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Background: Mindfulness-based interventions (MBIs) are effective for some, but not all patients with anxiety disorders, but no clinical features have been consistently able to differentiate which patients are more likely to respond. In this study, we tested heart rate variability (HRV), a proposed correlate of regulated emotional response, as a moderator of treatment response to an MBI compared with pharmacotherapy. Methods: Seventy-seven patients with GAD had HRV data collected before randomization to pharmacological treatment with fluoxetine or Body-in-Mind Training (an MBI focused on bodily movement attention). HRV was used to predict treatment response measured by the Hamilton anxiety rating scale at 0 (baseline), 5, and 8 weeks (end of the intervention). Results: The HF (nu) index of HRV was a strong moderator of treatment response between BMT and fluoxetine (estimate = 4.27 95%CI [1.19, 8.19]). Although fluoxetine was overall slightly superior to BMT in this study, no differences were found between groups in patients with high HF (nu) scores (estimate = -1.85 CI95% [-9.21, 5.52]). In contrast, patients with low HF (nu) achieved lower anxiety rating scores with fluoxetine treatment when compared with BMT (estimate = -10.29, 95% CI [-17.59, -2.99]). Limitations: A relatively small sample of patients was included. Conclusions: HRV was able to identify a subgroup for which MBI was less effective than pharmacotherapy and is a promising candidate as a selective biomarker for treatment response between an MBI and fluoxetine.

Increased CO2 sensitivity is common in panic disorder (PD) patients. Free divers who are known for their exceptional breathing control have lower CO2 sensitivity due to training effects. This study aimed to investigate the immediate effects of cold facial immersion (CFI), breath holding and CO2 challenges on panic symptoms. Healthy participants and patients with PD were subjected to four experimental conditions in a randomly assigned order. The four conditions were (a) breath-holding (BH), (b) CFI for 30 s, (c) CO2 challenge, and (d) CO2 challenge followed by CFI. Participants completed a battery of psychological measures, and physiological data (heart rate and respiration rate) were collected following each experimental condition. Participants with PD were unable to hold their breath for as long as normal controls; however, this finding was not significant, potentially due to a small sample size. Significant reductions in both physiological and cognitive symptoms of panic were noted in the clinical group following the CFI task. As hypothesized, the CFI task exerted demonstrable anxiolytic effects in the clinical group in this study by reducing heart rate significantly and lessening self-reported symptoms of anxiety and panic. This outcome demonstrates the promise of the CFI task for clinical applications.

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

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.

Objective To identify which clinical features and personality traits are associated with quality of life (QoL) in panic disorder (PD) patients. Methods This was a cross-sectional study with PD patients. The brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the Big Five Inventory (BFI) were used to assess QoL and personality traits respectively. The strength of correlations was measured with Pearson’s, Spearman’s, and point-biserial correlation coefficients. We also performed multiple linear regressions, considering sociodemographic data and scores from clinical scales as independent variables and QoL scores as dependent variables. Results A total of 98 patients were evaluated. Depressive symptoms had a strong negative correlation with QoL and, to a lesser extent, panic and anxiety symptoms were also negatively correlated with QoL. While consciousness, extraversion, and agreeableness had mild positive correlations with QoL, neuroticism had a strong negative correlation. Conclusion Symptoms of depression, anxiety, and panic seem to have a negative impact on the QoL of PD patients. Personality traits, especially neuroticism, may also influence QoL in these 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-1β, 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.

Anxiety disorders are the largest group of mental disorders and a leading cause of impairment, implicating in high costs for health systems and society. Effective pharmacological and psychological treatments are available, but a significant fraction of these patients does not respond adequately to these treatments. The objective of this study is to identify neuroimaging findings that could predict response to psychotherapy in anxiety disorders. Methods The authors reviewed psychotherapy clinical trials with neuroimaging conducted with patients with anxiety disorders. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science. Results From the studies included in this review, 24 investigated anxiety disorder patients, and findings in the amygdala, dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC) and insula predicted response to psychotherapy in social anxiety disorder. Findings in ACC, hippocampus, insula, dlPFC, amygdala and inferior frontal gyrus (iFG) predicted response to psychotherapy in panic disorder and generalized anxiety disorder. Limitations There was great heterogeneity between the included studies regarding neuroimaging techniques and the tasks performed during functional neuroimaging. Conclusion Neuroimaging studies suggest that abnormalities in hippocampus, amygdala, iFG, uncus and areas linked with emotional regulation (dlPFC and ACC), predict a good outcome to psychotherapy in anxiety disorders.

Background The considerable rise of mental health challenges during the COVID-19 pandemic has had detrimental effects on the public health sector and economy. To meet the overwhelming and growing demand for mental health care, innovative approaches must be employed to significantly expand mental health care delivery capacity. Although it is not feasible to increase the number of mental health care providers or hours they work in the short term, improving their time efficiency may be a viable solution. Virtually and digitally delivering psychotherapy, which has been shown to be efficient and clinically effective, might be a good method for addressing this growing demand. Objective This research protocol aims to evaluate the feasibility and efficacy of using an online, digital, asynchronous care model to treat mental health issues that are started or aggravated by stressors associated with the COVID-19 pandemic. Methods This nonrandomized controlled trial intervention will be delivered through the Online Psychotherapy Tool, a secure, cloud-based, digital mental health platform. Participants will be offered a 9-week electronically delivered cognitive behavioral therapy program that is tailored to address mental health problems in the context of the COVID-19 pandemic. This program will involve weekly self-guided educational material that provides an overview of behavioral skills and weekly homework. Participants (N=80) will receive personalized feedback from and weekly interaction with a therapist throughout the course of the program. The efficacy of the program will be evaluated using clinically validated symptomology questionnaires, which are to be completed by participants at baseline, week 5, and posttreatment. Inclusion criteria includes the capacity to consent; a primary diagnosis of generalized anxiety disorder or major depressive disorder, with symptoms that started or worsened during the COVID-19 pandemic; the ability to speak and read English; and consistent and reliable access to the internet. Exclusion criteria includes active psychosis, acute mania, severe alcohol or substance use disorder, and active suicidal or homicidal ideation. Results This study received funding in May 2020. Ethics approval was received in June 2020. The recruitment of participants began in June 2020. Participant recruitment is being conducted via social media, web-based communities, and physician referrals. To date, 58 participants have been recruited (intervention group: n=35; control group: n=23). Data collection is expected to conclude by the end of 2020. Analyses (ie, linear regression analysis for continuous outcomes and binomial regression analysis for categorical outcomes) are expected to be completed by February 2021. Conclusions If proven feasible, this care delivery method could increase care capacity by up to fourfold. The findings from this study can potentially influence clinical practices and policies and increase accessibility to care during the COVID-19 pandemic, without sacrificing the quality of care. Trial Registration ClinicalTrials.gov NCT04476667; https://clinicaltrials.gov/ct2/show/NCT04476667 International Registered Report Identifier (IRRID) DERR1-10.2196/24913

Highlights • COVID-19 could increase the rates of the respiratory subtype of panic disorder.

Objective Treatment for major depressive disorder (MDD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the non-transcranial magnetic stimulation (non-TMS) neurostimulation treatment for MDD. Methods The authors reviewed non-TMS neurostimulation clinical trials for MDD between 2010 and 2020. Electroconvulsive therapy was not included in this review. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science. Results Only 20 articles met the inclusion criteria. Randomized controlled trials demonstrated efficacy of transcranial direct current stimulation (tDCS) in five of seven trials. tDCS augmented with sertraline, fluoxetine, citalopram and escitalopram was superior to placebo and to tDCS only. A comparative trial demonstrated that the duration of tDCS sessions can modulate the effectiveness of this treatment. Open trials indicated that deep brain stimulation, epidural cortical stimulation, trigeminal nerve stimulation, magnetic seizure therapy and vagus nerve stimulation may be effective in treatment-resistant depression. Conclusion This review confirmed the efficacy of tDCS in MDD. Despite new evidence showing effectiveness for other non-TMS neurostimulation, their effectiveness is still unclear. Non-TMS neurostimulation RCTs with large samples and head-to-head studies comparing non-TMS neurostimulation and gold standard pharmacological treatments are still lacking.

In the recent months, the world was taken by surprise by the outbreak of a coronavirus (SARS-CoV-2) pandemic (COVID-19). The COVID-19 pandemic is a unique opportunity to advance the understanding of the association of respiratory viruses with mood disorders and suicide. In this editorial, we explore three insights to the neuropsychoneuroimmunology of mood disorders that could be taken from the COVID-19 pandemic.

Objective Treatment for panic disorder (PD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the pharmacological and neuromodulatory treatment of PD. Methods MEDLINE, Cochrane Library, PsycINFO and Thomson Reuters's Web of Science were searched for clinical trials published between 2010 and 2018. We included all prospective experimental studies including randomized controlled trials (RCT) and other clinical trials with more than 10 patients. Results Only 11 articles met the inclusion criteria, including 4 RCT, 3 open clinical trials and 5 comparative clinical trials. RCT demonstrated efficacy of transcranial magnetic stimulation (TMS) in only one of two trials. Neither pindolol nor d-fenfluramine were effective in blocking flumazenil-induced panic attacks. Augmentation with quetiapine was not superior to placebo. Open trials indicated that escitalopram, vortioxetine and TMS may be effective. Comparative trials did not demonstrate superiority from any drug, but confirmed tranylcypromine, paroxetine, clonazepam and alprazolam as effective options. Conclusion The current study confirmed the efficacy of tranylcypromine, paroxetine, clonazepam, alprazolam and escitalopram. Vortioxetine and TMS, with duration of 4 or more weeks, also seems to be effective. Quetiapine, pindolol and d-fenfluramine were not considered effective compounds.

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.

Panic disorder (PD) is characterized by repeated and unexpected attacks of intense anxiety, which are not restricted to a determined situation or circumstance. The coherence function has been used to investigate the communication among brain structures through the quantitative EEG (qEEG). The objective of this study is to analyze if there is a difference in frontoparietal gamma coherence (GC) between panic disorder patients (PDP) and healthy controls (HC) during the Visual oddball paradigm; and verify if high levels of anxiety (produced by a computer simulation) affect PDP's working memory. Nine PDP (9 female with average age of 48.8, SD: 11.16) and ten HC (1 male and 9 female with average age of 38.2, SD: 13.69) were enrolled in this study. The subjects performed the visual oddball paradigm simultaneously to the EEG record before and after the presentation of computer simulation (CS). A two-way ANOVA was applied to analyze the factors Group and the Moment for each pair of electrodes separately, and another one to analyze the reaction time variable. We verified a F3-P3 GC increased after the CS movie, demonstrating the left hemisphere participation during the anxiety processing. The greater GC in HC observed in the frontal and parietal areas (P3-Pz, F4-F8 and Fp2-F4) points to the participation of these areas with the expected behavior. The greater GC in PDP for F7-F3 and F4-P4 pairs of electrodes assumes that it produces a prejudicial "noise" during information processing, and can be associated to interference on the communication between frontal and parietal areas. This "noise" during information processing is related to PD symptoms, which should be better known in order to develop effective treatment strategies.

Panic disorder (PD) is often correlated with high neuroticism and low extraversion. This study aims to ascertain whether PD patients differ from healthy controls in regard to personality traits and determine if these traits are correlated with comorbid disorders, anxiety, and depression symptoms. Personality traits of 69 PD patients and 42 controls were compared using the Maudsley Personality Inventory. In PD patients, comorbidities, anxiety, and depression symptoms were also evaluated. PD patients showed higher neuroticism and lower extraversion compared with healthy controls. Patients without comorbidities presented similar results to controls, whereas those with comorbidities presented higher neuroticism and lower extraversion scores. PD per se may be unrelated to deviant personality traits, although comorbidities with major depressive disorder and agoraphobia are probably associated with high neuroticism and low extraversion. These traits show a strong correlation with the accumulation and severity of these disorders.

Many pharmacological treatments were proved effective in the treatment of panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD); still many patients do not achieve remission with these treatments. Neurostimulation techniques have been studied as promising alternatives or augmentation treatments to pharmacological and psychological therapies. The most studied neurostimulation method for anxiety disorders, PTSD, and OCD was repetitive transcranial magnetic stimulation (rTMS). This neurostimulation technique had the highest level of evidence for GAD. There were also randomized sham-controlled trials indicating that rTMS may be effective in the treatment of PTSD and OCD, but there were conflicting findings regarding these two disorders. There is indication that rTMS may be effective in the treatment of panic disorder, but the level of evidence is low. Deep brain stimulation (DBS) was most studied for treatment of OCD, but the randomized sham-controlled trials had mixed findings. Preliminary findings indicate that DBS could be affective for PTSD. There is weak evidence indicating that electroconvulsive therapy, transcranial direct current stimulation, vagus nerve stimulation, and trigeminal nerve stimulation could be effective in the treatment of anxiety disorders, PTSD, and OCD. Regarding these disorders, there is no support in the current literature for the use of neurostimulation in clinical practice. Large high-quality studies are warranted.

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.

Objective: To determine whether people with a Sardinian genetic background who live in the megacities of South America have a higher frequency of hypomania than residents of Sardinia. Methods: A community survey of Sardinian immigrants was carried out in four Brazilian metropoles (n=218) and Buenos Aires (n=306). The results were compared with those of a study involving a similar methodology (Mood Disorder Questionnaire [MDQ] as a screening tool) conducted in seven Italian regions, including a sub-sample from Sardinia. Results: There was a higher prevalence of lifetime hypomania among Sardinians living in the Brazilian metropoles than among those living in Sardinia. This result was also consistent with Sardinian immigrants in Buenos Aires. After stratification by sex and age, the lifetime prevalence of MDQ scores ≥ 8 among Sardinians in South-American megacities and Sardinia was 8.6% vs. 2.9%, respectively (p < 0.0001). Conclusions: The higher frequency of hypomania in migrant populations appears to favor an evolutionary view in which mood disorders may be a maladaptive aspect of a genetic background with adaptive characteristics.

Background Computer simulations (CS) and virtual reality exposure are promising techniques for research and treatment of panic disorder with agoraphobia (PDA). The objective of this study was to ascertain whether a given CS was a stimulus capable of producing panic attacks (PAs), anxiety and psychophysiological changes in patients with PDA. Methods Thirty PDA patients and 30 healthy subjects were recruited for this study. Subjects were exposed to a 3-min CS of a situation relevant to agoraphobic patients. Anxiety, panic symptoms, PAs, heart rate, skin conductance and respiration were recorded before, during and after the CS exposure. Results The CS effectively induced anxiety, hyperventilation and electrodermal responses in PDA patients but not in healthy subjects. Forty percent of PDA patients had a PA while none of the control subjects had a PA. A subgroup of patients who were less sensitive to the CS than the other subgroup of PDA patients and did not present full-blown PAs still had more panic symptoms, higher anxiety levels and more respiratory irregularities than the controls. Limitations Low immersion and low sense of presence, lack of interaction with the environment. Conclusions Exposure to the CS produced effects similar to in vivo exposure, respiratory and caffeine challenges. Subsequent studies should: make direct comparisons between CS and other challenges for PDA; investigate if CS can be a tool for predicting effects of medication; determine the potential of CS as a desensitization technique for situational PAs.

Introduction: Although anxiety and impulsivity are intuitively thought to be inversely correlated, increased impulsivity has been associated both with generalized anxiety disorder (GAD) diagnosis and GAD symptoms in non-clinical samples. The emotional dysregulation model of GAD posits that patients experience more frequent and intense negative emotions while having poor regulatory control over emotional states and greater negative reactivity to their emotions. We hypothesized that poor regulatory control in the presence of negative emotions might explain the increased impulsivity found in GAD patients. In this study, we examined if negative affect mediates the relationship between GAD and impulsivity. Methods: Thirty-four GAD patients and 35 healthy controls were included, and evaluated with measurements of impulsivity, negative and positive emotions, the severity of worrying and GAD symptoms, depression, and 5-factor personality traits. Results: Global impulsivity scores and the attentional facet of impulsivity were higher in the patient group when compared to the controls. Negative affect was correlated with global impulsivity in the patient group only and explained impulsivity in our regression model while worrying and depressive symptoms did not. An indirect relationship was found between diagnosis and impulsivity through negative affect. Conclusion: Our study showed that the cardinal symptom of GAD – worrying – was not independently related to impulsivity in our sample. Increased impulsivity in GAD seems to be mediated by the increased presence of negative emotions, as it is common in mood and impulse-control disorders, indicating an unspecific shared vulnerability factor to psychopathology.

AimsTo ascertain if virtual reality exposure therapy (VRET) is an effective add-on tool in the treatment of Panic Disorder (PD).BackgroundThe exposure to virtual stimuli has been studied as a useful treatment for PD. However, the studies with PD are still scarce and use dissimilar protocols, with effectiveness varying according to the protocol applied.MethodEight PD patients received VRET as an add-on treatment to pharmacotherapy. The treatment protocol consisted of eight sessions. The first session is for the patient to understand the treatment and to answer the questionnaires. The second and third sessions were to prepare the patients for exposures with breathing training using diaphragmatic breathing and others breathing techniques to manage anxiety. From the fourth to eighth sessions, the patients followed a hierarchy of tasks during virtual reality exposure. Clinicians rated the Clinical Global Impression Scale (CGI) and the Panic Disorder Severity Scale (PDSS). The patients rated the Diagnostic Symptom Questionnaire (DSQ); the Mobility Inventory (MI), the Anxiety Sensibility Index (ASI-R), the Beck Depression Inventory (BDI), the Beck Anxiety Inventory (BAI) and the WHOQOL-BREF before and after the protocol. After all exposures, the Igroup Presence Questionnaire (IPQ) was applied to measure the sense of presence experienced in the virtual environment. The virtual environment simulated the subway of Rio de Janeiro.ResultThere were no statistically significant improvements in the CGI-S, PDSS, BAI, MI or WHOQOL. There was a significant improvement in the BDI scores (P = 0.033). There was a trend towards improvement of anxiety measured by the ASI-R (P = 0.084) and of panic symptoms measured by the DSQ (P = 0.081) scores. There was also a significant improvement of sense of presence (IPQ – general presence) through the exposure sessions.ConclusionOur study demonstrated that VRET as an add-on to pharmacological therapy could benefit PD patients. Despite the lack of significant differences in the means, the dispersion of PDSS and BAI scores were smaller after treatment compared to before treatment, suggesting that patients with more severe anxiety, panic and agoraphobia symptoms benefited more of the VRET protocol so, at the end of the treatment, differences were found in important measures of panic. Randomized controlled clinical trials are warranted to confirm the efficacy of VRET.This study was funded by the Brazilian National Council for Scientific Development (Cnpq). The authors report no conflicts of interest.

Objective: It is our aim to elaborate on the new developments in regard to the respiratory subtype (RS) of panic disorder (PD) since it was first described. We will present psychopathological features, diagnostic criteria, genetic and physiopathological hypotheses, as well as therapeutic and prognostic characteristics. Method: Two searches were performed in the Thomson Reuters Web of Knowledge (http://wokinfo.com/): 1 - search terms: “panic disorder” AND (“respiratory symptom” OR “respiratory symptoms” OR “respiratory subtype” OR “respiratory panic” OR “cardiorespiratory”); 2 - all articles citing Briggs and colleagues’ 1993 article “Subtyping of Panic Disorder by Symptom Profile” (Br J Psychiatry 1993;163: 201-9). Only those articles involving human subjects and written English were included. Results: In comparison with patients of the non-respiratory subtype (NRS), RS patients showed greater familial history of PD, and higher comorbidity rates for anxiety disorders and depressive disorders. These patients were also more sensitive to CO 2 , hyperventilation and caffeine. Conclusion: Certain characteristics, such as heightened sensitivity to CO 2 and the higher incidence of a family history of PD, clearly distinguished the Respiratory Subtype patients from the Non-Respiratory. Nonetheless, some studies failed to demonstrate differential responses to pharmacological treatment and CBT across the subtypes. RS patients seem to respond faster than NRS to pharmacological treatment with antidepressants and benzodiazepines, but more studies are needed to confirm this finding.

Acid-sensitive ion channels, such as amiloride-sensitive cation channel (ACCN), transient receptor potential vanilloid-1 (TRPV1), and T-cell death-associated gene 8 (TDAG8) are highly related to the expression of fear and are expressed in several regions of the brain. These molecules can detect acidosis and maintain brain homeostasis. An important role of pH homeostasis has been suggested in the physiology of panic disorder (PD), with acidosis as an interoceptive trigger for panic attacks. To examine the effect of acid-sensitive channels on PD symptoms, we conducted a systematic review and meta-analysis of these chemosensors in rodents and humans. Following PRISMA guidelines, we systematically searched the Web of Science, Medline/Pubmed, Scopus, Science Direct, and SciELO databases. The review included original research in PD patients and animal models of PD that investigated acid-sensitive channels and PD symptoms. Studies without a control group, studies involving patients with a comorbid psychiatric diagnosis, and in vitro studies were excluded. Eleven articles met the inclusion criteria for the systematic review. The majority of the studies showed an association between panic symptoms and acid-sensitive channels. PD patients appear to display polymorphisms in the ACCN gene and elevated levels of TDAG8 mRNA. The results showed a decrease in panic-like symptoms after acid channel blockade in animal models. Despite the relatively limited data on this topic in the literature, our review identified evidence linking acid-sensitive channels to PD in humans and preclinical models. Future research should explore possible underlying mechanisms of this association, attempt to replicate the existing findings in larger populations, and develop new therapeutic strategies based on these biological features.

Background: The aim is to measure the association between fibromyalgia syndrome (FMS) and post-traumatic stress disorder (PTSD), mood and anxiety disorders using reliable psychiatric diagnoses according to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and with a case–control design. Methods: Case–control study with cases (71 consecutive female patients with FMS) and controls (284 subjects without FMS), randomly drawn after a gender- and age-matching technique from the database of an epidemiological survey. Psychiatric diagnoses were conducted according to DSM-IV and carried out by clinical staff using a structured interview (Advanced Neuropsychiatric Tools and Assessment Schedule). QoL was measured by Short Form Health Survey (SF-12). Results: The lifetime prevalence of major depressive disorder (MDD; 43.7% vs 8.1%, p Conclusion: FMS is a disorder that ‘in itself’ can have a devastating impact on an individual’s life. The frequency of the association with major depressive and bipolar disorders increases the impact on the QoL of people with FMS. One of the causes of this association appears to be the extreme vulnerability to chronic stress that this disorder involves. The findings have important clinical significance: the physician must interpret in the right dimension and with dignity the suffering of the people with FMS.

There have been reports of the medical use of electricity since the classical antiquity, but only in the second half of the eighteenth century the effects of electricity in animals and humans were systematically studied, establishing the foundations for the electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial direct-current stimulation (tDCS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and repetitive transcranial magnetic stimulation (TMS). The most important difference between these methods is that ECT and MST induce seizures, while the other methods produce more subtle acute effects. Magnetic stimulation methods seem to produce an effect that is similar to the one induced by direct electrical stimulation. Nevertheless, all techniques induce electrical currents in the brain, producing functional and structural modifications. Neurostimulation induces neuronal depolarization and increase or decrease of neuron excitability, producing immediate changes in membrane receptors and channels. These effects are followed by a cascade of changes within the neuron, including changes in gene expression and second messengers. Neurostimulation modulates glutamatergic, serotonergic, dopaminergic, GABAergic, and cholinergic neurotransmission. The HPA and sympathoadrenal systems are also modulated by neurostimulation, which reduces the release of corticotrophins and cortisol. These techniques also play a role in the regulation of glial cell activity, neuroinflammation, and oxidative stress.

The neurostimulation techniques, such as electroconvulsive therapy (ECT), repeated transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), have been successfully used in the treatment of depressive disorders. The stimulation is focused on brain areas involved in major depressive disorder and produce symptom improvement, but it frequently affects other regions, producing unwanted effects. Studies indicate that neurostimulation methods with a narrow focus, like TMS, tend to be associated with less adverse events, compared to those with a broad focus, such as ECT. Bitemporal ECT is the most effective neurostimulation method, but it is also associated to higher risks and more side effects, compared to other methods. Compared to bitemporal ECT, there are fewer cognitive side effects with right unilateral and bifrontal ECT, but the effect size for these techniques is also reduced. TMS has been extensively studied, and currently it is considered a first-line treatment for treatment-resistant depressive disorders. High-quality studies with the other neurostimulation methods are still scant. Neurostimulation is a good alternative treatment for patients who did not achieve remission after several psychopharmacological treatments and psychotherapy. When deciding the best treatment for each patient, clinicians should take into account that, depending on the method, neurostimulation can have a very fast antidepressant effect or it could take many months to take effect. Risk and benefits of neurostimulation methods should also be weighted in each case.

Background & objective Epilepsy is one of the most complex neurological disorders and its study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. Conclusion Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors.

We investigated the rates of current and past benzodiazepine (BZD) use in a sample of 102 subjects attending specialized anxiety disorder clinics, including panic disorder (PD; N = 36), social anxiety disorder (SAD; N = 28) and obsessive-compulsive disorder (OCD; N = 38) patients. Almost 56% of the entire sample was using BZDs at the moment of the assessment, and 74.5% described having used them at some point during their lifetimes. The duration of psychiatric treatment and a lifetime history of PD, but not any other "transdiagnostic" measure of severity (such as the Panic and Agoraphobia Scale, the Social Phobia Inventory, the Dimensional Obsessive-Compulsive Scale, the Anxiety Sensitivity Index-36, and the Beck Inventories) were independent risk factors for current prescription of BZDs. Patients who continued to use BZDs differed from patients who stopped them by being older (both currently and when firstly seen in the clinic), by having a later age at onset of their most significant anxiety disorder, by being more agoraphobic/avoidant, and by believing to be less capable of stopping their BZDs for the fear of not being able to sleep.

The aim of this study was to identify factors associated with relapse in panic disorder (PD).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.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.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.

Generalized anxiety disorder (GAD) is a persistent anxiety disorder with a high rate of relapse. While several trials have demonstrated the efficacy of pharmacotherapy for GAD treatment, fewer studies have investigated its efficacy in preventing symptom relapse in long-term treatment. The aim of this study is to evaluate if long-term pharmacotherapy may prevent relapses in GAD patients. This is a systematic review of the relapse prevention trials with GAD patients. Eight trials were included in this review with 5304 patients in total. All patients showed a higher risk of relapse if treatment was not maintained for at least 6 months after remission, with hazard ratios ranging from 0.12 to 0.58 and mostly moderate effect sizes (0.19–1.06). Long-term pharmacotherapy may prevent symptom relapse in GAD patients. As the relapse rate is very high, the data support the continuation of pharmacotherapy for as long as possible.

OBJECTIVE: To investigate the effectiveness of a treatment for Internet addiction and anxiety disorders, using cognitive behavioral therapy combined with medication, and to analyze the relationship between anxiety and Internet addiction. METHOD: An open clinical trial included 84 patients (42 in the "comorbidities" group; 42 in the "no comorbidities" group) seeking treatment for anxiety symptoms and/or Internet Addiction. The subjects responded to The Mini International Neuropsychiatric Interview 5.0; the Hamilton Anxiety Scale (HAM-A), the Hamilton Depression Scale (HDRS), Clinical Global Impressions Severity and Improvement (CGI-S and CGI-I) and the Young Internet Addiction Scale (IAT). Patients who had only Internet addiction received psychoeducation on conscious internet use and bibliotherapy; they were defined as the group without comorbidities; patients diagnosed with Internet addiction and anxiety disorder (the group with comorbidities) were forwarded for pharmacotherapy and psychotherapy. RESULTS: Both Internet Addiction and anxiety decreased after treatment; the average of Hamilton Anxiety Scale of the "comorbidities" group at the beginning was 33.9 ± 7.6, suggesting severe anxiety, and at the end of treatment it was 15.0 ± 5.1, suggesting mild anxiety and a significant improvement. The average Internet Addiction score at the beginning was 67.8 ± 9.0; at the end of the psychotherapy an average score of 37.7 ± 11.4 was registered, indicating a notable and highly significant improvement. CONCLUSIONS: The relationship between anxiety and Internet Addiction existed and was strong. Treatment significantly improved both. OBJETIVO: Investigar a eficácia de tratamento para dependência de internet e transtornos de ansiedade, utilizando terapia cognitivo comportamental combinada com medicação, e analisar a relação entre ansiedade e dependência de internet. MÉTODO: Ensaio clínico aberto realizado no Laboratório de Pânico e Respiração no Instituto de Psiquiatria da Universidade Federal do Rio de Janeiro (IPUB/UFRJ) com 84 pacientes (42 do grupo com comorbidades e 42 do grupo sem comorbidades) que procuravam tratamento para transtornos de ansiedade e/ou dependência de internet. Os sujeitos responderam ao MINI Entrevista Neuropsiquiátrica Internacional 5.0; a Escala Hamilton de Ansiedade (HAM-A), a Escala Hamilton de Depressão (HDRS), a Escala Clínica de Impressão Global de Severidade e de Melhora (CGI-S e CGI-I) e a Escala de Dependência de Internet de Young (IAT). Os pacientes com apenas dependência de internet receberam psicoeducação sobre o uso consciente da internet e biblioterapia, e foram considerados o grupo sem comorbidades, enquanto que, os pacientes com transtornos de ansiedade e dependência de internet foram encaminhados para o tratamento medicamentoso e psicoterapia. RESULTADOS: Tanto a dependência de internet quanto a ansiedade diminuíram após o tratamento, a média da HAM-A no grupo com comorbidades no início foi de 33,9 ± 7,6, sugerindo ansiedade grave e ao final do tratamento foi de 15 ± 5,1, sugerindo uma significativa melhora. A media de dependência de internet obtida na IAT no início do tratamento foi de 67.8 ± 9.0 e ao final da psicoterapia a maioria dos participantes apresentou média de 37.7 ± 11.4 indicando uma melhora notável. CONCLUSÃO: A relação entre ansiedade e dependência de internet existe e é forte.

Background Pharmacotherapy for generalized anxiety disorder (GAD) may be effective in reducing symptoms in the majority of patients. The study of moderators and predictors of treatment response may help clinicians both to select appropriate interventions to maximize the probability of response and to inform the general prognosis. Methods A systematic literature search of electronic databases, selected authors, and reference lists was used to identify articles that reported trials of drug monotherapy in GAD. Data on predictors and moderators were extracted. Quality of evidence was determined by the presence of a priori hypotheses, number of variables investigated, adequate quality of the measurement, and use of interaction-effects testing. Results From the 98 articles meeting inclusion criteria, 24 reported a total of 22 factors associated with treatment response. The reported results were heterogeneous, ranging over sociodemographic, clinical, comorbidity, genetic, and functional-imaging studies. Major depressive symptoms were found to moderate treatment outcome in favor of antidepressants versus benzodiazepines. Neuroticism, previous treatment, genetic polymorphisms (including serotonin receptor gene 2A), and functional activation of the anterior cingulate cortex and amygdala were identified as potential predictors of treatment response. Conclusions Correlates of poor emotion regulation predicted poor treatment response, but subclinical depression was the only variable capable of informing treatment selection in this review. Future research should focus on further exploring the value of depression as a moderator and on a narrower list of potential genetic, brain-imaging, and temperament predictors of response to pharmacotherapy in GAD.

Background: Generalized anxiety disorder (GAD) is a prevalent anxiety disorder, but its neurobiological basis has been poorly studied. A few cognitive models have been proposed for understanding GAD development and maintenance. The aim of this study is to review functional Magnetic Resonance Image (fMRI) studies conducted with GAD patients and evaluate if they support and underpin the theoretical cognitive models proposed for this anxiety disorder. Methods: A literature systematic review was undertaken in PubMed and ISI databases with no time limits. Results: From the studies included in this review, 10 explored the “emotional dysregulation model” ,s howing, prefrontal cortex (PFC) and anterior cingulate cortex (ACC) hypofunction and deficient top-down control system during emotion regulation tasks, despite conflicting techniques and results. Only one study explored the “conditioned fear overgeneralization theory”, other the “intolerance of uncertainty model” and two studies were unspecific (worry induction tasks). Between those, there were 4 studies evaluating pre- and posttreatment with antidepressants or “mindfulness”. Limitations: The studies' methodologies differ between one another making it difficult to identify a common finding. Conclusion: Emotion dysregulation seems to be an important cognitive dysfunction in GAD patients and fMRI studies suggest that it is related to PFC and ACC hypofunction as well as a deficient cortex–amygdala functional connectivity.

The aim of this review was to summarize the recent evidences regarding the pharmacological treatment of panic disorder (PD). The authors performed a review of the literature regarding the pharmacological treatment of PD since the year 2000. The research done in the last decade brought strong evidences of effectiveness for paroxetine, venlafaxine, sertraline, fluvoxamine, citalopram, fluoxetine, clonazepam, and the relatively novel agent escitalopram. There are evidences indicating that the other new compounds inositol, duloxetine, mirtazapine, milnacipran, and nefazodone have antipanic properties and may be effective compounds in the treatment of PD. The effectiveness of reboxetine and anticonvulsants is a subject of controversy. In addition to selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines and atypical antipsychotics may be valid alternatives in the treatment of PD. Recent data indicate that augmentation strategies with aripiprazole, olanzapine, pindolol or clonazepam may be effective. D-cycloserine is a promising agent in the augmentation of cognitive behavioral therapy.

Driving phobia is associated with serious consequences such as restriction of freedom, career impairments and social embarrassment. The main objective of this paper is to compare clinical characteristics and quality of life between women with driving phobia and women without this phobia. These factors were assessed using structured interviews, semi-structured questionnaires, scales and inventories. We accessed diagnoses, depressive symptoms, anxiety symptoms, anxiety traits, driving cognitions and quality of life. There was no difference between groups with regard to demographic data and driving history. Both groups were also equivalent in the number of traumatic events and accidents experienced while driving or riding. The fear of driving group showed higher state and trait anxiety scores. A high frequency of cognitive distortions can explain why people with driving phobia often engage in maladaptive safety behaviors in an attempt to protect themselves from unpredicted dangers when driving. Regarding quality of life, the control group had slightly higher scores on all subscales, but significant differences were observed for only three scales: “functional capacity”, “social aspects”, and “mental health”. More studies with larger samples more instruments and other contexts are needed to further investigate the clinical characteristics and personality traits of people who have a fear of driving.

Background Panic attacks are thought to be a result from a dysfunctional coordination of cortical and brainstem sensory information leading to heightened amygdala activity with subsequent neuroendocrine, autonomic and behavioral activation. Prefrontal areas may be responsible for inhibitory top-down control processes and alpha synchronization seems to reflect this modulation. The objective of this study was to measure frontal absolute alpha-power with qEEG in 24 subjects with panic disorder and agoraphobia (PDA) compared to 21 healthy controls. Methods qEEG data were acquired while participants watched a computer simulation, consisting of moments classified as “high anxiety”(HAM) and “low anxiety” (LAM). qEEG data were also acquired during two rest conditions, before and after the computer simulation display. Results We observed a higher absolute alpha-power in controls when compared to the PDA patients while watching the computer simulation. The main finding was an interaction between the moment and group factors on frontal cortex. Our findings suggest that the decreased alpha-power in the frontal cortex for the PDA group may reflect a state of high excitability. Conclusions Our results suggest a possible deficiency in top-down control processes of anxiety reflected by a low absolute alpha-power in the PDA group while watching the computer simulation and they highlight that prefrontal regions and frontal region nearby the temporal area are recruited during the exposure to anxiogenic stimuli.

OBJECTIVE: The respiratory ratio is a dimensional construct of the respiratory subtype of panic disorder (PD). The respiratory subtype has been correlated with an increased sensitivity to CO2 inhalation, positive family history of PD and low comorbidity with depression. The objective of our study was to determine whether the respiratory ratio is correlated with CO2-induced panic attacks and other clinical and demographic features. METHODS: We examined 91 patients with PD and submitted them to a double-breath 35% CO2 challenge test. The respiratory ratio was calculated based on the Diagnostic Symptom Questionnaire (DSQ) scores recorded in a diary in the days preceding the CO2 challenge. The scores of the respiratory symptoms were summed and divided by the total DSQ score. RESULTS: The respiratory ratio was correlated with CO2 sensitivity, and there was a non-statistically significant trend towards a correlation with a family history of PD. CONCLUSIONS: The positive correlation between the respiratory ratio and the anxiety elicited by the CO2 inhalation indicates that the intensity of respiratory symptoms may be proportional to the sensitivity to carbon dioxide.

Clonazepam was initially licensed as an anti-epileptic agent, but its use in a wide variety of psychiatric conditions, including panic disorder (PD) has now been well established. This overview evaluates the current role of clonazepam alone or in combination with antidepressants and/or behavioral therapy in the treatment of PD. We review the data establishing the use of clonazepam in the treatment of PD as well as new information, particularly confirmation of longterm efficacy and safety. We also discuss a regimen for safely tapered withdrawal of clonazepam, the characteristics of the respiratory subtype of PD, and CO2-induced panic attacks as a diagnostic measure and predictor for therapeutic success. It has been shown that panic attacks can more readily be induced by CO2 in PD patients with the respiratory subtype than those with the non-respiratory subtype. More than 25 years after the first report of efficacy in PD in 1984, clonazepam, alone or combined with selective serotonin reuptake inhibitors (SSRIs) and/or behavioral therapy, remains an important therapeutic modality for the management of PD.