Minocycline Augmentation of Clozapine for Treatment Resistant Schizophrenia

Schizophrenia Clinical Trial

Official title:

Minocycline Augmentation of Clozapine for Treatment Resistant Schizophrenia: A Randomised Placebo-controlled Double-blind Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02533232
• Other study ID #: PILL-MAC-001
• Status: Recruiting
• Phase: Phase 1
• Start date: August 30, 2022
• Est. completion date: December 30, 2022

Study information

• Verified date: April 2022
• Source: Pakistan Institute of Living and Learning
• Contact: Dr.Inti Qurashi, MD
• Email: Inti.Qurashi[@]merseycare.nhs.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This a randomized double-blind placebo controlled trial which aims to determine the beneficial effects of minocycline augmentation to clozapine in partial responders to Treatment Resistant Schizophrenia (TRS).

Description:

The primary objective is to determine if the addition of minocycline to Clozapine, Treatment as Usual (TAU) Improves negative symptoms and/or positive symptoms.

The secondary objectives are to determine:

• Effects on cognitive functioning.

• Effects on social functioning and quality of life.

• Safety and tolerability.

• Possible additive effects of Minocycline added to TAU

• The effect on inflammatory biomarkers associated with schizophrenia. 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 study will be a randomized double-blind placebo controlled trial of minocycline added to clozapine (Treatment as Usual) in TRS. There will be two treatment arms: one arm receiving TAU with minocycline and the other TAU with placebo for a period of twelve weeks.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 30, 2022
• Est. primary completion date: December 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male and female patients aged between 18-65 years, IQ >70 (to complete assessments) identified by treating psychiatrist.

• Confirmation of schizophrenia by using The MINI psychiatric interview (at baseline only)

• Assessed as competent to provide informed consent by treating psychiatrist.

• Antipsychotic medication has remained stable 4 weeks prior to baseline *. Assessed as a partial responder to clozapine: patients prescribed clozapine at a stable therapeutic dose for a minimum of 3 months with total Positive and Negative Syndrome Schizophrenia (PANSS) score >70.

Exclusion Criteria:

• Prior history of intolerance or serious side effects (hepatotoxicity, photosensitivity, blood dyscrasias) to any of the Tetracyclines.

• Concomitant Penicillin therapy or concomitant anticoagulant therapy.

• Active substance abuse (except nicotine or caffeine) or dependence within the last three months according to ICD 10 criteria.

• Treatment with Warfarin or Lamotrigine.

• Current or previous treatment with minocycline or other tetracycline antibiotics in the preceding three months before study entry.

• Relevant current or past hematologic, hepatic, renal, neurological or other medical disorder that in the opinion of the principal investigator may interfere with the study.

• Pregnant or breast-feeding females

Related Conditions & MeSH terms

• Disease
• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia
• Schizophreniform Disorder

Intervention

Drug:
• Minocycline
Minocycline 200mg per day

Locations

Country	Name	City	State
Pakistan	Abasi Shaheed Hospital	Karachi	Sindh
Pakistan	Civil hospital Karachi	Karachi	Sindh
Pakistan	Institute of Behavioral Sciences	Karachi	Sindh
Pakistan	Karwn e Hayat	Karachi	Sindh

Sponsors (1)

Lead Sponsor	Collaborator
Pakistan Institute of Living and Learning

Country where clinical trial is conducted

Pakistan, 

References & Publications (15)

Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16720-5. doi: 10.1073/pnas.1208494109. Epub 2012 Sep 25. — View Citation

Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001 Apr;158(4):518-26. — View Citation

Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull. 1997;23(4):663-74. Review. — View Citation

Deakin JF, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008 Feb;65(2):154-64. doi: 10.1001/archgenpsychiatry.2007.37. — View Citation

Domercq M, Matute C. Neuroprotection by tetracyclines. Trends Pharmacol Sci. 2004 Dec;25(12):609-12. Review. — View Citation

Farber NB. The NMDA receptor hypofunction model of psychosis. Ann N Y Acad Sci. 2003 Nov;1003:119-30. Review. — View Citation

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991 Oct;148(10):1301-8. Review. — View Citation

Labrie V, Roder JC. The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev. 2010 Mar;34(3):351-72. doi: 10.1016/j.neubiorev.2009.08.002. Epub 2009 Aug 18. Review. — View Citation

Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E, Pioli R, Altamura C, Scharpé S, Maes M. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998 Jun 22;32(1):9-15. — View Citation

Meltzer HY. Treatment-resistant schizophrenia--the role of clozapine. Curr Med Res Opin. 1997;14(1):1-20. Review. — View Citation

Qurashi I, Collins JD, Chaudhry IB, Husain N. Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia. J Psychopharmacol. 2014 Jul;28(7):707-8. doi: 10.1177/0269881114527358. Epub 2014 Mar 19. — View Citation

Rössler W, Salize HJ, van Os J, Riecher-Rössler A. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol. 2005 Aug;15(4):399-409. Review. — View Citation

Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. 2012 Sep;38(5):1003-11. doi: 10.1093/schbul/sbr004. Epub 2011 Mar 21. Review. — View Citation

Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001 Apr 15;21(8):2580-8. — View Citation

van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008 Nov 1;64(9):820-2. doi: 10.1016/j.biopsych.2008.04.025. Epub 2008 Jun 4. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Social Functioning Scale	Self-rating questionnaire assessing social functioning in 7 domains.	3 Month
Primary	Positive and Negative Syndrome Scale PANSS	PANSS is an assessment measures to assess severity of symptoms of schizophrenia	3 months
Secondary	CogState	Measuring all seven domains recommended by MATRICS (NIMH initiative). These domains include speed processing, attention/vigilance, Working memory (nonverbal & verbal), verbal learning, visual learning, reasoning and problem solving and social cognition's.	3 Month

External Links

•   Website of Pakistan Institute of Learning and Living