Depression as a Microglial Disease

doi:10.1016/j.tins.2015.08.001

Trends in Neurosciences

Volume 38, Issue 10, October 2015, Pages 637-658

https://doi.org/10.1016/j.tins.2015.08.001 Get rights and content

Trends

Microglia are best known as the immune cells of the brain, but emerging data indicate that they also influence brain development, synaptic plasticity, neurogenesis, memory, and mood under quiescent physiological conditions.

Deviation from microglial homeostasis, caused either by microglial activation during inflammatory conditions (e.g., infections, stress, stroke, or neurodegenerative diseases) or by microglial decline and senescence (e.g., during aging or chronic unpredictable stress), can lead to depression.

Conventional antidepressant drugs and electroconvulsive therapy modulate microglial structure and function, suggesting a novel mechanism of action for these treatments.

Microglia represent a promising therapeutic target for the treatment of depression; either microglia-suppressing or -stimulating drugs can serve as antidepressants, depending on the microglial status of the patient.

Despite decades of intensive research, the biological mechanisms that causally underlie depression are still unclear, and therefore the development of novel effective antidepressant treatments is hindered. Recent studies indicate that impairment of the normal structure and function of microglia, caused by either intense inflammatory activation (e.g., following infections, trauma, stroke, short-term stress, autoimmune or neurodegenerative diseases) or by decline and senescence of these cells (e.g., during aging, Alzheimer's disease, or chronic unpredictable stress exposure), can lead to depression and associated impairments in neuroplasticity and neurogenesis. Accordingly, some forms of depression can be considered as a microglial disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglial status of the depressed patient.

Section snippets

Major Depression and Microglial Homeostasis

Major depression, which afflicts one in six people at some point in life, is one of the main causes of human suffering and the leading global cause of years of life lived with disability (www.who.int). Despite recent progress in understanding the molecular, cellular, and circuit-level correlates of depression, the biological mechanisms that causally underlie this disease are still unclear, and therefore the development of novel effective antidepressive procedures has been slow and frustrating.

The Role of Microglial Activation in Illness-Associated Depression

Various bacterial and viral infections (e.g., influenza virus, Epstein–Barr virus, herpesvirus, cytomegalovirus, Borna disease virus, and gastroenteritis-related viruses) are associated with a range of depressive symptoms [9]. Many of these infectious pathogens have a special affinity for the brain, where they induce microglial activation [10]. These pathogens also induce the secretion of proinflammatory cytokines [11], whose plasma levels are correlated with depressive symptomatology 12, 13.

Microglial Status in Depressed Patients

Microglial status in major depression patients without a comorbid medical condition was assessed in postmortem and positron emission tomography (PET) imaging studies. In general, the results of these studies were negative or inconclusive, probably because depression may be associated with either microglial activation or decline, and therefore averaging microglial status for entire samples can lead to null results. Specifically, one postmortem study demonstrated the presence of activated

Microglia-Suppressive Properties of Antidepressant Drugs

Recent studies suggest that in addition to their classical effects on neurotransmission, antidepressant drugs can also inhibit the production of proinflammatory cytokines and suppress microglial activation [71]. Specifically, several SSRIs were found to inhibit the ability of cultured murine or rat microglia to produce tumor necrosis factor α (TNFα) and the free radical nitric oxide 71, 72, 73, 74, 75. Other classes of antidepressants [including TCAs, serotonin/norepinephrine reuptake

Antidepressant Properties of Anti-Inflammatory/Microglial-Inhibiting Drugs

Ample studies examined the antidepressive properties of anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs), as add-ons to conventional antidepressants. A recent meta-analysis of 14 randomized clinical trials (RCTs) (10 with NSAIDs, three with TNFα inhibitors, and one with an IL-12/IL-23 blocker) demonstrated that overall, anti-inflammatory drugs produced a significant reduction in depressive symptoms [81]. Most of the studies reporting significant

Microglia Activation Induced by Infectious and Noninfectious Inflammatory Responses

As noted above, peripheral and central inflammatory challenges can affect behavior and lead to the development of depression. Conserved pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) elicit infectious or noninfectious (sterile) inflammatory responses, respectively, and induce peripheral immune cells to secrete inflammatory mediators, which in turn relay information on the body's immune status to brain microglia via humoral and neural pathways 91,

Microglial Activation-Induced Suppression of Neurogenesis and Neuroplasticity

Impaired hippocampal neurogenesis is considered as an important mechanism underlying major depression and is a target for antidepressant actions 112, 113. Several lines of evidence implicate microglial activation as a key mechanism of neurogenesis suppression under inflammatory and stressful conditions 114, 115, 116. Specifically, treatment with LPS or irradiation resulted in marked suppression of hippocampal neurogenesis, whereas treatment with minocycline counteracted this effect 117, 118.

The Role of Microglia Decline/Suppression in Depression

While the studies discussed above provide strong evidence for the involvement of microglial activation in depression, other studies do not lend support to the inflammatory/microglial-activation hypothesis of depression and even suggest that decreases, rather than increases, in the inflammatory status in general and in microglial activation in particular may be associated with depression. Specifically, although in many studies depression was found to be associated with significant increases in

Inflammatory Effects of Antidepressants and Electroconvulsive Therapy (ECT)

Although under some circumstances antidepressant drugs, particularly SSRIs, were shown to exhibit anti-inflammatory effects, these results are highly heterogeneous, and in many studies antidepressants induced an increase, rather than decrease, in TNFα and IL-6 levels [148]. Consistently, administration of the SSRI drug citalopram in mice induced significant increases in the expression of the proinflammatory cytokines IL-1β, IL-6, TNFα, and IFN-γ in the frontal cortex [149]. The latter findings

Anti-inflammatory Drugs Are Not Always Antidepressant and May Even Be Depressogenic

As noted above, studies on the antidepressive effects of NSAIDs yielded mixed findings. In fact, several case reports and clinical studies demonstrated that treatment with NSAIDs for pain due to rheumatoid arthritis, osteoarthritis, or other musculoskeletal syndromes could elicit a moderate to severe major depressive episode in otherwise psychiatrically healthy individuals 162, 163, 164. The depressive symptoms remitted when the drugs were stopped, and returned upon re-use. Furthermore,

Antidepressive Properties of Microglia-Stimulating Drugs

Evidence for the possible antidepressive effect of immune stimulation in humans has been provided by only one study [168]. This study demonstrated that a single administration of endotoxin to severely depressed patients, which induced a short-term elevation in IL-1, IL-6, and TNFα levels, significantly but transiently improved their depressed state for 24 h. Importantly, a high correlation was found between the endotoxin-induced increases in cytokine levels and the mood improvement [168].

Concluding Remarks Determining the Appropriate Microglia-Related Personalized Medical Approach for the Individual Depressed Patient

Based on the data presented in this review, we postulate that at least some forms of depression can be considered as microgliopathies in which either microglial activation or microglial decline and suppression constitute the direct etiology of the depressive syndrome (Figure 3). Accordingly, deviations from microglial homeostasis should be regarded as important therapeutic targets for major depression. This implies that depression cannot be treated uniformly, but should instead be treated by a

Acknowledgments

We thank Mr Joseph Kippen for the helpful comments and suggestions, as well as Ms Zehava Cohen for help in preparation of the figures. This research was supported by the by the Israel Science Foundation grant 206/12 and by the Israel Science Foundation – First Program grant 1357/13 (to R.Y.).