A pilot study of minocycline for the treatment of bipolar depression: Effects on cortical glutathione and oxidative stress in vivo

Journal of Affective Disorders 230 (2018) 56–64

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Research paper

A pilot study of minocycline for the treatment of bipolar depression: Effects on cortical glutathione and oxidative stress in vivo

T

⁎

James W. Murrougha,b, , Kathryn M. Hurykc, Xiangling Maod, Brian Iacovielloa,e, ⁎⁎ Katherine Collinsa, Andrew A. Nierenbergf, Guoxin Kangd, Dikoma C. Shungud, , ⁎⁎⁎ Dan V. Iosifescua,g, a

Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA Department of Neuroscience, Icahn School of Medicine at Mount Sinai, USA c Fairleigh Dickinson University, USA d Department of Radiology, Weill Cornell Medicine, USA e Click Therapeutics, Inc, USA f Bipolar Clinic and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, USA g Nathan Kline Institute and New York University School of Medicine, USA b

A B S T R A C T Background: The antibiotic minocycline appears to promote neuroprotection through antioxidant and other mechanisms that may be relevant to the pathophysiology of bipolar disorder. The present study assessed the efficacy of minocycline in bipolar depression and examined the association between minocycline treatment and brain glutathione (GSH), an essential regulator of oxidative stress. Method: Twenty patients with bipolar disorder experiencing acute depressive symptoms enrolled in an 8-week, open-label trial of adjuvant minocycline. Depression was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and proton magnetic resonance spectroscopy (1H MRS) measures of cortical GSH within a voxel prescribed in the precuneus and aspects of the occipital cortex were obtained from a subset of patients (n=12) before and after treatment. Results: The daily dose of minocycline at study end was 256 mg (SD: 71 mg). Treatment was associated with improvements in depression severity [MADRS score change: –14.6 (95% CI: –7.8 to –21.3)]. Ten patients (50%) were classified as responders based on a ≥50% reduction in MADRS score and 8 patients (40%) were classified as remitters (MADRS score ≤ 9). Higher baseline GSH levels were associated with greater improvement in MADRS score following treatment (ρ=0.51, p=0.05). Increases in GSH levels at study end were higher in nonresponders than in responders (p=0.04). Limitations: Small sample size, lack of a placebo group. Conclusion: Minocycline may be an effective adjuvant treatment for bipolar depression, particularly in patients with high baseline GSH levels. Further research is needed to evaluate the potential of minocycline in this population.

1. Introduction Bipolar disorder is a lifelong, chronic and recurrent mood disorder associated with high disability (Mitchell et al., 2004) and mortality (Judd et al., 2002; Osby et al., 2001). Among different phases of the illness, depressive episodes have the largest public health impact due to the higher proportion of time spent depressed, the disability associated

with this phase of the illness (Judd et al., 2008, 2002), and the high association with suicide attempts (occurring in 25–56% of patients), and deaths by suicide (occurring in 10–19%) (Nierenberg et al., 2001). Only three medications are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of bipolar depression. However, the clinical benefits of these interventions are limited (De Fruyt et al., 2012; Vázquez et al., 2015). Many patients continue to

⁎ Corresponding author at: Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY 10029, USA. ⁎⁎ Correspondence to: Citigroup Biomedical Imaging Center, Weill Cornell Medicine, 516 E 72nd Street, New York, NY 10065, USA. ⁎⁎⁎ Correspondence to: NYU School of Medicine, One Park Avenue, 8th Floor, New York, NY 10016, USA. E-mail addresses: [email protected] (J.W. Murrough), [email protected] (D.C. Shungu), [email protected] (D.V. Iosifescu).

https://doi.org/10.1016/j.jad.2017.12.067 Received 30 June 2017; Received in revised form 25 November 2017; Accepted 31 December 2017 Available online 02 January 2018 0165-0327/ © 2018 Elsevier B.V. All rights reserved.

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2. Methods

experience symptoms of bipolar depression despite optimized therapy (Frye et al., 2014), so that the identification of safe and effective medications with novel mechanisms of action represents a critical but unmet medical need. Bipolar disorder has been associated with elevated levels of circulating inflammatory factors (Rosenblat and McIntyre, 2016; Sayana et al., 2017) and the pathophysiology of bipolar disorder is postulated to involve aberrant activation of pro-inflammatory pathways leading to oxidative stress, impairments in neuroplasticity, and ultimately to neurotoxicity (Goldstein et al., 2009; Rosenblat and McIntyre, 2016). Within this context, there has been considerable interest in identifying novel therapeutic strategies for bipolar disorder that may reverse the effects of cellular stress and enhance neuroprotection. Minocycline, a highly lipophilic semi-synthetic tetracycline analog with excellent blood-brain barrier permeability, is clinically well tolerated and completely absorbed when taken orally as an antibiotic (Aronson, 1980; Barza et al., 1975). Beyond its antibiotic activity, minocycline has been found to have multiple cellular effects that converge on neuroprotective pathways relevant to the putative pathophysiology of bipolar disorder. These include the ability to modulate glutamatergic neurotransmission, and to provide neuroprotection through anti-inflammatory and antioxidant effects (Bhattacharya and Drevets, 2017; Kraus et al., 2005; Plane et al., 2010). Minocycline has been shown to modulate microglia and immune cell activation and to blunt the subsequent release of cytokines, chemokines, lipid mediators of inflammation, matrix metalloproteases (MMPs) and nitric oxide (NO) (Plane et al., 2010). Downstream effects of the activation of these pathways includes the generation of free radicals, which is balanced under physiological conditions by cellular defense mechanisms that include glutathione (GSH) – the most abundant and one of the most important antioxidants in living tissue (Cobb and Cole, 2015). Minocycline, therefore, may confer neuroprotection through the upregulation of cellular mechanisms that protect against the deleterious effects of oxidative stress (Cobb and Cole, 2015; de Melo et al., 2017). Preclinical studies have suggested that minocycline alone or in combination with a conventional monoaminergic antidepressant drug may possess antidepressant properties (Arakawa et al., 2012; MolinaHernández et al., 2008a, 2008b). Minocycline reversal of depressivelike behaviors induced by pro-inflammatory cytokines (Zheng et al., 2015) or organophosphate pesticides (Saeedi Saravi et al., 2016) has been documented. To date, three human studies have tested the efficacy of minocycline in patients with mood disorders, with promising initial results (Dean et al., 2017; Miyaoka et al., 2012; Soczynska et al., 2017). One of these studies, conducted in patients with bipolar depression, showed a reduction in depressive symptoms over an eight-week period. Significantly, recent population-scale data derived from FDA adverse event reporting systems found that minocycline was associated with protection against depression (Cohen et al., 2017). The aims of the present study were to evaluate the therapeutic effects of minocycline augmentation of mood stabilizers in patients with bipolar depression, and to assess whether oxidative stress and redox imbalance are treatment targets of minocycline. We utilized proton magnetic resonance spectroscopy (1H MRS) to measure levels of brain GSH within a voxel prescribed in the precuneus and aspects of the occipital cortex before and after an eight-week treatment course with minocycline. The precuneus is a component of the default mode network (DMN) in which prior work has demonstrated functional abnormalities (Sheline et al., 2010) as well as alterations in GSH measurements in adults with unipolar depression (Godlewska et al., 2015; Shungu et al., 2012). We hypothesized that low GSH levels at baseline will be associated with greater symptom severity, and that increased GSH following treatment with minocycline will be associated with clinical improvement in bipolar depression.

2.1. Participants and screening Study procedures were conducted between June 2011 and June 2013. Subjects were identified through advertisement in the community and through referrals from physicians or clinics in New York City. Eligible subjects were men and women aged 18–68 years with a primary diagnosis of bipolar I or bipolar II disorder, currently in a major depressive episode (MDE), according to the Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (DSM-IV), and confirmed by a diagnostic interview with a study psychiatrist. Participants were required to have a score of ≥18 on the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) at screening and at baseline. Eligible participants were on a stable dose of a mood stabilizing medication as defined by the Texas Implementation of Medication Algorithm (TIMA) revised guidelines (Suppes et al., 2005) for at least two weeks prior to participating and agreed to remain on a steady dose of their medication during the study. Exclusion criteria consisted of non-response to two or more medication trials in the current episode, serious suicidal ideation, any unstable medical condition, clinical or laboratory evidence of hypothyroidism, or drug or alcohol dependence or abuse within the past 30 days. Physical examination with vital signs, blood tests, and urine toxicology confirmed the absence of unstable medical illnesses, pregnancy, and drug use. Participants with a DSM-IV diagnosis of bipolar not otherwise specified, cyclothymia, schizoaffective disorder, or a personality disorder that was considered the primary presenting problem were excluded. Women of childbearing potential were required to have a negative pregnancy test before enrollment and agreed to use adequate contraception during their participation in the study. Participants with MRI-incompatible metallic implants or claustrophobia were excluded from the neuroimaging component of the study. The Icahn School of Medicine at Mount Sinai and Weill Cornell Medicine Institutional Review Boards approved the study, and written informed consent was obtained from all subjects before participation. Participants were compensated for their time and effort. The study was registered at http://clinicaltrials.gov (ID: NCT01514422). 2.2. Study design, treatment and assessments Eligible participants completed baseline assessments of symptom severity, functional capacity, quality of life, neurocognitive functioning, and cortical GSH levels as measured in vivo with 1H MRS, prior to initiating an open-label trial of minocycline as adjunctive treatment for bipolar depression. Symptom questionnaires included the MADRS and the Young Mania Rating Scale (YMRS) (Young et al., 1978), and a study psychiatrist provided a global assessment of bipolar symptom severity using the Clinical Global Impression Scale-Severity (CGI-S)-Bipolar Version (CGI-BP) (Spearing et al., 1997). Functional capacity and quality of life was assessed using the Longitudinal Interval Follow-up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT) (Leon et al., 1999) and the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) (Endicott et al., 1993), respectively. Neurocognition was assessed using the Repeatable Battery of the Assessment of Neuropsychological Status (RBANS) (Randolph et al., 1998) as well as selected subtests of the Delis-Kaplan Executive Functioning System (D-KEFS) (Delis et al., 2004). The RBANS includes subscales for immediate and delayed memory, attention, language, and visuospatial functioning. Raw scores were converted to index scores with a mean of 100 and a standard deviation of 16 based on age and gender corrected norms, yielding an RBANS total index score and index scores for each subscale. Minocycline was titrated as follows: 100 mg per day for two weeks, then 200 mg per day for two weeks, then 300 mg per day for the remaining duration of the eight-week trial. The dose was adjusted based 57

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frequency of the GSH α-cysteinyl resonance at 4.56 ppm, while avoiding excitation of oxidized GSH α-cysteinyl at 3.28 ppm (Nepravishta et al., 2012). This resulted in two subspectra in which the reduced form of glutathione (i.e., GSH), but not the oxidized or disulfide form (GSSG), was alternately inverted or not inverted. Subtracting these two subspectra yielded a 1H MR spectrum consisting of only the edited GSH β-cysteinyl resonance at 2.98 ppm. Spectral data for this study were acquired in 13.3 min using 256 interleaved excitations (512 total) with the editing pulses on or off. Using our previously described spectral quality assessment criteria (Shungu et al., 2012) and frequency-domain spectral fitting (Fig. 1), the area under the GSH resonance, which is proportional to the concentration of GSH in the voxel-of-interest, was obtained and then expressed semi-quantitatively as ratios relative to the unsuppressed intravoxel water (W) signal for normalization across subjects, before being used in group analyses. To estimate the proportions of gray matter, white matter and cerebrospinal fluid (CSF) contained in our voxel of interest, MEDx software (Medical Numerics, Germantown, MD) was used to segment the brain tissue based on the signal-intensity histogram of each subject's volumetric (SPGR) MRI. In-house software developed in MATLAB (MathWorks, Natick, MA) was then implemented to generate a segmentation mask for the voxel, from which the proportions of gray matter, white matter and cerebrospinal fluid were derived. These were then compared between the groups and, in case of significant differences, included in the statistical model as covariates.

upon the study clinician's assessment of safety, tolerability, and efficacy so that patients were eventually receiving 100–300 mg/day minocycline. This dose range was selected because minocycline in doses of 100–300 mg/day is approved and determined to be safe for the treatment of infection and inflammatory disorders. Every effort was made to encourage patients to comply with this dosage regimen, and pill counts were conducted at each visit. Study subjects returned to the clinic every two weeks during the eight-week trial to complete safety and efficacy assessments. 2.3. Magnetic resonance neuroimaging data acquisition and analysis All subjects underwent a standardized structural MRI scan of the brain and single-voxel 1H MRS on a research-dedicated 3T GE MR system with an 8-channel phased-array head coil. The MRI protocol consisted of a spoiled gradient-recalled (SPGR) echo volumetric scan for tissue segmentation and an axial fast fluid-attenuated inversion recovery (FLAIR) scan to exclude focal pathology. In vivo 1H MRS data were obtained from a 3.0 × 3.0 × 2.0 cm3 voxel prescribed in the medial parietal lobe to include the posterior cingulate gyrus and precuneus – a region in which we previously found abnormally low GSH levels in unipolar depression (Shungu et al., 2012). The standard J-edited spin echo difference method or simply “Jediting”, was used with TE/TR 68/1500 to measure the levels of GSH, as previously described (Shungu et al., 2012; Weiduschat et al., 2014) and illustrated in Fig. 1. Although it has been suggested that a TE of 120 ms is optimal for GSH detection by J-editing (An et al., 2009), we opted to use a TE of 68 ms because it yields a difference spectrum in which the co-edited aspartyl (CH2) resonances of NAA around 2.5 ppm are inverted and clearly separated from the non-inverted GSH resonance (Fig. 1), facilitating spectral fitting. Briefly, a pair of frequencyselective inversion pulses was inserted into the standard point-resolved spectroscopy (PRESS) method and applied on alternate scans at the

2.4. Efficacy and safety outcomes Participants completed safety and efficacy assessments at baseline, week 2, week 4, week 6, and week 8 (trial end). The primary efficacy outcome was change in MADRS score at trial end compared to baseline. Secondary efficacy outcomes included the CGI-BP, LIFE-RIFT, Q-LES-Q, RBANS, and D-KEFS as described above. General tolerability and Fig. 1. [A] Axial and [B] sagittal MR images of a human brain, with depiction of the size, location of the voxel of interest prescribed in the medial parietal lobe to include the posterior cingulate gyrus and precuneus. [C] Demonstration of cortical glutathione (GSH) detection with J-edited 1H MRS: (a) and (b), single-voxel subspectra acquired in 13.3 min with the editing pulse on and off and 256 (512 total) interleaved averages, and processed with exponential filter corresponding to a linewidth broadening of 3 Hz to decrease background noise; spectrum (c), difference between spectra (a) and (b) showing the edited brain GSH resonance at 2.98 ppm; spectrum (d), model fitting of spectrum c to obtain the GSH peak area; spectrum (e), residual of the difference between spectra (c) and (d). NAA, N-acetylaspartate; tCho, total choline; tCr, total creatine).

58

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adverse events were measured using the patient-reported Systematic Assessment for Treatment Emergent Events (SAFTEE) (Levine and Schooler, 1986) and the clinician-reported Frequency and Intensity of Side Effects Ratings (FISER) (Wisniewski et al., 2006). Treatmentemergent suicidal ideation (SI) and suicidal behavior (SB) was measured using the Concise Health Risk Tracking Scale (CHRT) (Trivedi et al., 2011) and treatment-emergent mania was assessed using the YMRS.

Table 1 Characteristics of Study Sample. Characteristic

Value

Participants, n (%) Female, n (%) Age at enrollment (Years)

20 (100) 8 (40%) 43.6

Race, n (%) Caucasian Asian African-American Married (%) Employed (%) Bipolar subtype (%) Bipolar I Bipolar II Past substance use disorder (%) Current anxiety disorder (%) Age of onset (years) Baseline MADRS Baseline YMRS

2.5. Statistical analyses Subjects who initiated treatment with minocycline and had at least one post-baseline assessment constituted the analyzed study sample [modified intent to treat sample (mITT)]. Missing data was handled using the last observation carried forward (LOCF) method. This single imputation method was selected as a conservative approach based on the assumptions that subjects, on average, would tend to improve over time in the trial, and that data may not be missing at random since subjects exhibiting a poor response may be more likely to dropout prior to the end of the study. Baseline demographic and clinical characteristics were described using summary statistics. Safety and tolerability was characterized by examining protocol adherence, dropout rate, adverse events, treatment-emergent suicidal ideation or behavior (SI/SB), and change in YMRS score. Efficacy was assessed by examination of change in depression severity using a one-way repeated measures analysis of variance (ANOVA) with MADRS score as a within-subject factor following assessment of sphericity using the Mauchly's test. Change in CGI-BP over time, response rate (defined as change in MADRS score of ≥ 50% for each individual compared to baseline), and remission rate (defined as a final MADRS score ≤ 9) are additionally reported. Paired t-tests compared pre- and post-treatment values for functioning, quality of life, neurocognitive assessments and 1H MRS measures. Follow up non-parametric tests were conducted to assess the sensitivity of the results given the small sample sizes. Correlations between continuous symptom measures and 1H MRS measures were evaluated with Spearman-rank correlation coefficients. 1H MRS measures were also examined as a function of responder status determined post-hoc. All statistical procedures were performed using IBM SPSS Statistics version 23.

± 12.7 Range: 22–67

11 1 8 5 6

(55) (5) (40) (25) (30)

18 2 12 7 16.4 29.0 1.8

(90) (10) (60) (35) ± 7.1 ± 5.7 ± 2.4

Participants represent modified intent to treat sample (mITT). Values represent mean ± SD or count. Abbreviations: MADRS, Montgomery-Asberg Depression Rating Scale; YMRS, Young Mania Rating Scale.

MADRS Score

30

**

** **

20

**

10

ks 8

w

ks 6

w

ks w 4

2

w

ks

0

0

Responders (n=10) Non-Responders (n=10)

3. Results

30

MADRS Score

3.1. Demographic and clinical characteristics Thirty-three subjects provided informed consent and underwent screening. Of these, 23 met all eligibility criteria and completed the baseline assessments; 20 took at least one dose of the study medication and returned for a least one follow-up study visit and constitute the modified intention to treat (mITT) sample. Demographic and clinical characteristics of the sample are summarized in Table 1. Participants were on average 43.6 years of age, and 40% were female; 90% of the sample had a primary diagnosis of bipolar I while the remainder of the sample had a primary diagnosis of bipolar II. All subjects had moderate to severe depressive symptoms at enrollment. Supplemental material Table S1 online provides a listing of concomitant mood stabilizer medication in the study sample.

20

10

ks 8

w

ks 6

w

ks w 4

2

w

ks

0

0

Fig. 2. Change in depression severity following treatment with minocycline in patients with bipolar depression. Top: Observed mean reduction in symptom severity in the mITT sample (n=20). “**” indicates a p-value of ≤ 0.01 associated with a paired ttest comparing MADRS score at a given time point to baseline. Bottom: Change in depression symptom severity over time for treatment responders (n=10) and non-responders (n=10) are displayed for illustrative purposes only. Treatment response was defined as ≥ 50% improvement in symptoms at week 8 compared to baseline. Error bars represent 95% confidence intervals. MADRS, Montgomery-Asberg Depression Rating Scale.

3.2. Efficacy, functioning and quality of life Of the 20 patients in the mITT sample, 19 completed the trial and one patient discontinued after week 2. The mean minocycline dose at study end was 256 mg daily (Range: 100 – 300 mg, SD: 71 mg). There was approximately equal variability between pairs of MADRS score during the study (Mauchly's W = 0.417, p = 0.09). Study subjects experienced a significant reduction in MADRS score over the course of the trial (F4,76 = 22.3, p < 0.001, partial η2= 0.54) (Fig. 2). 59

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ideation (SI) without intent four days after starting minocycline resulting in hospitalization. The event represented a serious adverse event (SAE), and was considered by the investigators to be unrelated to study participation. The patient was reenrolled six weeks later and completed the study with decreased suicidal ideation and improved depression.

Table 2 Patient-Rated Side Effects Associated with Minocycline in Bipolar Depression. Item

n (%)

Frequent Need to Urinate Trouble Sleeping Feeling Drowsy or Sleepy Dry Mouth Muscle Cramps or Stiffness Diarrhea Appetite Increased Difficulties Finding Words Feeling Nervous or Hyper Irritable Feeling Strange or Unreal Stomach or Abdominal Discomfort Difficulty Starting Urination Weight Gain Nightmares or Other Sleep Disturbance Weakness or Fatigue Dizziness or Faintness Drooling or Increase Salivation Nausea or Vomiting Constipation Problems with Sexual Arousal Delayed or Absent Orgasm Appetite Decreased Skin Rash or Allergy Diminished Mental Acuity Apathy/Emotional Indifference Bruising Hot Flashes Strange Taste in Mouth Unable to Sit Still Do These Symptoms Impair Normal Functioning?

5 4 4 4 4 4 4 4 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

(25) (20) (20) (20) (20) (20) (20) (20) (15) (15) (15) (15) (15) (15) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10) (10)

3.4. Neurocognition Seventeen subjects had complete neurocognitive data available for analysis at baseline and study end. There were no significant changes in any neurocognitive domain from baseline to study end tested using the RBANS or the D-KEFS (all p values > 0.20). There was no association between change in neurocognitive performance and change in depression severity (ρ = −0.15, p = 0.58). 3.5. 1H MRS measures Out of the 20 subjects in the mITT sample, two subjects declined to undergo MRS imaging, and MRS data from one subjects did not meet our quality criteria (Shungu et al., 2016), yielding a sample of 17 subjects with baseline MRS data. Of these 17 subjects, two dropped out and did not complete a post-treatment scan, and MRS data for three subjects did not meet our quality criteria, yielding a sub-sample of 12 subjects with usable MRS data at baseline and post-treatment. Analyses of voxel tissue composition found no effect of time on gray matter or white fraction. There was a small trend-level change in the fraction of CSF at post-treatment compared to baseline (p = 0.053). Conducting ANCOVA with CSF fraction as a covariate did not alter the outcome of the analyses. Lastly, mean unsuppressed voxel tissue water signal levels (W) did not differ between baseline and post-treatment, so that GSH/W and GSH will be used interchangeably. Data comparing voxel tissue composition, including W, and spectral quality parameters at baseline and post-treatment are provided in Supplemental Material Table S2. The relationships between GSH, time, and clinical response to minocycline are shown in Fig. 3. GSH levels did not differ between responders and non-responders either at baseline or post-treatment. There was a trend-level increase in GSH following treatment among non-responders (p = .06, Cohen's d = 0.95), but not among responders (p=0.36, Cohen's d = 0.40) (Fig. 3A). A follow up non-parametric Signed-Rank test of the hypothesis that the median of differences in GSH at baseline and post-treatment equals zero yielded similar results (for responders, p = 0.46; for non-responders, p = 0.028). The change in GSH levels from baseline to post-treatment in non-responders (i.e., ΔGSH) was higher than mean ΔGSH in responders [t(10)=2.4, p = 0.04, Cohen's d = 1.40] (Fig. 3B). Similarly, a non-parametric MannWhitney U test yielded a p-value of 0.041. Lastly, percent change in MADRS score from baseline to study end was positively associated with baseline GSH levels (ρ = 0.51, p = 0.05) (Fig. 3C). Exploratory examination of associations between baseline depressive symptomatology and GSH revealed an inverse correlation between GSH and SI (MADRS item 10; ρ = −0.65, p = 0.008), and between GSH and anhedonia (MADRS item 8; ρ = −0.64, p = 0.01). The association between GSH and anhedonia remained significant even after controlling for total depression score (ρ = 0.61, p = 0.02) (Fig. 4). GSH did not correlate with total depression score or any other clinical symptom. None of the other major brain metabolites (i.e., N-acetylaspartate [NAA], total creatine [tCr], total choline [tCho]) present in subspectra acquired with the editing pulse turned off changed from baseline to post-treatment or showed an association with clinical response.

Table depicts number of participants in modified intention-to-treat group (n=20) endorsing moderate or severe self-reported side effects that represent a worsening from pre-study baseline according to the Systematic Assessment For Treatment Emergent Events - Self-Report Inventory (SAFTEE). Items included in table have a reported frequency of > 5% (e.g. > 1 participant).

The mean difference in MADRS from baseline to study end (week 8) was −14.6 (Bonferroni adjusted p < 0.001; 95% CI: −7.8 to −21.3). Ten patients (50%) achieved response and 8 patients (40%) achieved remission. Thirteen patients (65%) were rated as much improved or very much improved (i.e., achieved a “1” or a “2” on the CGI-I) at study end, while 10 (50%) were rated as not at all ill, or borderline ill (i.e., achieved a “1” or a “2” on the CGI-S). Eighteen subjects had functional capacity and quality of life ratings available for analysis at baseline and week 8. Patients showed reduced functional impairment (measured by the LIFE-RIFT) from baseline to study end [mean difference: 3.78 (SD: 2.7), t17 = 5.8, p < 0.001]. Patients additionally showed increased quality of life measured by the Q-LES-Q [mean difference: −8.8 (SD: 13.2), t17 = −2.85, p = 0.01]. 3.3. Safety and tolerability The most common patient-reported treatment emergent adverse effects were frequent need to urinate, trouble sleeping, feeling drowsy or sleepy, dry mouth, muscle cramps or stiffness, diarrhea, increased appetite, and difficulties finding words (Table 2). The most common clinician-rated treatment emergent adverse effects were gastrointestinal symptoms and somnolence. Two participants experienced moderate functional impairment due to side effects, one for dizziness and one for nausea. There was no evidence of treatment emergent mania. Weekly YMRS scores did not vary significantly as a function of time during the trial [F2.1,39.2 = 1.78, p = 0.18 (Huynh-Feldt correction for non-sphericity applied)]; Mean difference YMRS score from baseline to week 8 was −0.65 (95% CI: 0.57 to −1.9). One patient experienced worsening of depression and suicidal

4. Discussion The present study examined the open label efficacy and tolerability of minocycline up to 300 mg daily over eight weeks in patients with 60

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A.

0.0020 p = 0.36

p = 0.06

Baseline Post-Treatment

GSH/W

0.0020

GSH/W (a.u.)

0.0025

0.0015 0.0010 0.0005 0.0000

0.0015 0.0010 0.0005 0.0000

er

er

0

nd

nd

po

po

2

4

6

Anhedonia

N

on

-R

R

es

es

= -0.64 p = 0.011

0.0020

B. 0.0015

GSH/W (a.u.)

t(10) = 2.4, *p = 0.036

GSH/W

0.0010 0.0005 0.0000

= -0.65 p = 0.008

0.0015 0.0010 0.0005

-0.0005

0.0000 0

nd

nd

er

er

s

s

-0.0010

po es

po

-R

es

N

on

R

4

6

Fig. 4. Association between glutathione (GSH) and anhedonia and suicidal ideation in patients with bipolar depression. Figure displays inverse correlation between GSH and anhedonia (Top), and between GSH and suicidal ideation (bottom) at baseline in patients with bipolar depression. Anhedonia reflects score on the anhedonia item of the MADRS (item 8; score range: 0–6); suicidal ideation likewise reflects the corresponding item of the MADRS (item 10; score range: 0–6). Analysis includes n=17 subjects with GSH measurement available at baseline prior to treatment with minocycline.

C. MADRS Score % Change

2

Suicidal Ideation

100

= 0.514 p = 0.05 50

than responders. Glutathione is essential for multiple cellular functions. It plays a key role in redox reactions and homeostasis, with one of its primary biological functions being that of a free radical scavenger that protects against oxidative stress (Rae and Williams, 2017). Using 1H MRS, we previously measured cortical GSH levels in patients with major depressive disorder (MDD) and found a 21% deficit compared to healthy subjects (Shungu et al., 2012). Insofar as oxidative stress is defined as an excess of free radicals relative to total tissue antioxidant reserves, our finding of a cortical GSH deficit in depression suggests a role for oxidative stress and redox imbalance in the disorder. Therefore, for the present study, it was of interest to explore whether oxidative stress is a treatment target for minocycline, especially in light of evidence suggesting that redox imbalance may play a role in bipolar depression. Due to the absence of a healthy comparison group in the current study, it is unclear whether there was a cortical GSH deficit in the present cohort of patients with bipolar disorder at baseline. Nevertheless, the present results are potentially informative, if preliminary. While we found that minocycline had no effect on GSH levels in responders, there was trend toward an elevation of GSH in non-responders following treatment (Fig. 3A) – a finding that seems both paradoxical and counter-intuitive, as one would have expected the opposite, i.e., elevated GSH in responders and no effect on GSH in nonresponders. However, this apparent paradox may have a plausible explanation within the context of the known mechanism of in vivo GSH synthesis. As seen in Fig. 3B, the mean change in GSH at week 8 relative to baseline (i.e., ΔGSH) within the non-responders is significantly higher than mean ΔGSH within the responders, which suggests that in response to minocycline there might have been a significantly higher

0 0.0005

0.0010

0.0015

0.0020

GSH/W -50

Fig. 3. Associations between brain glutathione (GSH) and treatment with minocycline in patients with bipolar depression. A. Top Panel. Effects of time and response status on GSH. Data shows pairs of assessments on 12 subjects with available GSH measurements with subjects groups according to clinical response status (n=6 responders; n=6 non-responders). Treatment response was defined as ≥ 50% improvement in MADRS score from baseline to end of treatment (Week 8); non-response was defined at less than 50% improvement. B. Change in mean GSH (ΔGSH) level following treatment in responders (n=6) and non-responders (n=6). C. Association between baseline GSH level and subsequent improvement in depression severity as measured by percent change in MADRS score from baseline to end of treatment (analysis includes n=15 subjects with baseline GSH and a post-treatment MADRS score available).

bipolar depression and the impact of treatment and clinical response on brain GSH. Among the twenty treated patients, 19 completed the trial and, overall, minocycline demonstrated good tolerability in this cohort. We observed a large decrease in depression severity with a mean decrease in MADRS score of −14.6 (95% CI: −7.8 to −21.3) and a response and remission rate of 50% and 40%, respectively. We likewise observed beneficial effects of minocycline on daily functioning and quality of life. We did not find a specific effect of minocycline on neurocognitive performance. Elevated GSH levels at baseline were associated with larger improvements in depression severity, and, rather unexpectedly, there was a greater relative increase in GSH levels (i.e., ΔGSH) following treatment with minocycline among non-responders 61

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the biological mechanisms of therapeutic action. Another limitation of this study is that the flexible dosing of minocycline up to 300 mg daily does not allow an analysis of the potential effect of dose. It is conceivable that either higher or lower doses of minocycline may be optimal in this population. This study did not include any peripheral measures of oxidative stress or inflammation. It could be informative in future studies to examine the association between central and peripheral levels of markers of oxidative stress and inflammation. The present bipolar patient cohort was on stable doses of several mood stabilizers, which, along with the small sample size, precluded meaningful testing of whether any specific bipolar treatments would be particularly efficacious when combined with minocycline. In summary, we have examined the open-label therapeutic effect and tolerability of minocycline as adjunctive treatment to mood stabilizers in patients with bipolar depression and have investigated the effect of glutathione on treatment outcomes. Consistent with prior reports, our study provides preliminary evidence supporting the antidepressant effect of minocycline in bipolar depression. Larger follow up studies of minocycline and the role of oxidative stress and other putative components of the pathophysiology of bipolar disorder in patient selection and mechanism of action are warranted.

relative increase in GSH within the non-responders than responders. We also found a positive correlation between the percent change in MADRS scores following treatment and baseline GSH levels (Fig. 3C), indicating that higher GSH levels at baseline may be associated with greater improvement in MADRS score following minocycline treatment. It is well established that in vivo synthesis of GSH is controlled by nonallosteric feedback inhibition (Richman and Meister, 1975), whereby GSH regulates its own synthesis by activating or inhibiting γ-glutamylcysteine ligase (GCL), the rate-limiting enzyme in the synthesis pathway, to start or stop synthesis when tissue of levels GSH are low or adequate, respectively. Together, the preceding considerations may account for why minocycline had no effects on GSH in responders, but spurred an increase in GSH only among non-responders: in situ GSH synthesis might have been feedback inhibited in responders but not in non-responders. This speculation indicates that minocycline does not ameliorate depressive symptoms in bipolar disorder through direct stimulation of GSH levels. Although preliminary, it also suggests that individuals with relatively high baseline GSH levels may be more responsive to minocycline via an as-yet undetermined mechanism. Finally, the results of the present study suggest that patients with bipolar disorder who do not respond to minocycline may become responsive if their baseline cortical GSH levels can first be raised with a GSH synthesis precursor such as Nacetylcysteine (NAC) (Berk et al., 2011, 2008). The results of the present study suggest a number of studies that could potentially elucidate the mechanism of action of minocycline for bipolar disorder. These include studies that (a) use normal and placebo control groups to establish, respectively, in vivo levels of GSH that would be sufficiently high so as to potentiate adjuvant minocycline as an effective treatment for bipolar disorder, and the specificity and efficacy of the therapeutic response; and (b) examine other mechanisms (e.g., glutamatergic system, mitochondrial dysfunction, neuroinflammation) that may underlie the mechanism of action of minocycline. The present study adds to a growing literature examining the therapeutic potential of minocycline in mood disorders (Dean et al., 2017; Miyaoka et al., 2012; Soczynska et al., 2017). An early open label trial assessed the effects of minocycline up to 150 mg/day added to a serotonin selective reuptake inhibitor (SSRI) for up to six weeks in patients with unipolar psychotic depression and found that the intervention was well tolerated and associated with a significant improvement in depression severity as measured by the Hamilton Depression Rating Scale (HAM-D) (Miyaoka et al., 2012). More recently, a randomized controlled trial compared minocycline up to 200 mg/day to placebo as adjunctive treatment in patients with major depressive disorder (MDD) (Dean et al., 2017). Although minocycline did not separate from placebo on the MADRS score primary outcome at 12 weeks, the investigators did observe a benefit of minocycline over placebo on multiple secondary outcomes, including clinical global impression and quality of life. Finally, Soczynska et al. recently assessed the effects of adjunctive minocycline up to 200 mg/day over eight weeks in patients with bipolar depression and found treatment to be associated with a significant reduction in depression scores as measured by both the MADRS and by the HAM-D (Soczynska et al., 2017). The latter study also examined changes in cognitive performance and in circulating inflammatory cytokine levels during treatment and found improvement in psychomotor speed (but not in verbal memory or executive function) that was specific to clinical responders. The effects of minocycline have also been explored in patients with schizophrenia, and initial findings suggest that the treatment may be beneficial for the negative symptoms of schizophrenia, in particular (Ghanizadeh et al., 2014; KhodaieArdakani et al., 2014). This study has several limitations. Primary among these is that the lack of a control condition limits the conclusions that can be dawn about the efficacy of minocycline. The small sample size, likewise, limits the precise interpretation of the effect of minocycline on symptoms or GSH levels. An adequately powered randomized controlled trial will be required to establish both the efficacy profile of minocycline and

Acknowledgements The authors would like to express their sincere thanks to the patients who participated in this clinical trial. Funding This work was supported by the Icahn School of Medicine at Mount Sinai. Disclosures In the past 3 years, Dr. Murrough has provided consultation services to Novartis, Allergan, Janssen Research and Development, and Genentech; he is named on patents pending for neuropeptide Y as a treatment for mood and anxiety disorders, a patent pending for the combination of ketamine and lithium for suicidal ideation, and a patent pending for ketamine plus lithium to extend the antidepressant response of ketamine. In the past 5 years, Dr. Iosifescu was a consultant for Avanir, Axsome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, and Sunovion; he has received research support (through the Icahn School of Medicine at Mount Sinai) from Alkermes, Astra Zeneca, Brainsway, Euthymics, Neosync, Roche, and Shire, and he has received speaker honoraria from the Massachusetts General Hospital Psychiatry Academy, Medscape, and Global Medical Education. Dr. Iacoviello is a full time employee of Click Therapeutics, Inc. He is named on a patent pending for a cognitive-emotional training exercise for depression. Dr. Nierenberg reports grants and personal fees from Takeda/Lundbeck, grants and personal fees from Pamlabs, grants from GlaxoSmithKlein, personal fees from Alkermes, grants from NeuroRx Pharma, personal fees from PAREXEL, personal fees from Sunovian, personal fees from Naurex, personal fees from Hoffman La Roche/Genentech, personal fees from Eli Lilly & Company, personal fees from Pfizer, personal fees from SLACK Publishing, personal fees from Physician's Postgraduate Press, Inc., grants from Marriott Foundation, grants from National Institute of Health, grants from Brain & Behavior Research Foundation, grants from Janssen, grants from Intracellular Therapies, grants from Patient Centered Outcomes Research Institute, outside the submitted work. All other authors declare no conflicts. Role of funding This work was supported by the Icahn School of Medicine at Mount 62

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Sinai. No entities external to Mount Sinai provided funding for the study.

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