This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Mental, neurological and substance use disorders (MNS) constitute 13% of the global disease burden, surpassing both cardiovascular diseases and cancers. Major depressive disorder (MDD) and schizophrenia are among the three most disabling MNS illnesses worldwide. The contribution of chronic inflammation to major mental disorders has received increased attention in the last decade, which revealed a host of pharmacological targets. Multiple recent reviews clearly demonstrate that schizophrenia is associated with a dysregulation of immune responses, as reflected by the observed abnormal profiles of circulating pro- and anti-inflammatory cytokines in affected patients. Moreover, some anti-inflammatory drugs have shown their effectiveness in the treatment of schizophrenia. Anti-inflammatory drugs have shown effectiveness in major psychiatric disorders, especially major depressive disorder (MDD) and schizophrenia. Four major classes of anti-inflammatory drugs have been studied to date: polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. We discuss the positive results of PUFAs in MDD, the mixed results for COX-2 specific inhibitors and minocycline in schizophrenia, and the positive preliminary data on aspirin and n-acetyl-cysteine. Adjunctive aspirin was shown to significantly improve psychotic symptoms in schizophrenia, but only two randomized controlled trials were carried out to date. Anti-TNFalpha showed also important effectiveness in resistant MDD with blood inflammatory abnormalities, which may highlight potential biomarkers of interest. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD or schizophrenia. If used with caution, they may be reasonable therapeutic alternatives for resistant symptomatology.

Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.