International study of the Complex Stress Reaction Syndrome: Implications for transdiagnostic clinical practice.

BACKGROUND: The debate regarding diagnostic classification systems in psychiatry (categorial vs dimensional systems) has essential implications for the diagnosis, prevention and treatment of stress reactions. We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries, and termed it the Complex Stress Reaction Syndrome (CSRS). AIM: To investigate CSRS, Type A (psychiatric symptoms, spanning anxiety, depression, stress symptoms, and post-traumatic stress disorder (PTSD)), with or without long-coronavirus disease (COVID) residuals (CSRS, Type B, neuropsychiatric symptoms spanning cognitive deficits and fatigue, excluding systemic symptoms). Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population (Type A) or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals (Type B). METHODS: 977 individuals in four continents (North America, Europe, Australia and the Middle East) completed the online study questionnaire in six languages using the Qualtrics platform. The study was managed by six teams in six countries that promoted the study on social media. The questionnaire assessed anxiety, depression, stress symptoms and PTSD (CSRS, Type A), cognitive deficits and fatigue (CSRS, Type B). The data were analyzed using Proportion Analyses, Multivariate Analysis of Co-Variance (MANCOVA), linear regression analyses and validated clinical cutoff points. RESULTS: The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety, depression, stress symptoms, and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents, age groups, and gender. This supports the transdiagnostic argument embedded in the CSRS (Type A). The same pattern of results was found in infected/recovered individuals. The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms, when adding cognitive deficits and fatigue, respectively. MANCOVA showed a significant three-way interaction (age × gender × continent). Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk: (1) Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS, Type A at young age groups (< 50 years old) in North America compared to (self-identified) women and men located in the 4 continents studied, and to other ages across the adult life span; and (2) This pattern of results (CSRS, Type A) was found also in women at young ages (< 40 years old) in North America who scored higher compared to men and women in other continents and other ages. Linear regression analyses confirmed the MANCOVA results. CONCLUSION: These results show a combined mental health risk factor related to stress reactivity, suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations. It also supports the transdiagnostic approach for more accurate prevention and treatment. Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

Not one thing at a time: When concomitant multiple stressors produce a transdiagnostic clinical picture.

A condition of exposure to multiple stressors resulting in a mixed clinical picture spanning conventional categories without meeting any of them in full, encompasses a risk for a list of comorbidities preventing appropriate prevention and treatment. New transformative transdiagnostic approaches suggest changes spanning conventional categories. They base their systems of classification on biomarkers as well as on brain structural and functional dysregulation as associated with behavioral and emotional symptoms. These new approaches received critiques for not being specific enough and for suggesting a few biomarkers for psychopathology as a whole. Therefore, they put the value of differential diagnosis at risk of avoiding appropriate derived prevention and treatment. Multiplicity of stressors has been considered mostly during and following catastrophes, without considering the resulting mixed clinical picture and life event concomitant stressors. We herewith suggest a new category within the conventional classification systems: The Complex Stress Reaction Syndrome, for a condition of multiplicity of stressors, which showed a mixed clinical picture for daily life in the post coronavirus disease 2019 era, in the general population. We argue that this condition may be relevant to daily, regular life, across the lifespan, and beyond conditions of catastrophes. We further argue that this condition may worsen without professional care and it may develop into a severe mental health disorder, more costly to health systems and the suffering individuals. Means for derived prevention and treatment are discussed.

Transdiagnostic considerations of mental health for the post-COVID era: Lessons from the first surge of the pandemic.

BACKGROUND: The Coronavirus disease 19 (COVID-19)-related psychiatric burden partly results from prolonged social stress world-wide. Studies have examined the psychiatric impact of COVID-19 on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) and International Classification of Diseases 11th Revision (ICD-11) categories, implicating multiple diagnoses, complicating clinical management. AIM: To verify whether COVID-19-related psychopathology spans multiple DSM-5 and ICD-11 diagnoses, but not in a random pattern. Consequently, empirical analysis of the multiple associated symptoms will better describe COVID-19-related psychopathology. METHODS: We conducted a bi-national study during the first surge of the pandemic: an Italian sample (n = 21217, studied March-April 2020); and three representative longitudinal samples from Israel (n = 1276, 1189, and 1432 respectively, studied May-July 2020). Data in Italy were collected by a national internet-based survey with an initially approached sample of about one million persons and in Israel by the Israeli Central Bureau of Statistics using probability-based national representative sampling. Data analysis focused on the frequency and patterns of reported multiple mental health symptoms. RESULTS: Combinations with all symptoms were more prevalent than combinations with fewer symptoms, with no majorities-minorities differences in both countries, demonstrating the generalizability of the transdiagnostic pattern of mental health issues in both nations. A history of previous mental disorder (Italian study) and an increase in symptom prevalence over time (Israel study) were associated with an increased number of symptoms. Conclusions: Based on finding correlated symptom diversity spanning conventional diagnostic categories, we suggest that the pattern of mental health issues associated with the COVID-19 pandemic is transdiagnostic. CONCLUSION: The findings have implications for improving prevention and treatment of COVID-19 related psychopathology and for post-pandemic times in conditions resulting from multiplicity of stressors with mixed symptomatology in the clinical picture.

Does COVID-19 related symptomatology indicate a transdiagnostic neuropsychiatric disorder? - Multidisciplinary implications.

The clinical presentation that emerges from the extensive coronavirus disease 2019 (COVID-19) mental health literature suggests high correlations among many conventional psychiatric diagnoses. Arguments against the use of multiple comorbidities for a single patient have been published long before the pandemic. Concurrently, diagnostic recommendations for use of transdiagnostic considerations for improved treatment have been also published in recent years. In this review, we pose the question of whether a transdiagnostic mental health disease, including psychiatric and neuropsychiatric symptomology, has emerged since the onset of the pandemic. There are many attempts to identify a syndrome related to the pandemic, but none of the validated scales is able to capture the entire psychiatric and neuropsychiatric clinical presentation in infected and non-infected individuals. These scales also only marginally touch the issue of etiology and prevalence. We suggest a working hypothesis termed Complex Stress Reaction Syndrome (CSRS) representing a global psychiatric reaction to the pandemic situation in the general population (Type A) and a neuropsychiatric reaction in infected individuals (Type B) which relates to neurocognitive and psychiatric features which are part (excluding systemic and metabolic dysfunctions) of the syndrome termed in the literature as long COVID. We base our propositions on multidisciplinary scientific data regarding mental health during the global pandemic situation and the effects of viral infection reviewed from Google Scholar and PubMed between February 1, 2022 and March 10, 2022. Search in-clusion criteria were "mental health", "COVID-19" and "Long COVID", English language and human studies only. We suggest that this more comprehensive way of understanding COVID-19 complex mental health reactions may promote better prevention and treatment and serve to guide implementation of recommended administrative regulations that were recently published by the World Psychiatric Association. This review may serve as a call for an international investigation of our working hypothesis.

Development of the Ontogenetic Self-Regulation Clock.

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed "the self-regulation clock" and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the "clock" circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates.

Between Action and Emotional Survival During the COVID-19 era: Sensorimotor Pathways as Control Systems of Transdiagnostic Anxiety-Related Intolerance to Uncertainty.

Objectives: The COVID-19 pandemic and aligned social and physical distancing regulations increase the sense of uncertainty, intensifying the risk for psychopathology globally. Anxiety disorders are associated with intolerance to uncertainty. In this review we describe brain circuits and sensorimotor pathways involved in human reactions to uncertainty. We present the healthy mode of coping with uncertainty and discuss deviations from this mode. Methods: Literature search of PubMed and Google Scholar. Results: As manifestation of anxiety disorders includes peripheral reactions and negative cognitions, we suggest an integrative model of threat cognitions modulated by sensorimotor regions: "The Sensorimotor-Cognitive-Integration-Circuit." The model emphasizes autonomic nervous system coupling with the cortex, addressing peripheral anxious reactions to uncertainty, pathways connecting cortical regions and cost-reward evaluation circuits to sensorimotor regions, filtered by the amygdala and basal ganglia. Of special interest are the ascending and descending tracts for sensory-motor crosstalk in healthy and pathological conditions. We include arguments regarding uncertainty in anxiety reactions to the pandemic and derive from our model treatment suggestions which are supported by scientific evidence. Our model is based on systematic control theories and emphasizes the role of goal conflict regulation in health and pathology. We also address anxiety reactions as a spectrum ranging from healthy to pathological coping with uncertainty, and present this spectrum as a transdiagnostic entity in accordance with recent claims and models. Conclusions: The human need for controllability and predictability suggests that anxiety disorders reactive to the pandemic's uncertainties reflect pathological disorganization of top-down bottom-up signaling and neural noise resulting from non-pathological human needs for coherence in life.

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico-Striatal Loop That Are Implicated in Major Depression.

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico-striatal-dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

Early life stress and development of the endocannabinoid system: A bidirectional process in programming future coping.

The endocannabinoid system (ECS) critically regulates stress responsivity and emotional behavior throughout development. It regulates anxiety-like behaviors in humans and animal models. In addition, it is sensitive to early life stress at the gene expression level in a sex-dependent and region-dependent manner, and these changes are already evident in the adolescent brain. The ECS modulates the neuroendocrine and behavioral effects of stress, and is also capable of being affected by stress exposure itself. Early life stress interferes with the development of corticolimbic circuits, a major location of endocannabinoid receptors, and increases vulnerability to adult psychopathology. Early life stress alters the ontogeny of the ECS, resulting in a sustained deficit in its function, particularly within the hippocampus. Specifically, exposure to early stress results in bidirectional changes in anandamide and 2-AG tissue levels within the amygdala and hippocampus and reduces hippocampal endocannabinoid function at puberty. CB1 receptor densities across all brain regions are downregulated later in life following exposure to early life stress. Manipulations affecting the glucocorticoid and the endocannabinoid systems persistently adjust individual emotional responses and synaptic plasticity. This review aims to show the bidirectional trajectories of endocannabinoid modulation of emotionality in reaction to early life stress.

The association between somatization and perceived ability: roles in dysmenorrhea among Israeli Arab adolescents.

OBJECTIVE: The aim of this study was to investigate whether somatization and attitudes toward menstruation predict the incidence of pain intensity and dysmenorrhea among Israeli Arab adolescent females. METHODS: Participants were 160 Israeli Arab adolescents, including 50 Muslims, 50 Christians, and 60 Druze. A 20-item questionnaire was used to assess attitudes regarding menstruation. The short version of the Brief Symptom Inventory was used to measure the level of somatization. RESULTS: Factor analysis of the Attitudes Toward Menstruation Instrument revealed two significant composites: perceived ability and impurity during menstruation. High levels of somatization predicted pain intensity and low levels of perceived ability predicted the prevalence of dysmenorrhea. Although the Israeli Muslim adolescents revealed higher levels of somatization as compared with their Christian and Druze counterparts and the Druze revealed the lowest levels of perceived ability compared with the other subgroups, no significant role for ethnicity and impurity was found. No differences were found between groups in scores of menstrual pain and prevalence of dysmenorrhea. Higher levels of somatization and lower levels of perceived ability, as well as a greater portion of Muslim and Druze and higher levels of religiosity, were found among rural residents. CONCLUSIONS: The role of cultural variables and personality traits in the complexity of dysmenorrhea as a socio-bio-psychological phenomenon is proposed in light of contemporary interactive models. It is suggested that within the Israeli Arab minorities the impact of cultural background on health affects more the perceptual and cognitive levels and are not generalized to overt behavior and morbidity such as dysmenorrhea.

Gender differences in the perception of chest pain.

This study investigated gender differences in pain perception as characterized by pain symptoms in patients diagnosed with unstable angina pectoris. Twenty-nine women and 32 men were asked to characterize their chest pain using a semi-open questionnaire assessing pain intensity (by numerical rating), pain location, pain characteristics, complaints following chest pain, factors that evoked or reduced chest pain, and whether the chest pain was related to heart disease. Significant gender differences were found. Women scored the intensity of their chest pain significantly higher than men (Chi-square 14.8, P < 0.0001), and related their chest pain less to heart disease (Chi-square 24.6, P < 0.0001). The women described an atypical clinical picture of chest pain that was significantly different from men's. The results are discussed in light of pschological theories regarding gender differences in pain perception. These findings imply the need for special attention to the unique clinical pictures that appear for women and men.