Anti-Inflammatory Agents to Treat Depression

​
​Author: David P Soskin
Mentor: Maurizio Fava

Title: Double-Blind, Placebo Controlled Randomized Trial of an IL-6 Antagonist for Resistant Major Depressive Disorder
 
I. Background & Rationale
 
Major depressive disorder (MDD) has the highest lifetime prevalence rate of any psychiatric disorder (Kessler et al., 2005), and is associated with significant medical comorbidity and functional disability (Kessler et al., 2003). Current pharmacological treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with an serotonin reuptake inhibitor (SRI) will respond (Agency for Health Care Policy and Research, 1993) and fewer will remit (Trivedi et al., 2006). Perhaps more problematic, between 40% and 60% of responders will relapse within one year (Ramana et al., 1995; Rush et al., 2006). Given the limited efficacy of existing treatments and the historical decline in the development of antidepressants (Shorter & Tyrer, 2003), there is increasing clinical urgency to develop novel agents.
 
The Inflammatory Hypothesis of Depression
 
There is growing evidence that inflammatory processes contribute to the pathophysiology of MDD. Pro-inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) have been shown to be increased in individuals with MDD (Mossner et al., 2007; Simon et al., 2008; Zorrilla et al., 2001) or risk factors for MDD (stress, medical illness, obesity, sedentary lifestyle, diet, insomnia, social isolation, low socioeconomic status) (Raison, Lowry, & Rook, 2010) compared to healthy controls. In animal models, administration of pro-inflammatory cytokines or cytokine inducers have been associated with depression-like behavioral changes, including increased immobility time on the forced swim test, anhedonia, sleep disruption, and anorexia (Miller, Maletic, & Raison, 2009). These symptoms can be reversed through acute treatment with an anti-inflammatory cytokine (IL-10) or cytokine antagonist (IL-1RA), or chronic treatment with a serotonergic antidepressant (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).
 
In humans, similar links between cytokine activity and mood changes have been established. Approximately 20% to 50% of patients treated with the pro-inflammatory cytokine, interferon-alpha, for hepatits C or malignant melanoma will develop a clinical depression (Miller et al., 2009), and these rates can be dramatically reduced (approximately fourfold) following pre-treatment with the antidepressant, paroxetine (Musselman et al., 2001). In a study of patients with psoriasis, Tyring and colleagues found that individuals randomized to treatment with the tumor necrosis factor (TNF)-alpha antagonist, etanercept, had significantly greater improvements in depressive symptoms (measured by the HAM-D-17) compared to controls; changes in core features of depression were only weakly correlated with objective measures of skin clearance and joint pain (Tyring et al., 2006). In a proof-of-concept study, Muller and colleagues found that depressed patients randomized to treatment with reboxetine combined with the cyclooxygenase-2 (COX-2) inhibitor, celecoxib, showed greater improvements in depression (measured by the HAM-D-17) compared to controls treated with reboxetine alone (Muller et al., 2006).
 
Another recent discovery is that peripheral cytokine networks can affect molecular and cellular pathways in the central nervous system. Cytokines are able to penetrate the blood brain barrier through leaky regions, active transport systems, and efferent nerve conduction, and can then be converted to centrally released cytokines by microglial cells (Capuron & Miller, 2011). Within the CNS, pro-inflammatory cytokines have been shown to modulate neurotransmitter systems, neurotrophic factors, and neurocircuitry associated with mood regulation. Serotonin and dopamine neurotransmissions appear to be reduced through downregulation of presynaptic synthesis and upregulation of postsynaptic transporters (Dantzer et al., 2008; Kitagami et al., 2003; Zhu et al., 2010). Pro-inflammatory cytokines induce the enzyme, indoleamine 2,3-dioxygenase (IDO), which shunts tryptophan metabolism toward the production of kynurenine and quinolinic acid rather than serotonin (Lestage, Verrier, Palin, & Dantzer, 2002). Kynurenine and quinolinic acid have opposing actions on glutamatergic NMDA receptors, and quinolinic acid has been shown to increase release of glutamate by astrocytes, possibly contributing to excitotoxicity and loss of glial elements. Other pro-inflammatory cytokine-induced changes associated with the pathophysiology of MDD include decreases in BDNF levels; hypoactivity in prefrontal regions and hyperactivity in the basal ganglia (thought to represent increased oscillatory bursts from depleted DA neurons); acute HPA hyperactivity; and chronic glucocorticod resistance (Capuron & Miller, 2011).
 
Biological Rationale
 
Given these encouraging clinical and mechanistic findings, in addition to the evolutionary and phenomenological overlap between MDD and cytokine-induced "sickness behavior," there is reason to believe that immunological agents, such as Etanercept, targeting pro-inflammatory cytokine pathways may represent a novel class of antidepressants.
 
Additionally, a recent proof-of-concept study by Raison and colleagues (Raison et al., 2012) testing the TNF-alpha inhibitor, etanercept, as an antidepressant for patients with treatment-resistant depression found that patients with elevated baseline levels of inflammation, as measured by s-CRP concentration greater than 5 mg/L, demonstrated a clinically significant and preferential treatment response compared to placebo controls.
 
These results provide further support for the inflammatory hypothesis of depression in a specific subgroup of treatment-resistant patients with elevated baseline inflammatory biomarkers.
 
II. Hypotheses and Aims
 
This protocol aims to identify a novel antidepressant agent for refractory symptoms of major depression and to assess the relationship between baseline inflammatory biomarkers and treatment response.
 
Primary Aims
 
Hypothesis 1: Patients with treatment-resistant MDD assigned to add-on treatment with tocilizumab will demonstrate higher rates of response (HAM-D-17 score reduction = or > 50%) compared to controls.
 
Hypothesis 2: Patients with treatment-resistant MDD and baseline s-CRP concentration greater than 5 mg/L assigned to add-on treatment with tocilizumab will demonstrate higher rates of response (HAM-D-17 score reduction = or > 50%) compared to controls.
 
Hypothesis 3: Patients with treatment-resistant MDD assigned to add-on treatment with tocilizumab will experience no significant differences in the number of adverse events, as measured by the SAFTEE-SI, compared to controls.
 
Exploratory Aims
 
Exploratory Aim 1: To assess the magnitude and rate of response to tocilizumab, as measured by change on the HAM-D-17, compared to placebo; given the dramatic and rapid normalization of s-CRP found in previous studies (within 1 week), tocilizumab may possess a unique antidepressant signature distinct from the more gradual rates of symptom change characteristic of both placebo response and response to first-line antidepressant agents.
 
Exploratory Aim 2: To assess the relationship between baseline IL-6 levels and response to IL-6 receptor antagonism. Patients with treatment-resistant MDD and higher levels of serum IL-6 at baseline may also demonstrate a preferential response to add-on treatment with tocilizumab compared to controls with comparatively lower levels.
 
III. Design and Methodology
 
1. Recruitment: participants will be recruited by referral or local advertisements.
2. Subject selection: subjects will be selected from outpatients between 18 and 65 years of age, who have treatment-resistant depression, defined here as having failed at least two adequate trials of antidepressant therapy.
3. Inclusion criteria: subjects must meet DSM-IV diagnostic criteria for MDD during the present episode of illness; subjects must have failed at least two adequate trials of antidepressant therapy, defined here as a minimum of 8 weeks at a therapeutic dose of an antidepressant based one the MGH ATRQ; subjects must be on the same antidepressant regimen for a minimum of 8 weeks prior to study entry and a stable dose for the past 4 weeks; subjects must have a 17-item HAM-D score of 18 or greater at screening and randomization.
4. Exclusion criteria: a primary diagnosis of an Axis I disorder other than MDD; history of a psychotic disorder, dysthymia, antisocial personality disorder, borderline personality disorder, or mental retardation; untreated or poorly controlled comorbid medical conditions; significant suicide risk; history of a substance use disorder, with the exception of nicotine dependence, within 12 months prior to screening; women who are pregnant or breastfeeding.
5. Design: patients meeting inclusion and exclusion criteria above will be block randomized according to baseline levels of CRP into two subgroups: abnormally high levels of CRP, defined here as greater than 5 mg/L (n=30), versus normal range levels of CRP, defined here as less than 5 mg/L (n=30). They will then be randomly allocated in a double-blind fashion to treatment with either tocilizumab (n=30) or placebo (n=30) for 8 weeks.
6. Concomitant medications: concomitant medications for medical conditions will be continued as long as they are kept stable during the course of the study. The treating physician may prescribe and/or increase hypnotic agents for patients with insomnia. The addition of other psychotropics is prohibited.
7. Safety: physical exam will be performed at initiation and completion of study; side effects will be evaluated with ratings of frequency, intensity, and burden at follow-up. Vital signs will be monitored at screening, baseline, and weeks 1, 2, 4, 6, and 8. Urine drug testing will be conducted at screening to ensure that patients are not using prohibited agents.
 
IV. Proposed Analyses
 
The data will be analyzed using a repeated measures analysis of variance with the primary contrast being the treatment effect at 8 weeks.  With no missing data this would be equivalent to an analysis of covariance with the baseline as covariate but it allows patients with missing data to be included in the analysis according to recent guidelines (http://www.nap.edu/openbook.php?record_id=12955).
 
We approximate the power of this procedure by the power of a t-test based on change from baseline. Assuming a standard deviation of 7 for the change from randomization to week 8 in the HAM-D-17 (Raison et al., 2012), a total sample size of 60 subjects (30 drug; 30 placebo) will provide 80% power to detect a difference of 4.17 units between the active and placebo treatment groups at a two-sided 0.15 significance level.
 
To test exploratory Aim 2, we will use a random slopes model. The dependent variable will be the HAM-D score and the independent variables will be a treatment times time interaction that measures the overall treatment effect; an IL-6 level-time interaction that measures the IL-6 effect; and an IL-6 treatment times time interaction that measures whether the baseline IL-6 level affects the patients response to treatment. We expect that patients with a higher IL-6 level will demonstrate a more robust treatment effect.
 
Similarly, we will test whether changes in serum CRP level are associated with changes in HAM-D. In this random slopes model, we will jointly model serum CRP level and HAM-D as a function of time and treatment.
 
VI. Significance
 
The results of this proof-of-concept study could be of considerable importance for advancing clinical and biological research. A positive finding would provide preliminary evidence for a novel antidepressant agent and may also correlate a clinically viable cytokine marker with a preferential pattern of antidepressant response.

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