COX-2 Inhibitors, Aspirin, and Other Potential Anti-Inflammatory Treatments for Psychiatric Disorders

Müller, Norbert

doi:10.3389/fpsyt.2019.00375

Cited by 92 publications

(64 citation statements)

References 69 publications

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“…Neuro-inflammatory processes as a result of stress-induced immune system activation (Halaris, 2019) are discussed as potential mechanisms in the pathogenesis of mental disorders, e.g., depression (Berk et al, 2013). This hypothesis was recently supported by systems genomics studies (Sharma, 2016) and clinical intervention studies with COX-2 inhibitors and aspirin (Muller, 2019). A negative phenotypical correlation of the level of systemic inflammation biomarkers with general intelligence in children also has been observed (Lee et al, 2016).…”

Section: Discussionmentioning

confidence: 95%

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

et al. 2020

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Anthropometric traits and mental disorders or traits are known to be associated clinically and to show genetic overlap. We aimed to identify genetic variants with relevance for mental disorders/traits and either (i) body mass index (or obesity), (ii) body composition, (and/or) (iii) body fat distribution. We performed a look-up analysis of 1,005 genomewide significant SNPs for BMI, body composition, and body fat distribution in 15 mental disorders/traits. We identified 40 independent loci with one or more SNPs fulfilling our threshold significance criterion (P < 4.98 × 10 −5) for the mental phenotypes. The majority of loci was associated with schizophrenia, educational attainment, and/or intelligence. Fewer associations were found for bipolar disorder, neuroticism, attention deficit/hyperactivity disorder, major depressive disorder, depressive symptoms, and well-being. Unique associations with measures of body fat distribution adjusted for BMI were identified at five loci only. To investigate the potential causality between body fat distribution and schizophrenia, we performed two-sample Mendelian randomization analyses. We found no causal effect of body fat distribution on schizophrenia and vice versa. In conclusion, we identified 40 loci which may contribute to genetic overlaps between mental disorders/traits and BMI and/or shape related phenotypes. The majority of loci identified for body composition overlapped with BMI loci, thus suggesting pleiotropic effects.

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Section: Discussionmentioning

confidence: 95%

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

et al. 2020

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“…60 Further still, our findings that genetic liability for NSAIDs use increased the risk for MDD and ASRD supports observational evidence suggesting NSAIDs have adverse neural effects, including neuropsychiatric symptoms, 61,62 although the association direction is opposite to reported RCTs using NSAIDs as adjunct therapies for depression. 63 The NSAIDrelated adverse neuropsychiatric symptoms are most often reported with indomethacin and selective cyclooxygenase-2 inhibitors, which may modulate neural processes and synaptic signaling processes where cyclooxygenase-2 is localized. 61…”

Section: Discussionmentioning

confidence: 99%

Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders

2021

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IMPORTANCEGrowing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult.OBJECTIVE To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods. DESIGN, SETTING, AND PARTICIPANTSWe performed 2-sample mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020.MAIN OUTCOMES AND MEASURES Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid). RESULTSThe GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22; P < .001) and ASRD (OR, 1.24; 95% CI, 1.07-1.44; P = .004). Using multivariable MR, these opioid use estimates remained after accounting for other nonopioid pain medications (MDD OR, 1.14; 95% CI, 1.04-1.25; P = .005; ASRD OR, 1.30; 95% CI, 1.08-1.46; P = .006), and in separate models, accounting for comorbid pain conditions. Bidirectional analyses showed that genetic liability for MDD but not ASRD was associated with increased prescription opioid use risk (OR, 1.18; 95% CI, 1.08-1.30; P < .001). These estimates were generally consistent across single-variable and multivariable inverse variance-weighted (MV-IVW) and MR-Egger sensitivity analyses. Pleiotropy-robust methods did not indicate bias in any MV-IVW estimates. CONCLUSIONS AND RELEVANCEThe findings of this mendelian randomization analysis suggest evidence for potential causal associations between the genetic liability for increased prescription opioid use and the risk for MDD and ASRD. While replication studies are necessary, these findings may inform prevention and intervention strategies directed toward the opioid epidemic and depression.

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“…One of the most commonly used non-selective COX inhibitors, Aspirin (acetylsalicylic acid), has been shown to have a potential use for various disorders and illnesses ranging from preventing myocardial infarction to treating psychiatric illness (Barbarawi et al, 2019;Müller, 2019). Aspirin salts previously have been investigated as potential therapeutics for ALS in transgenic SOD1 mice.…”

Section: Aspirin Aspirin Derivatives and Combating Inflammationmentioning

confidence: 99%

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2019

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G 4 C 2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G 4 C 2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G 4 C 2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular

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COX-2 Inhibitors, Aspirin, and Other Potential Anti-Inflammatory Treatments for Psychiatric Disorders

Cited by 92 publications

References 69 publications

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

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