Minocycline as an Adjunct for the Treatment of Depressive Symptoms: Pilot Randomized Controlled Trial
Condition: Depressive Disorder; Mood Disorders; Depressive Disorder, Treatment Resistant; Antidepressive Agents
MeSH terms: Depressive Disorder; Depression; Mood Disorders; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 4

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
    

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.
    

Intervention name(s): Minocycline
Intervention type(s): Drug
Intervention description(s): Minocycline 200mg perday
Other intervention name(s): mesodrum
Intervention MeSH terms: Minocycline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment