Bipolar Depression: Innovative Tx Approach Flops in Trial

Neither nonsteroidal anti-inflammatory drugs (NSAID) nor tetracycline antibiotics improved symptoms for patients with bipolar depression, according to a randomized trial done in Pakistan.

Among 266 patients with bipolar depression, no significant improvements were observed on the 17-item Hamilton Depression Rating Scale (HAMD-17) versus placebo at 12 weeks with adjunct celecoxib (mean adjusted difference -0.74, 95% CI -2.61 to 1.14, P=0.443) or minocycline (mean adjusted difference 1.48, 95% CI -0.14 to 3.36, P=0.123), reported Muhammad Ishrat Husain, MD, of the Centre for Addiction and Mental Health in Toronto, and colleagues.

However, there was a signal that celecoxib could improve the odds of remission, defined as a HAMD-17 score of 7 or less, versus placebo, although this did not reach significance of the Bonferroni-corrected P value of 0.025 (odds ratio 3.02, 95% CI 1.07-8.48, P=0.036), they wrote in The Lancet Psychiatry.

“The results are disappointing because we were hoping to discover a new treatment that would help a significant group of individuals not responding to current treatment,” Husain told MedPage Today. “This is not the end of the story for the inflammatory hypothesis in mood disorders; it just means we have to take a step back and investigate what is going on mechanistically, both physiological and psychologically.”

Prior research has shown people with mood disorders, including bipolar depression, can have abnormal levels of circulating inflammatory proteins, and that patients with chronic inflammatory conditions are more likely to have psychiatric comorbidities and depressed mood, Husain said.

This led to the hypothesis that minocycline (Minocin), which penetrates the blood-brain barrier and affects the inflammatory system, and celecoxib (Celebrex), which can disrupt serotonin production and has been shown in small trials to improve depressive symptoms in patients with bipolar depression, could target this apparent link between inflammatory response and bipolar depression, Husain said.

“[Future trials] need to be targeted towards people that show some evidence of inflammation at baseline,” Hussain said, adding that a reliable biomarker of inflammation in psychiatric illness is yet to be established.

Managing Depression

Current FDA-approved treatments for bipolar depression are limited to mood stabilizing medication, like lithium, and atypical antipsychotic medications, including quetiapine (Seroquel XR and Seroquel), lurasidone (Latuda), and combination olanzapine-fluoxetine (Symbyax).

Managing depression is the “principal unmet need” in treating bipolar disorder and treating inflammation in a subset of patients with depression was a “promising” option, noted Michael Berk, MMed, PhD, of Deakin University in Victoria, Australia, and colleagues in an accompanying editorial.

That’s why the findings presented here are “very disheartening,” they stated.

In addition to the lackluster primary analysis, inflammation indexed by c-reactive protein (CRP) concentrations did not predict whether patients would respond to treatment, although additional biomarkers like inflammatory cytokines were not measured in this study, the researchers reported.

Although this was a post-hoc analysis and should be interpreted cautiously, Berk and colleagues noted it further thwarts “the promise of biomarker stratification to enable precision psychiatry approaches.”

However, this trial should “not be regarded as a definitive dismissal of the promise of these or related agents,” Berk’s group wrote, and could be “construed as a failed rather than a true negative study.”

The researchers used a four-arm factorial design in which patients were assigned to receive either drug with placebo, both drugs, or a double placebo. This design is “complex, can involve between-cell interactions, and does reduce power,” Berk and colleagues noted.

At baseline, most patients were also taking mood stabilizers (93%) or adjunctive antidepressants (82%), which are not recommended first-line treatments for bipolar depression and may have “biased the results,” the editorialists added.

Moreover, more than half of patients showed substantial decreases in depression scores on the HAMD-17 at 12 weeks, including the placebo group, suggesting a high antidepressant placebo effect. The high placebo response rate might be even higher in Pakistan because it is a low-resource setting where routine clinical care is low, Husain and colleagues noted.

Altogether, the editorialists agreed that “this might not be the last word on the potential role of anti-inflammatory drugs in the treatment of bipolar depression,” but noted that the promise of targeting this pathway has been made “somewhat weaker” by these findings.

Husain and colleagues acknowledged this commentary in a Lancet Psychiatry correspondence, in which they pointed out that inflammation is not a unitary target so the design, testing both agents alone and in combination, was a way to examine multiple targets.

In the study, there was no interaction between the treatment groups at 12 weeks (b=0.71, 95% CI -3.04 to 4.48, P>0.07), they reported.

“We believe the overall negative effect of minocycline, which opposed our a priori hypothesis, is a true negative result and not due to the methodological issues raised by Berk and colleagues,” Husain’s group wrote.

Study Details

Across four outpatient psychiatric clinics in Pakistan, patients with bipolar I or II disorder currently experiencing a major depressive episode — defined as scores of at least 18 on the HAMD-17 — were enrolled. Participants assigned to minocycline took 100 mg daily for the first 2 weeks and 200 mg daily thereafter, while patients assigned to celecoxib were started on a 200 mg daily dose for the first 2 weeks and then 400 mg daily thereafter. Patients continued to receive standard care, but did not undergo psychological therapy during the trial.

Of the 266 patients enrolled, 35 (13%) discontinued the intervention, mostly due to a manic switch (31 cases) or for self-harm (two cases). One patient died in a car accident during the study period, and seven others (3%) dropped out, the authors reported.

At baseline, the cohort (mean age 35; 71% male) had severe depression (mean HAMD-17 score 25) and CRP concentrations were mostly unremarkable (median 4 mg/L), they stated.

Neither celecoxib or minocycline was superior to placebo in secondary analyses measuring a treatment response (at least 50% reduction in HAMD-17 scores), Patient Health Questionnaire (PHQ-9) scores, or Generalized Anxiety Disorder 7-item (GAD-7) scores, the researchers reported.

In an exploratory analysis, neither CRP or white blood cell levels at baseline mitigated the null effects of minocycline or celecoxib, they added. Baseline antidepressant use did not change the findings in a sensitivity analysis either.