Bipolar Disorder Depression
Conditions
Keywords
Bipolar Disorder, Minocycline
Brief summary
The purpose of this study is to determine whether minocycline and aspirin are effective in the treatment of depression in individuals with bipolar disorder.
Detailed description
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.
Interventions
DRUGAspirin
81 mg po bid for 6 weeks
DRUGplacebo
placebo for minocycline and/or aspirin
DRUGMinocycline
100 mg po bid for 6 weeks
Sponsors
Stanley Medical Research Institute
University of Oklahoma
Laureate Institute for Brain Research, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response | Six weeks | Response to treatment defined as a \>50% decrease in Montgomery-Asberg Depression Rating Scale scores for the final two consecutive visits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission Rate | Six weeks | Remission defined as a score of \<11 on Montgomery-Asberg Depression Rating Scale scores for the final two consecutive visits. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo & Placebo Placebo for minocycline & placebo for aspirin
placebo: placebo for minocycline and/or aspirin | 30 |
| Minocycline & Aspirin Minocycline 100mg PO BID for 6 weeks & Aspirin 81 mg PO BID for 6 weeks
Minocycline: 100 mg po bid for 6 weeks
Aspirin: 81 mg po bid for 6 weeks | 31 |
| Placebo + Minocycline placebo aspirin + active minocycline | 19 |
| Placebo + Aspirin placebo minocycline + active aspirin | 19 |
| Total | 99 |
Baseline characteristics
| Characteristic | Placebo & Placebo | Minocycline & Aspirin | Placebo + Minocycline | Placebo + Aspirin | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 31 Participants | 19 Participants | 19 Participants | 99 Participants |
| Age, Continuous | 40.8 Years STANDARD_DEVIATION 10.4 | 40.8 Years STANDARD_DEVIATION 9.7 | 44.8 Years STANDARD_DEVIATION 8.7 | 40.6 Years STANDARD_DEVIATION 10.2 | 41.5 Years STANDARD_DEVIATION 9.8 |
| Interleukin 6 (IL-6) | 0.9 pg/ML STANDARD_DEVIATION 0.5 | 1.0 pg/ML STANDARD_DEVIATION 0.7 | 0.9 pg/ML STANDARD_DEVIATION 0.5 | 1.1 pg/ML STANDARD_DEVIATION 0.7 | 1.0 pg/ML STANDARD_DEVIATION 0.6 |
| Measure of Inflammation using the C-Reactive Protein (CRP) measurement | 4.4 mg/L STANDARD_DEVIATION 5.3 | 8.2 mg/L STANDARD_DEVIATION 12.9 | 4.3 mg/L STANDARD_DEVIATION 5.5 | 4.5 mg/L STANDARD_DEVIATION 4.9 | 5.6 mg/L STANDARD_DEVIATION 8.5 |
| Montgomery-Asberg Depression Rating Score | 29.2 units on a scale STANDARD_DEVIATION 6.2 | 28.0 units on a scale STANDARD_DEVIATION 5.7 | 27.2 units on a scale STANDARD_DEVIATION 5.2 | 25.9 units on a scale STANDARD_DEVIATION 6.5 | 27.8 units on a scale STANDARD_DEVIATION 5.9 |
| Region of Enrollment United States | 30 Participants | 31 Participants | 19 Participants | 19 Participants | 99 Participants |
| Sex: Female, Male Female | 22 Participants | 26 Participants | 13 Participants | 13 Participants | 74 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 6 Participants | 6 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 31 | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 30 | 0 / 31 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Treatment Response
Response to treatment defined as a \>50% decrease in Montgomery-Asberg Depression Rating Scale scores for the final two consecutive visits.
Time frame: Six weeks
Population: Note numbers do not match the participants flow because participants who did not return for at least one post treatment visit could not be included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo & Placebo | Treatment Response | 21 Percentage of Participants |
| Minocycline & Aspirin | Treatment Response | 44 Percentage of Participants |
| Placebo + Minocycline | Treatment Response | 25 Percentage of Participants |
| Placebo + Aspirin | Treatment Response | 50 Percentage of Participants |
Secondary
Remission Rate
Remission defined as a score of \<11 on Montgomery-Asberg Depression Rating Scale scores for the final two consecutive visits.
Time frame: Six weeks
Population: Note numbers do not match the participants flow because participants who did not return for at least one post treatment visit could not be included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo & Placebo | Remission Rate | 14 percentage of participants |
| Minocycline & Aspirin | Remission Rate | 26 percentage of participants |
| Placebo + Minocycline | Remission Rate | 6 percentage of participants |
| Placebo + Aspirin | Remission Rate | 28 percentage of participants |