Mental disorders remain high in resistance to treatment and burden of illness and disability worldwide (GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). It is evident, therefore, that current treatments are adequate but insufficient. What contributes to persistence of symptoms and distress, even within advances in pharmacological and psychosocial treatments? Our theories of mental disorders focus on psychosocial and environmental causation and neurophysiological dysfunctions; however, these theories leave many gaps to sufficiently guide care in alleviating symptoms.
The field of psychoneuroimmunology began in the 1970s and research has slowly entered into clinical practice. The monoamine theory, upon which most pharmacological treatments are based, fails to incorporate additional neural pathways including glutamate and gamma aminobutyric acid. More recently, inflammatory process has been posited as an explanation for upstream events that indirectly contribute to neuroimmunological dysfunction that can lead to mental disorders (Najjar, Pearlman, Alper, Najjar, & Devinsky, 2013). Specifically, inflammation leads to oxidative stress that contributes to glutamatergic and monoamine neurotransmitter dysfunction (Radtke, Chapman, Hall, & Syed, 2017).
Overview of the Inflammatory Process
Stimulation of the sympathetic nervous system activates the hypothalamic-pituitary-adrenal axis to release glucocorticoids that modulate the peripheral immune response. Chronic stress alters sympathetic nerve fibers, increasing hematopoietic stem cell proliferation and the release of inflammatory monocytes and neutrophils. Neutrophils under chronic stress resist the anti-inflammatory effects of glucocorticoids (Najjar et al., 2013). Underlying psychiatric disorders is a common mechanism of excitotoxicity in which there is an excessive release of glutamate that triggers the production of free radicals and oxidative stress. Oxidative stress contributes to mitochondrial dysfunction and cell death (Olloquequi et al., 2018). A free radical is an ion with unpaired valance; therefore, it is highly reactive and releases reactive oxygen species (ROS) that have beneficial and deleterious effects (i.e., excess formation of ROS damages monoamine receptors, yet they also destroy pathogens) (Olloquequi et al., 2018).
Microglia are one source of immune cells in the central nervous system (CNS). These cells regulate synaptic pruning, and like macrophages in the periphery, they rush to injury sites to clean up debris by means of microglial activation and proliferation (MAP). In postmortem studies of individuals with major depressive disorder (MDD), bipolar disorder, and schizophrenia, the MAP is dysfunctional and increased in those who died by suicide (Radtke et al., 2017). Microglia secrete proinflammatory cytokines, promote cyclooxygenase-2 (COX-2) expression, glutamate release, and the secretion of prostaglandins. The prominent proinflammatory cytokines include interleukin-1β (IL-1β), IL-2, IL-6, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ). Ultimately, the inflammatory cytokines:
- increase the expression of monoamine transporters, and thereby sabotage the serotonin reuptake inhibitors;
- decrease monoamine precursors through activation of the breakdown of tryptophan into kynurenine;
- decrease the availability of tetrahydrobiopterin needed as the rate limiting enzyme for the synthesis of serotonin, norepinephrine, and dopamine;
- inhibit neurogenesis; and
- decrease the expression of glutamate transporters and increase glutamate release from astrocytes thereby contributing to excitotoxicity (Raison, Felger, et al., 2013).
Astroglia secrete anti-inflammatory cytokines that are neuroprotective. These cytokines facilitate healing and limit neuronal injury by promoting the anti-inflammatory cytokines of brain-derived neurotrophic factor, IL-4, IL-5, and IL-10. Curiously, regular mild physical exercise and meditation are associated with increased parasympathetic tone and anti-inflammation (Raison, Felger, & Miller, 2013). The pro- and anti-inflammatory cytokines function on a seesaw with tryptophan metabolism at the pivot point (Figure 1). Tryptophan is metabolized into kynurenic acid, which is an N-methyl-D-aspartate (NMDA) receptor antagonism; quinolinic acid, which is an NMDA receptor agonist; and serotonin (Najjar et al., 2013). NMDA antagonist can lead to reduced glutamate, which contributes to schizophrenia. NMDA agonism can lead to excessive glutamate, which contributes to MDD, and breakdown in serotonin can also contribute to MDD.
Cytokine seesaw. Adapted from Najjar et al. (2013).
The blood brain barrier (BBB) effectively protects the brain from neurotoxins as long as the membrane remains intact. However, inflammation, oxidative stress, mitochondrial dysfunction, and bacterial translocation cause and accelerate BBB permeability placing the brain at risk for downstream effects. IL-1β also increases BBB permeability directly and indirectly by potentiating the effects of TNF-α (Morris et al., 2018). Proinflammatory cytokines can signal the CNS to activate microglia to secrete neurotoxins, such as nitrous oxide, COX-2, and quinolinic acid, resulting in detrimental effects on the integrity of the BBB. The downstream effect of damage to the BBB is compromised neural activity, especially glutamatergic neurotransmission (Morris et al., 2018).
Role of Inflammation in Mental Disorders
Epidemiological studies have identified activation of the maternal immune system as a possible precursor to many psychiatric disorders, including schizophrenia, autism spectrum disorder, and bipolar disorder. Maternal infections are risk factors for these disorders (Brown & Meyer, 2018). Infants and children who have been treated in intensive care units frequently show subsequent psychiatric symptoms that may be attributed to acute infections (Caspani et al., 2018). Autoimmune disorders, such as systemic lupus, rheumatoid arthritis, and autoimmune encephalitis, and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection have been associated with psychiatric disorders, including depression and psychosis (Hamdani, Doukhan, Kurtlucan, Tamouza, & Leboyer, 2013; Leboyer, Oliveira, Tamouza, & Groc, 2016; Najjar et al., 2013). Several studies have identified inflammatory markers associated with schizophrenia (Hartwig, Borges, Horta, Bowden, & Davey Smith, 2017; Steullet et al., 2016), bipolar disorder (Hamdani et al., 2013; Marrie et al., 2017; Rosenblat, 2019), depressive disorders (Berk, Walker, & Nierenberg, 2019; Keaton et al., 2019; Li, Soczynska, & Kennedy, 2011), anxiety disorders (Belem da Silva et al., 2017; Hirschtritt, Bloch, & Mathews, 2017; Marrie et al., 2017; Walss-Bass, Suchting, Olvera, & Williamson, 2018), Alzheimer's disease (Shimasaki, 2016), and autism spectrum disorders (Brown & Meyer, 2018; Shimasaki, 2016). However, all of these studies need to be cautiously considered as the mechanisms involved in inflammation and the development of psychiatric symptoms is still unclear. It is difficult to pinpoint how inflammation contributes due to the indirect process and the multi-system involvement, especially as the inflammatory process presents upstream and downstream of symptom development. What is convincing is that inflammation is a significant contributor to development of psychiatric symptoms and that early and chronic stress, such as adverse childhood events, can activate the immune system in such a way that neurological changes occur at the cellular level.
Given that there are clear biomarkers for neuroinflammatory response, what are some innovative approaches to guide treatment? Aspirin, a nonsteroidal anti-inflammatory drug (NSAID) that irreversibly inhibits COX-1 and COX-2 and reduces levels of C-reactive protein (CRP), TNF-α, and IL-6, has been studied as an adjunctive treatment for depressive disorders and schizophrenia. However, adverse effects limit aspirin's utility, and results are contradictory (Berk et al., 2013; Çakici, van Beveren, Judge-Hundal, Koola, & Sommer, 2019; Cho et al., 2019; Glaus et al., 2015; Veronese et al., 2018). At this point, the evidence does not support the use of aspirin in treating schizophrenia or depression or preventing depression. Data from a large randomized controlled study among older adults show that aspirin may help prevent and reduce symptoms of depression in this population (Berk et al., 2016); however, the addition of aspirin to a complicated medication regimen may also invite drug interactions that counterbalance the benefits.
Celecoxib (Celebrex®), another COX-2 inhibitor, has shown promise in reducing depressive symptoms at 200 mg twice daily in combination with antidepressant agents (Akhondzadeh et al., 2009; Najjar et al., 2013). However, other studies showed little improvement in symptoms when combined with serotonin reuptake inhibitors (Alboni, Benatti, Capone, Tascedda, & Brunello, 2018; Fields, Drye, Vaidya, & Lyketsos, 2012; Medici et al., 2017). Lack of consistency in these results reflects heterogenicity in mental disorder categories as well as the difficulty in grasping contributory factors when the immune system is involved.
Minocycline (Dynacin®, Minocin®) (in dosages from 100 mg twice daily to 150 mg twice daily) as adjunctive treatment for schizophrenia, depression, and obsessive-compulsive disorder demonstrated significant reduction in positive and negative symptoms, decrease in depressive symptoms, and reduction in Yale-Brown Obsessive Compulsive Scale scores (Dean, Data-Franco, Giorlando, & Berk, 2012; Murrough et al., 2018; Najjar et al., 2013). In a meta-analysis, however, efficacy of adjunctive minocycline in treating depression or bipolar depression could not be demonstrated (Zheng et al., 2019).
Monoclonal antibody technology has opened many doors to innovations in medical treatments directed at the immune system. Not surprisingly, monoclonal antibodies invite exploration in psychopharmacology. Infliximab (Remicade®) is used to treat autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and severe plaque psoriasis. This TNF-α inhibitor was used in a single-site, parallel-group, randomized, double-blind study for treatment-resistant depression and found to significantly reduce symptoms of anhedonia, depressed mood, psycho-motor retardation, anxiety, and suicidal ideation over a 4-week time period (Raison, Rutherford, et al., 2013). However, the placebo group also had reduced severity of symptoms. What distinguished the placebo from the treatment group was the baseline CRP level. Infliximab was more effective when baseline CRP was >5 mg/L, suggesting that effectiveness was related to severity of inflammation, and severity of inflammation may be a critical factor in treatment-resistant depression (Raison, Rutherford, et al., 2013).
Nutraceuticals have also been studied with particular focus on N-acetylcysteine (NAC), vitamins C and E, and omega-3 oils. Melatonin demonstrates broad anti-inflammatory effects and protective and restorative effects on the integrity of the BBB and is also a potent scavenger of free radicals. Melatonin's antioxidant properties help upregulate glutathione; however, studies failed to show robust effectiveness in treating depression and schizophrenia (Morris et al., 2018). Although all of these nutraceuticals showed some improvement in immune function, only NAC demonstrated consistent and significant efficacy in treating depression, schizophrenia, anxiety, and cognitive function (Naguy, 2018; Natacci et al., 2018). NAC as an antioxidant precursor to glutathione shows promise in the treatment of substance use craving (Duailibi et al., 2017), bipolar depression (Berk et al., 2019), impaired cognition (Bortolato et al., 2016), and schizophrenia (Breier et al., 2018; Çakici et al., 2019; Cho et al., 2019). NAC scavenges oxidants directly to reduce the free radicals and penetrates the BBB to increase the levels of glutathione. By altering the glutathione levels in the brain, NAC modulates glutamate and dopamine. Further glutathione potentiates NMDA receptor response to glutamate and alters dopamine release (Dean, Giorlando, & Berk, 2011).
The research on substance use disorders and NAC is contradictory, with more robust results in reducing craving and reward behaviors in nicotine and marijuana use, especially with concurrent alcohol use; however, cocaine use shows limited effectiveness and the studies have small sample and effect sizes (Gray et al., 2017; Lebourgeois et al., 2018). The strongest evidence is in improved executive function and positive symptoms in schizophrenia by modulating glutamate in the anterior cingulate cortex (McQueen et al., 2018; Ooi, Green, & Pak, 2018). NAC is safe and well-tolerated and can be given with other medications in dosages between 2,000 and 2,400 mg per day (Ooi et al., 2018).
Summary and Tips for Practice
Based on these connections of the inflammatory process with psychiatric symptoms, it is tempting to add NSAIDs to off-label pharmacopeia; however, the research literature is still evolving and requires more replication. Minocycline and monoclonal antibodies in conjunction with conventional medications and treatments offer promise in bringing about full remission or at least significant improvement in symptoms of depression, psychosis, and anxiety. Furthermore, the use of NAC as a supplement to other treatments can improve outcomes for patients with these disorders. Some tips for the prudent psychiatric nurse are:
- Include nutritional and exercise practices when assessing patient's responses to medication.
- Consider supplementing the treatment regimen with NAC 2,000 to 2,400 mg daily for patients struggling with cocaine, marijuana, methamphetamine, nicotine, and alcohol cravings.
- Although vitamins C and D fail to show consistent efficacy in treatment-resistant conditions, side effects are minimal and may provide relief for some patients with schizophrenia, mood and bipolar disorders, and attention disorders.
- Melatonin in doses of 50 to 100 mg daily is needed to achieve anti-inflammatory effects; however, side effects at this dosage may outweigh its benefits.
In the near future, monoclonal antibodies, antibiotics, prebiotics, and probiotics may be approved by the U.S. Food and Drug Administration for treatment-resistant mental disorders, but these treatment modalities have yet to receive such approval.
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