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

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

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 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.