Minocycline and Aspirin in the Treatment of Bipolar Depression

Abstract:

New medication classes are needed to improve treatment effectiveness in the depressed phase
of bipolar disorder (BD). Extant evidence suggests that BD is not only characterized by
reduced monoaminergic signaling, but also by neural changes such as dendritic remodeling,
demyelination, and glial and neuronal cell loss. These changes have been hypothesized to
result from chronic inflammation, based partly on convergent evidence that proinflammatory
cytokines are elevated in depressed patients with BD. The principal aims of the proposed
research is to evaluate the antidepressant efficacy in bipolar depression of minocycline, a
drug with neuroprotective and immune-modulating properties, and of aspirin, at doses expected
to selectively inhibit cyclooxygenase 1 (COX-1), within the context of a randomized,
double-blind, placebo-controlled, parallel-group clinical trial following a 2 x 2 design.

Specific Aims Specific Aim 1: To evaluate the efficacy of augmentation therapy with
minocycline and/or aspirin for bipolar depression.

The investigators will test the hypothesis that compared with placebo, participants receiving
minocycline and/ or aspirin will show a greater treatment response rate (defined as a >50%
increase on the MADRS for the final two consecutive visits).

Specific Aim 2: To investigate the relationship between the response to minocycline, aspirin
and markers of inflammation (serum concentrations of IL-6 and CRP).

The investigators will test the hypotheses that: a) minocycline treatment will reduce
inflammation to a greater extent than placebo; b) during minocycline treatment the change in
inflammatory cytokine expression will correlate with the change in depression ratings; c) the
baseline elevation of inflammatory markers will predict greater antidepressant response to
minocycline.

Inclusion Criteria:

One hundred and twenty male or female outpatients between 18 and 65 years of age, who meet
DSM-IV-TR criteria for BD (type I or II or NOS) and for a current major depressive episode
will be recruited. The depressive syndrome must have been present for at least 4 weeks and
the minimum threshold for depression severity will be set at a Quick Inventory of
Depressive Symptomatology (QID-C16) score >10. Subjects will provide written informed
consent as approved by the Western Institutional Review Board.

Exclusion Criteria:

(a) Illness onset after 40 years of age; (b) serious risk of suicide; (c) current delusions
or hallucinations sufficient to interfere with the capacity to provide informed consent;
(d) current manic symptoms of sufficient severity to pose a substantial risk of the
development of a manic episode; (e) current treatment with more than four psychotropic
medications; (f) medical illness including hepatic impairment, renal dysfunction, bleeding
diatheses, cerebrovascular disease, hypertension or diabetes mellitus that is inadequately
controlled by diet and/or medication, or known active peptic ulcer disease; (g) abuse of
drugs or alcohol within the preceding 6 months, or substance dependence within the last
year; (h) daily alcoholic beverage consumption equivalent to >3 oz. of alcohol; (i) known
allergies or hypersensitivities to tetracycline antibiotics, aspirin or other NSAIDs; (j)
current use of drugs that could increase the risks associated with aspirin or minocycline
administration, (k) chronic infection, (l) use of antibiotics, (m) pregnant or nursing
women, (n) asthma which in the opinion of the investigator would increase the likelihood of
an asthmatic attack, and (o) regular use of steroidal or non-steroidal anti-inflammatory
medications (occasional use of NSAIDS was allowed).