Depressive Disorder Clinical Trial
Official title:
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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