Adjunctive Minocycline in Clozapine Treated Schizophrenia Patients

Not Applicable

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Sugar Pill	Placebo	-
Minocycline	Minocycline	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.