Schizophrenia
Conditions
Keywords
Schizophrenia, Cognitive Symptoms, Clozapine
Brief summary
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.
Interventions
DRUGMinocycline
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.
DRUGPlacebo
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.
Sponsors
National Institute of Mental Health (NIMH)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo. | 10 Weeks | Adjunct minocycline to clozapine will be compared to placebo to test its efficacy to improve positive psychotic symptoms. The 4 item positive sub factor of the Brief Psychiatric Rating Scale (BPRS) will be the primary outcome over the 10 week randomized study. Total maximum score is 28, and total minimum score is 4. The positive domain score consists of conceptual disorganization (item 4), suspiciousness (item 11) hallucinatory behavior (item 12), and unusual thought content (item 15). All data is reported as the difference between baseline and 10 weeks. The lower the score the better the outcome. |
| Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery. | 10 Weeks | Adjunct minocycline 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. This assessment total minimum score of -10 and maximum score of 80. He higher the score the better the outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS) | 10 Weeks | Adjunct minocycline 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. This assessment has 22 items (scored 0-5) with a total minimum score of 0 and maximum score of 110. The lower the score the better the outcome. |
| The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale | 10 Weeks | 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. This assessment has 9 items (scored 0-3) with a total minimum socre of 0 and maximum score of 27. The lower the score the better the outcome. |
| The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms. | 10 Weeks | The Clinical Global Impression Severity score will be used to examine the effect of minocycline compared to placebo. This assessment has 2 items (scored 0-7) with a total minimum socre of 0 and maximum score of 14. The lower the score the better the outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Minocycline 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. | 27 |
| Sugar Pill 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. | 23 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Diagnosed with cancer unrelated to study | 1 | 0 |
| Overall Study | Severely elevated triglycerides at entry | 1 | 0 |
Baseline characteristics
| Characteristic | Sugar Pill | Minocycline | Total |
|---|---|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 11 | 42.9 years STANDARD_DEVIATION 14.2 | 42.6 years STANDARD_DEVIATION 12.8 |
| Race/Ethnicity, Customized Black | 8 participants | 8 participants | 16 participants |
| Race/Ethnicity, Customized Other | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized White | 13 participants | 17 participants | 30 participants |
| Region of Enrollment United States | 23 participants | 27 participants | 50 participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 18 Participants | 19 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 27 | 22 / 23 |
| serious Total, serious adverse events | 0 / 27 | 0 / 23 |
Outcome results
Primary
Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo.
Adjunct minocycline to clozapine will be compared to placebo to test its efficacy to improve positive psychotic symptoms. The 4 item positive sub factor of the Brief Psychiatric Rating Scale (BPRS) will be the primary outcome over the 10 week randomized study. Total maximum score is 28, and total minimum score is 4. The positive domain score consists of conceptual disorganization (item 4), suspiciousness (item 11) hallucinatory behavior (item 12), and unusual thought content (item 15). All data is reported as the difference between baseline and 10 weeks. The lower the score the better the outcome.
Time frame: 10 Weeks
Population: The BPRS is a scale that measures major psychotic and non psychotic symptoms in persons with psychotic disorders. It is an 4 item scale with a score range of 1-7 on each item. Results are reported as total score. Total maximum score is 28, and total minimum score is 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline | Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo. | Baseline | 14.5 units on a scale | Standard Deviation 3.5 |
| Minocycline | Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo. | 10 weeks (Endpoint) | 12.9 units on a scale | Standard Deviation 3.2 |
| Sugar Pill | Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo. | Baseline | 14.5 units on a scale | Standard Deviation 3.5 |
| Sugar Pill | Brief Psychiatric Rating Scale (BPRS) Positive Symptom Domain Scores Between Minocycline and Placebo. | 10 weeks (Endpoint) | 14.2 units on a scale | Standard Deviation 3.2 |
Primary
Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery.
Adjunct minocycline 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. This assessment total minimum score of -10 and maximum score of 80. He higher the score the better the outcome.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline | Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery. | Baseline | 30.4 units on a scale | Standard Deviation 11.6 |
| Minocycline | Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery. | 10 Weeks (Endpoint) | 35.6 units on a scale | Standard Deviation 10.7 |
| Sugar Pill | Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery. | Baseline | 35.1 units on a scale | Standard Deviation 11.7 |
| Sugar Pill | Effect of Minocycline on Cognitive Symptoms as Measured by the MATRICS Consensus Cognitive Battery. | 10 Weeks (Endpoint) | 34.2 units on a scale | Standard Deviation 12.2 |
Secondary
The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms.
The Clinical Global Impression Severity score will be used to examine the effect of minocycline compared to placebo. This assessment has 2 items (scored 0-7) with a total minimum socre of 0 and maximum score of 14. The lower the score the better the outcome.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline | The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms. | Baseline | 4.0 units on a scale | Standard Deviation 0 |
| Minocycline | The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms. | 10 Weeks (Endpoint) | 3.6 units on a scale | Standard Deviation 0.6 |
| Sugar Pill | The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms. | Baseline | 4.0 units on a scale | Standard Deviation 0.1 |
| Sugar Pill | The Effect of Adjunct Minocycline to Placebo on Global Clinical Improvement of Symptoms. | 10 Weeks (Endpoint) | 4.0 units on a scale | Standard Deviation 0.7 |
Secondary
The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale
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. This assessment has 9 items (scored 0-3) with a total minimum socre of 0 and maximum score of 27. The lower the score the better the outcome.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline | The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale | 10 Weeks (Endpoint) | 2.4 units on a scale | Standard Deviation 3 |
| Minocycline | The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale | Baseline | 3.3 units on a scale | Standard Deviation 3.1 |
| Sugar Pill | The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale | 10 Weeks (Endpoint) | 2.9 units on a scale | Standard Deviation 2.7 |
| Sugar Pill | The Effect of Adjunct Minocycline to Placebo to Improve Depressive Symptoms as Measured by the Calgary Depression Scale | Baseline | 2.6 units on a scale | Standard Deviation 2.7 |
Secondary
The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS)
Adjunct minocycline 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. This assessment has 22 items (scored 0-5) with a total minimum score of 0 and maximum score of 110. The lower the score the better the outcome.
Time frame: 10 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline | The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS) | Baseline | 29.7 units on a scale | Standard Deviation 13.3 |
| Minocycline | The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS) | 10 Weeks (Endpoint) | 28.2 units on a scale | Standard Deviation 12.4 |
| Sugar Pill | The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS) | Baseline | 33.3 units on a scale | Standard Deviation 10.3 |
| Sugar Pill | The Effect of Minocycline Compared to Placebo to Improve Negative Symptoms as Measured by the Scale for the Assessment of Negative Symptoms (SANS) | 10 Weeks (Endpoint) | 35.1 units on a scale | Standard Deviation 10.7 |