Articulo de Minociclina

HELLMANN-REGEN J, CLEMENS V, GRÖZINGER M, KORNHUBER J, REIF A,
PRVULOVIC D, ET AL. EFFECT OF MINOCYCLINE ON DEPRESSIVE SYMPTOMS IN

PATIENTS WITH TREATMENT-RESISTANT DEPRESSION: A RANDOMIZED CLINICAL
TRIAL: A RANDOMIZED CLINICAL TRIAL. JAMA NETW OPEN [INTERNET]. 2022
[CITADOEL 16 DE OCTUBRE DE 2022];5(9): E2230367. DISPONIBLE EN:
HTTPS://PUBMED.NCBI.NLM.NIH.GOV/36103181/
ALUMNA: LUZ NAYANA HERRERA CERDA
DOCENTE: DR. JAVIER PEDRAZA CHAVEZ
GRADO Y GRUPO: 3°I
ASIGNATURA: FARMACOLOGIA BASICA
TEMA: TRATAMIENTO DE LA DEPRESION
FECHA: 15 OCTUBRE 2022
TITULO DEL ARTICULO: EFFECT OF MINOCYCLINE ON DEPRESSIVE SYMPTOMS

INPATIENTS WITH TREATMENT – RESISTANT DEPRESSION. A RANDOMIZED
CLINICALTRIAL.
El trastorno depresivo mayor es una enfermedad discapacitante mundialmente, donde las
tasas de respuesta al tratamiento son de aproximadamente el 50% con carecimiento de
remisión completa , se sugiere la participación del sistema inmunitario y de mecanismos
neurotróficos que son los principales fundamentos patogénicos en el TDM, donde los procesos
inflamatorios interfieren en la respuesta a los antidepresivos habituales, por lo que intervenir
entre estos procesos inflamatorios son base en el tratamiento y aún más en aquella depresión
resistente al tratamiento. La minociclina es un antibiótico de tetraciclina con propiedades
antineuroinflamatorias pleiotrópicas que atraviesa la barrera hematoencefálica y que inhibe la
activación proinflamatoria, mejora la señalización de retinoides neuro protectores y ejerce
efectos neuro protectores generales, dado esto se sugirió este medicamento como nuevo
enfoque en tratamiento antidepresivo. En este estudio se estudia a dicho fármaco con
administración de dosis a 200 mg de clorhidrato de minociclina, 2 capsulas de 50 mg por la
mañana y 2 capsulas de 50 mg por la noche, por día administrados por vía oral por 6 semanas
como complemento del tratamiento antidepresivo estándar, de igual forma se tuvo un grupo
placebo. El grupo con minociclina se concluyó con 67 pacientes y el grupo placebo con 72
pacientes. Los criterios para incluir a los pacientes fueron tener diagnostico actual de Trastorno
depresivo mayor según el manual diagnóstico y estadístico de los trastornosmentales 5ta
edición, edad entre 18 y 75 años, capacidad para dar su consentimientoinformado a
participar, puntuación de al menos 16 pts. en la escala Hamilton de 17 ítems, régimen
antidepresivo durante al menos 6 semanas sin cambios de dosis en las últimas 2 semanas
previas a la inclusión y respuesta inadecuada al tratamiento antidepresivo convencional según
los criterios del cuestionario de respuesta al tratamiento antidepresivo delHospital General de
Massachusetts. En este estudio se demostraron efectos similares para un antagonista de FNT
– alfa, sin embargo, este era más eficaz en los pacientes con marcadores inflamatorios
aumentados. Dado esto y los efectos dirigidos por minociclina dieron resultado en los efectos
secundarios, mientras que los resultados que se relacionan con la depresión primaria no
mejoraron con la minociclina adjunta al tratamiento habitual en el TDM. En otros pacientes los
efectos de la minociclina fueron bastantes fuertes en comparación con el grupo placebo que
se hicieron evidentes a las 8 semanas. Este estudio sugiere que la duración de 6 semanas de
tratamiento fue muy corta para poder detectar diferencias en los efectos farmacológicos. Otro
punto para destacar es que se sugiere que los enfoques antiinflamatorios pueden ser más
eficientes en pacientes con marcadores inflamatorios elevados, se estratificaron los niveles
iniciales de PCR, pero no se concluyó a ningún apoyo a la hipótesis de que la minociclina sea
más efectiva en los pacientes con inflamación inicial de mayor grado. Por lo que al leer este
estudio se concluye que a pesar de tener buena tolerancia del fármaco con las dosis
mencionadas no se logran reducir los síntomas depresivos en pacientes con Trastorno
depresivo mayor refractario al tratamiento encomparación con el placebo, ni siquiera como
tratamiento complementario, por lo que se sugiere hacer un seguimiento más prolongado de
minociclina para establecer su eficacia en pacientes con trastorno depresivo mayor.
Effect of Minocycline on Depressive Symptoms in Patients

With Treatment-Resistant Depression
A Randomized Clinical Trial
Julian Hellmann-Regen, MD; Vera Clemens, MD; Michael Grözinger, MD; Johannes Kornhuber, MD; Andreas Reif, MD; David Prvulovic, MD; Roberto Goya-
Maldonado, MD;
Jens Wiltfang, MD; Oliver Gruber, MD; Cornelius Schüle, MD; Frank Padberg, MD; Marcus Ising, PhD; Manfred Uhr, MD, PhD; Tim Friede, PhD; Cynthia Huber, MSc;
André Manook, MD; Thomas C. Baghai, MD; Rainer Rupprecht, MD; Isabella Heuser, MD, PhD INTERVENTIONS Participants were
randomized (1:1) to receive adjunct
minocycline (200 mg/d) or placebo for
Abstract 6 weeks.
IMPORTANCE Insufficient treatment response and resulting chronicity constitute a major problem in
depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant MAIN OUTCOMES AND MEASURES
depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory Primary outcome measure was the
interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, change in MontgomeryÅsberg
represents a promising repurposing candidate in the treatment of TRD. Depression Rating Scale (MADRS) score
from baseline to week 6 analyzed by
intention-totreat mixed model
OBJECTIVE To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as
repeated measures. Secondary
usual can significantly reduce depressive symptoms in patients with TRD.
outcome measures were response,
remission, and various other clinical
rating scales.
DESIGN, SETTING, AND PARTICIPANTS The study was conducted in Germany and designed as a
multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a
course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to
RESULTS Of 173 eligible and
August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a
randomized participants (84
diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental
randomized to minocycline and 89
Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression
randomized to placebo), 168 formed
Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18
the intention-to-treat sample (79
to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately
[47.0%] were women, 89
respond to an initial antidepressant standard medication as per Massachusetts General Hospital
[53.0%] were men, 159 [94.6%] were
Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total
White, 9 [6.4%] were of other race and
of 258 patients were screened, of whom 173 were randomized and 168 were included into the
ethnicity, including Asian and unknown
intention-to-treat population. Statistical analysis was performed from April to November 2020.
ethnicity), with 81 in the minocycline
group and 87 in the placebo group. The
mean (SD) age was 46.1 (13.1) years,
HELLMANN-REGEN J, CLEMENS V, GRÖZINGER M, KORNHUBER J, REIF A, PRVULOVIC
D, ET AL. EFFECT OF MINOCYCLINE ON DEPRESSIVE SYMPTOMS IN PATIENTS WITH
TREATMENT-RESISTANT DEPRESSION: A RANDOMIZED CLINICAL TRIAL: A
RANDOMIZED CLINICAL TRIAL. JAMA NETW OPEN [INTERNET]. 2022 [CITADOEL 16 DE
OCTUBRE DE 2022];5(9): E2230367. DISPONIBLE EN:
and the mean (SD) MADRS score at baseline was 26.5 (5.0). an initial treatment are estimated at
There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the roughly 50% with a substantial
proportion lacking full remission even
(continued)
following various switching and
Open Access. This is an open access article distributed under the terms of the CC-BY License. augmentation strategies of the
antidepressant regimen.2
JAMA Network Open. 2022;5(9):e2230367. doi:10.1001/jamanetworkopen.2022.30367 (Reprinted)
Accumulating evidence from
Key Points
clinical and preclinical studies suggests
Question Does 6 weeks of minocycline treatment as add-on to standard antidepressant treatment
involvement of the immune system and
reduce depressive symptoms in patients with treatment-resistant depression?
neurotrophic mechanisms as pivotal
Findings In this randomized clinical trial of 168 patients with treatmentresistant depression, 6 weeks of neurobiological underpinnings in the
minocycline treatment did not show a statistically significant advantage compared with placebo on the pathogenesis of MDD.3-5 Moreover,
overall course of depressive symptoms. low-grade inflammatory processes
Meaning The findings of this randomized clinical trial suggest the need for more effective therapeutic potentially interfere with response to
interventions and biomarkers in this heterogeneous clinical condition. the usual antidepressants.3,5-7 Clinical
evidence for efficacy of anti-
inflammatory interventions in MDD is
based on nonsteroidal anti-
+ Visual Abstract inflammatory drugs (NSAIDs), cytokine-
inhibiting drugs and statins, with
+ Supplemental content studies showing varying efficacy and
Author affiliations and article information are listed at the end of this article. large heterogeneity in trial designs. 8,9
Abstract (continued)
While some NSAIDs carry a risk for
placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression adverse events such as infections or
severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of hemorrhage in combination with
treatment (1.46 [−1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically serotonergic antidepressants, selective
significant effect on secondary outcomes. COX-2 inhibiting drugs appear to
exhibit only transient efficacy, if at all.10
Targeting inflammatory processes in a
CONCLUSIONS AND RELEVANCE In this large randomized clinical trial with minocycline at a dose of
more specific manner may provide a
200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated
promising treatment rationale,
but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of
particularly for treatment-resistant
this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD.
depression.7,11
Minocycline is a tetracycline
TRIAL REGISTRATION EU Clinical Trials Register Number: EudraCT 2015-001456-29
antibiotic with pleiotropic
JAMA Network Open. 2022;5(9):e2230367. doi:10.1001/jamanetworkopen.2022.30367

antineuroinflammatory properties that
readily crosses the blood-brain barrier,
inhibits proinflammatory microglial
activation, enhances neuroprotective
Introduction retinoid signaling, and exerts overall
Major depressive disorder (MDD) is an important cause of disability worldwide. 1 Insufficient
neuroprotective effects.12-15 There is
response rates, persistent residual symptoms, frequent relapse or recurrence of symptoms
profound evidence for antidepressant
constitute unsatisfactory outcomes of conventional antidepressant treatments. Response rates for
effects of minocycline in animal
models,16 most likely mediated through beneficial effects on microglial activation. 17-20 Thus, was significantly larger compared with
minocycline treatment has been suggested as a novel antidepressant approach21 and indeed, a few the placebo group. Another small,
small randomized clinical trials (RCTs) suggest antidepressant efficacy of minocycline in MDD recently published trial included 39
patients.22 Emadi-Kouchak and colleagues showed that patients with HIV with mild-to-moderate patients with TRD selected for at least
depression who underwent a 6-week treatment with 100 mg minocycline exhibited larger marginally increased levels of serum C-
improvement of depressive symptoms compared with the placebo group. 23 In another trial of 71 reactive protein (CRP) greater than or
patients with non-treatment-refractory MDD, 12 weeks of treatment with 200 mg minocycline equal to 0.1 mg/dL (to convert to
resulted in significantly larger improvements in clinical global impression scores, quality of life- and milligrams per liter, multiply by 10).26
functioning-related scores in the minocycline vs the placebo group, but remained without effect on Exploratory analyses suggested a
the primary depression-related outcome parameter.24 With respect to treatment-resistant positive effect of minocycline
depression, Husain and colleagues25 treated 41 patients with TRD with up to 200 mg minocycline or
placebo over a period of 12 weeks. The decrease of depressive symptoms in the minocycline group
treatment on depressive symptoms compared with placebo, yet only for a small group of patients
with CRP levels of at least 0.3 mg/dL.
However, small sample sizes and heterogeneous populations of previous studies warrant
larger, well-controlled trials to demonstrate a putative antidepressant effect of minocycline. 21 Here,
we investigated whether minocycline (200 mg/d) given for 6 weeks as add-on to a stable
antidepressant medication reduces depressive symptoms in patients with a major depressive
episode classified as treatment resistant.
Methods
Study Design
The Minocycline in Treatment-Resistant Depression (MinoTRD) trial was a double-blind,
placebocontrolled and randomized multicenter clinical trial investigating whether 200 mg of
minocycline hydrochloride per day administered orally for 6 weeks as an adjunct to antidepressant
standard treatment reduces depressive symptoms in patients with MDD without, so far, adequate
response to an initial antidepressant regimen.
Patients were recruited from inpatient and outpatient departments of 9 university hospitals in
Germany that served as study sites. A list of sites and principal investigators is provided in
Supplement 1. The first patient was recruited in January 2016, and the last visit was completed in
August 2020. Key inclusion criteria were a current diagnosis of MDD according to Diagnostic and
Statistical Manual of Mental Disorders (Fifth Edition) criteria, aged between 18 and 75 years, ability
to give informed consent for participation, a score of at least 16 points on the 17-item Hamilton
rating scale for depression (HAM-D 17), an antidepressant regimen for at least 6 weeks without dose
changes within the last 2 weeks prior to inclusion and inadequate response to conventional
antidepressant treatment according to the criteria of the Massachusetts General Hospital
antidepressant treatment response questionnaire (MGH-ATRQ). Ethnicity was assessed by
selfreport. Race and ethnicity were assessed because they may affect pharmakokinetics. Key
exclusion criteria were prevalence of neurodegenerative disorder, any severe, unstable general
medical condition, including chronic inflammatory disease, concurrent anti-inflammatory
medication, pregnant or nursing women and tetracycline allergy. To improve recruitment, criteria
were slightly adapted. In addition to antidepressant monotherapy, therapy with more than 1
HELLMANN-REGEN J, CLEMENS V, GRÖZINGER M,
KORNHUBER J, REIF A, PRVULOVIC D, ET AL. EFFECT OF
MINOCYCLINE ON DEPRESSIVE SYMPTOMS IN PATIENTS
WITH TREATMENT-RESISTANT DEPRESSION: A
RANDOMIZED CLINICAL TRIAL: A RANDOMIZED CLINICAL
TRIAL. JAMA NETW OPEN [INTERNET]. 2022 [CITADOEL 16
DE OCTUBRE DE 2022];5(9): E2230367. DISPONIBLE EN:
antidepressant was permitted. Details on inclusion and exclusion criteria are presented in
Supplement 1. The MinoTRD trial was conducted in accordance with the International Conference
on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki.27 The trial is
registered with the European Union
Clinical Trials Register (EudraCT 2015-001456-29) and ClinicalTrials.gov (identifier: NCT02456948).
The study protocol, patient information sheets, and informed consent forms were approved by the
ethics committee of the state of Berlin (Landesamt für Gesundheit und Soziales Berlin) and the Federal
Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und
Medizinprodukte, BfArM). This study followed the Consolidated Standards of Reporting Trials
(CONSORT) reporting guideline. Participants were randomized to receive minocycline 200 mg/d or
placebo. The randomization was carried out centrally using a computerized system based on a
permuted block procedure with block stratification by study center.
Trial Procedures
Study medication was provided as gelatin capsules containing 50 mg of minocycline hydrochloride or
identically appearing placebo capsules (Mibe Pharmaceuticals) in blister packs. Medication was
dispensed initially and after 3 weeks. Trial group dosing was as follows: minocycline, 200 mg (2 × 50
mg capsules in the morning and 2 × 50 mg in the evening) and placebo (2 placebo capsules in the
morning and 2 capsules in the evening). Group assignment was masked to prescribing clinicians,
participants, and all trial staff members except pharmacy staff and the trial statistician (TF).
Participants visited the clinic at baseline, and on a weekly basis during the 6 weeks of receiving
study medication (treatment period). Prior to inclusion, participants had to be on an antidepressant
regimen for at least 6 weeks without dose changes within the last 2 weeks prior to inclusion.
Continuous pharmacotherapy with any antidepressant approved for the treatment of depression in a
sufficient and stable dosage was mandatory. Concomitant psychotherapy was accepted and
concurrent use of lorazepam (maximum: 4 mg/d) or Z-hypnotics (zolpidem [maximum 10 mg/d],
zopiclone [maximum 7.5 mg/d]) was permitted as comedication only for treatment of acute agitation
and/or anxiety or severe sleep disorders. Additionally, established augmentation strategies with
either quetiapine or aripiprazole as well as additional antidepressants outside the indicated target
range, for example for improving sleep, were allowed. Follow-up visits took place 6 weeks and 6
months (the latter by telephone) after the end of the treatment period. Routine laboratory safety
analyses were performed on a weekly basis, additional biosamples (peripheral blood mononuclear
cells, plasma, and serum) were collected. Minocycline serum level analyses were performed by liquid
chromatography and mass spectrometry on samples from baseline, week 2, week 4, and week 6 at
the end of the trial and after finalization of the database. Additional information on adherence was
gathered at each assessment and through dispensing records. Outcome assessments and adverse
events were recorded at each visit.
Outcome Measures
Primary outcome was the change of depression severity from baseline to week 6, assessed by the
Montgomery-Åsberg Depression Rating Scale (MADRS).28 Secondary outcomes were response (50%
reduction in MADRS score) and remission (MADRS score <9) after 6 weeks of treatment.
Change on HAMD-17,29 Beck Depression Inventory (BDI),30 Clinical Global Impressions Scale (CGI-S),31
Trail Making Tests (TMT) A and B and Symptom Checklist 90-R (SCL-90-R)32 were also assessed
weekly and evaluated after 6 weeks of treatment. Exploratory outcomes included subscales and
stratification for inflammation-associated parameters or gender as well as follow up measurements
outside of the core treatment period of 6 weeks.
Statistical Analysis
Based on a standardized mean difference (Cohen d) of 0.5 as suggested by a similar study,33 a sample
size of 64 patients per group yields a power of 80% at a a 1-sided significance level of 2.5% with a
2-sample t test for the primary end point (ie, change in MADRS from baseline [week 0] to week 6).
Adjusting for approximately 20% dropout results in a target group size of 80 participants per study
group and a total case number of 160. As the mixed model for repeated measures (MMRM)
approach is used for the analysis of the primary end point, which is more efficient than the 2-sample
t test, the power was expected to be higher than 80% and the approach taken conservative. The
sample size calculation was carried out using nQuery Advisor 7.0. The primary evaluation sample
follows the intention-to-treat (ITT) principle and includes all patients that received the randomized
medication at least once plus had at least 1 postbaseline MADRS score.
Continuous baseline characteristics are given as median (range) or mean (SD) as appropriate and
categorical variables as frequencies. The primary end point was change in MADRS from baseline (week
0) to week 6. The primary end point was evaluated by a MMRM and reported by the difference of
marginal means of the 2 treatment groups at week 6. The model includes the factors treatment group
(placebo, minocycline), study center (center 1 to center 9), time point of measurement (week 1 to
week 6) as fixed effects. Other covariates treated as fixed effects were the MADRS sum score at
baseline, the time point by MADRS sum score at baseline interaction and the treatment by time point
interaction. Patient-specific effects enter the model as a random effect with normal distribution and
expected value 0. An unstructured covariance matrix for the residuals was used. The evaluation of the
secondary outcomes such as CGI-S, BDI, HAMD-17, and SCL-90 as well as TMT A and B were performed
analogously to the evaluation described above for MADRS. Similarly, laboratory parameters such as
CRP and leukocyte values were transformed using the natural logarithm and evaluated analogously
to the primary end point. The secondary end points of remission and response to treatment were
evaluated using logistic regression, with dropouts defined as no remission and no response to
treatment, respectively. In the logistic regression model, treatment was included as factor, and
MADRS sum score at baseline was included as a covariate.
As exploratory end points HAMD-6 and subscales based on items of MADRS and HAMD
measuring a composite for anhedonia, sickness behavior, and fear and/or suicidality 3,34 were
analyzed analogously to the evaluation described for the primary end point. In an exploratory
subgroup analysis for severity of depressive symptoms at baseline measured by MADRS, we split the
population into 2 subgroups based on the MADRS median value at baseline. We included the
resulting variable as factor and its interaction with treatment into the MMRM model described for
the primary analysis. The same approach was used for gender, childhood trauma as assessed by the
childhood trauma questionnaire (CTQ), and subgroups defined by median-split for baseline CRP and
body mass index (BMI) at baseline. Significance was indicated by 2-sided P < .05; no correction for
multiple testing of exploratory outcomes was applied. All analyses were done in SAS version 9.4 (SAS
Institute). For further details, see statistical analysis plan and trial protocol (Supplement 1).
Results
Between January 7, 2016, and August 7, 2020, a total of 253 patients were screened for eligibility
from 9 different university hospitals in Germany, of whom 168 participants entered the trial (Figure
1). Eighty-nine patients were randomized to placebo, 84 received minocycline. A total of 5 patients
did not start trial medication and were thus excluded from all analyses per protocol definition. The
ITT sample consisted of 81 patients in the minocycline group and 87 patients in the placebo group.
Of the 168 participants, 79 (47.0%) were women, 89 (53.0%) were men, 159 (94.6%) were White,
and 9 (6.4%) were of other race and ethnicity, including Asian and unknown ethnicity.
The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0).
Baseline characteristics of these 168 participants were similar between treatment groups (Table 1).
Excluded
Not meeting inclusion criteria
Per protocol analysis set Per protocol analysis set

However, there were more female participants in the placebo group (55.2% [n = 48]) compared with
the minocycline group (38.3% [n = 31]). Median (range) CRP levels at baseline were 1.2 mg/dL (0.02-
22.1) in the minocycline and 0.60 mg/dL (0.05-7.30) in the placebo group (to convert to milligrams
per liter, multiply by 10). Participants had a median (range) duration of the present episode of 41 (6-
952) weeks in the minocycline and 52 (4-624) weeks in the placebo group (Table 1).
Of the 168 participants from the ITT sample, 144 completed the study up to week 6 and 125
completed the 6-month follow-up period. The time course of depression severity (MADRS scores)
during the 6-week-treatment period and changes from baseline of MADRS scores at the end of the 6-
week-treatment period are shown in Figure 2. There was a mean (SD) reduction of 8.46 (7.08) points
in the MADRS score in the minocycline group and of 8.01 (9.07) points in the placebo group after 6
weeks of treatment. The primary end point as assessed by the MMRM analysis, the difference of the
least squares means at week 6 for the 2 treatment groups, was not statistically significant (1.46 [95%
CI, −1.04 to 3.96]; P = .25). Adjustments of MMRM analysis for the variables gender, SSRI, and months
of current medication, which showed differences between treatment groups at baseline, did not
result in statistically significant differences between treatment groups for the primary end point.
Response and remission, as defined by 50% reduction of initial depression severity or reaching a
Table 1. Baseline Characteristics of the Intention-to-Treat Population

Patients, No. (%)
Minocycline (n = 81) Placebo (n = 87)

Baseline characteristics
Gender
Female 31 (38.3) 48 (55.2)
Male 50 (61.7) 39 (44.8)
Age, mean (SD) 44.8 (13.6) 47.3 (12.5)
Ethnicity
White 77 (95.0) 82 (94.3)
Othera 4 (4.9) 5 (5.7)
Current smoker 21 (25.9) 25 (28.7)
BMI, mean (SD) 27.4 (5.3) 26.5 (4.8)
Current medication
SSRI 47 (58.0) 37 (42.5)
SNRI 30 (37.0) 40 (46.0)
MAO inhibitor 4 (4.9) 5 (5.7)
Tricyclic/tetracyclic AD 6 (7.4) 10 (11.5)
Other 29 (35.8) 40 (46.0)
No. of ADs
1 59 (72.8) 60 (69.0)
2 16 (19.8) 17 (19.5)
>2 6 (7.4) 10 (11.5)

Months on current medication, median (range) 180.0 (19.3-585.0) 90.0 (9.7-540.0)
First depressive episodeb 14 (18.0) 23 (26.7)
Duration of the current depressive episode, median (range), wk 41 (6-952) 52 (4-624)
No of previous episodes, median (range) 2.5 (0-30) 2 (1-25)
Current inpatient stay or dayclinic 13 (16.7) 13 (15.1)
Depression duration from onset, mean (SD), y 16.52 (12.69) 18.64 (12.02)
Baseline MADRS, mean (SD) 26.4 (4.8) 26.6 (5.1)
Baseline HAMD-17, mean (SD) 20.0 (3.5) 20.3 (3.5)
Baseline BDI II, mean (SD) 32.3 (9.0) 32.9 (10.4)
Baseline SCL-90-R, mean (SD) 68.7 (6.8) 66.9 (6.9)
Baseline CGI, mean (SD) 4.8 (0.6) 4.9 (0.7)
Baseline TMT-A, mean (SD) 34.7 (16.6) 35.1 (14.3)
Baseline TMT-B, mean (SD) 77.5 (32.7) 76.1 (32.3)
Baseline hsCRP, median (range), mg/dL 0.121 (0.002-2.210) 0.060 (0.005-0.730)
Abbreviations: AD, antidepressant; BDI II, Beck Depression Inventory; BMI, body-mass index; CGI, clinical global impression scale; HAMD-17, Hamilton Depression Rating Scale;
hsCRP, high sensitivity
C-reactive protein; MADRS, Montgomery–Åsberg
Depression Rating Scale; SCL-90-R, Symptom Checklist-90-R.
SI conversion factor: To convert hsCRP to milligrams per liter, multiply by 10. a Other ethnicities included Asian and unknown ethnicity. b Data not available for all randomized
patients.
total MADRS score of less than 9 points after week-6 of minocycline treatment, were not statistically
significant different between groups as assessed by the odds ratio estimated by the logistic
regression model (Table 2). Secondary outcome measures included changes in BDI, CGI-S, HAMD-17,
and SCL-90, as well as TMT A and B and CRP levels (Figures 2C and 2D, Table 3; eTable 3, eFigures 1-9
in Supplement 2). The difference between minocycline treatment and placebo of these secondary
outcomes was not statistically significant, neither was the difference between baseline and week 6
for the 2 treatment groups as assessed by the mixed model. For exploratory analyses, leukocyte
count showed a statistically significant difference between the treatment groups from baseline to
week 6 (0.06 [95% CI, 0.00-0.12]; P = .047) as assessed by the difference of the least squares means
between the treatment groups based on the linear mixed model. The leukocyte count in the
minocycline group decreased compared with the count in the placebo group (Table 3).
Adherence to trial medication was assessed by means of therapeutic drug monitoring during the trial.
Presence of minocycline was observable in all patients randomized to the intervention group.
Exploratory end points included measures for anhedonia, sickness behavior, and fear and/or
suicidality, based on items of MADRS and HAMD (eTable 2). There were no significant differences
between the treatment groups based on the least square differences for the change of these
MADRS, Montgomery-Åsberg Depression Rating Scale. Error bars in panels A, C, and D error bars in panel B indicate upper and lower values as calculated by the Tukey method.
indicate 95% CIs. Box plots in panel B were created by the Tukey method; horizontal line
Table 2. Response and Remission Rates

Patients, No. (%)
a Remission was defined as a MARDS score of less than 9
Odds ratio for placebo
points.
Secondary end points Minocycline Placebo vs minocycline (95% CI) P value
b Response was defined as a 50% reduction of MADRS
Remissiona 10 (12.4) 10 (11.5) 0.93 (0.36-2.38) .88
scores at week 6 to baseline.
Responseb 14 (17.3) 21 (24.1) 1.53 (0.72-3.26) .27
exploratory outcome measures from baseline to week 6 based on linear mixed effects models for
repeated measures.
Exploratory subgroup analyses of the primary end point (MADRS score) were conducted for
gender and by median-split for baseline CRP levels, severity of depressive symptoms at baseline,
body mass index (BMI), and childhood trauma as assessed by the childhood trauma questionnaire
(CTQ; eFigures 10-14 in Supplement 2). Neither stratification for gender, nor for CRP levels at
baseline or baseline severity of depressive symptoms, BMI nor stratification for type or intensity of
childhood trauma had effects on separating minocycline from placebo (eFigures 10-14 in Supplement
2).
Minocycline was well tolerated; discontinuation rates and adverse events were similar in the
intervention and placebo group. In total, 85.2% of participants (69 of 81) in the minocycline and 86.2%
of participants (75 of 87) in the placebo group completed the 6-week trial. The reasons for
discontinuation are summarized in Figure 1. There were a total of 6 severe adverse events within the
minocycline group and 7 within the placebo group (eTable 1 in Supplement 2).
Discussion
To our knowledge, MinoTRD is the largest randomized clinical trial of minocycline in TRD. Major
findings included: (1) six weeks of minocycline as adjunct to standard antidepressant medication did
not outperform placebo in patients with TRD; and: (2) 200 mg daily of the teracycline was well
tolerated over a treatment period of 6 weeks in this sample. The failure of minocycline treatment to
reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for
antiinflammatory treatment strategies in this clinical population, given the suggestive evidence for
advantageous effects of minocycline from prior, albeit considerably smaller, trials. 23-26
Table 3. Primary, Secondary, and Exploratory End Points

Mean (SD) Difference of
Pre-treatment week 6 and
baseline
between Placebo
Primary, secondary Post-treatment and minocycline
and exploratory Patients, Minocycline, Patients, Placebo, Patients, Minocycline, Patients, Placebo, (95% CI)a
end points No. mean (SD) No. mean (SD) No. mean (SD) No. mean (SD) P value
MADRS 81 26.4 (4.8) 87 26.6 (5.1) 69 17.6 (7.8) 75 18.7 (9.0) 1.46 (−1.04 to .25
3.96)
BDI II 78 32.3 (9.0) 87 32.9 (10.4) 66 21.6 (12.0) 72 23.6 (13.2) 1.56 (−2.00to .39
5.11)
CGI 81 4.8 (0.6) 87 4.9 (0.7) 69 3.9 (1.1) 75 4.0 (1.2) 0.05 (−0.29 to .77
0.40)
HAMD-6 81 11.4 (2.2) 87 11.4 (2.1) 69 7.4 (3.5) 71 7.6 (6.7) 0.33 (−0.77 to .56
1.42)
HAMD-17 77 20.0 (3.5) 81 20.3 (3.5) 68 13.1 (5.9) 71 14.2 (6.7) 1.16 (−0.62 to .20
2.93)
SCL-GSI 81 68.7 (6.7) 87 66.9 (7.0) 66 62.3 (10.7) 72 62.0 (10.1) 1.24 (−1.76 to .42
4.25)
SCL-PSDI 81 66.3 (4.9) 87 66.1 (6.0) 65 60.2 (8.3) 72 60.2 (8.9) 0.68 (−1.83 to .59
3.18)
SCL-PST 81 64.4 (6.6) 87 62.2 (6.0) 66 60.5 (10.1) 72 59.5 (8.9) 0.85 (−3.53 to .39
5.24)
TMT-A 80 34.7 (16.6) 87 35.1 (14.3) 69 29.9 (12.2) 74 30.4 (14.1) 0.56 (−3.81 to .80
4.93)
TMT-B 79 77.5 (32.7) 85 76.1 (32.3) 69 68.1 (27.6) 72 68.8 (29.1) 1.67 (−7.73 to .73
11.11)
Log CRP 81 −0.10 (1.6) 86 −0.49 (1.4) 50 0.37 (1.2) 57 0.03 (1.3) 0.24 (−0.04 to .09
0.53)
Log Leukocytes 76 1.96 (0.31) 79 1.95 (1.85) 66 1.77 (0.29) 69 1.82 (0.28) 0.06 (0.00 to .05
0.12)
a
Abbreviations: BDI II, Beck’s depression inventory Version II; CGI, clinical global
The differences week 6 to baseline between the two treatment groups are based
impression scale; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery
on the difference of least square means of linear mixed effects models for
Asberg Depression Rating Scale; SCL-GSI, global severity index; SCL-PSDI, positive
repeated measures.
symptom distress; SCL-PST, positive symptom total; TMT, trail making test, version A
or B.
The data from our trial are partly in contrast to previous studies that suggested an
antidepressant effect of minocycline.23-26,35,36 However, all RCTs of minocycline in depression were
characterized by comparably small sample sizes and highly heterogenous populations of depressed
patients.23-26,37 In TRD, Nettis and colleagues26 have recently published a study suggesting efficacy of
minocycline only in participants with higher baseline levels of CRP, while no treatment effects on the
primary outcome were identified. In their study, only patients with at least marginally elevated levels
of CRP were included, and the positive findings were observed in a subgroup of only 6 participants
with CRP levels at least 3 mg/L. Conversely, our trial was powered to detect clinical differences in
patients with TRD, where elevated inflammation may be expected per se, without the need to stratify
patients a priori based on absolute values of calibrated paraclinical parameters. Our study therefore
included all patients fulfilling the clinical definition of treatment resistance. Inflammation status and
numerous other paraclinical parameters were monitored as putative biomarkers throughout the
treatment period.
Similar effects were demonstrated for a TNF-α antagonist being more efficient in patients with
increased inflammatory markers.11 However, based on the hypothesis of chronic, subthreshold
inflammation in TRD that may well be present at the level of microglial activation even without
measurable traces in the periphery, also patients without significantly elevated peripheral
inflammation may have exhibited a minocycline-targetable central inflammation and might thus have
responded to minocycline treatment. In a small proof-of-concept trial assessing a potential
antidepressant effect of 12 weeks of minocycline in non–treatment-resistant patients, positive
changes in secondary outcomes were observed, while primary depression-related outcomes were not
improved by adjunct minocycline to treatment as usual.24 In contrast, another small study focusing on
TRD conducted by Husain and colleagues25 demonstrated quite strong effects of minocycline
compared with placebo which became evident by and after 8 weeks of treatment. Thus, one
explanation for the null result of the MinoTRD trial could be that treatment duration (ie, 6 weeks) was
too short to reveal detectable differences. However, a closer look at the data from Husain et al 25
suggests that their overall effect in the intervention group was due to an almost complete lack of
improvement in the placebo group, which is very unusual. In our sample, for instance, the mean (SD)
decrease in the MADRS scores was 8.01 (9.07) points for placebo and 8.46 (7.08) points for
minocycline, which represents a magnitude of improvement for placebo that is well expected from
similar trials in TRD.33,38
While prior research had suggested that anti-inflammatory approaches may be more efficient
in patients with increased inflammatory markers,11 we purposely sought to recruit a naturalistic
population of TRD, assuming elevated baseline inflammation as a potentially underlying cause in at
least a subgroup of the recruited patients. Interestingly, post hoc stratification for baseline CRP
levels did not yield any results supporting a hypothesis of minocycline treatment possibly being
more effective in participants exhibiting higher-grade baseline inflammation (eFigures 8 and 12 in
Supplement 2).
Strengths and Limitations
The MinoTRD trial has strengths and limitations. We included inpatients and outpatients and
recruited via a broad network of trial-experienced academic centers. The rather wide range of
eligibility criteria and the approach to include patients regardless of a priori–determined
inflammatory parameters allowed for a naturalistic sample of patients with TRD. From a
methodological standpoint, the study was well powered and controlled, thus, adding reliable
evidence to the discussion about possible advantages of anti-inflammatory strategies in patients
with TRD.
A possible limitation of the MinoTRD trial could be that the chosen treatment duration of 6 weeks
may be too short, and longer treatment periods would have been required to yield detectable
differences. However, one of the goals of novel treatment strategies is a more rapid onset of action
suggesting that a treatment period limited to 6 weeks should be considered advantageous
compared
with longer treatment regimens for any novel treatment strategy in TRD. Another limitation may be seen
in the drug being an antibiotic, possibly limiting a broader use with respect to potential effects on the
microbiome, particularly development of antibiotic resistance.
Interestingly, gender distribution was almost equally balanced for male and female participants and
thus different from an epidemiologically expected 2:1 ratio for female-to-male genders. One possible
explanation for this could be that certain contraceptive measures were required for women participating
in the present trial.
Finally, we purposely did not preselect the study population based on increased peripheral
inflammation markers, arguing that subthreshold inflammation might generally co-occur in TRD. This may
be considered a limitation on the one hand, while including all patients regardless of their individual
inflammatory status, on the other hand, may also be considered a strength of the design.
Conclusions
This randomized clinical trial aimed to assess the antidepressant efficacy of add-on minocycline in a
naturalistic clinical population with TRD given the great clinical relevance of this subgroup of patients
with depression. Six weeks of 200 mg adjunct minocycline treatment was well tolerated yet failed to
reduce depressive symptoms in patients with treatment-refractory MDD compared with placebo. Our
results from this large RCT of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient
population are of great clinical importance, robustly demonstrating that minocycline add-on treatment
does not outperform placebo, not even in those participants with elevated levels of CRP prior to
treatment initiation.
A thorough assessment of biomarker profiles, including alterations of various cytokines and plasticity-
modulating retinoids over the course of the treatment period promises further options for stratification of
subgroups and identification of potential response-predicting biomarker profiles, including potential
biomarkers from transcriptome-wide analyses that are presently ongoing.
ARTICLE INFORMATION
Accepted for Publication: July 22, 2022.
Published: September 14, 2022. doi:10.1001/jamanetworkopen.2022.30367

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Hellmann-
Regen J et al. JAMA Network Open.
Corresponding Author: Isabella Heuser, MD, PhD, Department of Psychiatry and Neurosciences, Charité -
Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany (isabella.heuser @charite.de).
Author Affiliations: Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Campus
Benjamin Franklin, Germany (Hellmann-Regen, Clemens, Heuser); Department of Psychiatry, Psychotherapy and
Psychosomatics, University Hospital RWTH Aachen, Germany (Grözinger); Department of Psychiatry and
Psychotherapy, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen, Erlangen, Germany
(Kornhuber); Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital
Frankfurt, Germany (Reif, Prvulovic); Department of Psychiatry, University Medical Center Göttingen, Germany
(Goya-Maldonado, Wiltfang); Department of Psychiatry, Heidelberg University Hospital, Germany (Gruber);
Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany (Schüle,
Padberg); Max Planck Institute of Psychiatry, Munich, Germany (Ising, Uhr); Department of Medical Statistics,
Universitätsmedizin Göttingen, Göttingen, Germany (Friede, Huber); Department of Psychiatry, University Hospital,
Regensburg, Germany (Manook, Baghai, Rupprecht).
LUZ HERRERA NAYANA CERDA 3°I

Author Contributions: Drs Hellman-Regen and Clemens had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis. Drs Hellmann-Regen and Clemens
contributed equally.
Concept and design: Hellmann-Regen, Wiltfang, Uhr, Friede, Heuser.
September 14, 2022

Acquisition, analysis, or interpretation of data: Hellmann-Regen, Clemens, Grözinger, Kornhuber, Reif, Prvulovic,
Goya-Maldonado, Gruber, Schüle, Padberg, Ising, Friede, Huber, Manook, Baghai, Rupprecht, Heuser.
Drafting of the manuscript: Hellmann-Regen, Clemens, Heuser.
Critical revision of the manuscript for important intellectual content: Hellmann-Regen, Grözinger, Kornhuber, Reif,
Prvulovic, Goya-Maldonado, Wiltfang, Gruber, Schüle, Padberg, Ising, Uhr, Friede, Huber, Manook, Baghai,
Rupprecht, Heuser.
Statistical analysis: Hellmann-Regen, Friede, Huber.
Obtained funding: Hellmann-Regen, Kornhuber, Schüle, Rupprecht, Heuser.
Administrative, technical, or material support: Hellmann-Regen, Clemens, Kornhuber, Reif, Prvulovic,

GoyaMaldonado, Wiltfang, Schüle, Padberg, Uhr, Baghai, Rupprecht.
Supervision: Hellmann-Regen, Grözinger, Goya-Maldonado, Wiltfang, Padberg, Ising, Friede, Baghai, Heuser.
Conflict of Interest Disclosures: Dr Reif reported receiving personal fees from Medice, Shire/Takeda, SAGE/ Biogen,
Boehringer Ingelheim, Janssen, and Cyclerion outside the submitted work. Dr Wiltfang reported receiving personal
fees from Abbott, Biogen, Boehringer-Ingelheim, Immungenetics, Janssen, Lilly, MSD Sharp & Dohme, Pfizer, Roche
Pharma, Actelion, Amgen, Beijing Yibai Science and Technology Ltd, and Roboscreen outside the submitted work; in
addition, Dr Wiltfang had a patent for PCT/EP 2011 001724 issued and a patent for PCT/EP 2015 052945 issued. Dr
Schüle reported receiving personal fees from Janssen Cilag GmbH outside the submitted work. Dr Padberg reported
receiving personal fees from Sooma, Finland (Scientific Advisory Board), Brainsway Inc, Israel (Scientific Advisory
Board, speaker’s honorarium), Mag & More, Germany (speaker’s honorarium), neuroCare Group, Germany
(speaker’s honorarium, nonfinancial support, and technical equipment) outside the submitted work. Dr Friede
reported receiving personal fees from Novartis (statistical consultancies including data monitoring committees),
Bayer (statistical consultancies including data monitoring committees), Roche (statistical consultancies including data
monitoring committees), Enanta (statistical consultancies including data monitoring committees), BiosenseWebster
(statistical consultancies including data monitoring committees), Lilly (statistical consultancies including data
monitoring committees), Recordati (statistical consultancies including data monitoring committees), Recardio
(statistical consultancies), BMS (statistical consultancies), Fresenius Kabi (training), Galapagos (statistical
consultancies), CSL Behring (statistical consultancies), Kyowa Kirin (statistical consultancies), and Pfizer (statistical
consultancies) outside the submitted work. Dr Baghai reported receiving personal fees from Janssen, Neuraxpharm,
and Servier outside the submitted work. Dr Heuser reported receiving minocycline and placebo capsules during the
conduct of the study from Mibe Pharmaceuticals; grants from Compass for the multicenter study Psilocybin in TRD,
personal fees from European Research Council received for referee activity for this agency, nonfinancial support from
Hirnliga as president of this society, and personal fees from Elsevier Psychoneuroendocrinology received as Editor in
Chief outside the submitted work. No other disclosures were reported.
Funding/Support: The trial was supported by a grant from the German Federal Ministry of Education and Research
(Bundesministerium für Bildung und Forschung [BMBF]) within the Consortium Optimizing Treatment of Depression
(OptiMD, speaker Rainer Rupprecht) as part of the Research Network for Psychiatric Disorders (Forschungsnetz
psychische Erkrankungen), grant No. 01EE1401F.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management,
analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit
the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Information: We thank Mibe Pharmaceuticals for generously providing the trial medication.

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SUPPLEMENT 1.
Trial Protocol
SUPPLEMENT 2.
eTable 1. Adverse Events eTable 2.
Exploratory Endpoints eTable 3. Exploratory
Subgroup Analysis eFigure 1. CGI eFigure 2.
Boxplot HAMD-17 eFigure 3. BDI eFigure 4.
SCL-90 eFigure 5. TMT-A/B
eFigure 6. Distribution of Remission by Assignment
eFigure 7. Distribution of Response by Assignment
eFigure 8. CRP eFigure 9. Leukocytes eFigure 10.
Gender eFigure 11. MADRS at Baseline eFigure 12. CRP
eFigure 13. BMI eFigure 14. CTQ
SUPPLEMENT 3.
Data Sharing Statement

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HELLMANN-REGEN J, CLEMENS V, GRÖZINGER M, KORNHUBER J, REIF A,

PRVULOVIC D, ET AL. EFFECT OF MINOCYCLINE ON DEPRESSIVE SYMPTOMS IN

ALUMNA: LUZ NAYANA HERRERA CERDA

DOCENTE: DR. JAVIER PEDRAZA CHAVEZ

GRADO Y GRUPO: 3°I

ASIGNATURA: FARMACOLOGIA BASICA

TEMA: TRATAMIENTO DE LA DEPRESION

FECHA: 15 OCTUBRE 2022

TITULO DEL ARTICULO: EFFECT OF MINOCYCLINE ON DEPRESSIVE SYMPTOMS

Effect of Minocycline on Depressive Symptoms in Patients

JAMA Network Open. 2022;5(9):e2230367. doi:10.1001/jamanetworkopen.2022.30367

Not meeting inclusion criteria

Per protocol analysis set Per protocol analysis set

Table 1. Baseline Characteristics of the Intention-to-Treat Population

Minocycline (n = 81) Placebo (n = 87)

Female 31 (38.3) 48 (55.2)

Male 50 (61.7) 39 (44.8)

Age, mean (SD) 44.8 (13.6) 47.3 (12.5)

White 77 (95.0) 82 (94.3)

Othera 4 (4.9) 5 (5.7)

Current smoker 21 (25.9) 25 (28.7)

BMI, mean (SD) 27.4 (5.3) 26.5 (4.8)

SSRI 47 (58.0) 37 (42.5)

SNRI 30 (37.0) 40 (46.0)

MAO inhibitor 4 (4.9) 5 (5.7)

Tricyclic/tetracyclic AD 6 (7.4) 10 (11.5)

Other 29 (35.8) 40 (46.0)

>2 6 (7.4) 10 (11.5)

First depressive episodeb 14 (18.0) 23 (26.7)

Duration of the current depressive episode, median (range), wk 41 (6-952) 52 (4-624)

No of previous episodes, median (range) 2.5 (0-30) 2 (1-25)

Current inpatient stay or dayclinic 13 (16.7) 13 (15.1)

Baseline MADRS, mean (SD) 26.4 (4.8) 26.6 (5.1)

Baseline HAMD-17, mean (SD) 20.0 (3.5) 20.3 (3.5)

Baseline BDI II, mean (SD) 32.3 (9.0) 32.9 (10.4)

Baseline SCL-90-R, mean (SD) 68.7 (6.8) 66.9 (6.9)

Baseline CGI, mean (SD) 4.8 (0.6) 4.9 (0.7)

Baseline TMT-A, mean (SD) 34.7 (16.6) 35.1 (14.3)

Baseline TMT-B, mean (SD) 77.5 (32.7) 76.1 (32.3)

Baseline hsCRP, median (range), mg/dL 0.121 (0.002-2.210) 0.060 (0.005-0.730)

Table 2. Response and Remission Rates

Table 3. Primary, Secondary, and Exploratory End Points

Published: September 14, 2022. doi:10.1001/jamanetworkopen.2022.30367

LUZ HERRERA NAYANA CERDA 3°I

September 14, 2022

Obtained funding: Hellmann-Regen, Kornhuber, Schüle, Rupprecht, Heuser.

Administrative, technical, or material support: Hellmann-Regen, Clemens, Kornhuber, Reif, Prvulovic,

LUZ HERRERA NAYANA CERDA 3°I

LUZ HERRERA NAYANA CERDA 3°I

LUZ HERRERA NAYANA CERDA 3°I

LUZ HERRERA NAYANA CERDA 3°I

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