Exploring Clinical Subgroups of Participants with Major Depressive Disorder that may Benefit from Adjunctive Minocycline Treatment
Gerard Anmella1,2,3,4,5, Alcy Meehan6, Melanie Ashton6, Mohammadreza Mohebbi6,7, Giovanna Fico1,2,3,4,5, Chee H. Ng8, Michael Maes6,9, Lesley Berk6, Michele De Prisco1,2,3,4,5, Ajeet B. Singh6, Gin S. Malhi10,11,12, Michael Berk6,13,14,15, Seetal Dodd6,13,14, Diego Hidalgo-Mazzei1,2,3,4,5, Iria Grande1,2,3,4,5, Isabella Pacchiarotti1,2,3,4,5, Andrea Murru1,2,3,4,5, Eduard Vieta1,2,3,4,5, Olivia M. Dean6,15
1Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain
2Bipolar and Depressive Disorders Unit, Digital Innovation Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
3Biomedical Research Networking Centre Consortium on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
4Department of Medicine, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
5Institute of Neurosciences (UBNeuro), Barcelona, Spain
6Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, VIC, Australia
7Deakin University, Faculty of Health, Biostatistics Unit, Geelong, VIC, Australia
8The Melbourne Clinic, Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia
9Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
10Department of Psychiatry, Northern Clinical School, The University of Sydney, Faculty of Medicine and Health, Sydney, NSW, Australia
11Academic Department of Psychiatry, Northern Clinical School, The University of Sydney, Sydney, NSW, Australia
12CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia
13Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia
14Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia
15Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
Correspondence to: Olivia M. Dean
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, HERB B Level 3, P.O. Box 281, Geelong 3220, Australia
E-mail: o.dean@deakin.edu.au
ORCID: https://orcid.org/0000-0002-2776-3935
Received: May 24, 2023; Revised: July 5, 2023; Accepted: July 6, 2023; Published online: August 28, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective: To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT).
Methods: This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity (illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA.
Results: There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects.
Conclusion: Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications.
Keywords: Minocycline; Depression; Treatment; Clinical trial; Theragnostic; Inflammation

Major depressive disorder (MDD) is the leading cause of disability worldwide, with significant morbidity, mortality and social cost, with a lifetime prevalence up to 20% of the population [1]. Despite this disease burden, there is a lack of knowledge about the pathophysiology of MDD contributing to lack of treatment options and poor treatment outcomes [2]. Therefore, there is an urgent need to identify factors that may enhance treatment response in MDD.

The clinical course of MDD is highly variable, but over their lifetime, around 80% of people affected by this illness manifest recurrent depressive episodes [3], especially if antidepressant treatment is discontinued [4]. Predictably, recurrent depressive episodes, in particular those with higher severity of symptoms, are associated with a poorer prognosis, greater residual symptoms, and functional impairment [5]. At the same time, MDD is associated with an increased risk of many systemic medical illnesses, including, for example, premorbid status such as insulin resistance [6] to morbid disorders such as diabetes mellitus, cardiovascular diseases, obesity, cancer, and neurodegenerative diseases [7]. Hence, the presence of MDD increases mortality risk by up to 80% [8].

Both MDD with comorbid systemic illness, as well as MDD with recurrent episodes and longer illness duration, are associated with treatment resistance and poorer course outcomes, necessitating alternative and often more complex treatment strategies [9]. One of the underlying pathophysiological mechanisms shared by chronic MDD and comorbid medical illness is a dysregulated immune system [10-12] manifesting by persistent inflammation [13- 16]. Thus, targeting inflammation has been proposed as a new strategy that may potentially treat MDD patients and open the door to exciting novel therapies [17]. Meta-analytic evidence suggests that anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, statins, pioglitazone, glucocorticoids and minocycline have antidepressant effects when administered as add-on treatments compared to placebo in randomized clinical trials (RCTs) of patients with MDD and depressive symptoms [18]. In particular, its hypothesized that those who exhibit increased peripheral blood concentrations of inflammatory biomarkers and a lack of response to standard antidepressants may benefit from such adjunctive therapies [19]. Nevertheless, these results have not been consistently replicated in many studies [20,21].

Minocycline is a tetracycline antibiotic with broad anti-inflammatory properties and good penetration into the central nervous system. Therefore, it has been proposed as a potential novel adjunctive treatment for MDD and other psychiatric disorders, such as bipolar disorder and schizophrenia [22]. A recent meta-analysis [23] showed that minocycline treatment may improve depressive symptoms compared to placebo in studies of unipolar [24-26] and bipolar depression [27], both as an add-on treatment and monotherapy. However, the conclusions from such analyses are limited by the paucity and heterogeneity of the primary studies and the overall lack of trials that have attempted to identify those clinical subgroups that are more likely to benefit from minocycline treat-ment. This is critical as it is likely that within the heterogeneity of MDD there are subtypes that are preferentially responsive to such treatments.

Therefore, to further explore the clinical phenotypes of MDD related to minocycline efficacy, data from a recently conducted double-blinded placebo-controlled trial of add-on minocycline for MDD [24,28] was investi-gated. The overarching trial found a non-significant but clinically meaningful change in depressive symptoms (primary outcome) and significant improvements following adjunctive minocycline treatment in functioning, quality of life and global severity of illness. Here, using a secondary analysis of this same trial, we examined whether illness chronicity, systemic illness, or the presence of adverse effects would impact on clinical outcomes.

We hypothesized that minocycline treatment response would be influenced by:

(1) illness chronicity (measured with MDD illness duration and number of depressive episodes, according to the neuromodulation effect on synaptic promotions and potential neuroregeneration at early phases);

(2) systemic illness, including medical comorbidities and obesity, concordant with the concept of allostasis; and

(3) adverse effects.


A detailed description of the study procedures, as well as a complete description of baseline characteristics, has been previously published [24]. Briefly, this was a 12- week double-blind placebo-controlled trial of minocycline, in addition to treatment as usual, in 71 adults experiencing MDD. Participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM- IV) criteria for MDD, had a current depressive episode of at least moderate severity (Montgomery–Asberg Rating Scale [MADRS] ≥ 25), and were on stable treatment for at least two weeks prior to study commencement (or were not receiving psychopharmacological treatment). Exclusion criteria included having a diagnosis of bipolar disorder, having received three or more failed adequate trials of an antidepressant or electroconvulsive therapy for the current episode, having a known or suspected unstable systemic medical disorder, pregnant or breastfeeding women, or were taking a contraindicated medication up to one month prior to the study. All participants provided written informed consent. The participating institutions’ human ethics committees approved the trial, which was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000283875).

Participants received 100 mg of minocycline twice daily (total daily dose 200 mg/day) or matching placebo, in addition to treatment as usual. Outcomes were assessed at baseline and at weeks 4, 8, 12, and 16 (4 weeks after discontinuation of trial treatment). Efficacy measures included depressive symptomatology, assessed with the MADRS (primary outcome of the parent trial) [29]. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale (HAM-A) [30]. Symptom severity and improvement were assessed respectively with the Clinical Global Impression-Severity (CGI-S), the Clinical Global Impression-Improvement (CGI-I) scales, and the Patient Global Impression (PGI) [31]. Functioning was assessed with the Social and Occupational Functioning Assess-ment Scale (SOFAS) [32] and the Range of Impairment Functioning Tool (LIFE-RIFT) [33]. Quality of life was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [34].

The participant’s psychiatric history (including MDD illness duration and number of depressive episodes), medical comorbidities (self-reported at the clinical interview), and body mass index (BMI) were collected at base-line. Adverse events (captured using open-ended questions) were recorded at each visit.

For illness chronicity, groups were divided using cutoffs of (i) 5 years or more of MDD for illness duration and (ii) five depressive episodes independently. Here we reported on any cardiovascular or endocrine comorbidity, as these are considered the most relevant systemic clinical conditions in affective disorders, both in MDD [35] and bipolar disorder (BD) [36,37]. Obesity was defined by BMI exceeding 30 at baseline.

All analyses were based on the entire trial sample (n = 71), and complete case analyses were conducted [38]. We used the methodology explained by Kraemer et al. [39] for evaluating the modification of treatment effects in RCTs. Regression analysis of covariance (ANCOVA) was used to assess the impact on the outcome for each effect modifier (i.e., illness chronicity, systemic illness, adverse effects, minocycline) from baseline to endpoint (12 weeks), with pre-intervention baseline total scores at each scale as covariates [40]. Two-sided alpha = 0.05 was used as significant. Statistical analyses were performed using SPSS version 25 (IBM Co.).


A total of 71 participants were included in the study. The complete demographics of the study sample are published elsewhere [24], however all relevant baseline characteristics of the sample are summarized in Table 1. No statistically significant differences were found between groups on the variables presented in Table 1. The cohort was mostly female (> 65%), with a mean age over 45 years. The mean duration of illness (since diagnosis) was approximately 14 years, and more than 50% had undergone more than five previous depressive episodes, suggesting a chronic course of illness. Rates of comorbid cardiovascular or endocrine disorders were lower than 25%. More than 80% of the sample was on antidepressant medication. Rates of participants’ substance use, including tobacco and alcohol, were less than 5%.

The cohort 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. In the original study, at week 12, there were significant differences, favouring the minocycline group for CGI-I, Q-LES-Q, and LIFE-RIFT scores.

No significant two-way interactions (i.e., effect modification) were detected between treatment group and (i) systemic illness (including medical comorbidities or obesity), (ii) illness chronicity (including illness duration and number of depressive episodes), or (iii) adverse effects for any of the assessed outcomes (Fig. 1). However, there was a consistent trend in all outcomes favouring the use of minocycline in patients without systemic illness, less illness chronicity, and fewer adverse effects.


The study findings contribute to the identification of potential clinical subgroups that are more likely to benefit from adjunctive minocycline treatment. Overall, this study did not find statistically significant effects of systemic illness, illness chronicity or adverse event. However, there were trends to suggest that the use of add-on minocycline may be beneficial for patients with MDD without systemic illness, less illness chronicity, and fewer adverse effects—even though the findings do not meet statistical significance. The sample size of the subgroups presents the greatest limitation on these findings.

Activated immune-inflammatory and oxidative pathways are common underlying mechanisms relating MDD with systemic illness, illness chronicity and the presence of adverse effects [41]. Indeed, MDD with comorbid systemic illness is additive in contributing to allostatic load [35]. MDD with recurrent episodes and longer illness duration is associated with chronic inflammation that is thought to lead to neuroprogression [41]. This includes reduced neurogenesis, neuroplasticity [42] and consequent neurostructural [43] and cognitive changes [44]. Early pre-clinical and clinical investigations implicated inflammatory processes in MDD [41,45]. A significant number of individuals within a MDD subgroup present with higher levels of pro-inflammatory and immune-regulatory cytokines coupled with changes in diverse acute- phase proteins, which may play a role in the onset and recurrence of depressive episodes and staging as well [46, 47]. Minocycline has inhibitory actions on mechanisms relevant to ‘inflammation-induced depression’, such as the kynurenine [48,49] and the p-38 [50] pathways. More-over, evidence suggests that minocycline is also an anti-oxidant and anti-apoptotic compound, and modulates glutamate and monoamine neurotransmission [51].

Regarding systemic illness, cardiovascular and endocrinological diseases have been repeatedly associated with redox imbalance [52]. Also depressive episodes are linked to increased allostatic stress states and systemic toxicity [53,54]. Thus, the cumulative burden of depressive episodes and comorbidities may be responsible for an allostatic overload in MDD [55]. Therefore, comorbid clinical illness could be a marker for more severe oxidative stress states, and thus guide antioxidant use in MDD, and other affective disorders such as BD [37,56]. Accord-ingly, minocycline treatment may be of greater benefit to people with MDD without systemic illness. This is contrary to our initial hypothesis and may be related to the concept of allostatic overload, such that minocycline may be more useful in low allostatic stress states in MDD when redox imbalance is more easily reversed. In a preclinical study, minocycline was associated with reduction in neuroinflammation but not in neurodegeneration [57]. Con-sidering this, a possible explanation is that, in the subgroup of patients with MDD at earlier phases of the disease, neuroprogression is also less advanced. Thus, minocycline can have an effect on inflammatory pathways, but in later stages, when neuronal apoptosis is increased, inflammation is reduced and the effects of minocycline are reduced. These hypotheses need to be assessed in a quantitative manner in future studies in order to exclude a possible spurious finding in our analyses.

Another mechanism by which minocycline may alleviate depression symptoms is reversing the pathogenic phagocytic potential of neurotoxic microglia, thus increasing neurogenesis [58]. The neuroprotective role of minocycline reducing depression and anxiety symptoms has been replicated in preclinical trials [59] and confirmed in acute stroke patients [60]. Moreover, minocycline has shown potential use in preclinical trials on depressive-like behaviour by reducing microglial activation [61]. This has been replicated in studies of depression and alcohol use [62], in sleep deprivation and associated depressive and anxiety behaviours [63], and in diabetes-related depression [64]. In all cases pathological microglial activation was reduced by minocycline which seems to play a key role in depression symptoms mediation and resolution. Therefore, and in line with our results, minocycline may be able to reduce neurotoxicity and increase neuroregeneration, especially in the early phases of MDD (less illness duration and number of episodes). The beneficial effects of minocycline on later, more chronic phases of MDD may be diluted due to persistent or cumulative Central Nervous System (CNS) damage to the substrates of mood regulation as hypothesised by the neuroprogression model [65,66].

Regarding minocycline’s efficacy in MDD, the inconsistency in the results of the 4 RCTs may be because the inflammatory cascade leading to depression probably involves multiple pathways connecting the peripheral immune system to the CNS, and these may not be specifically targeted by classic anti-inflammatory treatments [67]. Recent post-hoc stratifications from two of the RCTs have showed that baseline levels of peripheral inflam-mation from participants are related to clinical response with add-on minocycline. One study [25] found that participants with elevated C-reactive protein (CRP) at baseline receiving minocycline showed significantly improved response in depressive symptoms at 4-week as well as higher interleukin (IL)-6 concentrations compared to those without elevated CRP [68]. Another study [24] showed that higher IL-6 at baseline was associated with greater improvement in anxiety scores in participants receiving minocycline. However, adjunctive minocycline compared to placebo did not alter IL-6, lipopolysaccharidebinding protein or brain-derived neurotrophic factor levels [69]. These post-hoc analyses [68,69] add evidence to the hypothesis of treatment selection on the basis of baseline inflammation for those more likely to benefit from minocycline anti-inflammatory treatment.

Borrowing from precision psychiatry [70], future research should consider whether combining clinical and peripheral markers may be a more precise means of identifying people with MDD who are more likely to benefit from minocycline treatment.

Post-hoc analyses may often have poor predictive value, even when they make sense theoretically [71]. None-theless, they are useful for hypothesis generation to be confirmed in further studies. Moreover, the original RCT study has many methodological strengths and thus allows generation of hypotheses for future research. Also, we were not able to assess the illness chronicity of participants in a continuous way, as both illness duration and number of depressive episodes had been registered using cut-offs of five years. However, we set clinically valid dichotomous cut-offs to differentiate between recent-onset and fewer-episode patients. Finally, the interactions found were not significant, and therefore no definitive conclusions could be drawn. Although the trends found were all in the same direction and the sample size was modest, with some subgroups having from 26 to 11 participants. Considering this, along with the consistent trends, it is likely that an increase in the sample size and consequent statistical power, will facilitate detection of significant interactions among the variables and outcomes proposed. Therefore, this study may be a starting point for future replication in other RCTs.

In conclusion, this study identified potential clinical subgroups within MDD that are more likely to benefit from minocycline treatment. It suggests that the use of add-on minocycline may be beneficial for patients with MDD without systemic illness, less illness chronicity, and those who have fewer adverse effects.


We acknowledge the contribution of all the participants of the study.

Gerard Anmella is supported by a Rio Hortega 2021 grant (CM21/00017) and M-AES mobility fellowship (MV22/00058), from the Spanish Ministry of Health financed by the Instituto de Salud Carlos III (ISCIII) and co-financed by the Fondo Social Europeo Plus (FSE+).

Giovanna Fico is supported by a fellowship from “La Caixa” Foundation (ID 100010434) - fellowship code - LCF/BQ/DR21/11880019.

Michael Berk is supported by a NHMRC Senior Princi-pal Research Fellowship and Leadership 3 Investigator grant (1156072 and 2017131). MB has received grant/research support from National Health and Medical Re-search Council, Wellcome Trust, Medical Research Future Fund, Victorian Medical Research Acceleration Fund, Centre for Research Excellence CRE, Victorian Govern-ment Department of Jobs, Precincts and Regions and Victorian COVID-19 Research Fund. He received honoraria from Springer, Oxford University Press, Cambridge University Press, Allen and Unwin, Lundbeck, Controver-sias Barcelona, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, Milken Institute, RANZCP, Abbott India, ASCP, Headspace and Sandoz (last 3 years).

Hidalgo-Mazzei is supported by a Juan Rodés JR18/ 00021 granted by the Instituto de Salud Carlos III (ISCIII).

Iria Grande thanks the support of the Spanish Ministry of Science and Innovation (MCIN) (PI19/00954) integrated into the Plan Nacional de I+D+I and cofinanced by the ISCIII-Subdirección General de Evaluación y el Fondos Europeos de la Unión Europea (FEDER, FSE, Next Gene-ration EU/Plan de Recuperación Transformación y Resiliencia_PRTR ); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); and the the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365), CERCA Programme/ Generalitat de Catalunya as well as the Fundació Clínic per la Recerca Biomèdica (Pons Bartran 2022-FRCB_ PB1_2022).

Andrea Murru thanks the support of the Spanish Mini-stry of Science and Innovation (PI19/00672) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER).

Eduard Vieta thanks the support of the Spanish Ministry of Science, Innovation and Universities (PI15/00283, PI18/00805, PI19/00394, CPII19/00009) integrated into the Plan Nacional de I+D+I and co-financed by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the ISCIII; the CIBER of Mental Health (CIBERSAM); the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365), and the CERCA Programme/Generalitat de Catalunya. We would like to thank the Departament de Salut de la Generalitat de Catalunya for the PERIS grant SLT006/17/ 00357.

Olivia M. Dean was an R.D. Wright Biomedical NHMRC Career Development Fellow (1145634) at the time of the parent trial.

Conflicts of Interest

Gerard Anmella has received CME-related honoraria, or consulting fees from Janssen-Cilag, Lundbeck, Lundbeck/ Otsuka, Rovi, Casen Recordati, and Angelini, with no financial or other relationship relevant to the subject of this article.

Chee H. Ng has participated as a consultant for Lundbeck, Grunbiotics, Servier, Janssen-Cilag, and Eli Lilly, received research grant support from Lundbeck, and speaker honoraria from Servier, Lundbeck, Sumitomo, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline, Janssen- Cilag, Astra-Zenaca, and Pfizer, unrelated to the submitted work.

Diego Hidalgo-Mazzei has received CME-related honoraria and served as consultant for Abbott, Angelini, Ethypharm Digital Therapy and Janssen-Cilag with no financial or other relationship relevant to the subject of this article.

Iria Grande has received grants and served as consultant, advisor or CME speaker for the following identities: Angelini, Casen Recordati, Ferrer, Janssen Cilag, and Lundbeck, Lundbeck-Otsuka, Luye, SEI Healthcare outside the submitted work.

Isabella Pacchiarotti has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag and Lundbeck (unrelated to the present work).

Andrea Murru has received grants and served as consultant, advisor or CME speaker for the following entities: Angelini, Idorsia, Lundbeck, Pfizer, Takeda, with no financial or other relationship relevant to the subject of this article.

Eduard Vieta has received research support from or served as consultant, adviser or speaker for AB-Biotics, Abbott, Abbvie, Adamed, Angelini, Biogen, Celon, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo SmithKline, Janssen, Lundbeck, Organon, Otsuka, Rovi, Sage pharmaceuticals, Sanofi- Aventis, Shire, Sunovion, Takeda, and Viatris, out of the submitted work.

Olivia M. Dean has received grant support from the Brain and Behavior Foundation, Marion and EH Flack Trust, Simons Autism Foundation, Australian Rotary Health, Stanley Medical Research Institute, Deakin University, Brazilian Society Mobility Program, Lilly, NHMRC, Australasian Society for Bipolar and Depressive Disorders and Sevier. She has also received in-kind support from BioMedica Nutracuticals, NutritionCare and Bioceuticals.

All other authors report no financial or other relationship relevant to the subject of this article.

Author Contributions

Original trial investigator: Olivia M. Dean, Michael Berk, Lesley Berk, Chee H. Ng, Melanie Ashton, Michael Maes, Ajeet B. Singh. Sub-study planning and project conception: Gerard Anmella, Andrea Murru, Olivia M. Dean, Michael Berk. Data analysis: Gerard Anmella, Alcy Meehan, Mohammadreza Mohebbi, Giovanna Fico, Michele De Prisco, Olivia M. Dean. Figure/table preparation: Gerard Anmella, Giovanna Fico, Michele De Prisco. Manuscript preparation: Gerard Anmella, Alcy Meehan, Melanie Ashton, Mohammadreza Mohebbi, Giovanna Fico, Chee H. Ng, Michael Maes, Lesley Berk, Michele De Prisco, Ajeet B. Singh, Gin S. Malhi, Michael Berk, Seetal Dodd, Diego Hidalgo-Mazzei, Iria Grande, Isabella Pacchiarotti, Andrea Murru, Eduard Vieta, Olivia M. Dean.

Fig. 1. Differential change from baseline to week 12 in depression-anxiety symptoms, severity, global experience, functioning and quality of life scores according to treatment group (minocycline/placebo) and illness chronicity, systemic illness, and adverse effects.
Scale ranges: MADRS (0−60), HAMD (0−52), Q-LES-Q (14−70), LIFE-RIFT (4−20), SOFAS (0−100), PGI (1−7), CGI-S (1−7), CGI-I (1−7). Positive change is indicative of favorable results for every scale in the graph. In all clinical scales, higher scores indicate worse outcomes, except for Q-LES-Q and SOFAS. Therefore the latter were inverted. Changes in PGI and CGI-I were evaluated between week 2 and week 12.
BMI, body mass index; CGI-S, Clinical Global Impression-Severity; CGI-I, Clinical Global Impression-Improvement; HAM-A, Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale; LIFE-RIFT, Range of Impairment Functioning Tool; MADRS, Montgomery–Asberg Rating Scale; PGI, Patient Global Impression; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; SOFAS, Social and Occupational Functioning Assessment Scale.

Baseline characteristics of the sample

Variable Placebo (n = 35) Minocycline (n = 36)
Completers of 12 weeks evaluations 30 (85.7) 28 (77.7)
Female 23 (65.7) 24 (66.6)
Mean age in years 47.8 ± 14.8 51.0 ± 14.6
BMI 26.5 ± 5.4 28.1 ± 5.4
Illness chronicity
Duration of illness since diagnosis (yr) 12.0 ± 11.5 15.9 ± 13.4
Number of previous depressive episodes, median range (%)a 1−5 (44.1) 1−5 (37.7)
Systemic illness comorbiditiesb
Cardiovascular disorder, frequency 9 (25.7) 8 (22.2)
Endocrine disorder, frequency 8 (22.8) 6 (16.7)
Baseline medicationc
Antidepressant, frequency 32 (91.4) 30 (83.3)

Values are presented as number (%) or mean ± standard deviation.

BMI, body mass index.

aThe number of depressive episodes were registered using cutoffs of five episodes (1−5, 6−10, 11−15, 16−20, > 20). bRespiratory system disorders were significantly different (p = 0.044) among groups. cTotal frequency, including multiple agents for the same participant.

  1. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nat Rev Dis Primers 2016;2:16065.
    Pubmed CrossRef
  2. Malhi GS, Mann JJ. Depression. Lancet 2018;392:2299-2312.
    Pubmed CrossRef
  3. Vos T, Haby MM, Barendregt JJ, Kruijshaar M, Corry J, Andrews G. The burden of major depression avoidable by longer-term treatment strategies. Arch Gen Psychiatry 2004;61:1097-1103.
    Pubmed CrossRef
  4. Lewis G, Marston L, Duffy L, Freemantle N, Gilbody S, Hunter R, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med 2021;385:1257-1267.
    Pubmed CrossRef
  5. Boschloo L, Schoevers RA, Beekman AT, Smit JH, van Hemert AM, Penninx BW. The four-year course of major depressive disorder: The role of staging and risk factor determination. Psychother Psychosom 2014;83:279-288.
    Pubmed CrossRef
  6. Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neurosci Biobehav Rev 2022;139:104758.
    Pubmed CrossRef
  7. Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: Biological mechanisms and the role of depression symptom profile. BMC Med 2013;11:129.
    Pubmed KoreaMed CrossRef
  8. Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease burden implications: A systematic review and meta-analysis. JAMA Psychiatry 2015;72:334-341.
    Pubmed KoreaMed CrossRef
  9. McAllister-Williams RH, Arango C, Blier P, Demyttenaere K, Falkai P, Gorwood P, et al. The identification, assessment and management of difficult-to-treat depression: An international consensus statement. J Affect Disord 2020;267:264-282.
    Pubmed CrossRef
  10. Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nat Neurosci 2015;18:1386-1393.
    Pubmed KoreaMed CrossRef
  11. Kim JM, Kang HJ, Kim JW, Choi W, Kim SW, Kim JC, et al. Possible link between serotonin and interleukin 18 on suicidality in patients with acute coronary syndrome. Clin Psycho-pharmacol Neurosci 2023;21:386-390.
    Pubmed KoreaMed CrossRef
  12. Reddy PV, Talukdar PM, Subbanna M, Bhargav PH, Arasappa R, Venkatasubramanian G, et al. Multiple complement pathway-related proteins might regulate immunopathogenesis of major depressive disorder. Clin Psychopharmacol Neurosci 2023;21:313-319.
    Pubmed KoreaMed CrossRef
  13. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 2015;49:206-215.
    Pubmed KoreaMed CrossRef
  14. Choi W, Kim JW, Kang HJ, Kim HK, Kang HC, Lee JY, et al. Interactive effects of serum leptin levels and physical comorbidity on the pharmacotherapeutic response of depressive disorders. Clin Psychopharmacol Neurosci 2022;20:662-674.
    Pubmed KoreaMed CrossRef
  15. Karimi Z, Chenari M, Rezaie F, Karimi S, Parhizgari N, Mokhtari-Azad T. Proposed pathway linking respiratory infections with depression. Clin Psychopharmacol Neurosci 2022;20:199-210.
    Pubmed KoreaMed CrossRef
  16. Liu ST, Lin SC, Chang JP, Yang KJ, Chu CS, Yang CC, et al. The clinical observation of inflammation theory for depression: The initiative of the formosa long COVID multicenter study (FOCuS). Clin Psychopharmacol Neurosci 2023;21:10-18.
    Pubmed KoreaMed CrossRef
  17. Vieta E. [Disruptive treatments in psychiatry]. Rev Psiquiatr Salud Ment (Engl Ed) 2020;13:1-4. Spanish.
  18. Köhler-Forsberg O, N Lydholm C, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: Meta- analysis of clinical trials. Acta Psychiatr Scand 2019;139:404-419.
  19. Miller AH, Raison CL. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nat Rev Immunol 2016;16:22-34.
    Pubmed KoreaMed CrossRef
  20. Baune BT, Sampson E, Louise J, Hori H, Schubert KO, Clark SR, et al. No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial. Eur Neuropsychopharmacol 2021;53:34-46.
    Pubmed CrossRef
  21. Strumila R, Lengvenyte A, Olie E, Courtet P, Guillaume S. Null effect of vortioxetine augmentation with celecoxib should not be generalized to other antidepressants. Eur Neuropsycho-pharmacol 2022;55:84-85.
    Pubmed CrossRef
  22. Nettis MA. Minocycline in major depressive disorder: And overview with considerations on treatment-resistance and comparisons with other psychiatric disorders. Brain Behav Immun Health 2021;17:100335.
    Pubmed KoreaMed CrossRef
  23. Cai DB, Zheng W, Zhang QE, Ng CH, Ungvari GS, Huang X, et al. Minocycline for depressive symptoms: A meta-analysis of randomized, double-blinded, placebo-controlled trials. Psychiatr Q 2020;91:451-461.
    Pubmed CrossRef
  24. Dean OM, Kanchanatawan B, Ashton M, Mohebbi M, Ng CH, Maes M, et al. Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial. Aust N Z J Psychiatry 2017;51:829-840.
    Pubmed CrossRef
  25. Husain MI, Chaudhry IB, Husain N, Khoso AB, Rahman RR, Hamirani MM, et al. Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial. J Psychopharmacol 2017;31:1166-1175.
    Pubmed CrossRef
  26. Emadi-Kouchak H, Mohammadinejad P, Asadollahi-Amin A, Rasoulinejad M, Zeinoddini A, Yalda A, et al. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: A double-blind, placebo-controlled, randomized trial. Int Clin Psychopharmacol 2016;31:20-26.
    Pubmed CrossRef
  27. Savitz JB, Teague TK, Misaki M, Macaluso M, Wurfel BE, Meyer M, et al. Treatment of bipolar depression with minocycline and/or aspirin: An adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry 2018;8:27.
    Pubmed KoreaMed CrossRef
  28. Dean OM, Maes M, Ashton M, Berk L, Kanchanatawan B, Sughondhabirom A, et al. Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: A double blind, randomised, placebo controlled trial. Clin Psychopharmacol Neurosci 2014;12:180-188.
    Pubmed KoreaMed CrossRef
  29. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-389.
    Pubmed CrossRef
  30. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50-55.
    Pubmed CrossRef
  31. Guy W. ECDEU assessment manual for psychopharmacology-revised. US Department of Health, Education, and Welfare Publication (ADM). National Institute of Mental Health. Scientific Research Publishing;1976. p.218-222.
  32. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV social and occupational functioning assessment scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 2000;101:323-329.
    Pubmed CrossRef
  33. Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, McDonald-Scott P, et al. The longitudinal interval follow-up evaluation. A comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987;44:540-548.
    Pubmed CrossRef
  34. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: A new measure. Psychopharmacol Bull 1993;29:321-326.
  35. Sanna L, Stuart AL, Pasco JA, Kotowicz MA, Berk M, Girardi P, et al. Physical comorbidities in men with mood and anxiety disorders: A population-based study. BMC Med 2013;11:110.
    Pubmed KoreaMed CrossRef
  36. Soreca I, Frank E, Kupfer DJ. The phenomenology of bipolar disorder: What drives the high rate of medical burden and determines long-term prognosis? Depress Anxiety 2009;26:73-82.
    Pubmed KoreaMed CrossRef
  37. Magalhães PV, Kapczinski F, Nierenberg AA, Deckersbach T, Weisinger D, Dodd S, et al. Illness burden and medical comorbidity in the systematic treatment enhancement program for bipolar disorder. Acta Psychiatr Scand 2012;125:303-308.
  38. Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol 2017;17:162.
    Pubmed KoreaMed CrossRef
  39. Kraemer HC, Wilson GT, Fairburn CG, Agras WS. Mediators and moderators of treatment effects in randomized clinical trials. Arch Gen Psychiatry 2002;59:877-883.
    Pubmed CrossRef
  40. Van Breukelen GJ. ANCOVA versus change from baseline: More power in randomized studies, more bias in nonrandomized studies. J Clin Epidemiol 2006;59:920-925.
    Pubmed CrossRef
  41. Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012;36:764-785.
    Pubmed CrossRef
  42. Egeland M, Zunszain PA, Pariante CM. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 2015;16:189-200.
    Pubmed CrossRef
  43. Schmaal L, Veltman DJ, van Erp TG, Sämann PG, Frodl T, Jahanshad N, et al. Subcortical brain alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group. Mol Psychiatry 2016;21:806-812.
    Pubmed KoreaMed CrossRef
  44. Salagre E, Solé B, Tomioka Y, Fernandes BS, Hidalgo-Mazzei D, Garriga M, et al. Treatment of neurocognitive symptoms in unipolar depression: A systematic review and future perspec-tives. J Affect Disord 2017;221:205-221.
    Pubmed CrossRef
  45. Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 2014;53:23-34.
    Pubmed CrossRef
  46. Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: A meta-analysis of 82 studies. Acta Psychiatr Scand 2017;135:373-387.
  47. Maes M, Carvalho AF. The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol 2018;55:8885-8903.
    Pubmed CrossRef
  48. Roman M, Irwin MR. Novel neuroimmunologic therapeutics in depression: A clinical perspective on what we know so far. Brain Behav Immun 2020;83:7-21.
    Pubmed KoreaMed CrossRef
  49. Marx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, et al. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: A meta-analysis of 101 studies. Mol Psychiatry 2021;26:4158-4178.
    Pubmed CrossRef
  50. Rojewska E, Ciapała K, Piotrowska A, Makuch W, Mika J. Pharmacological inhibition of indoleamine 2,3-dioxygenase- 2 and kynurenine 3-monooxygenase, enzymes of the kynurenine pathway, significantly diminishes neuropathic pain in a rat model. Front Pharmacol 2018;9:724.
    Pubmed KoreaMed CrossRef
  51. Hashimoto K, Ishima T. A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: Translation initiation factor eIF4AI. PLoS One 2010;5:e15430.
    Pubmed KoreaMed CrossRef
  52. Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis 2009;202:321-329.
    Pubmed CrossRef
  53. Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant'Anna M, Klamt F, et al. A systemic toxicity index developed to assess peripheral changes in mood episodes. Mol Psychiatry 2010;15:784-786.
    Pubmed CrossRef
  54. Malik S, Singh R, Arora G, Dangol A, Goyal S. Biomarkers of major depressive disorder: Knowing is half the battle. Clin Psychopharmacol Neurosci 2021;19:12-25.
    Pubmed KoreaMed CrossRef
  55. McEwen BS. Mood disorders and allostatic load. Biol Psychiatry 2003;54:200-207.
    Pubmed CrossRef
  56. Grande I, Magalhães PV, Kunz M, Vieta E, Kapczinski F. Mediators of allostasis and systemic toxicity in bipolar disorder. Physiol Behav 2012;106:46-50.
    Pubmed CrossRef
  57. Cheng S, Hou J, Zhang C, Xu C, Wang L, Zou X, et al. Mino-cycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep 2015;5:10535.
    Pubmed KoreaMed CrossRef
  58. Bassett B, Subramaniyam S, Fan Y, Varney S, Pan H, Carneiro AMD, et al. Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis. Brain Behav Immun 2021;91:519-530.
    Pubmed CrossRef
  59. Camargos QM, Silva BC, Silva DG, Toscano ECB, Oliveira BDS, Bellozi PMQ, et al. Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke. Brain Res Bull 2020;155:1-10.
    Pubmed CrossRef
  60. Malhotra K, Chang JJ, Khunger A, Blacker D, Switzer JA, Goyal N, et al. Minocycline for acute stroke treatment: A systematic review and meta-analysis of randomized clinical trials. J Neurol 2018;265:1871-1879.
    Pubmed CrossRef
  61. Wang B, Huang X, Pan X, Zhang T, Hou C, Su WJ, et al. Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons. Brain Behav Immun 2020;88:132-143.
    Pubmed CrossRef
  62. Lee JS, Lee SB, Kim DW, Shin N, Jeong SJ, Yang CH, et al. Social isolation-related depression accelerates ethanol intake via microglia-derived neuroinflammation. Sci Adv 2021;7:eabj3400.
    Pubmed KoreaMed CrossRef
  63. Ahmed A, Misrani A, Tabassum S, Yang L, Long C. Minocy-cline inhibits sleep deprivation-induced aberrant microglial activation and Keap1-Nrf2 expression in mouse hippocampus. Brain Res Bull 2021;174:41-52.
    Pubmed CrossRef
  64. Sakurai M, Iwasa R, Sakai Y, Morimoto M. Minocycline prevents depression-like behavior in streptozotocin-induced diabetic mice. Neuropathology 2021;41:109-117.
    Pubmed CrossRef
  65. Morris G, Puri BK, Walker AJ, Maes M, Carvalho AF, Bortolasci CC, et al. Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders. Neurosci Biobehav Rev 2019;107:862-882.
    Pubmed CrossRef
  66. Berk M. Neuroprogression: Pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol 2009;12:441-445.
    Pubmed CrossRef
  67. Enache D, Pariante CM, Mondelli V. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun 2019;81:24-40.
    Pubmed CrossRef
  68. Nettis MA, Lombardo G, Hastings C, Zajkowska Z, Mariani N, Nikkheslat N, et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: Results from a double-blind randomised clinical trial. Neuropsychopharmacology 2021;46:939-948.
    Pubmed KoreaMed CrossRef
  69. Hasebe K, Mohebbi M, Gray L, Walker AJ, Bortolasci CC, Turner A, et al. Exploring interleukin-6, lipopolysaccharide- binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression. Acta Neuropsychiatr 2022;34:220-227.
    Pubmed CrossRef
  70. Salagre E, Vieta E. Precision psychiatry: Complex problems require complex solutions. Eur Neuropsychopharmacol 2021;52:94-95.
    Pubmed CrossRef
  71. Berk M, Vieta E, Dean OM. Anti-inflammatory treatment of bipolar depression: Promise and disappointment. Lancet Psychiatry 2020;7:467-468.
    Pubmed CrossRef

This Article

Close ✕

Cited By Articles

Author ORCID Information

Funding Information
  • Brain and Behavior Research Foundation
      Young Investigator Grant – 18740
  • Australasian Society of Bipolar and Depressive Disorders/Servier
      ASBDD/Servier Grant
  • Mental Health Research Institute
  • Deakin University

Social Network Service