COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain.

There appear to be huge variations and aberrations in the reported data in COVID-19 2 years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases, and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

Long COVID, neuropsychiatric disorders, psychotropics, present and future.

Long COVID refers to the lingering symptoms which persist or appear after the acute illness. The dominant long COVID symptoms in the two years since the pandemic began (2020-2021) have been depression, anxiety, fatigue, concentration and cognitive impairments with few reports of psychosis. Whether other symptoms will appear later on is not yet known. For example, dopamine-dependent movement disorders generally take many years before first symptoms are seen. Post-stroke depression and anxiety may explain many of the early long COVID cases. Hemorrhagic, hypoxic and inflammatory damages of the central nervous system, unresolved systematic inflammation, metabolic impairment, cerebral vascular accidents such as stroke, hypoxia from pulmonary damages and fibrotic changes are among the major causes of long COVID. Glucose metabolic and hypoxic brain issues likely predispose subjects with pre-existing diabetes, cardiovascular or lung problems to long COVID as well. Preliminary data suggest that psychotropic medications may not be a danger but could instead be beneficial in combating COVID-19 infection. The same is true for diabetes medications such as metformin. Thus, a focus on sigma-1 receptor ligands and glucose metabolism is expected to be useful for new drug development as well as the repurposing of current drugs. The reported protective effects of psychotropics and antihistamines against COVID-19, the earlier reports of reduced number of sigma-1 receptors in post-mortem schizophrenic brains, with many antidepressant and antipsychotic drugs being antihistamines with significant affinity for the sigma-1 receptor, support the role of sigma and histamine receptors in neuroinflammation and viral infections. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

Treatment-induced mood switching in affective disorders.

Many patients under treatment for mood disorders, in particular patients with bipolar mood disorders, experience episodes of mood switching from one state to another. Various hypotheses have been proposed to explain the mechanism of mood switching, spontaneously or induced by drug treatment. Animal models have also been used to test the role of psychotropic drugs in the switching of mood states. We examine the possible relationship between the pharmacology of psychotropic drugs and their reported incidents of induced mood switching, with reference to the various hypotheses of mechanisms of mood switching.

Introduction.

The theme of this monograph reflects the growing research interest in the contribution of the microbiome-gut-brain axis to mental health. This chapter introduces readers to the study of the microbiome in psychiatric research and emphasises how research into the gut microbiome has had a significant impact on our understanding of mental health. A brief summary of the historical background for microbiome research in mental health is followed by examples of evidence linking gut microorganisms to changes in brain function. As novel technological developments have played a major role in providing the evidence for microbiome modulation of brain function, an overview of modern techniques and technologies is then provided. These have broadened our understanding of the range of microorganisms, in addition to bacteria, which contribute to the changes initiated by the microbiome. In addition, common experimental models are reviewed in light of the important role that animal studies, particularly in germ-free rodents, have played in establishing microbiome-gut-brain interactions. This introduction concludes with a summary of the challenges for future microbiome research, providing a forward-thinking perspective echoed in many of the following chapters.

Non-pharmacological and pharmacological approaches for psychiatric disorders: Re-appraisal and insights from zebrafish models.

Acute and chronic stressors are common triggers of human mental illnesses. Experimental animal models and their cross-species translation to humans are critical for understanding of the pathogenesis of stress-related psychiatric disorders. Mounting evidence suggests that both pharmacological and non-pharmacological approaches can be efficient in treating these disorders. Here, we analyze human, rodent and zebrafish (Danio rerio) data to compare the impact of non-pharmacological and pharmacological therapies of stress-related psychopathologies. Emphasizing the likely synergism and interplay between pharmacological and environmental factors in mitigating daily stress both clinically and in experimental models, we argue that environmental enrichment emerges as a promising complementary therapy for stress-induced disorders across taxa. We also call for a broader use of novel model organisms, such as zebrafish, to study such treatments and their potential interplay.

Cross-species Analyses of Intra-species Behavioral Differences in Mammals and Fish.

Multiple species display robust behavioral variance among individuals due to different genetic, genomic, epigenetic, neuroplasticity and environmental factors. Behavioral individuality has been extensively studied in various animal models, including rodents and other mammals. Fish, such as zebrafish (Danio rerio), have recently emerged as powerful aquatic model organisms with overt individual differences in behavioral, nociceptive and other CNS traits. Here, we evaluate individual behavioral differences in mammals and fish, emphasizing the importance of cross-species analyses of intraspecies variance in experimental models of normal and pathological CNS functions.

Inflammation, insulin resistance and neuroprogression in depression.

Chronic low-grade inflammation has been observed in major depression and other major psychiatric disorders and has been implicated in metabolic changes that are commonly associated with these disorders. This raises the possibility that the effects of dysfunctional metabolism may facilitate changes in neuronal structure and function which contribute to neuroprogression. Such changes may have implications for the progress from major depression to dementia in the elderly patient. The purpose of this review is to examine the contribution of inflammation and hypercortisolaemia, which are frequently associated with major depression, to neurodegeneration and how they detrimentally impact on brain energy metabolism. A key factor in these adverse events is insulin insensitivity caused by pro-inflammatory cytokines in association with desensitised glucocorticoid receptors. Identifying the possible metabolic changes initiated by inflammation opens new targets to ameliorate the adverse metabolic changes. This has resulted in the identification of dietary and drug targets which are of interest in the development of a new generation of psychotropic drugs.

Safety of traditional medicine and natural product supplements in psychiatry.

Traditional medicines in the form of health food and supplements are highly popular nowadays. They are often aggressively promoted with unsubstantiated health benefit claims. Patients suffering from chronic illness, such as psychiatric disorders may be attracted to these products and use them concurrently with their prescribed drugs. The potential danger of these health supplements and traditional medicines containing products have prompted repeated warnings by the US Food and Drug Administration in recent years. A new initiative by the Food and Drug Administration in 2019 was also implemented to strengthen the oversight of these supplements. The WHO global compendium will include traditional medicines in 2019, which has generated much debate about their safety. Many practising psychiatrists are not familiar with traditional medicines, and clinically useful information is also not easily available. In this review, we examine the nature and safety of commonly encountered traditional medicine in these health food products and supplements.

Herbal medicine for psychiatric disorders: Psychopharmacology and neuroscience-based nomenclature.

Objectives: Herbs are frequently and concurrently used with prescribed drugs by patients worldwide. While clinical trials have found some herbs to be as useful as standard psychiatric drugs, most clinicians are unaware of their pharmacological mechanisms.Methods: We searched English language and other language literature with English abstracts listed in PubMed website, supplemented by additional through Google Scholar's free academic paper abstract website for publications on herbs, focussing on their clinical use in mental disorders, their neurobiology and their pharmacology.Results: A major reason for herbs remaining outside of mainstream psychiatry is that the terminology and concepts in herbal medicine are not familiar to psychiatrists in general. Many publications regarding the use of herbal medicine for psychiatric disorders are deficient in details regarding diagnosis, criteria for response and the neurobiology details compared with publications on standard psychotropic drugs. Nomenclature for herbal medicine is usually confusing and is not conducive to an easy understanding of their mode of action in psychiatric disorders.Conclusions: The recent neuroscience-based nomenclature (NbN) for psychotropics methodology would be a logical application to herbal medicine in facilitating a better understanding of the use of herbal medicine in psychiatry.

Inflammation and depression: a causal or coincidental link to the pathophysiology?

This review summarises the evidence that chronic low grade inflammation triggers changes that contribute to the mental and physical ill health of patients with major depression. Inflammation, and the activation of the hypothalamic pituitary axis by stress, are normal components of the stress response but when stress is prolonged and the endocrine and immune system become chronic resulting in the activation of the peripheral macrophages, the central microglia and hypercortisolemia, the neuronal networks are damaged and become dysfunctional. The proinflammatory cytokines, in addition to activating the hypothalamic-pituitary-adrenal axis and thereby increasing cortisol synthesis, also activate the tryptophan-kynurenine pathway. This results in the synthesis of the neurotoxic N-methyl-d-aspartate (NMDA) glutamate agonist quinolinic acid and 3-hydroxykynurenine thereby enhancing oxidative stress and contributes to neurodegeneration which characterise major depression particularly in late life.While antidepressants attenuate some of the endocrine and immune changes caused by inflammation, not all therapeutically effective antidepressants do so. This suggests that drugs which specifically target the immune, endocrine and neurotransmitter systems may be more effective antidepressants.The preliminary clinical evidence that some non-steroidal anti-inflammatory drugs, such as the cyclooxygenase 2 inhibitor celecoxib, can enhance the response to standard antidepressant treatment is therefore considered and a critical assessment made of the possible limitations of such an approach to novel antidepressant development.

Animal inflammation-based models of depression and their application to drug discovery.

INTRODUCTION: Depression, anxiety and other affective disorders are globally widespread and severely debilitating human brain diseases. Despite their high prevalence and mental health impact, affective pathogenesis is poorly understood, and often remains recurrent and resistant to treatment. The lack of efficient antidepressants and presently limited conceptual innovation necessitate novel approaches and new drug targets in the field of antidepressant therapy. Areas covered: Herein, the authors discuss the emerging role of neuro-immune interactions in affective pathogenesis, which can become useful targets for CNS drug discovery, including modulating neuroinflammatory pathways to alleviate affective pathogenesis. Expert opinion: Mounting evidence implicates microglia, polyunsaturated fatty acids (PUFAs), glucocorticoids and gut microbiota in both inflammation and depression. It is suggested that novel antidepressants can be developed based on targeting microglia-, PUFAs-, glucocorticoid- and gut microbiota-mediated cellular pathways. In addition, the authors call for a wider application of novel model organisms, such as zebrafish, in studying shared, evolutionarily conserved (and therefore, core) neuro-immune mechanisms of depression.

Major Depression as a Neuroprogressive Prelude to Dementia: What Is the Evidence?

Epidemiological studies implicate chronic depression as a predisposing factor for dementia in later life. However, the link is incompletely understood and controversial. The aim of this review is to consider some of the biological factors that contribute to neuroprogressive brain dysfunction in late life as a consequence of prolonged, low-grade inflammation in the course of depressive episodes. As chronic inflammation is known to precipitate increased apoptosis of neurons and astrocytes, this could be a contributing factor to brain dysfunction. In addition, certain proinflammatory cytokines activate the neurotoxic derivatives of the tryptophan-kynurenine pathway. This results in the synthesis of the NMDA glutamate agonist, quinolinic acid, and kynurenine metabolites which initiate oxidative stress and insulin receptor resistance. As a consequence of these changes, combined with a structural and functional defect in brain mitochondria, glucose transport into the brain is affected. Due to the ensuing reduction in the metabolic energy needed to sustain brain function, brain cells die prematurely. These changes could provide a link between chronic inflammation and dementia, at least in some patients with recurrent and chronic depression. This outcome may be particularly true in poor responders and treatment-resistant depression.

Neurodegeneration, Neuroregeneration, and Neuroprotection in Psychiatric Disorders.

Prevention of deterioration of brain function over time is important in the long-term management of chronic brain disorders such as dementia, schizophrenia, and mood disorders. Although the possibility of neurogenesis in the adult human brain is attractive, and there are psychiatric drugs proven to be effective inducers of neurogenesis in animals, we have yet to see their utility in clinical practice. The terms neurodegeneration and neuroregeneration are often used in a nonspecific manner. Neuroregeneration may mean neurogenesis, dendritogenesis, spinogenesis, or axonogenesis. The term "neuroprotection" is attractive clinically and may involve different mechanisms. Many causative and protective factors of neurodegeneration and neuroregeneration have been proposed. However, the specificity of these factors and agents and differential neuronal vulnerability factors have generally been ignored in past studies. It is also hard to separate disease-modifying from "neuroprotective" effects of a drug. The application of stringent long-term neuroanatomical, neurochemical, neurophysiological, and therapeutic efficacy criteria should improve future research in this important area.

Managing interactions between cognitive enhancers and other psychotropics.

Polypharmacy is common in psychiatry. Usage of cognitive enhancers is increasing in the psychiatric population. Many clinicians are not familiar with these new psychoactive compounds. This paper reviews the potential drug-drug interactions when these cognitive enhancers are used together with psychotropic drugs and their confounding effects on diagnosis and clinical management.

Higher than recommended dosages of antipsychotics in male patients with schizophrenia are associated with increased depression but no major neurocognitive side effects: Results of a cross-sectional pilot naturalistic study.

INTRODUCTION: The current small pilot naturalistic cross-sectional study assesses whether higher dosages of antipsychotics are related to a satisfactory outcome concerning symptoms of schizophrenia but also to a worse outcome in terms of adverse events and neurocognitive function. MATERIAL AND METHODS: 41 male stabilized hospitalized schizophrenic patients were assessed by PANSS, Calgary Depression Rating Scale, UKU and Simpson-Angus Scale and a battery of neurocognitive tests. Medication and dosage was prescribed according to clinical judgement of the therapist. RESULTS: Clinical variables and adverse events did not differ between patients in the recommended vs high dosage groups. Higher dosage correlated with depressive symptoms but there was no correlation with neurocognitive measures except for impaired concentration. DISCUSSION: Results suggest that it is possible to achieve a good clinical response in refractory patients by exceeding recommended antipsychotic dosages at the price of depression and possible mild isolated concentration deficits but not other neurocognitive or extrapyramidal adverse events. Currently clinicians prefer first-generation antipsychotics when high dosages are prescribed, but considering the more favorable adverse effects profile of newer agents, it is important to study higher dosages of these agents and to test whether they should be preferably given when high dosages are necessary.

Patients on psychotropic medications and herbal supplement combinations: clinical considerations.

Populations using herbs and herbal preparations are widespread and growing. As many herbal ingredients exert actions on psychotropic drug targets, psychiatrists should be well informed and aware of potential drug-drug interactions in clinical practice. Reliable and clinically useful information in this area, however, is fragmented, if not deficient. This paper reviewed the clinical aspects of herb-drug interactions, focusing in particular on the monoamine oxidase enzyme and P450 cytochrome enzyme-inhibitory properties of herbs and their potential interference with psychotropic drug actions and clinical judgement.

The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression.

Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation, which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus-pituitary-adrenal (HPA) axis have close interactions with pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.

Pain, Depression and Inflammation: Are Interconnected Causative Factors Involved?

Co-morbid depression and chronic pain are highly prevalent. The purpose of this review is to examine the role of chronic inflammation as a common mediator of these co-morbidities. Dysfunctional bidirectional pathways between the brain and the immune, endocrine and neurotransmitter systems have been extensively described and implicated in pain and psychiatric disorders. This short review therefore accesses the evidence in favour of the psychoneuroendocrine hypothesis of psychiatric disorders under three main headings: (1) by illustrating how different types of stress play a crucial role in initiating chronic inflammation in major depression, (2) by accessing the evidence that pain is frequently an important component of, and an initiator of, depression, and (3) considering the evidence that chronic inflammation provides an important link between chronic pain and depression, and the possible cellular mechanisms involved in this process. By understanding the critical role that chronic inflammation plays in pain and depression, novel approaches to the development of drugs may emerge that offer improvements in treatment.

Impact of inflammation on neurotransmitter changes in major depression: an insight into the action of antidepressants.

This review summarises the evidence that chronic low grade inflammation plays an important role in the pathology of depression. Evidence is provided that pro-inflammatory cytokines, together with dysfunctional endocrine and neurotransmitter systems, provide a network of changes that underlie depression and may ultimately contribute to the neurodegenerative changes that characterise depression in the elderly. Antidepressants attenuate the inflammatory changes and hypercortisolaemia by reducing the release of the pro-inflammatory cytokines from activated microglia, and by sensitizing the glucocorticoids receptors in the HPA axis. These effects correlate with an improvement in monoamine neurotransmitter function. The possible mechanisms whereby this cascade of changes occurs are outlined. In conclusion, the mechanisms whereby antidepressants act should now consider the involvement of the immune and endocrine systems in addition to the central neurotransmitters. This may open up possibilities for a new generation of antidepressants in the future.