Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.

Autoantibodies and Psychosis.

Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.

A Brief History of Immunological Research into Psychosis and Pathways for Immune Influence of the Brain.

Infection and inflammation resulting from a malfunctioning of the immune system have been discussed as pathological factors in psychosis for more than 130 years. The first immune-modulating therapeutic approaches for psychosis were developed more than 100 years ago, but the breakthrough of antipsychotic treatment in the 1950s shifted the emphasis of research to catecholaminergic neurotransmission. In the 1990s, however, the unsatisfactory therapeutic effects of antipsychotics, and the fact that the pathological mechanisms of psychosis were still unknown, reignited the scientific interest in other topics, including inflammation. In parallel, the further development of immunological methods enabled a more sophisticated examination of immunological and inflammatory mechanisms. Psychiatrists' interest in this interdisciplinary field increased as a consequence of encouraging results of psychoneuroimmunological research and broader funding of the field. In the meantime, the benefits of anti-inflammatory treatment in psychosis have been demonstrated in clinical studies and meta-analyses. Future studies are warranted to evaluate the exact immunological mechanisms in the pathophysiology of the disease, optimize the anti-inflammatory treatment approach and develop more targeted, personalized therapies in psychosis.

Effects of omega-3 PUFA on immune markers in adolescent individuals at ultra-high risk for psychosis - Results of the randomized controlled Vienna omega-3 study.

Alterations of immune function have been reported in ultra-high risk (UHR) for psychosis patients causing expectations in terms of predictive meaningfulness and benefits of anti-inflammatory agents. According to a RCT in UHR-patients supplementation of omega-3 polyunsaturated fatty acids (PUFA) was effective in reducing transition to psychosis risk and to improve symptomatology. Based on preclinical findings, we now investigated state marker properties of and the influence of PUFA on immune markers in a RCT (clinical trials.gov Identifier: NCT00396643). In a longitudinal design we measured plasma levels of the pro-inflammatory interleukin 6 (IL-6), the soluble alpha (Tac) subunit of the interleukin 2 receptor (sIL-2r), and the circulating soluble form of the intercellular adhesion molecule one (sICAM-1), in 79 help-seeking UHR individuals (13-25years of age). Using linear mixed model (LMM) analysis, we investigated the effects of 12weeks supplementation of either 1.2g/d PUFA (n=38) or Placebo (n=41). At baseline, inflammatory markers were not altered in patients who later suffered transition to psychosis within one year (n=12; 11 PUFA-group, 1 PL-group). IL-6 was weakly inverse associated with omega-6 PUFA, and highly increased in nicotine users. In univariate tests of the LMM omega-3 PUFA caused a significant increase of sICAM-1 (p=0.022). PUFA did not significantly influence IL-6 or sIL-2r. The enhancement of sICAM-1 in the PUFA condition is suggestive for supportive effects on vascular immune response and immediate Th1 helper cell mediated immune answer, which was found disturbed in manifest schizophrenia, e.g. by facilitating the leukocyte adhesion and migration across the endothelium.

Low vitamin D is associated with negative and depressive symptoms in psychotic disorders.

BACKGROUND: There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers. METHODS: Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes. RESULTS: Low S-25(OH)D was significantly associated with negative symptoms (adjusted R2=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R2=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant. CONCLUSION: There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.

Is it time for immunopsychiatry in psychotic disorders?

INTRODUCTION: Immune dysregulation is suggested to play an important aetiological role in schizophrenia (SZ) and bipolar disorder (BD) potentially driving neurodevelopmental pathways. Immune dysfunction may precede the onset of psychiatric disorders and parallel the development of multiaxial comorbidity, including suicidal behaviour and metabolic and autoimmune disorders. Depicting the source of the chronic low-grade inflammatory component in SZ and BD is thus a research priority. Strong environmental insults early in life, such as infections, acting on a background of genetic vulnerability, may induce potent and enduring inflammatory responses setting a state of liability to second-hit environmental encounters, namely childhood trauma, drug abuse or additional infectious exposures. The immunogenetic background of susceptibility, suggested to be not only lying within the HLA locus but also implicating inherited deficits of the innate immune system, may amplify the harmful biological effects of infections/psychosocial stress leading to the manifestation of a broad range of psychiatric symptoms. OBJECTIVES: The present review aims to discuss the following: (i) biological arguments in favour of a chronic low-grade inflammation in SZ and BD and its potential origin in the interaction between the immunogenetic background and environmental infectious insults, and (ii) the consequences of this inflammatory dysfunction by focusing on N-methyl-D-aspartate (NMDA) receptor antibodies and activation of the family of human endogenous retroviruses (HERVs). CONCLUSIONS: Specific therapeutic approaches targeting immune pathways may lead the way to novel personalized medical interventions, improvement of quality of life and average life expectancy of psychiatric patients, if not even prevent mood episodes and psychotic symptoms.

Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness.

RATIONALE: Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before. OBJECTIVES: This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders. METHODS: A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text. RESULTS: Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus. CONCLUSIONS: There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.

Psychiatric symptoms in systemic lupus erythematosus: a systematic review.

OBJECTIVE: Systemic lupus erythematosus (SLE) presents with psychiatric symptoms in most patients that often remain undiagnosed and untreated. This study evaluates the prevalence of psychiatric symptoms in SLE on the basis of clinical trials that fulfilled diagnostic criteria specified by the American College of Rheumatology (ACR). Current hypotheses explaining the pathogenesis of psychiatric symptoms of lupus are reviewed to gain new insights into the neuroimmune pathogenesis of other psychiatric disorders. DATA SOURCE: A MEDLINE search of the literature (English language only) from April 1999 to August 2011 was performed using the search terms lupus and psychiatric to identify studies of neuropsychiatric SLE. STUDY SELECTION: Of 163 publications, 18 clinical studies were selected that focused on psychiatric symptoms, had a sample size of at least 20, and included patients of any age or gender as long as they fulfilled ACR criteria for neuropsychiatric SLE. DATA EXTRACTION: The following data were extracted: author name, year of publication, psychiatric diagnostic method, total number of patients with SLE, and percentage of patients with individual psychiatric diagnoses. The point prevalence of psychiatric symptoms was calculated for neuropsychiatric SLE diagnoses in every study included. RESULTS: Psychiatric symptoms are present in the majority of patients with SLE. Depression (in up to 39% of patients) and cognitive dysfunction (up to 80%) are the most common psychiatric manifestations. Genetic and environmental factors (eg, ultraviolet light, retroviruses, and medications) may play a role in the pathogenesis. In addition, the patient's reaction to the illness may result in anxiety (up to 24%) and depression. Currently known biomarkers are nonspecific for neuropsychiatric SLE and indicate inflammation, microglial activation, ischemia, oxidative stress, mitochondrial dysfunction, and blood-brain barrier dysfunction. CONCLUSIONS: Identification of lupus-specific biomarkers of psychiatric symptoms is a high priority. Our current diagnostic assessment methods need improvement. Development of evidence-based guidelines is needed to improve diagnosis, prevention, and treatment of disabling psychiatric complications in lupus.

T- and B-lymphocytes in patients with schizophrenia in acute psychotic episode and the course of the treatment.

Schizophrenia is associated with alterations of the immune system. There are, however, only limited data dealing with immune parameters in unmedicated schizophrenic patients and the course of these parameters during treatment. In this study, we monitored CD19+ (B)- and CD3+ (T)-lymphocytes in the course of antipsychotic treatment. Forty patients diagnosed with an acute exacerbation of schizophrenia were tested before and after 3 days, 2 weeks, 4 weeks and 3 months of treatment with antipsychotics. The percentages of CD19+- and CD3+ -lymphocytes were analysed by flow cytometry using fluorescence conjugated anti-CD19 and anti-CD3 antibodies. Twenty healthy volunteers served as controls. In the acute state of psychosis, a significant reduction of the CD3+ -lymphocyte subpopulation was observed, while the percentage of CD19(+)-lymphocytes was increased. Both subpopulations levelled to those of the control group in the course of treatment. As expected, the levels of the immune parameters did not change in the healthy controls during the course of the study. The observed alterations of the CD19+ - and CD3+ -lymphocytes in the acute state of psychosis especially in patients with the paranoid subtype of schizophrenia, and the "normalization" during the observation period are discussed under the aspect of the immune hypothesis of schizophrenia, in particular of the type-1/type-2 imbalance hypothesis.