Adjunctive Minocycline in Clozapine Treated Schizophrenia Patients
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Purpose
Schizophrenia is a devastating and costly illness. One-third to one-half of people with schizophrenia do not respond to the most current drugs leaving clozapine as the best alternative for treatment. However, over 60% of people treated with clozapine continue to have persistent symptoms and cognitive impairments. Little data is available to support evidence-based recommendations to guide clinicians in treating these patients. Preliminary data has suggested that adjunct treatment with minocycline may offer robust symptom improvement in patients with schizophrenia, including those taking clozapine. Minocycline has had interesting effects; including suggesting it may have a significant role in treatment of neurologic and psychiatric disorders. Minocycline is currently available generically; its side effects are well-described and minimal. The proposed double-blind treatment study seeks to demonstrate that adjunctive minocycline offers patients superior efficacy for persistent positive symptoms, cognitive impairments, and/or other components of schizophrenia pathology. This knowledge could lead to the more effective treatment of patients with schizophrenia. The research itself may lead to a better understanding of the pathophysiology of positive symptoms and cognitive impairments, which could contribute to improved treatments in the future.
| Condition | Intervention |
|---|---|
|
Schizophrenia |
Drug: Minocycline Drug: Placebo |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment |
| Official Title: | Adjunctive Minocycline in Clozapine Treated Schizophrenia Patients |
- The efficacy of minocycline compared to placebo to improve positive Psychotic Symptoms [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]Adjunct minocycline to clozapine will be compared to placebo to test its efficacy to improve positive psychotic symptoms. The 4 item positive subfactor of the Brief Psychiatric Rating Scale (BPRS) will be the primary outcome over the 10 week randomized study.
- The efficacy of minocycline compared to placebo to improve cognitive symptoms [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]Adjunct minocycline to clozapine will be compared to placebo to test its efficacy in improving cognitive function. Neuropsychological testing will be done at baseline and endpoint using the MATRICS battery. A composite score as well as individual scores will be will be the primary outcome over the 10 week randomized study.
- The efficacy of minocycline compared to placebo to improve negative symptoms. [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]Adjunct minocycline to clozapine will be compared to placebo to test its efficacy in improving negative symptoms of schizophrenia. The Scale for the Assessment of Negative Symptoms (SANS) will be used to test changes in the total SANS score in adjunct minocycline compared to placebo in the 10 week study.
- The effect of minocycline on inflammatory biomarkers associated with schizophrenia. [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]Both pro and anti-inflammatory cytokines will be drawn at baseline and endpoint. We will test to see if minocycline is associated with improvements in abnormal cytokines as compared to placebo.
- The safety of adjunct minocycline compared to placebo as defined by reported side effects, laboratory findings and extrapyramidal symptoms. [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]We will examine side effect reports by a standardized side effect checklist, various laboratory measures (hepatic, kidney, blood) and use the Simpson Angus Scale and Barnes Akathisia Scale to measure extrapyramidal side effects. We hypothesize that side effects rates will be similar to placebo. Additionally we will closely watch for skin pigmentation.
- The efficacy of adjunct minocycline to placebo to improve depressive symptoms [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]The total score of the Calgary Depression Rating Scale will be used to examine the efficacy of minocycline compared to placebo in improving depressive symptoms.
- The effect of adjunct minocycline to placebo on global clinical improvement of symptoms. [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]The Clinical Global Impression Severity score will be used to examine the effect of minocycline compared to placebo.
- The efficacy of adjunct minocycline compared to placebo on perceived health quality and general well being. [ Time Frame: 10 Weeks ] [ Designated as safety issue: No ]We will use the Short Form 36 Health Survey and the Psychological General Well Being Schedule to measure changes. We hypothesize that minocycline will be superior to placebo.
| Estimated Enrollment: | 60 |
| Study Start Date: | July 2011 |
| Estimated Study Completion Date: | July 2015 |
| Estimated Primary Completion Date: | July 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Active Comparator: Minocycline |
Drug: Minocycline
Minocycline Dosing: Minocycline (Dynacin® or generic) will be available in 50, 75 and 100 mg capsules. There will be matched placebo-minocycline capsules for each minocycline capsule strength. During the first week subjects will receive one 50 mg capsule twice per day (minocycline 100 mg total or matching placebo) and during weeks 2-10 subjects will receive 2- 50 mg capsules twice per day If a subject should complain of any side effect, then the blind psychiatrist will be allowed to omit the next dose of study medication and then continue the subject on the optimal treatment dose. If, despite this intervention, the subject is still unable to tolerate the 200 mg/day dose, then the dose may be lowered to 150 mg to alleviate side effects and minimize attrition. |
| Placebo Comparator: Sugar Pill |
Drug: Placebo
Placebo Dosing: Minocycline (Dynacin® or generic) will be available in 50, 75 and 100 mg capsules. There will be matched placebo-minocycline capsules for each minocycline capsule strength. During the first week subjects will receive one 50 mg capsule twice per day(minocycline 100 mg total or matching placebo) and during weeks 2-10 subjects will receive 2- 50 mg capsules twice per day If a subject should complain of any side effect, then the blind psychiatrist will be allowed to omit the next dose of study medication and then continue the subject on the optimal treatment dose. If, despite this intervention, the subject is still unable to tolerate the 200 mg/day dose, then the dose may be lowered to 150 mg to alleviate side effects and minimize attrition. |
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- DSM-IV diagnosis of schizophrenia or schizoaffective disorder
- Male or Female
- Age: 18 to 65 years
- Caucasian or Non-Caucasian
- At least six months of clozapine treatment
- Clozapine treatment for incomplete symptoms response (evidence of two failed previous trials of antipsychotics)
- Current dose of 200 mg/day for at least 3 months AND a documented clozapine blood level 350 ng/ml prior to study start (maximum clozapine dose of 900 mg/day)
- BPRS total score of 45 or more on the 18 item version (scale: 1-7)
- BPRS positive symptom item total score of 8 or more
- BPRS positive symptom score of 4 or greater on at least one item
Exclusion Criteria:
- History of organic brain disease
- DSM-IV diagnosis of Mental Retardation
- DSM-IV diagnosis of Alcohol or Substance Dependence within the last six months (except nicotine)
- DSM-IV diagnosis of Alcohol or Substance Abuse within the last one month (except nicotine)
- Pregnancy or lactation
- Significant renal or liver impairment
- Previous known hypersensitivity to tetracyclines
- Current treatment with tetracycline or derivative
- Current treatment with lamotrigine
- Treatment with oral contraceptives
- Current known infection
- Treatment with cholestyramine or colestipol
- Treatment with Urinary alkalinizers (e.g., sodium lactate, potassium citrate)
- Treatment with warfarin
- Abnormal (considered positive) Lyme titer
Contacts and Locations| Contact: Ann Kearns, B.S | 410-402-6854 | akearns@mprc.umaryland.edu |
| Contact: Stephanie Feldman, LCSW | 410-402-6885 | sfeldman@mprc.umaryland.edu |
| United States, Maryland | |
| Maryland Psychiatric Research Center | Recruiting |
| Catonsville, Maryland, United States, 21228 | |
| Contact: Ann Kearns, BS 410-402-6854 akearns@mprc.umaryland.edu | |
| Contact: Stephanie Feldman, LCSW 410-402-6885 sfeldman@mprc.umaryland.edu | |
| Principal Investigator: Deanna L. Kelly, Pharm.D., BCPP | |
| Principal Investigator: | Deanna Kelly, Pharm.D., BCPP | University of Maryland |
More Information
No publications provided
| Responsible Party: | MPRC, Deanna L. Kelly, Pharm.D., BCPP, University of Maryland |
| ClinicalTrials.gov Identifier: | NCT01433055 History of Changes |
| Other Study ID Numbers: | HP-00048900, 1R21 MH091184-01A1 |
| Study First Received: | July 21, 2011 |
| Last Updated: | April 30, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by University of Maryland:
|
Schizophrenia Cognitive Symptoms Clozapine |
Additional relevant MeSH terms:
|
Schizophrenia Schizophrenia and Disorders with Psychotic Features Mental Disorders Clozapine Minocycline Serotonin Antagonists Serotonin Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Physiological Effects of Drugs |
Antipsychotic Agents Tranquilizing Agents Central Nervous System Depressants Central Nervous System Agents Therapeutic Uses Psychotropic Drugs GABA Antagonists GABA Agents Anti-Bacterial Agents Anti-Infective Agents |
ClinicalTrials.gov processed this record on May 23, 2013