Clinical trial NCT02124811: Minocycline Augmentation to Clozapine
Official title: A Pilot Study of Minocycline Augmentation to Clozapine in Individuals With Treatment Resistant Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Schizoaffective Disorder
Keywords: Schizophrenia
Clozapine
Minocycline
Lead sponsor: Emory University
Sponsor class: OTHER
First posted: 2014-04-28
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The proposed pilot study will compare minocycline augmentation with clozapine in individuals with high vs low inflammation as measured by CRP. Investigators hypothesize that minocycline will be well tolerated and will result in an improvement in the symptoms of schizophrenia, cognition, as well as improve the quality of life for patients preferentially in patients with high CRPs. Investigators plan to use a variety of different scales to measure improvement in the varying symptoms of schizophrenia as well as cognitive function, which will be administered to patients at three week intervals for a total study time of twelve weeks. Investigators hypothesize that minocycline could prove to be an effective, well tolerated, and inexpensive medication for treatment resistant patients with schizophrenia whom have particular difficulties with social interactions, obtaining and maintaining employment, and overall quality of life. Furthermore, investigators hypothesize that the data obtained in this study will contribute to the ongoing exploration of the role of inflammation in the brain of patients with schizophrenia and help understand and target the role of various inflammatory markers in the pathophysiology and treatment of treatment resistant schizophrenia.

Detailed description: Schizophrenia is a major mental illness characterized by a variety of different symptoms including hallucinations, paranoia, difficulties with formulating and expressing thoughts, feelings similar to depression, and problems with cognitive processes. Individuals with schizophrenia are usually treated with a class of medications called anti-psychotics, which typically help alleviate some of the symptoms of the disorder. In general, anti-psychotic medications do not completely cure the disorder, and many patients are left with some degree of ongoing symptoms. Furthermore, it is estimated that 20-30% of individuals with schizophrenia are considered treatment refractory or resistant and do not respond to anti-psychotic medications. The Food and Drug Administration has approved one antipsychotic medication for use in patients who are considered to have treatment resistant schizophrenia (TRS). This medication, clozapine, has been shown to be beneficial for patients with TRS, though as many as 40-70% of patients fail to respond or are partially responsive to treatment with clozapine. In an extensive search of the medical and psychiatric literature, the study team has been impressed by the potential of minocycline, a tetracycline antibiotic, as an adjunctive therapy in patients with schizophrenia based on its reported neuroprotective and anti-inflammatory effects. It is a fairly inexpensive drug, well tolerated, and two randomized clinical trials have demonstrated favorable results in early-phase schizophrenia. Only one case series with two patients has investigated minocycline in patients with schizophrenia on clozapine. Minocycline is also an interesting medication for augmentation with clozapine, as investigators are interested in previous findings of increased inflammation in the brains of patients with schizophrenia and the potential role of inflammation in treatment resistant schizophrenia. Though there are many markers of increased inflammation in the brain, for this current study, investigators are interested in a general marker of inflammation called C-Reactive Protein (CRP). The study team hypothesizes that some patients may have increased levels of inflammation in the brain, as measured by the CRP level (drawn from peripheral blood), and that those patients with increased levels of CRP may respond better to augmentation with minocycline. The proposed pilot study will compare minocycline augmentation with clozapine in individuals with high vs low inflammation as measured by CRP. Investigators hypothesize that minocycline will be well tolerated and will result in an improvement in the symptoms of schizophrenia, cognition, as well as improve the quality of life for patients preferentially in patients with high CRPs. Investigators plan to use a variety of different scales to measure improvement in the varying symptoms of schizophrenia as well as cognitive function, which will be administered to patients at three week intervals for a total study time of twelve weeks. Investigators hypothesize that minocycline could prove to be an effective, well tolerated, and inexpensive medication for treatment resistant patients with schizophrenia whom have particular difficulties with social interactions, obtaining and maintaining employment, and overall quality of life. Furthermore, investigators hypothesize that the data obtained in this study will contribute to the ongoing exploration of the role of inflammation in the brain of patients with schizophrenia and help understand and target the role of various inflammatory markers in the pathophysiology and treatment of treatment resistant schizophrenia.

Eligibility criteria: Inclusion Criteria:

* Mini International Neuropsychiatric Interview 6.0 diagnosis of schizophrenia or schizoaffective disorder
* Persistent symptoms of schizophrenia as measured by one of the following PANSS items: Total score ≥60, negative subscale ≥ 15, positive subscale ≥ 15, general psychopathology subscale ≥ 30
* Currently taking clozapine and the dose has been adjusted within 100 mg of study enrollment
* Currently taking clozapine for 3 months and documented clozapine level ≥ 350 ng/ml prior to study start
* No other psychotropic medication changes for one month prior to study enrollment
* No new psychosocial interventions for one month prior to study enrollment
* No prior experience on minocycline for greater than 1 week
* May be taking any other psychotropic, dermatologic, or gastrointestinal drugs

Exclusion Criteria:

* History of organic brain disease
* Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-TR diagnosis of Mental Retardation or Dementia
* DSM-IV-TR diagnosis of Alcohol or Substance Dependence within the last six months (except nicotine)
* Pregnancy or lactation
* Known hypersensitivity to tetracyclines
* Current known infection
* Any known neurological disease or medical condition that could impact the measurement of the constructs being assessed
* Inpatient psychiatric hospitalization for worsening of psychiatric symptoms, OR worsening of symptoms requiring a new level of outpatient support, OR started on a new anti-inflammatory medication for greater than one week duration, OR addition of a new psychotropic medication for psychiatric symptom control
* A change in \> 15% in PANSS score from the "Lead-In Visit" to the "M0 visit"

Primary outcomes:
measure: Positive Subscale Score of the Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, Week 12
measure: Negative Subscale Score of the Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, Week 12
measure: Brief Assessment of Cognition in Schizophrenia (BACS) Score
timeFrame: Baseline, Week 12
measure: General Psychopathology Score of the Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Score
timeFrame: Baseline, Week 12
measure: Global Assessment of Functioning (GAF) Score
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Robert O Cotes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49. doi: 10.4088/JCP.08m04666yel. Epub 2009 Nov 3.
citation: Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin B. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012 Sep;26(9):1185-93. doi: 10.1177/0269881112444941. Epub 2012 Apr 23.
citation: Kelly DL, Vyas G, Richardson CM, Koola M, McMahon RP, Buchanan RW, Wehring HJ. Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res. 2011 Dec;133(1-3):257-8. doi: 10.1016/j.schres.2011.08.005. Epub 2011 Aug 26. No abstract available.