The interplay between sexual abuse and inflammation, oxidative stress, and DNA damage in drug-naïve panic disorder patients.

Although accumulating evidence suggests an interplay between child abuse and inflammatory processes and the pathophysiology of mental disorders, few studies have investigated the cellular mechanisms related to this matter. Furthermore, no studies to date have evaluated cytokine, oxidative stress, and DNA damage levels in drug-naïve panic disorder (PD) patients and their possible association with childhood trauma. The aim of the present study was to determine the levels of the proinflammatory interleukin (IL)-1B, the oxidative stress marker TBARS, and  8-hydroxy-2' -deoxyguanosine (8-OHdG; representing DNA damage) in drug-naïve PD patients compared to controls. Furthermore, this investigation aimed to determine whether early-life trauma could predict peripheral levels of the previously mentioned markers in unmedicated PD patients. This work showed that drug-naïve PD patients presented elevated levels of TBARS and IL-1B but not 8-OHdG compared to healthy controls. In addition, sexual abuse during childhood was associated with increased levels of IL-1B in PD patients. Our findings suggest that the microglial NLRP3 inflammasome complex might be activated in drug-naïve PD patients. This study is the first to associated sexual abuse with increased levels of IL-1B in drug-naïve PD patients and to demonstrate that this population presents high concentrations of oxidative stress and inflammation markers but not DNA damage markers when compared to healthy controls. Independent replication of these findings would support further clinical trials of inflammasome inhibitory drugs in PD patients, which could lead to effective novel treatments for people with PD and contribute to elucidating pathophysiological differences depending on trauma exposure in the immune disturbances accompanying PD.

The Effects of Tyrosine Kinase Inhibitors (TKIs) in Monotherapy and with Add-on Treatments on Health-related Quality of Life of People with Chronic Myeloid Leukemia: A Systematic Review of Randomized-Controlled Trials.

Background: The era of establishing tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) changed the outcome and the course of this life-threatening malignancy. People suffering from CML have now a better prognosis and a longer life expectancy due to the development of TKIs, even if it requires long-term, often lifelong, treatments that are nonetheless associated with improved Health-related Quality of life (HRQoL). However, data on the effects of TKIs on HRQoL are not always systematic; sometimes the data have been obtained by studies different from RCTs, or without a clear definition of what HRQoL is. The main purpose of this systematic review is to summarize all randomized-controlled trials (RCTs) including HRQoL as main or secondary outcome in patients with CML treated with TKIs or with TKIs plus an add-on treatment. Methods: A systematic review has been conducted by searching the relevant papers in PubMed/Medline and Web of Science with the following keywords: "quality of life" OR "health-related quality of life" OR "QoL" OR "HRQoL" OR "H-QoL" AND "chronic myeloid leukemia". Interval was set from January 2000 to December 2020. Results: 40 papers were identified through the search. Out of them, 7 RCTs were included. All the studies used standardized measures to assess HRQoL, even not always specific for CML. 5 RCTs randomized subjects to 2 or 3 arms to evaluate the effects of TKIs of the first, second and third generation in monotherapy. 2 RCTs randomized subjects to TKI therapy plus an add-on treatment versus TKI therapy as usual. The results of all these trials were examined and discussed. Conclusion: All the included RCTs pointed out significant findings regarding the positive effects of TKIs on HRQoL of people with CML, both when they were used in monotherapy or, notably, with an add-on treatment to enhance TKIs effects.

Clinical Utility of Semistructured Interview and Scales to Assess Withdrawal Syndromes With Dose Reduction or Discontinuation of Selective Serotonin Reuptake Inhibitors or Serotonin Norepinephrine Reuptake Inhibitors.

BACKGROUND: Withdrawal syndromes can occur after dose reduction or discontinuation of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Few measurement instruments are available to assess them: Diagnostic Clinical Interview for Drug Withdrawal 1-New Symptoms of SSRI and SNRI (DID-W1) and Discontinuation Emergent Signs and Symptoms (DESS) checklist. We assessed their interrater reliability, verified the percent agreement between the two, and tested DESS sensitivity and specificity on the basis of the diagnoses formulated via the DID-W1. METHODS: One-hundred thirty-four subjects who referred for withdrawal at 3 outpatient facilities were enrolled and assessed via the DESS and the DID-W1. Percent agreement and Cohen κ were calculated to measure DID-W1 and DESS interrater reliability, as well as the agreement between DID-W1 and DESS items. Sensitivity and specificity of DESS were derived from the identification of true-positive, false-negative, true-negative, and false-positive on the DID-W1. RESULTS: Both tools showed excellent interrater reliability (DID-W1 Cohen κ = 0.958; DESS Cohen κ = 0.81-1). The degree of agreement between DID-W1 and DESS items was poor or fair (Cohen κ < 0.40) for some items and moderate (Cohen κ = 0.41-0.60) for others. Sensitivity and specificity of DESS were 0.937 (true-positive = 60, false-negative = 4) and 0.285 (true-negative = 20, false-positive = 50), respectively. CONCLUSIONS: DID-W1 was a reliable method to identify and diagnose withdrawal syndromes. The DESS checklist showed to be a useful tool for detecting withdrawal SSRI/SNRI symptoms when the aim is to achieve high sensitivity to identify true positives.

Therapist-Guided Versus Self-Guided Cognitive-Behavioral Therapy: A Systematic Review.

Objective: To evaluate traditional versus guided cognitive-behavioral therapy (CBT) with the use of applications and technological innovations.Data Sources: A systematic search was conducted in the MEDLINE/PubMed, SciELO, and Cochrane Library databases and included randomized controlled trials (RCTs) from inception to March 30, 2023, with no language restrictions. Only RCTs with available text were included, which is valid from the app versus traditional CBT comparison perspective. The search terms were "apps" OR "app" AND "cognitive behavior therapy" OR "self-guided cognitive behavioral therapy" OR "cognitive behavior therapy" OR "CBT" OR "self-guided CBT" OR "iCBT" OR "unguided iCBT."Study Selection: Six RCTs were included in this review.Results: The results of all the studies were positive for the use of applications and the internet, and the findings were encouraging for new methods of guided therapy and the inclusion of technology.Conclusions: There is a need for studies that assess the mental health of individuals using and supporting technology, but these findings are encouraging for the continuation of the research.Prim Care Companion CNS Disord 2024;26(2):23r03566. Author affiliations are listed at the end of this article.

Challenges in the treatment of dysthymia: a narrative review.

INTRODUCTION: Despite its milder severity, the chronic nature of dysthymia leads to significant impairments and functional limitations. The treatment of dysthymia has received considerably less research attention compared to major depressive disorder (MDD). AREAS COVERED: The authors have conducted a comprehensive review on the treatment of dysthymia. Their primary objective was to identify therapeutic options that have demonstrated genuine efficacy. To do this, they searched the PubMed database, without any time restrictions, to retrieve original studies. The samples were exclusively comprised individuals diagnosed with dysthymia according to the diagnostic criteria outlined in DSM-III, DSM-III-R, DSM-IV, or DSM-IV-TR. EXPERT OPINION: Within the realm of dysthymia treatment, several antidepressants, including imipramine, sertraline, paroxetine, minaprine, moclobemide, and amineptine, in addition to the antipsychotic agent amisulpride, have demonstrated superiority over placebo. In certain studies, psychotherapeutic interventions did not distinguish themselves significantly from pharmacological treatments and failed to exhibit greater efficacy than a placebo. However, these findings remain inconclusive due to the limited number of studies and substantial methodological limitations prevalent in a significant proportion of them. Limitations include factors like small sample sizes, the absence of placebo comparisons, and a lack of study blinding.

The S20 Brazilian Mental Health Report for Building a Just World and a Sustainable Planet: Part II.

This is the second part of the Brazilian S20 mental health report. The mental health working group is dedicated to leveraging scientific insights to foster innovation and propose actionable recommendations for implementation in Brazil and participating countries. In addressing the heightened mental health challenges in a post-pandemic world, strategies should encompass several key elements. This second part of the S20 Brazilian Mental Health Report will delve into some of these elements, including: the impact of climate change on mental health, the influence of environmental factors on neurodevelopmental disorders, the intersection of serious mental illness and precision psychiatry, the co-occurrence of physical and mental disorders, advancements in biomarkers for mental disorders, the utilization of digital health in mental healthcare, the implementation of interventional psychiatry, and the design of innovative mental health systems integrating principles of innovation and human rights. Reassessing the treatment settings for psychiatric patients within general hospitals, where their mental health and physical needs are addressed should be prioritized in mental health policy. As the S20 countries prepare for the future, we need principles that stand to advance innovation, uphold human rights, and strive for the highest standards in mental health care.

An update on the pharmacotherapeutic strategies for the treatment of dysthymic disorder: a systematic review.

INTRODUCTION: Longer treatment times, more comorbidity, more severe impairments in social, psychological, and emotional functioning, increased healthcare use, and more hospitalizations are all factors that are related to dysthymia. Given the significant prevalence of dysthymia (including persistent depressive disorder) worldwide, its comorbidity with several mental disorders, and the detrimental effects of these comorbidities, it is important to conduct a systematic review to compare the effects of pharmacological acute and maintenance treatments for dysthymia with placebo and standard care in the last 10 years, based on the publication of DSM5. AREAS COVERED: This systematic review was performed according to PRISMA guidelines. Databases, including PubMed and Cochrane Central Register of Controlled Trials, were searched to assess the effects of pharmacological acute and maintenance treatments for dysthymia in comparison with placebo and treatment as usual. EXPERT OPINION: Our review shows that SSRIs and SNRIs present efficacy for dysthymia treatment, and L-Acetylcarnitine should be investigated further for this condition in elderly patients. The comparison of antidepressant medication versus placebo showed coherent results based on three studies favoring pharmacotherapy as an effective treatment for participants with dysthymia. However, the scarcity of research on continuation and maintenance therapy in people with dysthymia highlights the need for more primary research.

Cytokine profile in drug-naïve panic disorder patients.

Although accumulating evidence suggests that inflammatory processes play a role in the pathophysiology of mental disorders, few studies have investigated this matter in panic disorder (PD). Furthermore, no studies to date have evaluated cytokine levels in drug-naïve patients with PD. Therefore, little is known about the presence of inflammation at the onset of this disorder. The aim of the present study was to determine the levels of the proinflammatory interleukins IL-1B and IL-2R and the anti-inflammatory cytokine IL-10 in drug-naïve PD patients. Analysis of serum chemokine levels revealed increased proinflammatory activity in the early phase of PD through increased IL-2R and IL-1B levels and a decrease in IL-10 levels in drug-naïve PD patients compared to matched healthy controls. Neurotransmitters and neurocircuits that are targets of inflammatory responses are discussed, followed by an examination of brain-immune interactions as risk factors for PD. This study is the first to identify a proinflammatory cytokine response in drug-naïve PD subjects. These findings indicate that treatments targeting proinflammatory markers may ameliorate anxiety symptoms in PD patients.

A cross-sectional healthy-control study of serum inflammatory biomarkers interleukin (IL)-1B and IL-2R in panic disorder patients and their offspring.

Alterations in the immune system have been associated with a variety of mental illnesses. An increase in circulating inflammatory cytokines is observed not only in people with mental disorders but also in their first-degree relatives. A considerable amount of data support the link between immune system activation and panic disorder (PD) pathogenesis, while it is still unclear whether differential immunological reactivity represents a propensity, a measure of disease activity, or both. To better understand the role of cytokines in PD pathophysiology, we compared the levels of serum inflammatory biomarkers interleukin (IL)-1B and IL-2R among PD patients, offspring of PD patients and healthy controls. The offspring of PD patients were evaluated by a psychiatrist and were considered unaffected by any mental disorder at the time of the evaluation. Concentrations of the cytokines IL-1B and IL-2R were assessed using the Immulite System (Diagnostic Products Corporation). The levels of proinflammatory markers IL-1B and IL-2R were increased in PD patients compared to those of controls, but offspring of PD patients and healthy controls demonstrated no differences regarding peripheral interleukin levels. Our findings suggest that interleukins might represent a disease-dependent marker in PD.

The relationship between emotional regulation and hemispheric lateralization in depression: a systematic review and a meta-analysis.

From a neurobiological perspective, diverse studies have associated emotional regulation with cognitive deficits. Structural and/or metabolic changes in the frontal cortex are often inferred from dysfunction in cognitive-emotional processing. In addition, electroencephalographic findings support the idea that alpha band oscillations are responses to these same processes. Thus, the objective of this meta-analytical literature review is to verify whether the possible hemispheric lateralization attributed to frontal alpha asymmetry (FAA) correlates with emotional regulation and the cognitive deficits underlying depression. The data included in our meta-analysis are from articles published from 2009 to July 2020, which utilized DSM or ICD criteria to diagnose depression or anxiety disorders and included a control group. For statistical analysis, the measurements obtained through the 10-20 electroencephalography system were used. The frontal alpha asymmetry index was calculated from the difference between the logarithm of the absolute spectral values in the alpha rhythm observed from the F4 and F3 electrodes that were fixed to the scalp of the frontal region of the right and left hemispheres (ln µV² RH-ln µV² LH) = (F4-F3). Eighteen articles were included in the systematic review. Of these, 9 were homogeneous enough for statistical analyses (total N: 1061; NDep: 326; Ncont: 735). Nine others could not be statistically analyzed due to the absence of FAA measurements from the F4 and F3 electrodes. A random effects meta-analysis revealed low heterogeneity (Qt = 11,00, df = 8, p = 0.20, I2 = 27%) and an average effect size of the studies equal to -0.03 (CI = [-0.07 to 0.01]). The results, although not significant, suggested a slight tendency toward left lateralization in the depression group. Although the effects shown in these data did not confirm hemispherical lateralization in depressed patients, it was found that emotional regulation and cognitive processes share similar neural circuits. Therefore, future research on this complex relationship is encouraged, especially studies that are focused on the search for quantitative biological markers in depression.

Lifetime psychopathology in the offspring of parents with anxiety disorders: A systematic review.

BACKGROUND: The offspring of parents with Anxiety Disorders (AD) are at high risk for different types of psychopathology, including AD. However, little is known about how parental anxiety during pregnancy and/or the postnatal period might result in alterations in behavior or neurodevelopmental changes in offspring. To examine the effect of parental AD on offspring behavior and neurodevelopment, we conducted a systematic review. METHODS: Following PRISMA guidelines, we searched the Web of Science, PubMed, and PsycINFO databases. RESULTS: Forty-seven articles met the inclusion criteria for the systematic review. Prenatal maternal anxiety is related to negative temperament, increased attention to fearful vocalizations, decreased alertness, and impaired psychomotor and cognitive development in early and middle childhood. AD during the postnatal period is associated with greater negative temperament, internalizing symptoms, and anxiety symptoms in early childhood, middle childhood, and adolescence. CONCLUSION: Our review is the first to demonstrate that prenatal and postnatal AD symptoms impact offspring. Future research should explore the mediating and moderating factors leading to the development of psychopathology in the offspring of parents with AD.

Depression and anxiety among online learning students during the COVID-19 pandemic: a cross-sectional survey in Rio de Janeiro, Brazil.

BACKGROUND: The COVID-19 pandemic introduced a global need to explore the potential and challenges of online education. OBJECTIVE: To evaluate the presence of depression and anxiety in university students and their level of satisfaction with online learning during the period of social isolation caused by the COVID-19 pandemic. METHOD: A cross-sectional design was used to evaluate 152 online learning students from six different university courses: Medicine, Psychology, Law, Engineering, Physiotherapy, and Business. The evaluation of the participants was carried out through an online survey in Rio de Janeiro, Brazil. Also, the Hospital Anxiety and Depression Scale was used to assess participants mental health. RESULTS: Most of the participants reported emotional impact, followed by learning impact, financial impact, social impact, and technological impact, with a significant difference in the presence of depressive symptoms, but no significant difference in anxiety. The participants presented moderate anxiety levels, with no significant differences between genders, and mild levels of depressive symptoms with significant differences between genders. Also, younger students were more anxious than older students. In addition, female students with less social contact presented more depressive symtoms. CONCLUSION: From a clinical perspective, the findings provide insights into mental health among university students during the COVID-19 pandemic. These findings may help in the development of effective screening strategies and in the formulation of interventions that improve the mental health of students.

Maternal immune activation generates anxiety in offspring: A translational meta-analysis.

Maternal immune activation (MIA) during pregnancy is recognized as an etiological risk factor for various psychiatric disorders, such as schizophrenia, major depressive disorder, and autism. Prenatal immune challenge may serve as a "disease primer" for alteration of the trajectory of fetal brain development that, in combination with other genetic and environmental factors, may ultimately result in the emergence of different psychiatric conditions. However, the association between MIA and an offspring's chance of developing anxiety disorders is less clear. To evaluate the effect of MIA on offspring anxiety, a systematic review and meta-analysis of the preclinical literature was conducted. We performed a systematic search of the PubMed, Web of Science, PsycINFO, and Cochrane Library electronic databases using the PRISMA and World Health Organization (WHO) methodologies for systematic reviews. Studies that investigated whether MIA during pregnancy could cause anxiety symptoms in rodent offspring were included. Overall, the meta-analysis showed that MIA induced anxiety behavior in offspring. The studies provide strong evidence that prenatal immune activation impacts specific molecular targets and synapse formation and function and induces an imbalance in neurotransmission that could be related to the generation of anxiety in offspring. Future research should further explore the role of MIA in anxiety endophenotypes. According to this meta-analysis, MIA plays an important role in the pathophysiological mechanisms of anxiety disorders and is a promising therapeutic target.

Physical abuse during childhood predicts IL-2R levels in adult panic disorder patients.

BACKGROUND: Childhood maltreatment confers higher risk of adulthood mental disease. However, the biological mechanism mediating this association remains largely unknown, with evidence suggesting dysregulation of the immune system as a possible biological mediator. The present paper conducted a case-control study to establish whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult Panic Disorder (PD) individuals. METHODS: Eighty-four PD patients and seventy-eight matched healthy controls were assessed for peripheral serum levels of interleukin (IL)-2R, IL-1ß, IL-10, and for specific trauma types through child trauma questionnaire evaluation. RESULTS: Analyses for specific types of trauma (sexual, physical or emotional abuse or neglect) revealed that these impact differentially the single inflammatory markers, and a significant association between physical abuse and the inflammatory marker IL-2R in PD patients was observed (ß = 0.40, p = 0.013). The analysis demonstrates that childhood trauma contributes to a proinflammatory state in adulthood, with specific inflammatory profiles counting on the specific type of traumatic event. CONCLUSION: This study is unique in providing inflammatory biomarkers evidence of distinct biological modifications in PD in the presence or absence of exposure to childhood abuse. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in PD and may have implications for personalized medicine.

Panic disorder respiratory subtype: psychopathology and challenge tests - an update.

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Elevated peripheral kynurenine/tryptophan ratio predicts poor short-term auditory memory in panic disorder patients.

Abnormalities in the kynurenine pathway (KP) have been implicated in the cognitive deficits of psychiatry disorders, possibly through cytokines that increase the activity of indoleamine-2,3 dioxygenase (IDO), a key enzyme for tryptophan-to-kynurenine conversion. Some studies on panic disorder (PD) have detected elevated cytokines in blood. We aimed to determine the extent to which elevated peripheral cytokine levels and kynurenine/tryptophan (kyn/tryp) ratio (1) are biological markers for PD patients and (2) are related to cognition in PD. Seventy-eight PD patients and matched healthy controls were assessed for peripheral serum levels of interleukin (IL)-2R, IL-1ß, IL-10, kynurenine and tryptophan. The subjects were evaluated for episodic and short-term memory, selective attention and cognitive flexibility. In patients, IL-2R levels, which are involved in the regulation of IDO, were significantly associated with levels of kynurenine (p = .029), but this association was not observed in controls. Importantly, an elevated kyn/tryp ratio significantly predicted poor digit span forward (p = .004) and total (p = .004) scores in individuals with PD. This study is the first to link blood biomarkers of infiammation and the KP with cognitive deficits in PD subjects, suggesting that those with an elevated kyn/tryp ratio might have short-term auditory memory impairment. These findings indicate that treatments targeting the KP may ameliorate cognitive abnormalities in PD patients.

Selective serotonin reuptake inhibitors and benzodiazepines in panic disorder: A meta-analysis of common side effects in acute treatment.

BACKGROUND: Benzodiazepines (BZs) and selective serotonin reuptake inhibitors (SSRIs) are effective in the pharmacologic treatment of panic disorder (PD). However, treatment guidelines favor SSRIs over BZs based on the belief that BZs are associated with more adverse effects than SSRIs. This belief, however, is currently supported only by opinion and anecdotes. AIM: The aim of this review and meta-analysis was to determine if there truly is evidence that BZs cause more adverse effects than SSRIs in acute PD treatment. METHODS: We systematically searched Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and clinical trials register databases. Short randomized clinical trials of a minimum of four weeks and a maximum of 12 weeks that studied SSRIs or BZs compared to placebo in acute PD treatment were included in a meta-analysis. The primary outcome was all-cause adverse event rate in participants who received SSRIs, BZs, or placebo. RESULTS: Overall, the meta-analysis showed that SSRIs cause more adverse events than BZs in short-term PD treatment. Specifically, SSRI treatment was a risk factor for diaphoresis, fatigue, nausea, diarrhea, and insomnia, whereas BZ treatment was a risk factor for memory problems, constipation, and dry mouth. Both classes of drugs were associated with somnolence. SSRIs were associated with abnormal ejaculation, while BZs were associated with libido reduction. BZs were protective against tachycardia, diaphoresis, fatigue, and insomnia. CONCLUSION: Randomized, blinded studies comparing SSRIs and BZs for the short-term treatment of PD should be performed. Clinical guidelines based on incontrovertible evidence are needed.

The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders.

Increases in the activated state of microglia, the main neuroimmune cells, are widely reported in the brains of patients with neurological and psychiatric disorders. Microglia transform from the resting to the activated state by sensing their environment, aided by a variety of ion channels. To examine the effect of ion channels on microglial phenotypes, we conducted a systematic review of immunohistochemical analyses of these neuroimmune cells in animal models following administration of ion channel antagonists, compared to control conditions. A systematic search of the PubMed and Web of Science electronic databases using the PRISMA and WHO methodologies for systematic reviews yielded 15 original peer-reviewed studies. The majority (13 out of 15) of these studies reported a decrease in microglial activated state after ion signaling pharmacological blockade. The studies provide evidence that acute administration of ion channel antagonists leads to a reduction in microglial activation in rodent brains in the models for epilepsy, Parkinson's disease, inflammation, pain, ischemia, and brain and spinal cord injury. Future research should explore microglial-specific druggable targets for neurological and psychiatric disorders. The investigation of acute and chronic administration of ion channel antagonists in microglial phenotypes in primates and the development of microglia-like cells derived from human stem cells could be valuable sources in this direction.