Approximately 280 million individuals suffer from depression worldwide, and depression is now the leading cause of disability (1). Major Depressive Disorder (MDD), described as a persistent low mood for more than two weeks by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), can severely impact an individual’s ability to function (2). Current treatments for MDD are ineffective in approximately one-third of patients resulting in poor outcomes, a significant economic burden and reduced quality of life for a significant proportion of the global population (3).
Current pharmacological therapies for MDD primarily target the monoaminergic systems, based on the theory that depression is due to a reduction in monoaminergic neurotransmission (4). Conventional treatments such as selective-serotonin-reuptake-inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and selective noradrenaline reuptake inhibitors (SNRIs), all target the monoaminergic system by various mechanisms. Recent research demonstrates that depression is influenced by factors beyond monoamines, such as neuroinflammation (5, 6).
Depression is a heterogenous disorder with varying pathophysiology, and substantial evidence suggests increased inflammation may distinguish a sub-type of MDD, present in 30% of total MDD cases (7). Evidence of increased inflammation is demonstrated in MDD by a) elevated peripheral levels of cytokines, chemokines, and circulating immune cells (5) ; b) post-mortem and microarray studies (8); c) that depression is a common comorbid disorder in neurodegenerative conditions with a known inflammatory component (9); d) sickness behavior, characterized by fatigue, anhedonia, and loss of appetite, is observed in both MDD and in cases of infection or inflammation (10, 11) ; e) MDD is often associated with factors which increase inflammatory markers such as stress, reduced sleep, and obesity (12); and f) medications that modulate the immune system, such as interferon, appear to affect mood (6). Despite considerable evidence implicating inflammatory processes in MDD, there are no validated diagnostic tools or treatments for neuroinflammation in MDD.
Measurement of neuroinflammation in living patients is currently limited to two options. Lumbar puncture for acquisition of cerebrospinal fluid is invasive and unable to identify the site of neuroinflammation (8). Positron imaging tomography (PET) scanning utilizes ionizing radiation and is expensive, so it is not ideal for routine clinical use. Magnetic resonance imaging (MRI) is non-invasive, comparatively affordable, and more easily accessible. Advances in MRI techniques offer the possibility of measurement of neuroinflammation in people with MDD to better understand the pathophysiology of depression.
Quantitative magnetization transfer (qMT) and echo planar spectroscopic imaging (EPSI) demonstrate sensitivity to changes in markers associated with inflammatory activity in the brain, such as water content of tissue (13) and brain temperature, respectively. qMT measures the exchange of magnetization between immobile protons bound to macromolecules, such as in myelin or membrane lipids, and the mobile protons in free water in intra- and extra-cellular tissue. qMT parameters, such as the forward exchange rate, which quantifies the efficiency of the magnetization transfer, are sensitive to the effects of neuroinflammation (14).
EPSI is a technique used for brain thermometry by measuring the chemical shift of the temperature-dependent water resonance frequency compared to a temperature-independent metabolite such as creatine (15, 16). Brain temperature is expected to increase during neuroinflammation due to microglial activation, which increases metabolic demands leading to release of excess heat. In a study of patients with chronic fatigue/myalgic encephalomyelitis, a condition believed to represent chronic low-level neuroinflammation, elevations of regional brain temperature between 0.28 to 0.50oC were observed compared to control participants (17).
Diffusion-weighted imaging (DWI) techniques are used to investigate microstructural abnormalities in white matter. Recent advances in diffusion techniques show potential detecting neuroinflammatory components such as astrogliosis and demyelination (18, 19). A novel diffusion technique named diffusion kurtosis imaging (DKI) has been used to indicate neuroinflammation in conditions such as traumatic brain injury (20), stroke (21), and multiple sclerosis (22). qMT, EPSI, and DWI demonstrate promise for measurement of neuroinflammation in patients with MDD, and will be used to 1) investigate potential biomarkers of brain inflammation in participants with MDD compared to control participants and 2) to monitor the neurobiological response to anti-inflammatory adjunctive treatment.
There is evidence to suggest that anti-inflammatory treatments have anti-depressant effects. However, the research does little to elucidate the mechanisms by which the anti-depressant effects occur (23). Such studies have focused on the therapeutic efficacy of anti-inflammatory and immunomodulatory medications without clearly understanding the mechanism in action, thus leading to mixed results. Traditional non-steroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, omega-3 fatty acids, and N-acetylcysteine are among the medications trialed for an anti-depressant response (24, 25). There are critical limitations of these medications, however, including that they do not deeply penetrate the central nervous system tissue, are associated with adverse effects such as the increased risk of immunosuppression and stroke, and evidence suggests COX-2 selective NSAIDs may increase glial cell activation and neuroinflammation contrary to the anti-inflammatory hypothesis (26).
Low-dose naltrexone (LDN) is an atypical opioid antagonist with purported immunomodulatory and central anti-inflammatory effects (27). Naltrexone is most often used for the treatment of opioid and alcohol addiction. However, the use of daily low doses (4.5mg/day, 1/10th of the dose for addiction) appears to have anti-inflammatory effects in conditions such as Crohn’s disease (28, 29) and multiple sclerosis (29–31). In addition to its role as a competitive opioid receptor antagonist, naltrexone also has an antagonist effect on non-opioid receptors, including toll-like receptor-4 (TLR-4) found on microglia (32, 33). Microglia activation results in sickness behaviors due to the release of inflammatory factors. By blocking TLR-4, microglia may be prevented from assuming an inflammatory state, thus stopping the release of pro-inflammatory cytokines and neurotoxic superoxides (34). Furthermore, naltrexone causes a continuous blockade of the opioid growth factor receptor axis (OGFr), resulting in the proliferation of immune cells (35, 36). Though at the most common low dose of naltrexone, 4.5mg/day, there is reduced proliferation of T and B cells due to an intermittent blockade.
In a small pilot trial of individuals with fibromyalgia, a significant reduction in several pro-inflammatory cytokines as well as improved mood were observed following treatment with LDN (37). Furthermore, in a small trial of 12 individuals with MDD, LDN augmentation in addition to dopamine-enhancing agents was associated with reduced depressive symptomology (38). LDN may be an effective adjunctive anti-inflammatory treatment for depressive symptoms in MDD.
The current study explores the potential role of LDN, a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in people with MDD. Moreover, using MRI techniques including qMT, EPSI, and DWI will help elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. This double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach investigating inflammation as a pathophysiological contributor to MDD.