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Antibiotic Shows Promise for Major Depression

Minocycline (multiple brands), a broad-spectrum antibiotic frequently used to treat acne, may be a useful adjunct to improve global functioning and quality of life in people with major depressive disorder (MDD), new research shows.

"This study provides preliminary evidence of the usefulness of minocycline as an adjunctive therapy for depression. Furthermore, it will contribute to understanding the underlying biology of depression, and this, in turn, might provide targets for new agents," Olivia M. Dean, PhD, Deakin University School of Medicine, Victoria, Australia, told Medscape Medical News.

The study was published online June 1 in the Australian and New Zealand Journal of Psychiatry.

Inflammatory Hypothesis

Currently, conventional treatments for MDD provide "inadequate remission rates of around 30% on average. Adjuncts are needed to enhance standard treatment by focusing on pathways not usually targeted by standard therapy," the authors note.

The "inflammatory hypothesis" maintains that depression "arises from increased immune activation." This view is "supported by observations that depression is accompanied by increased levels of pro-inflammatory cytokines," the authors note.

Minocycline, a tetracycline antibiotic, has been used clinically for long-term acne treatment. Apart from its microbial action, preclinical studies have demonstrated that it can inhibit microglial activation, resulting in reductions in inflammation and lower levels of inflammatory cytokines.

"There is mounting clinical evidence of minocycline's potential benefits in the treatment of psychiatric disorders," including case reports of "significant amelioration of depressive symptoms with minocycline and recurrence on discontinuation." The authors add that minocycline has "good tolerability and low adverse effect profiles."

"Many people experience a shortfall between remission of depressive symptoms and full functional recovery," Dr Dean said. The study, as well as others performed by her department, are "dedicated to trying to find adjunctive therapies that might fill that gap. Minocycline is one such agent."

To further investigate the potential role of minocycline as adjunctive therapy for MDD, the researchers conducted a randomized controlled trial comparing minocycline 200 mg/day with placebo. The treatment period was 12 weeks, with a follow-up evaluation 4 weeks later.

Participants were required to meet DSM-IV criteria for unipolar depression, to have scored =25 on the Montgomery-Åsberg Depression Rating Scale (MADRS), and to have demonstrated stability on antidepressant therapy for at least 2 weeks before randomization. Participants were not required to undergo any therapy to take part in the study.

Validated measures of depressive symptomatology, global clinical impression, quality of life, and functional status were completed at baseline and at weeks 4, 8, 12, and 16 (after discontinuation of treatment).

The primary outcome was improvement in the MADRS score. Additional efficacy measures included the Clinical Global Impression–Improvement (CGII) and Clinical Global Impression–Severity (CGI-S) scales, the Patient Global Impression (PGI) scale, and the Hamilton Anxiety Rating Scale (HAM-A). The researchers assessed quality of life with the Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form and measured functioning using the Social and Occupational Functioning Scale.

The researchers randomly assigned 71 participants to receive minocycline (n = 36) or placebo (n = 35). All participants completed at least one post-baseline visit. A total of 57 participants completed the 12-week treatment phase, and 55 also completed the 4-week follow-up assessment. Both groups contained significantly more women than men, "reflecting the incidence of the disorder in the population," the authors suggest.

There were no differences in baseline use of medication between the patients receiving minocycline those receiving placebo. Overall, participants had moderate to severe depressive symptoms, with baseline MADRS scores of 31.7 (±4.0) and 31.0 (±4.6) in the placebo and minocycline groups, respectively. The mean duration of illness since diagnosis was approximately 14 years.

Approximately 73% of the sample met criteria for melancholic depression, and approximately 42% had comorbid anxiety disorders.

The researchers found no significant differences at week 12 between the minocycline and placebo groups in the change in the primary outcome — ie, MADRS (effect size 95% confidence interval [ES CI] = 0.46 [-7.1, 3.2]; P = .02). However, there was a 4-point difference between groups at treatment endpoint. There were no significant differences at week 16 on the MADRS (ES CI = 0.41 [-6.9, 3.5]).

There was a trend toward improvements in anxiety symptoms, as evidenced on HAM-A scores, following 12 weeks of minocycline treatment (ES CI = -0.36 [6.7, 0.8]; P = 0.057) and 4-week follow-up, (ES CI = -0.15 [-6.4, 2.1]; P = 0.068.

By contrast, the researchers found significant improvement (ES CI = 0.62 [-1.8, -0.3]; P = 0.022) over the 12-week treatment phase on the CGI-I, which was maintained in the follow-up period (ES CI = 0.33 [-1.5, 0.0]; P = .050). This improvement was reflected in the patient-rated PGI scale across the 16-week period, (ES CI = -0.14 [2.9, 3.8]; P = .017). However, despite a strong trend, the PGI did not reach significance at the end of the 12-week treatment phase.

There were "highly significant" improvements in functioning and quality of life in the minocycline group, compared to the patients receiving placebo. The minocycline group showed improvements over time to week 12, and the improvements were maintained at week 16 on the Range of Impaired Functioning Tool scale (ES CI = 0.79 [-4.5, -1.4] P = .0002; and ES CI = 0.57 [-4.3, -1.2], P = .0003, respectively).

Similar findings were obtained on the Q-LES-Q, which were also significant over time to week 12 and week 16 (ES CI = -0.12 [0.0, 0.2], P = 0.0048; and ES CI = -0.14 [0.0, 0.1], P = .0095 respectively).

There was no significant difference in the total number of adverse events (P = .999).

"While the 4-point difference between minocycline and placebo in the MADRS scores was not significant, this is on par with the magnitude of change seen with conventional antidepressants," the authors note.

Dr Dean commented that the study was "relatively small, with 71 people taking part. Standard antidepressant trials usually contain hundreds of people. This indicates that the improvements that we did see might be robust. So, while not statistically significant, the 4-point improvement on the MADRS might be seen as clinically significant."

She added that she was "excited that we did see improvements in functioning and quality of life in people who took part in the adjunctive minocycline group."

The researchers note that improvements in global impression, functioning, and quality of life "are increasingly being recognized as more comprehensive measures of clinical outcomes."

Commenting on the study for Medscape Medical News, David Marks, MD, associate professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, said that the study "appears to be well designed," although "a larger study would have a better chance of demonstrating the effectiveness of minocycline for depression."

Nevertheless, the study is "the first double-blind, placebo-controlled study of minocycline for depression, and an important step in the evaluation of the usefulness of minocycline for depression," he said.

Additionally and "perhaps more importantly, it adds to the growing body of literature addressing whether depression can be treated with drugs which reduce inflammation and foster nerve growth."

Dr Marks noted that the study does not have "immediately clinical applicability" because the results were "technically negative, in terms of supporting the antidepressant efficacy of minocycline on a group of subjects with depression." Moreover, "changes in treatment practices normally result form multiple larger studies and even meta-analyses."

However, in select patients who have failed to respond fully to more commonly used antidepressant drugs, "it is certainly appropriate to try minocycline, especially considering its good safety profile," he said.

Dr Dean agreed. "It is always best to be cautious with small studies. However, minocycline has been shown to be fairly well tolerated over longer periods of treatment and, as such, should be considered to be another option for the treatment of depression."

The research was supported by Deakin University, the Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Barwon Health, Chulalongkorn University, the Brain and Behavior Foundation (USA), and an Australasian Society for Bipolar and Depressive Disorders/Servier grant. Dr Dean has received grant support from the Brain and Behavior Foundation, the Simons Autism Foundation, the Stanley Medical Research Institute, Deakin University, Lilly, the National Health and Medical Research Council, and the Australasian Society for Bipolar and Depressive Disorders/Servier. Other study authors have disclosed multiple sources of research support.

SOURCE:

Antibiotic Shows Promise for Major Depression - Medscape - Jul 12, 2017


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