Bipolar Depression
Conditions
Keywords
Bipolar Disorder, Bipolar Depression, Inflammation, Bipolar
Brief summary
Studies show the presence of immuno-inflammatory disturbances in individuals with Bipolar Disorders (BD). Increased levels of circulating proteins known as cytokines that promote inflammation have been consistently reported in individuals with bipolar disorders. A particular cytokine referred to as Tumor Necrosis Factor (TNF)-alpha is among those cytokines that have been consistently identified across depressive, manic, and euthymic periods. Disturbances in inflammation however, are not seen in all individual with bipolar disorder. Those individuals with signs of inflammation also often present with higher prevalence of medical disorders that are also associated with inflammation. Those individuals with significant signs of inflammation may respond to anti-inflammatory treatments. In this study, individuals with bipolar depression who exhibit signs of high inflammation will be enrolled and treated with either an anti-inflammatory biologic known as infliximab or placebo (saline).
Interventions
DRUGInfliximab
Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation. Infliximab will be prescribed adjunctively to a conventional mood stabilizer or atypical antipsychotic agent.
OTHERSaline
Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency and will be administered adjunctively to conventional mood stabilizer or atypical antipsychotic agent.
Sponsors
Clinical Investigation Centre for Innovative Technology Network
Stanford University
University Health Network, Toronto
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
* Fifth edition of Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for major depressive episode as part of bipolar I/II disorder and are able to provide written informed consent * HAMD-17 score \>= 20 * Young Mania Rating Scale score \< 12 * Previous failed trial (i.e., inefficacy) of quetiapine and one other Canadian Network for Mood and Anxiety Treatments (CANMAT) BD guideline/FDA approved first line treatment for the depressive phase of BD during the index episode and/or during a prior episode * Currently prescribed conventional mood stabilizer or atypical antipsychotic agent * Received conventional treatment for bipolar depression for a minimum of 4 weeks prior to randomization * Females of childbearing potential must test negative for pregnancy and must be using adequate birth control measures throughout the study and must continue such precautions for 6 months after receiving the last study drug administration. Participants will also need to meet one of the following inflammatory indicators: 1. Central Obesity (ethnicity-specific waist circumference - see table below for specific values) OR BMI ≥30 kg/m2. AND * Raised triglycerides: ≥1.7 mmol/L (150 mg/dL) or specific treatment for this lipid abnormality OR * Reduced HDL-cholesterol: \<1.03 mmol/L (40 mg/dL) in males; \<1.29 mmol/L (50 mg/dL) in females or specific treatment for this lipid abnormality OR * Raised Blood Pressure: Raised blood pressure Systolic: ≥130 mm Hg or diastolic: ≥85 mm Hg or treatment of previously diagnosed hypertension. 2. Diabetes: 8-hour fasting plasma glucose ≥ 7.0 mmol/L or Hb-A1C test ≥ 6.5% (as per the 2013 CDA diagnostic criteria) or previously diagnosed type 1 or 2 diabetes (current prescription medication for diabetes acceptable of diagnosis). Participants with child onset of diabetes will be excluded. 3. Inflammatory bowel disorder (Ulcerative Colitis, Crohn's disease). 4. Rheumatological disorders (rheumatoid arthiristis); Psoriasis. 5. Smoking cigarettes (daily - minimum of ½ pack). 6. High sensitivity C-reactive protein level of ≥5 mg/L via blood test at screening
Exclusion criteria
* Another concurrent psychiatric disorder that requires primary clinical attention * History of schizophrenia * Active psychotic symptoms * Substance abuse and/or dependence within past 6 months * Electroconvulsive therapy in the past 6 months * Actively suicidal or evaluated as being a suicide risk \[HAMD-17 suicide item \>= 3 or Montogomery Asberg Depression Rating Scale (MADRS) suicide item \>= 4, or according to clinical judgement using the C-SSRS\] * Clinically significant unstable medical illness * Severe infections such as sepsis, abscess, tuberculosis and opportunistic infections * Viral hepatitis B * History of Hepatitis C ( documented or suspected) * Any autoimmune disorder * History of tuberculosis or a high risk of tuberculosis exposure * Human Immunodeficiency Virus confirmed by laboratory testing * Active fungal infection * History of recurrent viral or bacterial infections * Received within 3 months prior to screening or are expected to receive any live viral vaccine or live bacterial vaccinations during the trial or up to 3 months after the last administration of study agent * C. difficile infection within the past 4 months * History of lymphoproliferative disease * History of cancer, excluding basal cell or squamous cell carcinoma of the skin (fully excised with no recurrence) * Unstable cardiovascular, endocrinological, hematological, hepatic, renal or neurological disease determined by physical examination and laboratory testing * Concomitant diagnosis or any history of congestive heart failure * Concomitant treatment with non-steroidal and steroidal anti-inflammatory medications or other biologics * Current or past exposure to anti-TNF biologics * Previous immediate hypersensitivity response, including anaphylaxis to an immunoglobulin product (plasma-derived or recombinant, e.g. monoclonal antibody) * Known allergies, hypersensitivity or intolerance to infliximab or its excipients * Known allergy to murine proteins or other chimeric proteins * Currently on or have used any investigational drug within 30 days prior to screening, or within 5 half-lives of the investigational agent * Females who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Up to 12 weeks | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale scores are provided, with the range of possible values on the scale from 0 to 60. The higher the score, the worse the overall depressive symptoms. |
| Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Up to 6 weeks | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) scores, where the range of possible values on the scale is from 0 to 60. The higher the score, the worse the overall depressive symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Brain N-acetylaspartate Levels | Baseline to Week 12 | Changes in prefrontal metabolites concentration of N-acetylaspartate, using proton-magnetic resonance spectroscopy (1H-MRS), adjusted for age, sex, baseline values and % gray matter in the spectroscopic region of interest. |
| Changes in Anhedonia | Baseline to 12 weeks | Change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score. Total score range of 14 to 56, with greater scores indicative of greater hedonic capacity. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation
Infliximab: Intravenous infliximab (5mg/kg) at baseline, week 2 and 6 under clinical observation. Infliximab will be prescribed adjunctively to a conventional mood stabilizer or atypical antipsychotic agent. | 28 |
| Saline (Placebo) Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency.
Saline: Intravenous placebo (saline solution) at baseline, week 2 and 6 under clinical observation. Placebo will be matched to infliximab in color and consistency and will be administered adjunctively to conventional mood stabilizer or atypical antipsychotic agent. | 30 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Infliximab | Saline (Placebo) |
|---|---|---|---|
| Age, Continuous | 45.71 years STANDARD_DEVIATION 10.91 | 45 years STANDARD_DEVIATION 11.7 | 46.8 years STANDARD_DEVIATION 10.2 |
| Baseline MADRS total score | 30 units on a scale STANDARD_DEVIATION 7.01 | 30.6 units on a scale STANDARD_DEVIATION 7.2 | 29.5 units on a scale STANDARD_DEVIATION 7 |
| Baseline YMRS total score | 3.9 units on a scale STANDARD_DEVIATION 3.5 | 3.5 units on a scale STANDARD_DEVIATION 3 | 4.4 units on a scale STANDARD_DEVIATION 4.2 |
| Bipolar I disorder | 31 Participants | 16 Participants | 15 Participants |
| Bipolar II disorder | 27 Participants | 12 Participants | 15 Participants |
| BMI | 34.5 kg/m^2 STANDARD_DEVIATION 8.95 | 34.5 kg/m^2 STANDARD_DEVIATION 10 | 34.6 kg/m^2 STANDARD_DEVIATION 8 |
| CRP level, age-adjusted | 7.0 mg/L STANDARD_DEVIATION 8.3 | 4.5 mg/L STANDARD_DEVIATION 3.3 | 7.3 mg/L STANDARD_DEVIATION 8.1 |
| Educational level College or university | 41 Participants | 17 Participants | 24 Participants |
| Educational level Graduate school | 6 Participants | 5 Participants | 1 Participants |
| Educational level High school | 11 Participants | 6 Participants | 5 Participants |
| Inflammatory criteria met CRP level greater than or equal to 5 mg/L | 25 Participants | 10 Participants | 15 Participants |
| Inflammatory criteria met Daily cigarette smoking | 14 Participants | 6 Participants | 8 Participants |
| Inflammatory criteria met Diabetes type 1 or 2 | 12 Participants | 7 Participants | 5 Participants |
| Inflammatory criteria met Inflammatory bowel disorder | 3 Participants | 1 Participants | 2 Participants |
| Inflammatory criteria met Migraine headaches | 16 Participants | 9 Participants | 7 Participants |
| Inflammatory criteria met Obesity combined with hypertension or dyslipidemia | 45 Participants | 20 Participants | 25 Participants |
| Inflammatory criteria met Rheumatologic disorder | 14 Participants | 6 Participants | 8 Participants |
| Medications Antidepressant | 33 Participants | 13 Participants | 20 Participants |
| Medications Lamotrigine | 15 Participants | 8 Participants | 7 Participants |
| Medications Lithium carbonate | 11 Participants | 6 Participants | 5 Participants |
| Medications Lurasidone hydrochloride | 9 Participants | 4 Participants | 5 Participants |
| Medications Olanzapine and fluoxetine hydrochloride | 1 Participants | 0 Participants | 1 Participants |
| Medications Quetiapine fumarate | 13 Participants | 8 Participants | 5 Participants |
| Medications Valproate sodium | 8 Participants | 5 Participants | 3 Participants |
| Number of lifetime psychiatric hospitalizations | 1.65 Hospitalizations STANDARD_DEVIATION 2 | 1.8 Hospitalizations STANDARD_DEVIATION 1.9 | 1.6 Hospitalizations STANDARD_DEVIATION 2 |
| Race/Ethnicity, Customized Other | 10 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 48 Participants | 24 Participants | 24 Participants |
| Region of Enrollment Canada | 53 Participants | 26 Participants | 27 Participants |
| Region of Enrollment United States | 5 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 46 Participants | 20 Participants | 26 Participants |
| Sex: Female, Male Male | 12 Participants | 8 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 29 | 1 / 31 |
| other Total, other adverse events | 4 / 29 | 0 / 31 |
| serious Total, serious adverse events | 1 / 29 | 2 / 31 |
Outcome results
Primary
Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores
Baseline and Week 12 Montgomery-Asberg Depression Rating Scale scores are provided, with the range of possible values on the scale from 0 to 60. The higher the score, the worse the overall depressive symptoms.
Time frame: Up to 12 weeks
Population: The modified intent-to-treat analysis included all participants who had received at least 1 infusion of study medication and completed at least 1 after-baseline efficacy assessment. One participant from the Infliximab arm and one participant from the placebo arm were excluded fromt he analyses because they did not complete at least one efficacy assessment after baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline | 29.61 units on a scale | Standard Error 1.36 |
| Infliximab | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Week. 12 | 18.64 units on a scale | Standard Error 2.4 |
| Saline (Placebo) | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline | 27.79 units on a scale | Standard Error 1.59 |
| Saline (Placebo) | Baseline and Week 12 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Week. 12 | 16.06 units on a scale | Standard Error 2 |
Primary
Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores
Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) scores, where the range of possible values on the scale is from 0 to 60. The higher the score, the worse the overall depressive symptoms.
Time frame: Up to 6 weeks
Population: The modified intent-to-treat analysis included all participants who had received at least 1 infusion of study medication and completed at least 1 after-baseline efficacy assessment. One participant from the Infliximab arm and one participant from the placebo arm were excluded fromt he analyses because they did not complete at least one efficacy assessment after baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline | 29.61 units on a scale | Standard Error 1.36 |
| Infliximab | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Week 6 | 19.44 units on a scale | Standard Error 2.27 |
| Saline (Placebo) | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Baseline | 27.79 units on a scale | Standard Error 1.59 |
| Saline (Placebo) | Baseline and Week 6 Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Week 6 | 20.94 units on a scale | Standard Error 2.29 |
Secondary
Changes in Anhedonia
Change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score. Total score range of 14 to 56, with greater scores indicative of greater hedonic capacity.
Time frame: Baseline to 12 weeks
Population: Three participants in the Infliximab group did not complete at least one post-baseline efficacy assessment. Three participants did not complete at least one post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Changes in Anhedonia | Baseline | 34.04 Score on a scale | Standard Error 1.73 |
| Infliximab | Changes in Anhedonia | Week 12 | 37.17 Score on a scale | Standard Error 1.5 |
| Saline (Placebo) | Changes in Anhedonia | Baseline | 34.8 Score on a scale | Standard Error 1.45 |
| Saline (Placebo) | Changes in Anhedonia | Week 12 | 40.79 Score on a scale | Standard Error 1.69 |
Secondary
Changes in Brain N-acetylaspartate Levels
Changes in prefrontal metabolites concentration of N-acetylaspartate, using proton-magnetic resonance spectroscopy (1H-MRS), adjusted for age, sex, baseline values and % gray matter in the spectroscopic region of interest.
Time frame: Baseline to Week 12
Population: The number of total participants analyzed is lower than those previously reported in the primary outcome measure as only a subgroup of participants underwent this additional and optional MRS testing.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Infliximab | Changes in Brain N-acetylaspartate Levels | Baseline | 5.67 mmol/kg | Standard Error 0.09 |
| Infliximab | Changes in Brain N-acetylaspartate Levels | Week 12 | 5.71 mmol/kg | Standard Error 0.21 |
| Saline (Placebo) | Changes in Brain N-acetylaspartate Levels | Baseline | 5.65 mmol/kg | Standard Error 0.09 |
| Saline (Placebo) | Changes in Brain N-acetylaspartate Levels | Week 12 | 5.81 mmol/kg | Standard Error 0.18 |