SchizophreniaNCT01514682
Anti-Inflammatory Treatment of Schizophrenia
A study testing Anti-inflammatory Combination Therapy in people with Schizophrenia, run by University of Maryland, Baltimore at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Anti-inflammatory Combination Therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2012to 17 Apr 2017
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Participants will meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder.
- Participants will be required to meet the following symptom criteria:
- 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.
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Maryland Psychiatric Research Center
Baltimore, Maryland, 21228
About this study
Official title: Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia
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.
Read more
The investigators secondary hypotheses are:
- add-on anti-inflammatory combination therapy will be associated with improvements in depressive and negative symptoms and a reduction in pro-inflammatory cytokines
- add-on anti-inflammatory combination therapy compared to placebo will not be associated with elevated adverse risk.
Read the 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
- Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines;
- 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;
- 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.
- Conditions
- Schizophrenia
- Being tested
- Anti-inflammatory Combination Therapy, Placebo
- Keywords
- schizophrenia, anti-inflammatory, salsalate, statins, omega-3-fatty acids
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-inflammatory Combination TherapyDrug
- salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening
- fluvastatin: target dose 40 mg/day, administered in a single evening dose
- 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
PlaceboDrug
Non-medication pills; To be taken in morning and evening intervals.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Placebo pills to be assigned using a permuted randomization system Receives: Drug: Placebo |
| Anti-inflammatory Combination Therapy | Experimental | Salsalate, statin and omega-3-fatty acid combination therapy Receives: Drug: Anti-inflammatory Combination Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
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.
Measured: The MCCB was administered at baseline and end-of-study (Week 12).
Secondary outcomes (4)
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.
Measured: The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
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.
Measured: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
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.
Measured: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
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.
Measured: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2012 (estimated)
- Study startJun 2012
- Primary completion17 Apr 2017
- Study completion17 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by University of Maryland, BaltimoreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Robert Buchanan, University of Maryland, Baltimore
- Investigators
- Robert W Buchanan, MD, Principal investigator, Maryland Psychiatric Research Center, University of Maryland School of MedicineWilliam T Carpenter, MD, Principal investigator, Maryland Psychiatric Research Center, University of Maryland School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01514682
- Sponsor's protocol ID
- HP-00051603; 11T-002
- Status last verified
- Mar 2022
- First submitted
- 12 Jan 2012
- Last updated
- 3 Mar 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Buchanan RW, Weiner E, Kelly DL, Gold JM, Chen S, Zaranski J, Blatt F, Wehring H, Carpenter WT. Anti-inflammatory Combination Therapy for the Treatment of Schizophrenia. J Clin Psychopharmacol. 2020 Sep/Oct;40(5):444-450. doi: 10.1097/JCP.0000000000001253.
PubMed 32796391
Study at a glance
From the registry record, last updated by the sponsor on 3 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia
- ClinicalTrials.gov ID
- NCT01514682
- Acronym / sponsor ID
- HP-00051603; 11T-002
- Conditions
- Schizophrenia
- Keywords
- schizophrenia, anti-inflammatory, salsalate, statins, omega-3-fatty acids
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Study start
- Jun 2012 (actual)
- Primary completion
- 17 Apr 2017 (actual)
- Study completion
- 17 Apr 2017 (actual)
- First posted
- 23 Jan 2012 (estimated)
- Results
- Posted 29 Mar 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- add-on anti-inflammatory combination therapy will be associated with improvements in depressive and negative symptoms and a reduction in pro-inflammatory cytokines
- 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
- Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines;
- 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;
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPlacebo pills to be assigned using a permuted randomization system |
| Anti-inflammatory Combination Therapy | Experimental | Drug: Anti-inflammatory Combination TherapySalsalate, statin and omega-3-fatty acid combination therapy |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Participants will meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder.
- Participants will be required to meet the following symptom criteria:
- 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
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anti-inflammatory Combination Therapy1. 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 | Drug | Anti-inflammatory Combination Therapy |
| PlaceboNon-medication pills; To be taken in morning and evening intervals. | Drug | Placebo |
Primary outcome
Change in Persistent Positive Symptoms
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.
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
Time frame: 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.
4 secondary outcomes
Change in Depressive Symptoms
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.
Change in Negative Symptoms
Time frame: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks.
Change in Pro-inflammatory Cytokines
Time frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
Change in C-Reactive Protein (CRP)
Time frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Mar 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32796391Buchanan RW, Weiner E, Kelly DL, Gold JM, Chen S, Zaranski J, Blatt F, Wehring H, Carpenter WT. Anti-inflammatory Combination Therapy for the Treatment of Schizophrenia. J Clin Psychopharmacol. 2020 Sep/Oct;40(5):444-450. doi: 10.1097/JCP.0000000000001253.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert W Buchanan, MD principal investigator
Maryland Psychiatric Research Center, University of Maryland School of Medicine
William T Carpenter, MD principal investigator
Maryland Psychiatric Research Center, University of Maryland School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Anti-inflammatory Combination Therapy in people with Schizophrenia, run by University of Maryland, Baltimore at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Mar 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Persistent Positive Symptoms (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.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01514682, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2022.