Minocycline Augmentation to Clozapine

NCT02124811 | Completed Phase 4 Results FDA Drug

• 1 other identifier: IRB00071195
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Schizophrenia; Schizoaffective Disorder

Keywords

Schizophrenia; Clozapine; Minocycline

Outcome Measures

Primary Outcomes (4)

• Positive Subscale Score of the Positive and Negative Syndrome Scale (PANSS)

  Positive symptoms (representing unusual thought content) of schizophrenia/schizoaffective disorder were measured with the positive subscale of the Positive and Negative Syndrome Scale (PANSS). The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia. Seven items measure the positive symptoms of delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme. The total summed score for the positive subscale ranges between 7 and 49 where higher scores indicate more severe symptoms. A reduction in the score indicates an improvement in symptom severity.

  Baseline, Week 12

• Negative Subscale Score of the Positive and Negative Syndrome Scale (PANSS)

  Negative symptoms (representing a loss of normal functions) of schizophrenia/schizoaffective disorder were measured with the negative subscale of the Positive and Negative Syndrome Scale (PANSS). The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia. Seven items measure the negative symptoms of blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity \& flow of conversation, and stereotyped thinking. The items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme. The total summed score for the negative subscale ranges between 7 and 49 where higher scores indicate more severe symptoms. A reduction in the score indicates an improvement in symptom severity.

  Baseline, Week 12

• Brief Assessment of Cognition in Schizophrenia (BACS) Score

  The Brief Assessment of Cognition in Schizophrenia (BACS) is an instrument that assesses the aspects of cognition found to be most impaired and most strongly correlated with outcomes in patients with schizophrenia (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive function). BACS takes less than 35 minutes to complete and was administered on an electronic tablet for this study. The composite score is a T-score that averages the standardized scale scores of each of the six tests. The composite T-score has a mean of 50 and a standard deviation of 10. Scores below 50 indicate lower than average cognition while scores above 50 indicate higher than average cognition. A prior study found that the BACS mean composite score for schizophrenia patients was 25.96 while healthy controls had a mean score of 47.00.

  Baseline, Week 12

• General Psychopathology Score of the Positive and Negative Syndrome Scale (PANSS)

  General symptoms of schizophrenia/schizoaffective disorder were measured using the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS). The PANSS is scored by the clinician-researcher after an interview with the patient and it is the most commonly used measure for assessing the symptoms of schizophrenia. Sixteen items measure general psychopathology symptoms of somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance. Items are scored on a scale of 1 to 7 where 1 means the symptom is absent and 7 means the symptom is extreme. Total scores for this subscale can range from 16 to 112 where higher scores indicate more severe symptoms. A reduction in the score indicates an improvement in symptom severity.

  Baseline, Week 12

Secondary Outcomes (2)

• Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Score

  Baseline, Week 12

• Global Assessment of Functioning (GAF) Score

  Baseline, Week 12

Study Arms (2)

High CRP

EXPERIMENTAL

Subjects with a High Baseline CRP will receive Minocycline. During the first week, subjects will receive one 100 mg capsule daily. On weeks 2-12, the subject will receive two 100 mg capsules at bedtime. The blinded psychiatrist (blinded to CRP status) will be allowed to reduce the dose if the subject complains of any side effect. Pending tolerability, the subject will have 200 mg per day.

Drug: Minocycline

Low CRP

EXPERIMENTAL

Subjects with a Low Baseline CRP will receive Minocycline. During the first week, subjects will receive one 100 mg capsule daily. On weeks 2-12, the subject will receive two 100 mg capsules at bedtime. The blinded psychiatrist (blinded to CRP status) will be allowed to reduce the dose if the subject complains of any side effect. Pending tolerability, the subject will have 200 mg per day.

Drug: Minocycline

Interventions

Minocycline DRUG

High CRP; Low CRP

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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"

Sponsors & Collaborators

• Emory University: lead

Study Sites (1)

Grady Memorial Hospital

Atlanta, Georgia, 30303, United States

Location

Related Publications (3)

• 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.

  PMID: 19895780 BACKGROUND

• 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.

  PMID: 22526685 BACKGROUND

• 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.

  PMID: 21872445 BACKGROUND

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; cyclopia sequence

Interventions

Minocycline

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Limitations and Caveats

The small sample size limits the conclusions that can be drawn from the data collected in this pilot study.

Results Point of Contact

• Title: Robert Cotes, MD
• Organization: Emory University

robert.o.cotes@emory.edu

(404) 616-4752

Study Officials

• Robert O Cotes, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 25, 2014
• First Posted: April 28, 2014
• Study Start: February 1, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: September 26, 2018
• Results First Posted: August 29, 2018

Record last verified: 2018-08

Locations

US (1)