Minocycline as an Adjunct for the Treatment of Depressive Symptoms: Pilot Randomized Controlled Trial
Information source: Pakistan Institute of Learning and Living
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Depressive Disorder; Mood Disorders; Depressive Disorder, Treatment Resistant; Antidepressive Agents
Intervention: Minocycline (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: Pakistan Institute of Learning and Living Official(s) and/or principal investigator(s): Dr. Muhammad Ishrat, Principal Investigator, Affiliation: Institute of Psychiatry, Psychology and Neuroscience, Kings college London
Overall contact: Dr. Muhammad Ishrat, Phone: 00447862272533, Email: ishrat-h@doctors.net.uk
Summary
In this double blind randomised controlled pilot trial the investigators aim to determine
the efficacy of minocycline as an adjunct to treatment as usual in patients with major
depressive disorder. The investigators hypothesize that the multiple neuroprotective effects
of minocycline will lead to an improvement in depressive symptoms in participants that were
given minocycline plus treatment as usual
Clinical Details
Official title: Minocycline as an Adjunct for the Treatment of Depressive Symptoms: Pilot Randomized Controlled Trial
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: The primary clinical outcome measures will be mean change from baseline on the Hamilton Depression Scale scores
Secondary outcome: PHQ-9GAD-7 CGI
Detailed description:
Major depressive disorder is associated with significant morbidity and mortality. According
to the WHO, depression is the leading cause of disability worldwide in terms of years lost
due to disability [1]. Although depressive symptoms are amenable to antidepressant
treatment, a high proportion of patients does not respond or remit. For example in the
Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) study the response
and remission rates with stage 1 treatment (citalopram) were 49% and 37% respectively and
these rates decreased to 16% and 13% respectively over the subsequent next three treatment
steps [2]. Clearly there is a need for new treatment approaches.
Recently there has been significant preclinical and clinical study linking inflammatory
processes to a range of psychiatric illness including depression, schizophrenia, bipolar
disorder and Alzheimer's disease. The evidence that depression is an inflammatory related
disorder comes from multiple sources. Depression is associated with raised inflammatory
markers even in the absence of a medical illness [3]. More specifically depression has been
associated with higher levels of positive acute phase proteins (APPs) and low levels of
negative APPs [4] as well as increased levels of complement factors C3c and C4 and
immunoglobulin M (IgM) and IgG [5]. Inflammatory medical illness, both CNS and peripheral,
are associated with greater rates of depression. In patients with Crohns disease and
comorbid depression bouts of physical disease activity tend to co-occur with depressive
episodes [6]. Finally, patients treated with cytokines for various illnesses have an
increased risk of developing depressive illness [7]. For example, treatment with cytokine
IFN-α leads to the development of depressive symptoms in up to 45% of patients [8].
With this in mind it would seem logical to hypothesise that the addition of an
anti-inflammatory medication may be a treatment option in depressive illness. Muller et al
[9] were successful in showing this when they used Celcoxib in addition to Reboxetine for
the treatment of major depressive disorder in a double-blind, randomised, placebo-controlled
pilot study. Other studies have shown that TNF (tumour necrosis factor) blocking agents such
as Infliximab and Ethanercept improve mood independent of improvement in inflammatory
condition [10]. However some studies have found that anti-inflammatories may in fact have
an antagonistic effect on the antidepressant actions of SSRIs [11]. Further work is needed
in this area to clarify the role of inflammatory processes and anti-inflammatories in the
treatment of depression.
Alongside the current interest in the use of anti-inflammatories as novel treatments in
psychiatric illness, the antibiotic minocycline has also been proposed for the treatment of
depressive symptoms as well as negative symptoms in schizophrenia [12, 13]. Preliminary data
from an open label study of patients with psychotic unipolar depression also suggested that
minocycline augmentation of antidepressant treatment was effective and well tolerated [14].
Minocycline is a pleiotropic agent that exerts effects on multiple interacting symptoms
(e. g. anti-inflammatory, anti-oxidant, anti-apoptotic, anti-gutamatergic, monaminergic)
implicated in the pathophysiology of mood disorders. Despite such neuroprotective
properties, there have been no clinical trials to date investigating the antidepressant
effects of minocycline in individuals. The investigators have previously shown that the
addition of minocycline to treatment as usual early in the course of schizophrenia leads to
a predominant improvement in negative symptoms.
In this double blind randomised controlled pilot trial the investigators aim to determine
the efficacy of minocycline as an adjunct to treatment as usual in patients with major
depressive disorder. The investigators hypothesise that the multiple neuroprotective effects
of minocycline will lead to an improvement in depressive symptoms in participants that were
given minocycline plus treatment as usual.
Aim To investigate whether the addition of minocycline to treatment as usual (TAU) for 3
months in patients with major depressive disorder will lead to an improvement in depressive
symptoms compared with TAU.
Methods
Double blind randomised, placebo-controlled pilot trial.
The study will be conducted in Karachi, Pakistan. Patients will be recruited from
psychiatric units in Karachi. All patients will give written informed consent after reading
information in Urdu, witnessed almost always by a relative.
Eligibility
Minimum age: 18 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. patients aged 18-65 years
2. Diagnostic and Statistical Manual-IV (DSM-IV) diagnosis of major depressive disorder
3. competent and willing to give informed consent
4. taking the current antidepressant medication for a minimum of 4 weeks prior to
baseline
5. the current episode of depression has failed to remit with at least two courses of
antidepressant treatment (one of which is the current course)
6. able to take oral medication
7. if female, willing to use adequate contraceptive precautions and to have monthly
pregnancy tests.
Exclusion Criteria:
1. relevant medical illness (renal, hepatic, cardiac, serious dermatological disorders
such as exfoliative dermatitis, systemic lupus erythematosis)
2. prior history of intolerance to any of the tetracyclines
3. concomitant penicillin therapy
4. concomitant anticoagulant therapy
5. presence of a seizure disorder
6. currently taking valproic acid
7. any change of psychotropic medications within the previous 4 weeks
8. diagnosis of substance abuse (except nicotine or caffeine) or dependence within the
last 3 months according to DSM-IV criteria
9. pregnant or breast-feeding
10. presence of primary psychotic disorder.
Locations and Contacts
Dr. Muhammad Ishrat, Phone: 00447862272533, Email: ishrat-h@doctors.net.uk
Abasi Shaheed Hospital, Karachi, Sindh 72000, Pakistan; Recruiting Prof Munir Hamarani, FCPS, Phone: 00923009272002, Email: mmham@yahoo.com Prof Munir Hamarani, FCPS, Principal Investigator
Civil hospital Karachi, Karachi, Sindh 72000, Pakistan; Recruiting Prof Raza U Rahman, FCPS, Phone: 00-92-21-9215740-50, Ext: 2500, Email: razaur@yahoo.com Prof Raza U Rahman, FCPS, Principal Investigator
Karwan-e-Hayat, Karachi, Sindh, Pakistan; Recruiting Ajmal kazmi
Additional Information
Related publications: World Health Organization. The Global Burden of Disease. Geneva: WHO Press; 2012. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. O'Donovan A, Rush G, Hoatam G, Hughes BM, McCrohan A, Kelleher C, O'Farrelly C, Malone KM. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety. 2013 Apr;30(4):307-14. doi: 10.1002/da.22087. Epub 2013 Mar 15. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008 Jan;9(1):46-56. Review. Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994 Apr;30(4):283-8. Mardini HE, Kip KE, Wilson JW. Crohn's disease: a two-year prospective study of the association between psychological distress and disease activity. Dig Dis Sci. 2004 Mar;49(3):492-7. Van Gool AR, Kruit WH, Engels FK, Stoter G, Bannink M, Eggermont AM. Neuropsychiatric side effects of interferon-alfa therapy. Pharm World Sci. 2003 Feb;25(1):11-20. Review. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011 May;130(2):226-38. doi: 10.1016/j.pharmthera.2011.01.014. Epub 2011 Feb 17. Review. Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006 Jul;11(7):680-4. Epub 2006 Feb 21. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012 May;83(5):495-502. doi: 10.1136/jnnp-2011-301779. Epub 2012 Mar 15. Review. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9262-7. doi: 10.1073/pnas.1104836108. Epub 2011 Apr 25. Erratum in: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11297. Soczynska JK, Mansur RB, Brietzke E, Swardfager W, Kennedy SH, Woldeyohannes HO, Powell AM, Manierka MS, McIntyre RS. Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res. 2012 Dec 1;235(2):302-17. doi: 10.1016/j.bbr.2012.07.026. Epub 2012 Aug 10. Review. 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. Miyaoka T, Furuya M, Yasuda H, Hayashida M, Nishida A, Inagaki T, Horiguchi J. Yi-gan san as adjunctive therapy for treatment-resistant schizophrenia: an open-label study. Clin Neuropharmacol. 2009 Jan-Feb;32(1):6-9. doi: 10.1097/WNF.0b013e31817e08c3.
Starting date: October 2014
Last updated: August 18, 2015
|