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.

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.

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.

Inflammatory neuropsychiatric disorders and COVID-19 neuroinflammation.

Neuropsychiatric sequalae to coronavirus disease 2019 (COVID-19) infection are beginning to emerge, like previous Spanish influenza and severe acute respiratory syndrome episodes. Streptococcal infection in paediatric patients causing obsessive compulsive disorder (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long-term-specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favourable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease-modifying therapies are increasingly being applied to neuropsychiatric diseases characterised by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.

Opportunities in Novel Psychotropic Drug Design from Natural Compounds.

Multiple initiatives at the national and international level support natural drug discovery. Psychiatrists and patients are not well informed about natural psychotropics in general. Existing antidepressant and antipsychotic drugs were developed from atropine, a natural product. Subsequent drug developments were largely based on extension and modification of earlier molecular scaffolds. This limits their mechanisms of action to similar neuropathways. Natural psychotropic substances, particularly those with hallucinogenic and psychedelic properties and different chemical structures, may serve as new paths to novel psychotropic drug development.

Effect of corticosterone and paroxetine on masculine mating behavior: possible involvement of neurogenesis.

INTRODUCTION: Corticosterone inhibits male rodent sexual behavior while the mechanism remains obscured. Recent studies have disclosed that neurogenesis in the subventricular zone (SVZ) can be increased by pheromone exposure from the opposite sex, and neurogenesis is essential for normal mating behavior of female mice. Together with the neurogenesis-inhibiting effect of corticosterone, we hypothesize that cell proliferation in the olfactory system is essential for male rodent sexual functioning. AIM: The current study explored the relationship between cell proliferation in the olfactory system and male sexual behavior. MAIN OUTCOME MEASURES: Sexual behavior performance, proliferative cell counts, and c-fos-expressing cell counts. METHODS: Adult male rats were treated with corticosterone and/or paroxetine, an antidepressant, for 2 weeks. These two drugs were shown to suppress and enhance hippocampus and SVZ cell proliferation, respectively. Mating behavior was assessed after the treatment, and proliferation of new cells and c-fos-expressing cells, activated neurons in the mating-related regions in the brain, were analyzed. To further confirm the necessity of cell proliferation in mating, inhibition of cell proliferation was performed by intracerebroventricular infusion of cytostatic cytosine arabinose (Ara-c). RESULTS: Corticosterone treatment, which inhibited cell proliferation in both the SVZ and olfactory epithelium, led to inhibited male sexual performance. In contrast, paroxetine increased cell proliferation and improved the performance in corticosterone-treated animals. When cell proliferation in the brain was inhibited by Ara-c, a suppressed sexual performance was found. However, cell proliferation in olfactory epithelium was not inhibited by Ara-c and thus the sexual inhibition is unlikely to be linked to this region. Furthermore, a decrease in c-fos expression in the mating-related regions upon female pheromone stimulation was found. CONCLUSIONS: These results suggest that cell proliferation in the SVZ and hippocampus may be involved in the reproduction of the male rodents, and pharmacological treatments may affect sexual functioning through alteration of neurogenesis.

Hallucinations: diagnosis, neurobiology and clinical management.

Hallucinations are important diagnostic symptoms in schizophrenia, but also occur in other medical and neuropsychiatric conditions. Not all patients with hallucinations are psychotic. There has been a surge of interest in the topic of hallucinations, as new research data have begun to reveal their neurobiology. Hallucinogenic molecules may also serve as new scaffolds for the development of new psychotropic drugs. We searched and reviewed recent literature, focusing on the refinement of clinical management, which was inspired by new data regarding the neurobiology of hallucination subtypes. We concluded that the successful management of hallucinations depends on accurate differential diagnosis to identify subtypes, which would then determine the most appropriate treatment.

Predictors of poststroke quality of life in older Chinese adults.

AIM: This paper is a report of a study to identify the changes in poststroke quality of life and other clinical issues among older Chinese adults from 1 month to 6 months after stroke and the predictors of poststroke quality of life at 6 months. BACKGROUND: Stroke survivors are known to suffer from prolonged and multiple impairments leading to a compromised quality of life, but few studies report early predictors for quality of life among older Chinese adults after active rehabilitation has been undertaken during the first 6 months after stroke. METHOD: A total of 214 patients with first-ever ischaemic stroke were interviewed by a research nurse at 1 month and 188 patients were interviewed again 6 months after hospital admission for stroke. Assessment of quality of life was done using the Modified Rankin Scale for Quality of Life. Changes in and relationships between quality of life and variables in five domains were explored: bio-anatomical, physical, emotional, cognitive, communicative and social support. The data were collected in 2004-2005. RESULTS: Quality of life among two-thirds of participants was unchanged or lower when scores at 1 month and 6 months after stroke were compared. Length of hospital stay after admission for stroke and other 1-month factors - level of worry over current health, cognitive and self-care deficits - were identified as having independent effects on quality of life at 6 months. CONCLUSION: Clinicians need to observe for early signs of mild cognitive impairments and emotional needs of stroke survivors, as well as to consider longer-term interventions to enhance poststroke quality of life.

Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects.

The effect of short-term exercise (15 min step-exercise) on serum brain-derived neurotrophic factor (BDNF) levels was evaluated in healthy human subjects. Results showed a short-term, significant increase in serum BDNF levels after exercise. Intra-individual differences in serum BDNF levels were remarkably small on the rest day and also when compared to rest values on the day of the exercise test. Inter-individual differences, on the other hand, were larger by comparison. The result of this study supports the need for larger sample size in studies on BDNF changes in psychiatric disorders or psychiatric drug effects.

Depression in college: depressive symptoms and personality factors in Beijing and Hong Kong college freshmen.

OBJECTIVES: The present study investigated the 2-week prevalence of depressive symptoms in college freshmen from Beijing and Hong Kong. The relationship between depression and 3 personality factors in these college freshmen was analyzed. METHOD: Center for Epidemiologic Studies Depression Scale (CES-D), Eysenck Personality Questionnaire-Neuroticism, Rosenberg Self-esteem Scale, and Frost Multidimensional Perfectionism Scale were administered to 988 Beijing and 802 Hong Kong Chinese college freshmen. RESULTS: Approximately 24.8% of freshmen in Beijing had scores on the CES-D exceeding 16, whereas 8.9% reported scores of 25 or higher. There was no sex difference in prevalence in Beijing. Approximately 43.9% of freshmen in Hong Kong had scores on the CES-D exceeding 16, whereas 17.6% reported scores of 25 or higher. The prevalence is significantly different between sexes in Hong Kong, with approximately 36.1% of men having scores of 16 or higher and 13.4% having scores of 25 or higher and approximately 50.7% of women having scores of 16 or higher and 21.3% having scores of 25 or higher. High neuroticism, concern over mistakes, doubts about actions, low self-esteem, and poor organization were associated with current depressive symptoms in both sites. CONCLUSION: The higher prevalence of current depressive symptoms in college freshmen in Hong Kong suggests that their mental health is not as satisfactory as that of their counterparts in Beijing. The strong relationship between certain personality features and current depressive symptoms is similar in both regions. Personality differences in the 2 sites explain only part, but not all, of the difference in depressive symptoms between the 2 sites.

Corticosteroid decreases subventricular zone cell proliferation, which could be reversed by paroxetine.

PURPOSE: Major depressive disorder is often associated with elevated glucocorticoid levels, which in turn suppress cell proliferation and neurogenesis in the hippocampus. Increasing evidence supports that antidepressants induce hippocampal neurogenesis and this induces speculation that decrease in hippocampal neurogenesis has causal relationship with depression. There is, however, a lack of information about neurogenic effects of antidepressants on the subventricular zone, which is another CNS region with continuous neurogenesis throughout adulthood. In the present study, we investigated whether corticosterone and the SSRI paroxetine, have effects on SVZ cell proliferation. METHODS: Rats were treated with the corresponding drugs for 14 days and the proliferating cells were labeled with bromodeoxyuridine (BrdU). BrdU labeled cells in the SVZ were quantified and analyzed. RESULTS: In the corticosterone-treatment group, cell proliferation was decreased by 18% compared to vehicle-treatment group. Paroxetine-treatment group, in contrast, shows a 34% increase in cell proliferation. The decreased cell proliferation caused by corticosterone was prevented by paroxetine. CONCLUSIONS: Although corticosterone and antidepressants were found to affect cell proliferation in hippocampus, this is the first report to demonstrate that 1) corticosterone decreases cell proliferation in SVZ; 2) paroxetine promotes SVZ cell proliferation and 3) the suppressive effect on SVZ cell proliferation by corticosterone could be attenuated by paroxetine. These findings provide new insights into basic mechanisms of antidepressants, potential impact of steroid therapy on CNS neurogenesis, antidepressant mechanisms of action and potential involvement of the olfactory system in depression.

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.

Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats.

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.

Roles of paroxetine and corticosterone on adult mammalian ciliary body cell proliferation.

BACKGROUND: The neurogenesis in retina of adult mammals is generally abolished, and this renders the retina lack of regenerative capacity. Despite this, there is a small population of nestin-positive cells in the ciliary epithelium which retains neurogenic potential. The present study aimed at investigating the effect of two drugs, corticosterone and paroxetine, on the cell proliferation of the ciliary body. METHODS: Adult Sprague-Dawley rats were given vehicle, corticosterone, paroxetine, or both corticosterone and paroxetine treatment for 14 days. Cell proliferation in the ciliary body was quantified using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. Co-labelling of BrdU and stem cell marker was used to phenotype the BrdU immunoreactive cells. RESULTS: Corticosterone treatment suppressed while paroxetine treatment increased the cell proliferation of the ciliary body. Co-labelling with cell markers revealed that the BrdU positive cells also showed nestin expression but not glial fibrillary acidic protein (GFAP). CONCLUSIONS: The results illustrate that proliferation of retinal progenitor cells situated in ciliary body are subjected to regulation by selective serotonin reuptake inhibitors (SSRI) and corticosteroid, which is similar to our previous findings in neurogenic regions in central nervous system (CNS). Paroxetine treatment could reverse the suppressive effect of corticosterone on ciliary body cell proliferation. This provides information for future investigation of retinal stem cell biology and potential treatment of retinal degenerative diseases.

Intracerebroventricular infusion of cytosine-arabinoside causes prepulse inhibition disruption.

Adult neurogenesis in hippocampus is associated with behaviors such as learning. Hippocampus is involved in the regulation of prepulse inhibition (PPI), but the relationship between neurogenesis and PPI is unexplored. We conducted four experiments to determine the role of neural progenitor cell proliferation in PPI. Intracerebroventricular infusion of cytostatic cytosine arabinoside caused PPI disruption but repeated exposure to PPI sessions prevented the PPI disruption. Corticosterone treatment, which decreases hippocampal cell proliferation, caused PPI disruption, whereas antidepressant and exercise, which increased cell proliferation, did not affect PPI. These results suggest that cell proliferation is involved in the first encounter with PPI test while its importance may decrease upon repeated exposures to the tests.

Frequency of painful physical symptoms with major depressive disorder in asia: relationship with disease severity and quality of life.

OBJECTIVE: Patients with major depressive disorder (MDD) frequently report concomitant painful physical symptoms, which may negatively impact diagnosis and treatment. The purpose of this study was to estimate the frequency of painful physical symptoms in Asian patients treated for an acute episode of MDD and to describe the associated demographics, clinical status, treatment patterns, and socioeconomic burden. METHOD: This multicountry, observational study enrolled 909 patients with MDD (DSM-IV-TR or ICD-10 criteria) in the psychiatric care setting from June 14, 2006, to February 15, 2007. Patients were classified as positive for painful physical symptoms (PPS+) if they achieved a mean score >or= 2 on the modified Somatic Symptom Inventory. The Clinical Global Impressions-Severity of Illness scale (CGI-S) and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) determined depression severity, and the EuroQoL Questionnaire-5 dimensions (EQ-5D) assessed subjective well-being. RESULTS: Overall, 51.8% of patients were classified as PPS+. PPS+ patients were more likely to be female (72.2% vs. 65.1%, p = .022), had relatively more medical comorbidity (29.7% vs. 21.0% with >or= 1 comorbidity, p = .003), were more significantly depressed (CGI-S mean [SE] score = 4.84 [0.03] vs. 4.63 [0.04], p < .001; HAM-D(17) mean [SE] score = 24.80 [0.26] vs. 22.39 [0.27], p < .001), and reported a lower quality of life (EQ-5D health state mean [SE] score = 42.96 [0.92] vs. 52.92 [0.95], p < .001) than PPS- patients. PPS+ and PPS- patients did not differ markedly, however, in terms of MDD medications prescribed or MDD-related disability at work. CONCLUSION: Painful physical symptoms are experienced by approximately half of patients with MDD in Asia and are associated with poor clinical status and perceived quality of life.

Paroxetine.

BACKGROUND: Paroxetine is a widely used antidepressant that has received attention regarding suicide risk in younger patients. OBJECTIVE: The purpose of this paper is to review the pharmacology, efficacy and safety of paroxetine in the affective disorders. METHODS: The authors performed a PubMed search for all literature in English crossing the words 'paroxetine' and 'Paxil' against the words 'serotonin transporter,' 'clinical trials,' 'depression' and 'SSRI'. A search for paroxetine-related information at the FDA website and under the clinical trial register of the GSK website were also performed. RESULTS/CONCLUSION: Paroxetine is a serotonin re-uptake inhibitor with good selectivity and no significant active metabolites. Paroxetine is approved (ages >or= 18 years) for the treatment of major depressive disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder (social phobia), post-traumatic stress disorder, and generalized anxiety disorders. Drug - drug interactions involving the CYP enzyme system have been documented, as well as concern for increased suicidality risk in younger adults and recent FDA alerts regarding teratogenicity, serotonin syndrome and persistent pulmonary hypertension.

Incidence and predictors of depression after stroke (DAS).

Objective. Depression after stroke (DAS) poses a treble burden to patients, families and health care system. The purpose of this paper is to estimate the incidence of depression among first-ever ischemic stroke patients and identify the predictors of DAS. Methods. A longitudinal study design was undertaken. Of 836 patients admitted to the stroke unit of two regional hospitals in Hong Kong during the period 1 June 2004 to 31 May 2005, 295 patients fulfilled the inclusion and exclusion criteria. A total of 260 patients had given their consents and were interviewed at 1 month after stroke onset. Results. Nearly one-quarter of the first ischemic stroke patients, who were known to be free of personal and family history of psychiatric illnesses, were found to satisfy the criteria of depression using Diagnostic and Statistical Manual IV (24%, 48 out of 200 participants; 95% CI: 18.6%, 30.4%). This result was close to that assessed by the Geriatric Depression Scale (GDS) - 15 items. The psycho-emotional factor and level of dependency were found to be most significant predictors for DAS onset. Conclusion. The high incidence of DAS and low rate of accessibility to treatment indicate timely action to be undertaken.

Modulation of the suppressive effect of corticosterone on adult rat hippocampal cell proliferation by paroxetine.

OBJECTIVE: The literature has shown that cognitive and emotional changes may occur after chronic treatment with glucocorticoids. This might be caused by the suppressive effect of glucocorticoids on hippocampal neurogenesis and cell proliferation. Paroxetine, a selective serotonin reuptake transporter, is a commonly used antidepressant for alleviation of signs and symptoms of clinical depression. It was discovered to promote hippocampal neurogenesis in the past few years and we wanted to investigate its interaction with glucocorticoid in this study. METHODS: Adult rats were given vehicle, corticosterone, paroxetine, or both corticosterone and paroxetine for 14 d. Cell proliferation in the dentate gyrus was quantified using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. RESULTS: The corticosterone treatment suppressed while paroxetine treatment increased hippocampal cell proliferation. More importantly, paroxetine treatment could reverse the suppressive effect of corticosterone on hippocampal cell proliferation. CONCLUSION: This may have clinic application in preventing hippocampal damage after glucocorticoid treatment.

Web-based survey of depression, anxiety and stress in first-year tertiary education students in Hong Kong.

OBJECTIVE: The mental health of tertiary education students is an area of increasing concern worldwide. The objective of this study is to examine the prevalence of depression, anxiety and stress in first-year tertiary education students in Hong Kong. METHOD: Depression, anxiety and stress were measured by the 42-item Depression Anxiety Stress Scales, completed on the web by participating students anonymously. RESULTS: A total of 7915 students completed the survey, yielding a response rate of 27.5%. Depression, anxiety and stress levels of moderate severity or above were found in 21%, 41% and 27% of our respondents, respectively. CONCLUSIONS: The web-based survey methodology was well accepted by our sample group of tertiary education students. We found high rates of psychological morbidity in first-year tertiary education students in Hong Kong. The high prevalence of depression, anxiety and stress symptoms in the first year of college life is alarming. It illustrates the need for primary and secondary prevention measures, with development of adequate and appropriate support services for this group.