Treatment of mental illness is the next frontier in medicine, the Research Domain Criteria (RDoC) provides a framework for thinking about targeting psychopathology in a dimensional/domain-based approach. This framework provides a new perspective to investigate inter-individual variability in diagnosis, which has been a major challenge in psychiatric research. Given unmet need, NIMH has been supporting a Fast-Fail Trials initiative to bring candidate drugs to the greater population in an efficient manner. The identification of new brain targets identified via this approach will broaden avenues available for development and screening of new candidate compounds, thereby hastening the possibility that novel approaches with will demonstrate efficacy in treating psychiatric illness.
Pharmacological treatments of psychiatric illness have been largely based on work done in animal models. Much of this work has supported the monoamine hypothesis of mental illness, and more recently glutamatergic modulation. That said, a torrent of recent research has demonstrated, quite convincingly, that there are other pathophysiological mechanisms leading to psychiatric illness. Proposed mechanisms include inflammatory and microbiota interactions with central nervous system, kynurenine signaling, mitochondrial dysfunction, and oxidative and nitrosative stress. Appreciating the influence of interactions that systemic inflammation and the gut microbiome have on kynurenine and monoamine neurotransmission is a key step in designing novel treatment approaches for psychiatric conditions. These developments have contributed to a shift in the conceptualization of mental illness, from biochemical models focused on the nervous system, to a more holistic model that involves multiple organ systems.
The available evidence from large effectiveness studies of interventions for serious mental illnesses including major depression, bipolar disorder and schizophrenia [(e.g. STAR*D), bipolar disorder (e.g. STEP-BD) and schizophrenia (e.g. CATIE)] have revealed that current pharmacological interventions do not effectively address some psychiatric symptoms or have much of an impact on quality of life or functional outcomes. Many symptoms in psychiatric disorders are not addressed by current pharmacological interventions [1-3]. New therapeutic interventions are needed, and the growing understanding of the mechanisms underlying mental illness may facilitate the identification of existing pharmacological compounds that could help address this therapeutic gap. This paper will review existing literature on several mechanisms hypothesized to contribute to the development and progression of mental illness. There is a confluence of mechanistic underpinnings arising from recent research in previously distinct fields of inflammation, neurotransmission, the kynurenine pathway and gut microbiome that may give rise to a unification theory of psychiatric illness – exemplified in this article by mood and psychosis.
1. Pathophysiological mechanisms in psychiatry: – Inflammation, Kynurenine and the Gut Microbiome
A large proportion of patients with psychiatric disorders exhibit a chronic, low-grade inflammation, as measured by increased peripheral and central inflammatory cytokines, inflammatory mediators, and acute-phase reactants [4]. There is preclinical data in non-human primates and rodents to suggest that these effects are mediated by cytokines [5-7]. Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels. A meta-analysis of peripheral cytokines in acutely and chronically ill patients with depression, bipolar disorder and schizophrenia, demonstrated elevated baseline levels of levels of IL-6, TNF-α, one soluble cytokine receptor (sIL-2R), and the IL-1 receptor antagonist (IL-1RA), and that IL-6 decreased following treatment of patients with depression and bipolar mania [8]. A consensus is that therapeutic interventions that target peripherally-induced inflammatory mediators may also reduce the central inflammatory response and related behavior and thereby influence the disease course of patients with mental illness [9, 10].
2.1 Inflammation and Mood Disorders
Depressive symptoms have been linked to inflammatory processes in humans [11-17]. Multiple autoimmune conditions including psoriasis [18], rheumatoid arthritis [19], and multiple sclerosis [20], as well as some malignancies [21], are associated with increased levels of circulating inflammatory cytokines and high rates of comorbid depression [179-182, 189-192].
There appears to be a bi-directional relationship between inflammation and depression. Serotonergic and tricyclic antidepressants, specifically SSRIs inhibit immune activation; antidepressants been shown to decrease the level of pro-inflammatory factors such as interleukins 2 and 6, TNFα, and IFNγ [22-35]. Antidepressants shift T-helper 1 (pro-inflammatory) to T-helper 2 and 3 (anti-inflammatory) processes and counteract the adverse effects of cytokines on hypothalamus-pituitary-adrenal (HPA) axis function [36, 37]. The Whitehall II study of >3000 individuals showed baseline concentrations of inflammatory markers CRP and IL-6 predicted depressive symptoms over an approximately 10-year follow-up period, but baseline depressive symptoms did not predict inflammatory markers [38]. A study using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging demonstrated that increased plasma CRP in depressed patients is associated with aberrant functional connectivity in brain regions that influence reward processing and other goal-directed behaviors [4].
Treatment-resistant depression is associated with higher levels of inflammatory markers [27, 32, 39, 40]. Cytokines have been shown to elicit effects on neurotransmitter function, synaptic plasticity and neurogenesis [41], which may explain their ability to circumvent the mechanism of canonical antidepressant action.
Between 30 and 50% of patients receiving IFNα, for treatment of cancer and hepatitis C develop depressive or anxiety symptoms in a dose-dependent manner [42, 43] [49]. Remarkably, administration of selective serotonin reuptake inhibitors (SSRIs) prior to IFNα treatment attenuates the development of depressive symptoms, suggesting that the depressive symptoms in this population may be related to cytokine effects on serotonin metabolism [21, 44]. Lipopolysaccharide (LPS) induced systemic inflammatory response in heathy subjects has also been associated with the development of depressive symptoms [17]. Antidepressants fluoxetine and amitriptyline inhibited nitric oxide and prostaglandin release in synovial tissue exposed to lipopolysaccharide (LPS) or IL-1α and TNFα [45]. Also, tricyclic antidepressants amitriptyline and nortriptyline have been shown to suppress LPS-induced IL-1β and TNFα release in mixed glial cell cultures [30].
Activated peripheral monocytes/macrophages can cross into the brain and play a significant role in stress-induced behavioral change. This may be a means of establishing prolonged immunologic memory and sensitize brain parenchyma to future stress [46]. An additional pathway by which peripheral inflammation affects the brain is through the release of MCP-1 by activated microglia. MCP-1 recruits peripherally activated monocytes that can directly enter the brain and cause central inflammatory responses. In rodent experiments, cytokine-induced sickness behavior is mediated by IL-1β and modified by co-expression of other cytokines such as IL-6 and TNFα [47-49]. It has been notable that animal models have demonstrated the importance of activation of relevant inflammatory signaling cascades (e.g., nuclear factor kB and p38 mitogen-activated protein kinase) as well as the role of inflammation in stimulating indoleamine 2,3-dioxygenase (IDO) and the kynurenine pathway, and subsequently, glutamate, which leads to downstream effects on BDNF, neurogenesis and monoamine neurotransmission [50].
2.2 Kynurenine Pathway – Inflammation and MDD
Appreciation has steadily grown for the potential of kynurenic acid and is metabolites as NMDA receptor antagonists in the treatment and pathophysiology of mood disorders [51-53]. Kynurenine metabolites include quinolinic acid and kynurenic acid and within the brain, quinolinic acid is produced by kynurenine monooxygenase (KMO) in microglia, while kynurenic acid (KYNA) is produced mainly by kynurenine aminotransferase II (KATII) in astrocytes. Quinolinic acid is an endogenous NMDA agonist and can be neurotoxic. While NMDA receptor activation can enhance cognition, overstimulation may result in “excitoxicity” due to excessive calcium influx, and aberrant NMDA receptor stimulation may suppress BDNF translation and neurogenesis [54, 55]. While kynurenic acid can act as an endogenous NMDA antagonist, it seems likely that kynurenic acid, at endogenous concentrations, modulates glutamatergic and other neurotransmitter systems (specifically extracellular GABA and glutamate concentrations in the nucleus accumbens), in part through antagonism on presynaptic α7 nicotinic acetylcholine receptors [56] [57]. Cholinergic interneurons in the nucleus accumbens synapse with medium spiny neurons, having an important role in tonic control of GABAergic outputs [58]. . This neurochemical effect may be a common point of convergence of inflammatory effects on neurocognitive functions, and reward processing across both typical brain function and in psychiatric disorders.
Pro-inflammatory cytokines, including IFN-γ, IL-1β and TNF-α, induce the expression of IDO, the rate-limiting step in the conversion of tryptophan into kynurenine, suggested to be a plausible mediator of inflammation-induced depression-like symptoms [59]. Induction of IDO expression by inflammatory activity has been shown in several animal models to correlate with assays of anhedonia. Intra-hippocampal administration of IL-6 in rats induces IDO expression via the JAK/STAT pathway. Ido1 gene knockout or pharmacological inhibition of hippocampal IDO activity attenuates anhedonia [60]. This corresponds with other mouse studies, in which ido1 gene knockout or treatment with the IDO inhibitor 1-mehtyltryptophan, normalized LPS-induced decreases in sucrose preference, a measure of anhedonia in animal studies [61]. In a separate study, the viral mimetic Polyinosinic: polycytidylic acid (poly I: C) disrupted sucrose preference, increased expression of IL-1β, IL-6, TNF-α and CD11b, and decreased expression of BDNF and TrkB in the hippocampus and frontal cortex. In addition, poly I:C increased central IDO expression resulting in increased concentrations of tryptophan and kynurenine (KYN), but not central serotonin concentrations, suggesting that anhedonia is associated with reduced BDNF signaling and direct activities of KYN metabolites [62]. In adolescents, the ratio of kynurenine to tryptophan, an index of IDO activity, was correlated with clinician- and subject-rated measures of anhedonia, particularly in unmedicated subjects with MDD, while controlling for the severity of other depressive symptoms, and another study showed correlations with anterior cingulate cortex activity [63, 64]. Lastly, the ratio of the neuroprotective/neurotoxic kynurenine metabolites kynurenic acid/quinolinic acid inversely correlated with anhedonia assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) [65, 66].
2.3 Inflammation and Schizophrenia
Current evidence suggests that the pathophysiology of schizophrenia lies at the intersections between neuroinflammation, dopamine and glutamate signaling. The inflammatory hypothesis of schizophrenia has received a great deal of attention [67-71]. Elevated levels of pro-inflammatory substances have been described in the blood and cerebrospinal fluid patients with schizophrenia [72-76] [77]. Chronically activated macrophages produce pro-inflammatory cytokines which lead to abnormal neurogenesis, neural degradation and white matter abnormalities [78]. In addition, abnormal inflammatory processes contribute to a shift in T helper cells from cytotoxic cell immune function toward humoral immune reactivity [79, 80]., Epidemiological data as demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia [81-84]. Genetic studies have shown a high likelihood for schizophrenia risk on chromosome 6p22.1, a region related to the human leucocyte antigen (HLA) system among other immune functions [85-87].
There is some evidence demonstrating a link between the magnitude of elevation in inflammatory cytokines and the severity of symptoms of schizophrenia [88]. Antipsychotic treatment has been shown to significantly increases plasma levels of sIL-2R, IL-1β and interferon-γ, all of which are thought to have anti-inflammatory effects [89]. A meta-analysis concluded that treatment of schizophrenia resulted in a decrease in IL-6 levels, as well as an increase in sIL-2R [8].
Anti-NMDA autoimmune encephalitis has provided a link between immune system dysfunction and psychosis. In this disorder, there is acute development of psychiatric and behavioral changes in the setting which are thought to be secondary to alteration in glutamate transmission due to autoantibodies against an NMDA-type glutamate receptor [90, 91].
The kynurenine pathway may also be involved in the pathophysiology of psychosis. Endogenous KYNA is a potent antagonist of the α-7nAChR and NMDA and patients with schizophrenia have been shown to have excess KYNA [92]. The use of the acetylcholinesterase inhibitors galantamine and memantine may counteract the effects of KYNA and L-kynurenine through α-7nAChR and NMDA receptors, reducing glutamate transmission and associated neurotoxicity, and potentially providing a potential means of improving cognitive function [93-95]. On these bases, there are ongoing clinical trials with biological therapies developed aimed at reducing inflammation with the goal of normalizing neurotransmission [96-100]
2.4 The Gastrointestinal Microbiome and Psychiatric Illness
The adult human gastrointestinal tract is colonized by a diverse population of >100 trillion bacteria, including >1,000 species, and >7,000 strains [101]. The constitution of this population, which is more than 10 times the number of human cells in the body, is affected by a multitude of host and environmental factors, including diet, stress, early life events, pain, infection, the HPA axis, inflammation, brain parenchyma, serum metabolomics, and neurotransmitters [101]. Research in animal models and humans has demonstrated an important link between the microbiome and the development and function of the immune system. Furthermore, the microbiota–inflammatory–brain axis likely influences, if not mediates, human mood and behavior [102].
The gut microbiome is largely colonized postnatally, depending on the mode of delivery. The core composition of the gut microbiome is largely stable in adulthood, but differs in elderly populations [103]. There are three general enterotypes (Bacteroides, Prevotella, Runimococcus) [104] and the variance of microbial make-up may have diagnostic reliability. Specific microbes have been found to impact the development of multiple immunologic disorders including type 1 diabetes, asthma, and inflammatory bowel disease [105, 106].
Animal models suggest that the microbiome plays a role in the pathophysiology of neuropsychiatric conditions, including depression, anxiety [107], autism spectrum disorder [108], schizophrenia [109], Parkinson’s disease [110] and Alzheimer’s disease [111]. Microbiota have been found to alter inflammasome signaling that impacts pathways that affect depressive- and anxiety-like behaviors [102], [112] and depends on specific host factors [113]. In addition, mounting evidence suggests that the communication between the brain and gut microbial populations is bi-directional [114-119]. Germ-free (GF) mice, devoid of all microorganisms, exhibit increased risk-taking behaviors, hyperactivity, as well as learning and memory deficits compared to conventional mice [120-122]. They also show changes in expression of the 5-hydroxytryptamine receptor (5-HT1A), neurotrophic factors including BDNF, and NMDA receptor subunits in the hippocampus [123, 124]. They have impaired blood-brain barrier function, and increased myelination in the prefrontal cortex [125, 126]. In normal mice, maternal separation leads to elevated corticosterone and colonic acetylcholine release as well as anxiety, but in germ-free mice do not demonstrate these effects [127-129]. De Palma demonstrated that profound differences in the gut microbiome in response to early-life stress resulted in an anxiety-like phenotype [130]. Moreover, gene expression in the amygdala differs between GF and SPF animals [131]. A reciprocal effect by gut bacteria has been reported as well, where specific bacteria, or complete microbial assemblages, had effects on host stress- and depression-like behaviors [123, 124, 132].
The gut microbiome may play a role in depressive-like behaviors [133-135]. In humans, over 20% of patients with depression report symptoms of gastrointestinal distress [136]. Beta-diversity of the gut microbiome in major depressive disorder (MDD) patients is significantly different from that of healthy controls, with significantly more Actinobacteria and less Bacteroidetes in MDD-associated microbial populations. Further, GF mice received fecal transplants from humans with MDD and controls and the recipients of MDD samples exhibited depressive-like phenotypes, compared to control mice [113]. Another group was able to demonstrate that depressive-like phenotypes manifested after fecal transplantation into rats [137]. One hypothesis is that depression is a disorder of microglia, with the onset of depression often following intense inflammatory episodes in the brain or perhaps a result of a functional decline of microglia secondary to other factors [138]. In light of recent evidence on the role of the microbiome in microglia maturation and activation [139, 140], it has been hypothesized that the microbiome impacts depression by influencing microglial maturation and activation.
Neurogenesis in the dorsal hippocampus of adult GF mice is increased compared to conventional mice [141]. Interestingly, colonization of GF mice at weaning could not reverse this phenotype, indicating that microbial signals very early in life reduce rates of neurogenesis in the hippocampus. Moreover, compared to SRF mice, adult GF mice exhibit increased amygdala and hippocampus (specifically CA2/3 regions) volumes and have differences in dendrite morphology with no differences in total brain volume [142]. Gut microbes likely directly and indirectly influence pathways that orchestrate neuronal differentiation and survival, and thus have a significant impact on neurodevelopment and mental health.
Decades of observation have seen an associative link between autoimmunity, gastrointestinal disorders, and schizophrenia. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease, in which activation of innate immunity affects synapses in the brain. Gut microbiome research in schizophrenia is in its early stages, however data in related fields suggest disease-associated alterations in bacterial phylogenetic compositions [143]. For instance, the protozoa Toxoplasma gondii is considered an environmental risk factor for schizophrenia and it causes major changes to the gut microbiota [144, 145]. Additionally, there is evidence that Bifidobacteria is beneficial to the developing brain [146, 147], while C. difficile may be harmful [148]. There have been cases of schizophrenia and autism illustrating an association with a derivative of phenylalanine produced by C. difficile [149]. However, there have been no prospective studies to better elucidate these associations.
2. Therapeutics
3.1 Anti-inflammatory Agents as Treatments for Mood Disorders and Schizophrenia
Despite considerable evidence linking immune activation and inflammation with depression, surprisingly little research has examined the impact of anti-inflammatory agents on depressive symptoms. Studies have been performed using COX inhibitors, infliximab and etanercept, and this literature is reviewed below. Interestingly, in a study of patients with osteoarthritis, the rates of depression declined from 15% to 3% following the switch from the COX-2 inhibitor celecoxib to rofecoxib [149]. Several smaller studies have indicated that administration of anti-inflammatory agents including COX-2 inhibitors or acetylsalicylic acid may have antidepressant efficacy [150-152]. Furthermore, the addition of COX inhibitors to antidepressant therapy has been shown to improve remission rates of depression. Aspirin, a non-selective COX-1 and -2 antagonist, increased the rates of remission of major depression when added to fluoxetine therapy in patients who had not responded to fluoxetine monotherapy [152]. A double blind placebo controlled trial of the addition of celecoxib to the norepinephrine reuptake inhibitor antidepressant reboxetine demonstrated that the celecoxib plus reboxetine group experienced greater improvement in depression scores compared to those only on reboxetine [150].
Tumor necrosis factor receptor monoclonal antibodies have been used to treat inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis [153, 154]. In one study, patients with moderate to severe psoriasis treated with enteracept had greater improvements in depression and fatigue than those on placebo [10], and this effect was independent of improvement in other symptoms of psoriasis. Two subsequent studies supported the effect of etancercept on depression in patients with psoriasis [9, 155]. Similar results on depression were shown in a study of etanercept in rheumatoid arthritis patients [156]. Adalimumab, infliximab and tocilizumab also have been shown to decrease depressive symptoms [157-160], Currently, there is a phase 1b trial to test the effect of a humanized monoclonal antibody against the cell adhesion molecule α4-integrin currently used to treat multiple sclerosis and Crohn’s disease (natalizumab), on psychotic symptoms in a cohort of first episode psychosis patients (ClinicalTrials.gov Identifier: NCT03093064).
Anti-inflammatories may have a role as adjunctive treatment in bipolar disorder. A systematic review performed in 2016 concluded that anti-inflammatory agents decreased clinical signs of depression without increasing symptoms of mania or hypomania [8, 161]. Some evidence has demonstrated a connection between anti-inflammatory agents and improvement of symptoms of schizophrenia. One study demonstrated that the use COX-2 inhibitors in early stages of schizophrenia has a beneficial effect [162]. Additionally, anti-inflammatory and immunomodulatory effects of antipsychotic drugs have been known for a while, it may have been the first evidence of the role inflammation plays in schizophrenia [163].
Omega-3 polyunsaturated fatty acids (PUFAs), particularly long-chain omega-3 (LCn-3) fatty acids eicosapentaenic acid and docosahexaenoic acid, have been shown to modulate neurotransmitters, change neuroplasticity, reduce inflammation as well as oxidation, and their effects on mood disorders and schizophrenia has been investigated for over 15 years [164]. Reduced levels of cellular lipid membrane essential polyunsaturated fatty acids (EPUFAs) arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), are consistently associated with psychopathology and have been reported in both chronic-medicated schizophrenic patients as well as patients soon after the first episode of psychosis whom were never medicated. Abnormalities of EFAs has been found in lipid membranes in cells of patients with schizophrenia [165] and other studies have shown that supplementation with omega-3 EPUFAs (EPA>DHA) may have overall clinical benefits [166].
Cross-sectional evidence suggests that the mood disorders such as major depressive disorder and bipolar disorder are associated with low EPA and/or DHA levels and elevations in the pro-inflammatory LCn-6:LCn-3 fatty acid ratio, cytokines, and acute-phase reactants. Increasing LCn-3 fatty acid intake represents a reasonable notion to prevent the negative effects of inflammation on mental illness. Studies in rodents and humans have borne consistent evidence along these lines. In one study with improved depressive symptoms in which also demonstrated that changes in inflammatory biomarkers including IL-6 and CRP, were connected with clinical response to omega-3 fatty acids [164, 167-173].
Omega-3 may preserve cognitive function and prevent functional decline in patients with schizophrenia. On study in patients at ultra-high risk for psychosis demonstrated that consumption of 1.2g of omega-3 PUFA per day for 12-weeks significantly reduced the risk of transition to psychosis and improved positive, negative and general symptoms as well as functional status. Remarkably, the effect on the onset of psychosis in patients who received omega-3 PUFAs seems comparable to that of antipsychotics [174-179]. Another study showed that administration of omega-3 FA has been shown to improve functional outcomes and reduce the conversion to full-blown psychotic disorder in prodromal individuals with subthreshold psychotic symptoms [180].
3.2 Probiotics as Treatment for Mood and Psychotic disorders
Probiotic compounds are generally considered safe means to alter the GI track bacterial composition and thus the immune response to harmful antigens such as food-derived proteins. Probiotics have been studied in animal models and have shown benefits in trials of individuals with some gastrointestinal disorders and allergic conditions [181-183]. There has been interest in using probiotics to treat depressive symptoms for over a decade with recent meta-analysis demonstrating significant benefit, though the strain, dosing, and duration of treatment of probiotic varied widely and none assessed sleep disturbance [184-187].
One of the first trials of probiotic compounds in schizophrenia involved an add-on probiotic compound and there were no significant difference in psychiatric symptoms, however, those patients who received the probiotic compound were less likely to develop severe bowel difficulty, consistent with an effect of probiotics on the gastrointestinal tract [188]. In addition, the probiotic supplementation did significantly alter the levels of serum von Willebrand factor and brain-derived neurotrophic factor [189]. Probiotic treatment in schizophrenia has been shown lowered the level of antibodies to the fungus Candida albicans and associated gastrointestinal symptoms in males [190].
3.3 Minocycline as Treatment for Mood and Psychotic disorders
Minocycline is a tetracycline antimicrobial agent with a broad spectrum of antibacterial activity, and also is used for the treatment of some viruses. Minocycline also inhibits activation of microglia in the host subject, and it has been shown to diminish depressive behaviors in rodents [191, 192] and humans [193]. For this reason, this medication may be useful as an antidepressant. Minocycline’s antibiotic mechanism of action involves inhibition of bacterial protein synthesis by binding to the 30S ribosomal subunit [194]. Minocycline has been shown to reduce several inflammatory cytokines in rat models. For example, following bilateral carotid artery occlusion, levels of the inflammatory agents glial fibrillary acidic protein (GFAP), COX-2, and nuclear factor-kappa beta, were upregulated.
As demonstrated by western blotting, minocycline was able to successfully reduce the levels of those pro-inflammatory markers [195]. Additionally, the pro-inflammatory cytokines IL-1b, TNF-a, IL-4, and IL-10 were reduced in the brain and serum of mice treated with minocycline [196]. Additionally, there was an increase in bacteria such as Akkermansia spp. and Blautia spp., that decreased inflammation and rebalanced the gut microbiota. Also an increase in Lachnospiracea was linked with caspase-1 deficiency suggesting that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition [102]. Inflammation causes the maturation of caspase-1 and activation of IL-1β and IL-18, two proinflammatory cytokines involved in neuroinflammation and neurodegeneration [102]. Chronic stress and pharmacological inhibition of caspase-1 have been found to alter the gut microbiome. In a mouse model of caspase-1 deficiency, investigators found decreased depressive- and anxiety-like behaviors, and increased locomotor activity at baseline and following chronic stress. The administration of minocycline, a pharmacological caspase-1 antagonist, ameliorated stress-induced depressive-like behavior [197].
Minocycline was studied as an adjunctive treatment in patients with Bipolar I/II Depression. Those patients who demonstrated an improvement in depressive symptoms also had improvement in psychomotor speed, but not verbal memory or executive function. This study also demonstrated a relationship between minocycline treatment, cytokine levels and symptomatic response. In patients receiving minocycline, levels of interleukin IL-12/23p40 were increased while levels of IL-12p70 and C-C motif chemokine ligand 26 (CCL26) were decreased. Furthermore, reduction in CCL26 levels was associated with a less favorable treatment response [198]. Minocycline also significantly reduced depressive symptoms in antiretroviral naïve HIV-positive patients who had mild to moderate depression, though it had no impact on cognitive function [199, 200]. Furthermore, minocycline resulted in improvement in anxiety and mood-related behaviors on Visual Analogue [201].
In a study on hospitalized pateints with depression with psychotic features, the addition of minocycline to SSRI treatment resulted in a significant reduction of depressive and psychotic features after 6 weeks as measured by the HAM-D and BPRS scores [193, 202]. In 2014, an 8-week randomized, placebo-controlled clinical trial, minocycline significantly decreased the SANS score in the schizophrenia compared to controls with no adverse effects reported, indicating that minocycline is effective as an adjunct treatment of the negative symptoms of schizophrenia [202]. A 2017 meta-analysis showed that adjunctive minocycline appears to be safe and efficacious for treating negative symptoms in schizophrenia [203]. It is yet to be determined whether the antidepressive effects of minocycline are due to its antimicrobial properties, inhibition of microglial activation, anti-inflammatory effects, or a combination of all of these mechanisms.