Comorbid Obesity and Depression With an Anti-inflammatory Medication

Summary

Research suggests that only a subset of individuals with major depressive disorder (MDD) may benefit from anti-inflammatory treatments: those who have C-reactive protein (CRP) ≥3 mg/L, a commonly used threshold for "low-grade" inflammation. The emerging link between metabolic and immune abnormalities in MDD suggests that individuals with comorbid obesity and MDD are a subset of people who could particularly benefit from anti-inflammatory treatment. The coexistence of obesity and MDD has been shown to amplify the risk of clinically elevated CRP levels (≥3mg/L). Therefore, people with comorbid obesity, MDD, and CRP ≥3mg/L could be an ideal target population in future randomised clinical trials (RCTs). However, investigation into the feasibility and acceptability of inflammation-targeting treatment in this population is needed first. Meta-analyses identify minocycline (a tetracycline antibiotic that can cross the blood-brain barrier) as one of the most effective inflammation-targeting medications with antidepressant effects. Minocycline can safely be used long-term at dosages of up to 200mg per day and has low tendency to lead to antibiotic resistance. A pilot RCT of minocycline found a large effect size (Cohen's d=0.98, p\<0.001) for the reduction of MDD symptoms compared with placebo. This effect size was even larger (Cohen's d=1.5, p\<0.005) in another RCT using minocycline when considering only participants with CRP ≥3mg/L. One mechanism through which minocycline could ameliorate MDD symptoms appears to involve the activation of indoleamine 2,3-dioxygenase (IDO), which leads to an increase in the expression and function of the serotonin transporter. Studies exploring this anti-inflammatory effect in MDD demonstrate that minocycline indeed can inhibit IDO. Another pathway through which minocycline could ameliorate MDD symptoms is through the reduction of inflammation at the central level. Minocycline has been shown to reduce microglia activation in preclinical models. Previous literature reports an impact of neuroinflammation on white matter microstructure and brain structure in patients with MDD and in individuals with obesity. Minocycline's effect on white matter structure and myelination has not yet been investigated in humans in vivo. Investigating whether neuroimaging biomarker candidates associated with neuroinflammation could be detected in this study design is needed.

Eligibility

Inclusion Criteria:

* Sufficient communication skills to understand the intervention and complete the assessments.
* Able to give informed consent.
* Treatment resistant depressed (i.e., non-responders to current antidepressant treatment, for at least 6-weeks AND at least one other previous antidepressant).
* Tolerant to the current antidepressant.
* Able to undergo 2 MRI scans.
* Accepting augmentation with minocycline.
* CRP \>3mg/L at screening.
* No plans to change current therapy for the duration of participation.

Exclusion Criteria:

* Active suicidal ideation.
* Current primary diagnosis of psychotic disorder, bipolar disorder, obsessive-compulsive disorder, or post-traumatic stress disorder.
* Have an acute infection or an autoimmune disorder, because of both the rare but described association between minocycline and systemic lupus erythematosus, and the potential confounder effects of these conditions on immune biomarkers.
* Alcohol misuse disorder or drug addiction.
* Neurological disorders (Parkinson's, Alzheimer's).
* Current serious cardiovascular problems.
* Have acne or psoriasis.
* Currently taking any antibiotic, immunosuppressive medication, or warfarin.
* Taken any tetracycline within the last month.
* Currently taking Lithium or retinoids (Acitretin, Alitretinoin, Isotretinoin).
* Refuse that we contact their GP to inform them about their participation.
* \[OPTIONAL - if not met, cannot undergo the MRI\] Has any metal implants in their body such as pacemakers, dental fillings, IUD device (if applicable), or had any accidents where metal fragments might have entered the body or eye.
* Pregnant or breastfeeding
* Have a positive pregnancy test before starting the study/are unwilling to take a pregnancy test and are unwilling to agree to use an acceptable form of contraceptive throughout the study period (e.g., condoms, intrauterine device (IUD)/intrauterine system (IUS), injection, patch, ring). Female participants who use combined oral contraceptives as their main form of birth control will need to use an additional barrier method for the duration of treatment and for 7 days following completion of treatment.
* Are currently participating in another Clinical Trial of Investigational Medicinal Product (CTIMP).

Conditions4

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