| Placebo Placebo pills to be assigned using a permuted randomization system
Anti-inflammatory Combination Therapy: a. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening b. fluvastatin: target dose 40 mg/day, administered in a single evening dose c. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Placebo: Non-medication pills; To be taken in morning and evening intervals. | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Anti-inflammatory Combination Therapy | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 20 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 18 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 1 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 9 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 19 Participants |
| Region of Enrollment United States | 19 participants | 20 participants | 39 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 19 |
| other Total, other adverse events | 10 / 20 | 14 / 19 |
| serious Total, serious adverse events | 1 / 20 | 1 / 19 |
Outcome results
Primary
Change in Neuropsychological Test Performance
The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome.
Time frame: The MCCB was administered at baseline and end-of-study (Week 12).
Population: Participants completing the MCCB testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change in Neuropsychological Test Performance | Baseline Week 0 | 25 units on a scale |
| Placebo | Change in Neuropsychological Test Performance | Treatment Week 12 | 24 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Neuropsychological Test Performance | Baseline Week 0 | 36 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Neuropsychological Test Performance | Treatment Week 12 | 26 units on a scale |
Primary
Change in Persistent Positive Symptoms
The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from 1=Not Present to 7=Very Severe. The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.
Time frame: The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
Population: Participants completing the BPRS assessment rating.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 4 | 14 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 8 | 12 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 2 | 14 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 10 | 14 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 6 | 14 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Treatment Week 12 | 14 units on a scale |
| Placebo | Change in Persistent Positive Symptoms | Baseline Week 0 | 13 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 12 | 12 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Baseline Week 0 | 14 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 2 | 14 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 4 | 15 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 6 | 14 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 8 | 14 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Persistent Positive Symptoms | Treatment Week 10 | 14 units on a scale |
Secondary
Change in C-Reactive Protein (CRP)
Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.
Time frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
Population: Participants who had a cytokine profile collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in C-Reactive Protein (CRP) | Baseline CRP levels | 38953 ng/ml | Standard Deviation 27218 |
| Placebo | Change in C-Reactive Protein (CRP) | End of study CRP levels | 38759 ng/ml | Standard Deviation 21753 |
| Anti-inflammatory Combination Therapy | Change in C-Reactive Protein (CRP) | Baseline CRP levels | 42950 ng/ml | Standard Deviation 32468 |
| Anti-inflammatory Combination Therapy | Change in C-Reactive Protein (CRP) | End of study CRP levels | 31849 ng/ml | Standard Deviation 23176 |
Secondary
Change in Depressive Symptoms
The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. Total score calculated by adding scores for scales #1-#9. Each scale ranges from 0=Absent to 3=Severe. The minimum total CDS score is 0 and the maximum total CDS score is 27. A higher score indicates a more severe depression rating.
Time frame: The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
Population: Participants completing the CDS assessment rating.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change in Depressive Symptoms | Treatment Week 4 | 1 units on a scale |
| Placebo | Change in Depressive Symptoms | Treatment Week 8 | 2 units on a scale |
| Placebo | Change in Depressive Symptoms | Treatment Week 2 | 2 units on a scale |
| Placebo | Change in Depressive Symptoms | Treatment Week 10 | 2 units on a scale |
| Placebo | Change in Depressive Symptoms | Treatment Week 6 | 2 units on a scale |
| Placebo | Change in Depressive Symptoms | Treatment Week 12 | 1 units on a scale |
| Placebo | Change in Depressive Symptoms | Baseline Week 0 | 2 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 12 | 0 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Baseline Week 0 | 0 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 2 | 1 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 4 | 1 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 6 | 1 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 8 | 1 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Depressive Symptoms | Treatment Week 10 | 0 units on a scale |
Secondary
Change in Negative Symptoms
The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Median SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.
Time frame: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
Population: Participants completing the SANS rating assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change in Negative Symptoms | Treatment Week 4 | 32 units on a scale |
| Placebo | Change in Negative Symptoms | Treatment Week 8 | 30 units on a scale |
| Placebo | Change in Negative Symptoms | Treatment Week 2 | 28 units on a scale |
| Placebo | Change in Negative Symptoms | Treatment Week 10 | 30 units on a scale |
| Placebo | Change in Negative Symptoms | Treatment Week 6 | 28 units on a scale |
| Placebo | Change in Negative Symptoms | Treatment Week 12 | 28 units on a scale |
| Placebo | Change in Negative Symptoms | Baseline Week 0 | 27 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 12 | 28 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Baseline Week 0 | 26 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 2 | 24 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 4 | 30 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 6 | 27 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 8 | 24 units on a scale |
| Anti-inflammatory Combination Therapy | Change in Negative Symptoms | Treatment Week 10 | 30 units on a scale |
Secondary
Change in Pro-inflammatory Cytokines
Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.
Time frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
Population: Participants who had a cytokine profile collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Pro-inflammatory Cytokines | Baseline IL-2 levels | 59.16 pg/ml | Standard Deviation 88.38 |
| Placebo | Change in Pro-inflammatory Cytokines | Baseline IL-8 levels | 9.16 pg/ml | Standard Deviation 5.59 |
| Placebo | Change in Pro-inflammatory Cytokines | End of study IL-8 levels | 8.91 pg/ml | Standard Deviation 7.24 |
| Placebo | Change in Pro-inflammatory Cytokines | End of study IL-2 levels | 88.4 pg/ml | Standard Deviation 146 |
| Anti-inflammatory Combination Therapy | Change in Pro-inflammatory Cytokines | End of study IL-8 levels | 19.78 pg/ml | Standard Deviation 46.91 |
| Anti-inflammatory Combination Therapy | Change in Pro-inflammatory Cytokines | Baseline IL-2 levels | 34.94 pg/ml | Standard Deviation 77.01 |
| Anti-inflammatory Combination Therapy | Change in Pro-inflammatory Cytokines | End of study IL-2 levels | 47.5 pg/ml | Standard Deviation 86 |
| Anti-inflammatory Combination Therapy | Change in Pro-inflammatory Cytokines | Baseline IL-8 levels | 8.35 pg/ml | Standard Deviation 4.59 |