Minocycline as an Adjunct for the Treatment of Depressive Symptoms: Pilot Randomized Controlled Trial

Depressive Disorder Clinical Trial

Official title:

Minocycline as an Adjunct for the Treatment of Depressive Symptoms: Pilot Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02263872
• Other study ID #: MINDEP001
• Status: Completed
• Phase: Phase 4
• First received: October 8, 2014
• Last updated: September 2, 2016
• Start date: October 2014
• Est. completion date: August 2016

Study information

• Verified date: September 2016
• Source: Pakistan Institute of Learning and Living
• Contact: n/a
• Is FDA regulated: No
• Health authority: Pakistan: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: August 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Antidepressive Agents
• Depression
• Depressive Disorder
• Depressive Disorder, Treatment Resistant
• Depressive Disorder, Treatment-Resistant
• Disease
• Mood Disorders

Intervention

Drug:
• Minocycline
Minocycline 200mg perday

Locations

Country	Name	City	State
Pakistan	Abasi Shaheed Hospital	Karachi	Sindh
Pakistan	Civil hospital Karachi	Karachi	Sindh
Pakistan	Karwan-e-Hayat	Karachi	Sindh

Sponsors (2)

Lead Sponsor	Collaborator
Pakistan Institute of Learning and Living	King's College London

Country where clinical trial is conducted

Pakistan, 

References & Publications (14)

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. — View 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

World Health Organization. The Global Burden of Disease. Geneva: WHO Press; 2012.

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary clinical outcome measures will be mean change from baseline on the Hamilton Depression Scale scores		12 weeks	No
Secondary	PHQ-9		Baseline, Week 2, week 4, week 8, week 12	No
Secondary	GAD-7		Baseline, Week 2, week 4, week 8, week 12	No
Secondary	CGI		Baseline, Week 2, week 4, week 8, week 12	No