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.

Benzodiazepines: it's time to return to the evidence.

SUMMARY: We propose that discussions of benzodiazepines in the current psychiatric literature have become negatively biased and have strayed from the scientific evidence base. We advocate returning to the evidence in discussing benzodiazepines and adhering to clear definitions and conceptual rigour in commentary about them.

Sex, Digital Devices, Social Media, and Social Isolation: A Study on Sexual Behavioral During COVID -19 Pandemic.

INTRODUCTION: Coronavirus (COVID-19) pandemic has caused social and economic damages. People have adapted to a new reality of physical distance. OBJECTIVE: The study aimed to assess the use of digital devices and social media, focusing on psychosocial and demographic factors of people´s sexual behavior during the pandemic. METHODS: A total of 1,357 Brazilian adults participated in a cross-sectional online survey. They were recruited through social media to obtain information regarding sexual behavior and the use of digital devices and social media. RESULTS: Digital devices and social media were used by 38.8% of the participants. Among the group that used technological devices, most claimed to have changed their sexual behavior, with 76.9% consuming more sexual content through movies or series. CONCLUSION: In a smaller group, technological resources appeared as an alternative for safer sex, reducing the risks of COVID-19 transmission.

The Role of Anxiety Sensitivity and Expectancy Manipulation on Panic-Like Response to the 35% CO2 Challenge in Healthy Subjects.

BACKGROUND: The 35% CO2 challenge is a well-established method triggering panic attacks under laboratory-controlled conditions. There is an ongoing debate whether single or the joined effects of the instructional set and anxiety sensitivity (AS) can alter the outcome of the challenge. OBJECTIVES: The present study investigated the effects of instruction manipulation and AS on panic-like response to the 35% CO2 challenge. METHODS: Eighty healthy subjects, with high or low levels of AS, were randomized into 4 groups based on standard/manipulated instructional sets as well as 35% CO2 mixture/room air inhalation. Subjects filled in the Visual Analogue Scale of Anxiety (VAAS), the Visual Analogue Scale of Fear (VAS-F), the VAS of Discomfort (VAS-D), and the Panic Symptom List (PSL). Blood pressure and heart rate were measured at pre- and posttest. RESULTS: Hierarchical multiple regression analyses showed greater psychological responses at VAAS, VAS-F, VAS-D, and PSL and higher systolic blood pressure under 35% CO2 challenge if compared to room air inhalation while instructional set and AS did not influence the response. CONCLUSIONS: The present study confirms that neither instructional test nor AS alter the outcome of the 35% CO2 challenge.

Panic Disorder and Chronic Caffeine Use: A Case-control Study.

BACKGROUND: Acute administration of caffeine produces panic attacks in most Panic Disorder (PD) patients, but little is known about chronic caffeine use in these patients. OBJECTIVE: To assess caffeine use in patients with PD and to ascertain if caffeine consumption is associated with sociodemographic or clinical features. METHODS: 65 adults with PD and 66 healthy controls were included in the current study. Their caffeine intake within the previous week was quantified with a questionnaire and compared. Harmful caffeine use was defined as consumption above 400 mg/day of caffeine. We tested for correlations between caffeine intake, demographic and clinical features. RESULTS: Patients consumed significantly more caffeine than controls (P < 0.001). 14% (N = 9) of the PD patients made harmful use of caffeine. The use of caffeine-containing medications was observed in 40% (N = 26) of the PD patients and 6% (N = 4) of controls. Consumption of energy drinks was observed in 11% (N = 7) of PD patients and in none of the healthy subjects. Patients reported sleeping significantly less than controls (P < 0.001). In PD patients, caffeine consumption was not correlated with the presence of panic attacks or comorbidity with depression. The use of benzodiazepines or sedative medications was not correlated with caffeine intake. CONCLUSION: High caffeine consumption in PD patients could be explained by the development of tolerance with regular use of this substance. Subtypes of sensitive and non-sensitive PD patients could also explain why some of these patients are able to tolerate high doses of caffeine.

Tranylcypromine Plus Amitriptyline for Electroconvulsive Therapy-Resistant Depression: A Long-Term Study.

BACKGROUND: Few therapeutic options are available for patients with electroconvulsive therapy-resistant major depressive disorder (ECT-r MDD), leaving a substantial proportion of this population beyond treatment possibilities. The combination of monoamine oxidase inhibitors and tricyclic antidepressants could be a potential strategy for managing ECT-r MDD, and the specific association of amitriptyline and tranylcypromine may offer additional tolerability advantages. Although promising, in our knowledge, no studies have examined until now the effectiveness of this combination in ECT-r MDD. METHODS: We report a retrospective cohort of 31 patients with ECT-r MDD treated in an open-label fashion with the combination of amitriptyline and tranylcypromine. RESULTS: Overall, 80.6% of the sample met response criteria at the end of the first 12 weeks of treatment. Seventy-six percent (19 of 25) of the responders were followed for a mean of 9.37 ± 3.86 years. During this follow-up period, none of the patients had a recurring depressive episode. The combination was well tolerated, whereas minor adverse effects were common, and no severe or life-threatening events were reported throughout the study. CONCLUSIONS: These findings indicate that the combination tranylcypromine and amitriptyline is a potentially safe and effective candidate for future investigation in the treatment and long-term maintenance of ECT-r MDD.

A 6-Year Posttreatment Follow-up of Panic Disorder Patients: Treatment With Clonazepam Predicts Lower Recurrence Than Treatment With Paroxetine.

BACKGROUND: The aim of this study was to identify factors associated with relapse in panic disorder (PD). METHODS: This was an observational study conducted in the outpatient clinic of a psychiatric hospital in Rio de Janeiro, Brazil. In a previous study, 120 patients diagnosed as having PD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were randomized to receive clonazepam or paroxetine. After 3 years, treatment was discontinued in patients who had achieved remission. These subjects were included in the current study and were followed up for 6 years. The follow-up assessments were made at 1, 2, 3, 5, and 6 years after treatment discontinuation. Assessment included the number of panic attacks per month, Clinical Global Impression-Severity, and other measures. Patients who had initiated psychotherapy or pharmacological treatment because of PD symptoms or who had Clinical Global Impression-Severity scores greater than 1 or panic attacks in the month preceding the assessment were considered relapse cases. Data were collected from January 2003 to August 2012. RESULTS: Eighty-five patients completed the follow-up. Cumulative relapse rates were 50% (n = 33) at 1 year and 89.4% (n = 76) at 6 years. One-year relapse rates were lower in patients previously treated with clonazepam (P = 0.001) compared with those treated with paroxetine. Low 6-year relapse rates were associated with high Hamilton Anxiety Rating Scale scores before treatment (P = 0.016) and previous treatment with clonazepam. CONCLUSIONS: Relapse is a frequent problem in PD, and long-term treatment does not protect these patients in the long run. Treatment with clonazepam predicts lower relapse when compared with paroxetine.

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations.

Large-scale genotyping and next-generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

Agoraphobia Related to Unassertiveness in Panic Disorder.

Despite developments in panic disorder (PD) research, a significant percentage of patients do not benefit from conventional treatments. Interpersonal factors have been identified as potential predictors of treatment failures. We aimed to evaluate assertiveness in a sample of patients with PD and its implications for treatment. Forty-six symptomatic patients with PD and 46 college students responded to assessment scales regarding assertiveness and clinical data. Seventy-five percent of the patients had a secondary diagnosis of agoraphobia. We found that the PD group was characterized as nonassertive and slightly less assertive than control subjects. Furthermore, the deficit in the level of assertiveness correlated with the severity of the PD. The diagnosis of agoraphobia was correlated with unassertiveness (p < 0.05). Agoraphobia predisposes individuals to dependency and insecurity about their ability to overcome anxiogenic situations. These data demonstrate the importance of managing assertiveness in patients with PD accompanied by agoraphobia.

Mental Practice Combined with Motor Rehabilitation to Treat Upper Limb Hemiparesis of Post-Stroke Patients: Clinical and Experimental Evidence.

Stroke is one of the major causes of disability in the world. Due to the extended lifetime of the world's population, the number of people affected by stroke has increased substantially over the last years. Stroke may lead to sensorimotor deficits, usually causing hemiplegia or hemiparesia. In order to reduce motor deficits and accelerate functional recovery, MP combined with motor rehabilitation was introduced to the rehabilitation process of post-stroke patients. Evidence has shown that MP combining with motor rehabilitation based on activities of daily living was more effective than conventional motor rehabilitation used per se. This combination proved very useful and effective, with significant results in improvement of motor deficits in post-stroke patients. However, further studies must be conducted to determine specific parameters, such as type of imagery, frequency or duration.

Paranoid delusional disorder follows social anxiety disorder in a long-term case series: evolutionary perspective.

Social anxiety disorder (SAD) patients may have self-referential ideas and share other cognitive processes with paranoid delusional disorder (PDD) patients. From an evolutionary perspective, SAD may derive from biologically instinctive social hierarchy ranking, thus causing an assumption of inferior social rank, and thus prompting concerns about mistreatment from those of perceived higher rank. This naturalistic longitudinal study followed four patients with initial SAD and later onset of PDD. These four patients show the same sequence of diagnosed SAD followed by diagnosed PDD, as is often retrospectively described by other PDD patients. Although antipsychotic medication improved psychotic symptoms in all patients, those who also had adjunctive serotonin-specific reuptake inhibitors for SAD had much more improvement in both psychosis and social functioning. From an evolutionary perspective, it can be conjectured that when conscious modulation of the SAD social rank instinct is diminished due to hypofrontality (common to many psychotic disorders), then unmodulated SAD can lead to paranoid delusional disorder, with prominent ideas of reference. Non-psychotic SAD may be prodromal or causal for PDD.

Improvement of Psychotic Symptoms and the Role of Tissue Plasminogen Activator.

Tissue plasminogen activator (tPA) mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms.

Rimonabant effects on anxiety induced by simulated public speaking in healthy humans: a preliminary report.

OBJECTIVE: We investigated the hypothesis that rimonabant, a cannabinoid antagonist/inverse agonist, would increase anxiety in healthy subjects during a simulation of the public speaking test. METHODS: Participants were randomly allocated to receive oral placebo or 90 mg rimonabant in a double-blind design. Subjective effects were measured by Visual Analogue Mood Scale. Physiological parameters, namely arterial blood pressure and heart rate, also were monitored. RESULTS: Twelve participants received oral placebo and 12 received 90 mg rimonabant. Rimonabant increased self-reported anxiety levels during the anticipatory speech and performance phase compared with placebo. Interestingly, rimonabant did not modulate anxiety prestress and was not associated with sedation, cognitive impairment, discomfort, or blood pressure changes. CONCLUSIONS: Cannabinoid-1 antagonism magnifies the responses to an anxiogenic stimulus without interfering with the prestress phase. These data suggest that the endocannabinoid system may work on-demand to counteract the consequences of anxiogenic stimuli in healthy humans.