A Pilot Study of Minocycline for the Treatment of Bipolar Depression: Eﬀects T on Cortical Glutathione and Oxidative Stress in Vivo ⁎ James W

Journal of Affective Disorders 230 (2018) 56–64

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Journal of Aﬀective Disorders

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

ABSTRACT

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 non- responders 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 with this phase of the illness (Judd et al., 2008, 2002), and the high association with suicide attempts (occurring in 25–56% of patients), Bipolar disorder is a lifelong, chronic and recurrent mood disorder and deaths by suicide (occurring in 10–19%) (Nierenberg et al., 2001). associated with high disability (Mitchell et al., 2004) and mortality Only three medications are currently approved by the U.S. Food and (Judd et al., 2002; Osby et al., 2001). Among diﬀerent phases of the Drug Administration (FDA) for the treatment of bipolar depression. illness, depressive episodes have the largest public health impact due to However, the clinical beneﬁts of these interventions are limited (De the higher proportion of time spent depressed, the disability associated 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. J.W. Murrough et al. Journal of Affective Disorders 230 (2018) 56–64 experience symptoms of bipolar depression despite optimized therapy 2. Methods (Frye et al., 2014), so that the identification of safe and effective medications with novel mechanisms of action represents a critical but 2.1. Participants and screening unmet medical need. Bipolar disorder has been associated with elevated levels of circu- Study procedures were conducted between June 2011 and June lating inflammatory factors (Rosenblat and McIntyre, 2016; Sayana 2013. Subjects were identified through advertisement in the commu- et al., 2017) and the pathophysiology of bipolar disorder is postulated nity and through referrals from physicians or clinics in New York City. to involve aberrant activation of pro-inflammatory pathways leading to Eligible subjects were men and women aged 18–68 years with a pri- oxidative stress, impairments in neuroplasticity, and ultimately to mary diagnosis of bipolar I or bipolar II disorder, currently in a major neurotoxicity (Goldstein et al., 2009; Rosenblat and McIntyre, 2016). depressive episode (MDE), according to the Diagnostic and Statistical Within this context, there has been considerable interest in identifying Manual of Mental Disorders – Fourth Edition (DSM-IV), and confirmed novel therapeutic strategies for bipolar disorder that may reverse the by a diagnostic interview with a study psychiatrist. Participants were effects of cellular stress and enhance neuroprotection. required to have a score of ≥18 on the Montgomery-Asberg Depression Minocycline, a highly lipophilic semi-synthetic tetracycline analog Rating Scale (MADRS) (Montgomery and Asberg, 1979) at screening with excellent blood-brain barrier permeability, is clinically well tol- and at baseline. Eligible participants were on a stable dose of a mood erated and completely absorbed when taken orally as an antibiotic stabilizing medication as defined by the Texas Implementation of (Aronson, 1980; Barza et al., 1975). Beyond its antibiotic activity, Medication Algorithm (TIMA) revised guidelines (Suppes et al., 2005) minocycline has been found to have multiple cellular effects that con- for at least two weeks prior to participating and agreed to remain on a verge on neuroprotective pathways relevant to the putative pathophy- steady dose of their medication during the study. Exclusion criteria siology of bipolar disorder. These include the ability to modulate glu- consisted of non-response to two or more medication trials in the cur- tamatergic neurotransmission, and to provide neuroprotection through rent episode, serious suicidal ideation, any unstable medical condition, anti-inflammatory and antioxidant effects (Bhattacharya and Drevets, clinical or laboratory evidence of hypothyroidism, or drug or alcohol 2017; Kraus et al., 2005; Plane et al., 2010). Minocycline has been dependence or abuse within the past 30 days. Physical examination shown to modulate microglia and immune cell activation and to blunt with vital signs, blood tests, and urine toxicology confirmed the absence the subsequent release of cytokines, chemokines, lipid mediators of of unstable medical illnesses, pregnancy, and drug use. Participants inflammation, matrix metalloproteases (MMPs) and nitric oxide (NO) with a DSM-IV diagnosis of bipolar not otherwise specified, cy- (Plane et al., 2010). Downstream effects of the activation of these clothymia, schizoaffective disorder, or a personality disorder that was pathways includes the generation of free radicals, which is balanced considered the primary presenting problem were excluded. Women of under physiological conditions by cellular defense mechanisms that childbearing potential were required to have a negative pregnancy test include glutathione (GSH) – the most abundant and one of the most before enrollment and agreed to use adequate contraception during important antioxidants in living tissue (Cobb and Cole, 2015). Mino- their participation in the study. Participants with MRI-incompatible cycline, therefore, may confer neuroprotection through the upregula- metallic implants or claustrophobia were excluded from the neuroi- tion of cellular mechanisms that protect against the deleterious effects maging component of the study. of oxidative stress (Cobb and Cole, 2015; de Melo et al., 2017). The Icahn School of Medicine at Mount Sinai and Weill Cornell Preclinical studies have suggested that minocycline alone or in Medicine Institutional Review Boards approved the study, and written combination with a conventional monoaminergic antidepressant drug informed consent was obtained from all subjects before participation. may possess antidepressant properties (Arakawa et al., 2012; Molina- Participants were compensated for their time and effort. The study was Hernández et al., 2008a, 2008b). Minocycline reversal of depressive- registered at http://clinicaltrials.gov (ID: NCT01514422). like behaviors induced by pro-inflammatory cytokines (Zheng et al., 2015) or organophosphate pesticides (Saeedi Saravi et al., 2016) has 2.2. Study design, treatment and assessments been documented. To date, three human studies have tested the efficacy of minocycline in patients with mood disorders, with promising initial Eligible participants completed baseline assessments of symptom results (Dean et al., 2017; Miyaoka et al., 2012; Soczynska et al., 2017). severity, functional capacity, quality of life, neurocognitive functioning, One of these studies, conducted in patients with bipolar depression, and cortical GSH levels as measured in vivo with 1H MRS, prior to in- showed a reduction in depressive symptoms over an eight-week period. itiating an open-label trial of minocycline as adjunctive treatment for Significantly, recent population-scale data derived from FDA adverse bipolar depression. Symptom questionnaires included the MADRS and event reporting systems found that minocycline was associated with the Young Mania Rating Scale (YMRS) (Young et al., 1978), and a study protection against depression (Cohen et al., 2017). psychiatrist provided a global assessment of bipolar symptom severity The aims of the present study were to evaluate the therapeutic ef- using the Clinical Global Impression Scale-Severity (CGI-S)-Bipolar fects of minocycline augmentation of mood stabilizers in patients with Version (CGI-BP) (Spearing et al., 1997). Functional capacity and bipolar depression, and to assess whether oxidative stress and redox quality of life was assessed using the Longitudinal Interval Follow-up imbalance are treatment targets of minocycline. We utilized proton Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT) (Leon magnetic resonance spectroscopy (1H MRS) to measure levels of brain et al., 1999) and the Quality of Life, Enjoyment, and Satisfaction GSH within a voxel prescribed in the precuneus and aspects of the oc- Questionnaire (Q-LES-Q) (Endicott et al., 1993), respectively. Neuro- cipital cortex before and after an eight-week treatment course with cognition was assessed using the Repeatable Battery of the Assessment minocycline. The precuneus is a component of the default mode net- of Neuropsychological Status (RBANS) (Randolph et al., 1998) as well work (DMN) in which prior work has demonstrated functional ab- as selected subtests of the Delis-Kaplan Executive Functioning System normalities (Sheline et al., 2010) as well as alterations in GSH mea- (D-KEFS) (Delis et al., 2004). The RBANS includes subscales for im- surements in adults with unipolar depression (Godlewska et al., 2015; mediate and delayed memory, attention, language, and visuospatial Shungu et al., 2012). We hypothesized that low GSH levels at baseline functioning. Raw scores were converted to index scores with a mean of will be associated with greater symptom severity, and that increased 100 and a standard deviation of 16 based on age and gender corrected GSH following treatment with minocycline will be associated with norms, yielding an RBANS total index score and index scores for each clinical improvement in bipolar depression. 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 re- maining duration of the eight-week trial. The dose was adjusted based