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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.

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.

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

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.

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.

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.

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.

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.

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 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.

BACKGROUND: Studies have documented high use of tobacco, alcohol and illicit drugs in patients with panic disorder (PD). The comorbid substance use disorders worsen the prognosis of mood and anxiety disorders. The respiratory subtype (RS) of PD seems to represent a more severe and distinct form of this disorder associated with higher familial history of PD and more comorbidity with other anxiety disorders. OBJECTIVES: Describe the patterns of tobacco, alcohol or illicit drug use in PD patients, and also to ascertain if patients with the RS use these substances more than those of the non-respiratory subtype. METHODS: This is a cross-sectional study with 71 PD patients. The Alcohol Use Disorders Identification Test and Fagerstrom Tobacco Questionnaire were used in the evaluation. Patients with four or five respiratory symptoms were classified in the RS, the remaining patients were classified as non-respiratory subtype. RESULTS: In our sample 31.0% were smokers, 11.3% were hazardous alcohol users and none of them was using illicit drugs. There were no differences between the respiratory and non-respiratory subtypes regarding the use of tobacco, alcohol, cannabis, cocaine, stimulants and hallucinogens. DISCUSSION: The RS was not correlated to the use of tobacco, alcohol and illicit drugs. Additional epidemiological and clinical studies focusing the relationship between PD and substance use are warranted.

OBJECTIVE: Recent studies suggest that, when combined with pharmacotherapy, structured psychotherapy may modify the course of bipolar disorder. However, there are few studies that have examined the effects of cognitive behavioral group therapy on the course of this disorder. The aim of the present study was to evaluate the effectiveness of 14 sessions of cognitive behavioral group therapy, combined with pharmacotherapy, on the treatment of patients with bipolar disorder, and to compare our results against those from the use of pharmacotherapy alone. METHOD: Forty-one patients with bipolar I and II disorder participated in the study and were randomly allocated to one of two treatment groups; thirty-seven patients remained in the study until its completion. Mood and anxiety symptoms were measured in all subjects. Statistical analysis was used to investigate if the groups differed with respect to demographic characteristics and the scores recorded in the pre- and post-treatment stages, as well as during treatment (intra/inter groups). RESULTS: Patients showed statistically similar population characteristics. The association of cognitive behavioral group therapy and pharmacological treatment proved to be effective. Patients who had undergone cognitive behavioral group therapy presented fewer symptoms of mania, depression and anxiety, as well as fewer and shorter mood change episodes. CONCLUSION: Cognitive behavioral group therapy sessions substantially contributed to the improvement of depression symptoms. OBJETIVO: Estudos recentes sugerem que uma psicoterapia estruturada aplicada junto com a farmacoterapia pode alterar o curso do transtorno afetivo bipolar. Entretanto, poucos estudos investigam os resultados da terapia cognitivo-comportamental em grupo sobre este transtorno psiquiátrico. O objetivo desta pesquisa foi avaliar a eficácia de 14 sessões de terapia cognitivo-comportamental em grupo concomitante à farmacoterapia para bipolares e comparar com a farmacoterapia sozinha. MÉTODO: Quarenta e um pacientes com transtorno bipolar I e II participaram do estudo e foram alocados aleatoriamente para um dos dois grupos; trinta e sete preencheram todas as escalas. Os sintomas de humor e ansiedade de todos os participantes foram acessados. A análise estatística foi utilizada para investigar se os grupos diferiam com relação aos dados demográficos e entre os escores pré-, durante e pós-tratamento (intra/intergrupos). RESULTADOS: Os participantes dos dois grupos mostraram-se similares nas características demográficas. A adição da terapia cognitivo-comportamental em grupo ao tratamento farmacológico foi efetiva. O grupo da terapia cognitivo-comportamental em grupo apresentou menos sintomas de mania, depressão e ansiedade, bem como uma redução na frequência e duração dos episódios de humor. CONCLUSÃO: As sessões de terapia cognitivo-comportamental em grupo foram especialmente importantes na melhora dos sintomas depressivos.

Our objective is to summarize the new findings concerning the respiratory subtype (RS) of panic disorder (PD) since its first description.Two searches were made in the Institute for Scientific Information Web of Science: with the keywords "panic disorder" and "respiratory symptoms," and all articles that cited Briggs and colleagues' 1993 article "Subtyping of Panic Disorder by Symptom Profile" (Br J Psychiatry 1993;163:201-9). Altogether, 133 articles were reviewed.We describe and discuss RS epidemiology, genetics, psychopathology, demographic features, clinical features, correlations with the respiratory system, traumatic suffocation history, provocative tests, and nocturnal panic. Compared to patients with the nonrespiratory subtype (non-RS), the RS patients had higher familial history of PD, lower comorbidity with depression, longer duration of illness, lower neuroticism scores, and higher scores in severity scales, such as the Panic and Agoraphobia Scale, Panic-Agoraphobia Spectrum scale and the Clinical Global Impression scale. Tests to induce panic attacks, such as those with CO(2), hyperventilation, and caffeine, produce panic attacks in a higher proportion of RS patients than non-RS patients. Differences in the subtypes' improvement with the pharmacologic treatment were found. There are also some controversial findings regarding the RS, including the age of onset of PD, and alcohol and tobacco use in RS patients.Some characteristics, such as the increased sensitivity to CO(2) and the higher familial history of PD, clearly distinguish the RS from the non-RS. Nevertheless, there are also controversial findings. More studies are needed to determine the validity of the RS subtype.

Our objective was to explore the dose-response relationship in patients with panic disorder and social anxiety disorder comorbidity (DSM-IV). After 1 week of no-drug washout, 36 such patients were assigned to a double-blind controlled comparison of the effects of 30 mg and 60 mg of tranylcypromine, and were followed up for 12 weeks. The main instrument used to measure the number of panic attacks was the Sheehan Panic and Anticipatory Anxiety Scale. The primary outcome measure for social anxiety disorder symptoms was the mean change from baseline in the Liebowitz Social Anxiety Scale (LSAS). After 12 weeks of treatment, panic attacks were reduced 69.6% from baseline in the 30-mg group (n=19) compared with a 74.8% reduction in the 60-mg group (n=17). Twelve patients (70.6%) of the higher dose group and 14 patients (68.4%) of the lower dose were completely free of panic attacks. There was no difference in efficacy between the tranylcypromine groups in the panic disorder symptoms. The 60-mg dose was more efficacious as measured by the LSAS scores, showing a significant difference in relation to the lower group. Mean change from baseline in LSAS total score (mean+/-SD) for 30-mg group was 17.9+/-14.7 and for the 60-mg group was 35.0+/-14.8. The social anxiety symptom scale showed a two-fold greater change with the 60-mg dose, and the 30-mg dose group could be considered the equivalent of a placebo control group. Tranylcypromine--60 mg daily--was found effective in the treatment of panic disorder and social anxiety disorder comorbidity.

Aim: to compare the scores of the WHOQOL quality of life domains with the clinical features of patients with respiratory and non-respiratory panic disorders (PD) treated at the UFRJ Panic and Respiration Laboratory. Method: cross sectional study. Thirty-two PD outpatients under treatment were consecutively selected and evaluated by the MINI v.4.4. They were divided into two different groups according to Briggs et al. classification of respiratory and non-respiratory PD subtypes. Twelve (37.5%) patients had the respiratory subtype (SR) and 20 (62.5%) the non-respiratory subtype (SN). Results: the SN patients presented worse scores in the psychological domain of the WHOQOL. There were no differences between groups in gender, age, level of schooling, occupational status, marital status, smoking and comorbidities. There were no differences in the anxiety questionnaires and PD questionnaire (BAI, STAI-T, STAI-S, PAS) scores and in the age at the beginning of the disorder and the disorder's duration. Conclusion: non-respiratory subtype patients presented worse scores in the psychological domain of WHOQOL than the respiratory subtype group, when they had similar anxiety and PD scores. Resumo: Objectivo: comparar os scores dos diversos domínios de qualidade de vida e quadro clínico entre os doentes com subtipos respiratório e não respiratório de transtorno de pânico (TP) em tratamento no Laboratório de Pânico e Respiração da UFRJ. Método: estudo transversal com 32 doentes com TP com ou sem comorbidades em tratamento ambulatorial, selecionados consecutivamente e diagnosticados através do MINI v.4.4. Destes, 12 (37,5%) apresentam o subtipo respiratório (SR) e 20 (62,5%) o subtipo não respiratório (SN), de acordo com Briggs et al. Resultados: Em relação aos índices de qualidade de vida, houve apenas diferença no domínio psicológico, sendo que os doentes do subgrupo SN apresentaram piores scores. Os diferentes subtipos de TP (SR e SN) não apresentaram diferenças significativas quanto à distribuição por género, idade, escolaridade, ocupação, estado civil, tabagismo e comorbidades. Clinicamente também não foram encontradas diferenças significativas nos scores de ansiedade, nem de gravidade do TP (BAI, STAI-T, STAI-S, PAS), bem como não se observaram diferenças quanto à idade de início do transtorno ou tempo de evolução da doença. Conclusão: Doentes do subtipo não respiratório, que apresentam índices semelhantes de ansiedade e gravidade do TP, quando em tratamento, apresentam piores scores de qualidade de vida psicológica do que os do subtipo respiratório. Key-words: Anxiety, panic disorder, quality of life, respiratory subtype, Palavras-chave: Ansiedade, transtorno de pânico, qualidade de vida, subtipo respiratório

Anxiety disorders, particularly panic disorder (PD), are associated with respiratory abnormalities. PD consists of unexpected panic attacks (PA) with anxiety, fear and many autonomic and respiratory symptoms. There is a substantial body of literature demonstrating that stimulation of respiration is a common event in panic disorder patients during PA. A number of abnormalities in respiration, such as enhanced CO(2) sensitivity, have been detected in PD patients. As a result, some investigators advanced that there is a fundamental abnormality in the physiological mechanisms that control breathing in PD. Studies indicate that PD patients with dominant respiratory symptoms are particularly sensitive to respiratory tests compared with those who do not manifest dominant respiratory symptoms, possibly representing a distinct subtype. Accumulated evidence suggests that respiratory physiology remains normal in PD patients and that their tendency to hyperventilate and to react with panic to respiratory stimulants like CO(2) represents the triggering of a hypersensitive fear network. However, some recent evidences support the presence of subclinical abnormalities in respiration and other functions related to body homeostasis. The fear network, composed by the hippocampus, the medial prefrontal cortex, the amygdala and its brainstem projections, may be abnormally sensitive in PD patients. This theory might explain why both medication and psychosocial therapies are clearly effective. The evidence of abnormalities in several neurochemical systems might be just the expression of the complex interactions among brain circuits. Our aim was to review the relationship between respiration and panic disorder, addressing the respiratory subtype of panic disorder, the hyperventilation syndrome, the respiratory challenge tests, the current mechanistic concepts and the pharmacological implications.

OBJECTIVE: To determine the prevalence of anxiety and depression in patients complaining of chest pain who seek a chest pain unit attendance. INTRODUCTION: Patients arriving at a Chest Pain Unit may present psychiatric disorders not identified, isolated or co-morbid to the main illness, which may interfere in the patient prognosis. METHODOLOGY: Patients were assessed by the "Hospital Anxiety and Depression Scale" as a screening instrument wile following a systematized protocol to rule out the diagnosis of acute coronary syndrome and other potentially fatal diseases. Patients with 8 or more points in the scale were considered "probable case" of anxiety or depression. RESULTS: According to the protocol, 59 (45.4%) of 130 patients studied presented Chest Pain of Determined Cause, and 71 (54.6%) presented Chest Pain of Indefinite Cause. In the former group, in which 43 (33.1%) had acute coronary syndrome, 33.9% were probable anxiety cases and 30.5% depression cases. In the second group, formed by patients without acute coronary syndrome or any clinical conditions involving greater morbidity and mortality risk, 53.5% were probable anxiety cases and 25.4% depression. CONCLUSION: The high anxiety and depression prevalence observed may indicate the need for early and specialized approach to these disorders. When coronary arterial disease is present, this may decrease complications and shorten hospital stay. When psychiatric disorder appears isolated, is possible to reduce unnecessary repeated visits to emergency room and increase patient's quality of life.

BACKGROUND: Studies suggest an association between panic disorder (PD) and impairment of lung function. OBJECTIVES: To evaluate lung function in 11 asymptomatic PD patients and to investigate antipanic drug effects on respiratory function. METHOD: Lung function was evaluated on two different occasions (with antipanic drugs and after drug washout). It was comprised of a spirometric evaluation and a bronchodilation test (salbutamol inhalation). Subjective Units of Disturbance Scale (SUDS) was applied before and after each spirometric assessment. RESULTS: One patient showed mild obstructive airway impairment. Before bronchodilation test forced expiratory volume in 1 sec (FEV1) and forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25-75) were significantly higher in patients on antipanic drugs than in those in the washout period. After salbutamol inhalation, only FEV1 was significantly higher in patients with antipanic drugs in comparison to the other group, whereas a significant increase in FEV1 and FEF25-75 after salbutamol inhalation was detected in patients without antipanic drugs. The subjective anxiety level was not different among PD patients in both test days. DISCUSSION: These results suggest a possible beneficial effect of the antipanic drug on lung function in PD patients. CONTEXTO: Estudos sugerem uma associação entre transtorno de pânico (TP) e prejuízos na função pulmonar. OBJETIVOS: Avaliar a função pulmonar em 11 pacientes com TP assintomáticos e investigar efeitos da medicação antipânico na função respiratória. MÉTODO: A função pulmonar foi avaliada em duas ocasiões diferentes (com medicação antipânico e após "washout"). Consistiu de uma avaliação espirométrica e do teste de broncodilatação (inalação de salbutamol). Subjective Units of Disturbance Scale (SUDS) foi aplicada antes e após cada teste espirométrico. RESULTADOS: Um paciente apresentou obstrução leve de vias aéreas. Antes do teste de broncodilatação, o volume expiratório forçado no primeiro segundo (VEF1) e o fluxo expiratório forçado entre 25% e 75% da capacidade vital forçada (FEF25-75) foram significativamente maiores em pacientes com medicação antipânico do que no período de "washout". Após a inalação de salbutamol, apenas o VEF1 foi significativamente maior em pacientes com medicação antipânico em comparação ao outro grupo, embora tenha sido detectado aumento significativo em VEF1 e FEF25-75 em pacientes sem medicação antipânico depois da inalação de salbutamol. O nível de ansiedade subjetiva não foi diferente entre os pacientes em ambos os dias de testes. CONCLUSÃO: Os resultados sugerem uma possível ação benéfica da medicação antipânico na função pulmonar em pacientes com TP.

Our aim was to observe the induction of anxiety symptoms and panic attacks by a caffeine challenge test in panic disorder (PD) patients (DSM-IV) and their healthy first-degree relatives. We randomly selected 25 PD patients, 27 healthy first-degree relatives of probands with PD, and 22 healthy volunteers with no family history of PD. In a randomized double-blind experiment performed over two occasions 7 days apart, 480 mg caffeine and a caffeine-free solution were administered in a coffee form. Using specific panic attack criteria, 52.0% (n=13) PD patients, 40.7% (n=11) first-degree relatives (chi2=1.81, df=1, P=0.179), and none of the control subjects had a panic attack after the test (chi2=51.7, df=2, P

Background: Mood disorders are considered related to anxiety disorders and their association may determine clinical course and prognosis. We aimed to describe with retrospective methodology the demographic, clinical, and treatment features in a group of panic disorder comorbid with bipolar I disorder (PD–BI) patients who were been treated for at least 3 year-period and compare them with bipolar I (BI) patients who were treated during the same period. Method: We compared the demographic and clinical data of 26 PD–BI, 28 BI, and 25 panic disorder (PD) outpatients without history of comorbidity with mood disorder were diagnosed and treated for at least 3 years in the Federal University of Rio de Janeiro. Results: PD group have a higher educational level, are more married, and are more economically active. In the PD–BI and BI patients the disorders started earlier. They also turn out to have an equivalent pattern in the presence of drug abuse episodes, moderate or severe depressive episodes, psychotic episodes, suicide attempts, maniac episodes, mixed episodes, use of fewer days of antidepressants and benzodiazepines, and use of more days of antipsychotics and mood stabilizers. The PD–BI and the BI groups had a higher frequency of depressive episodes and psychotic episodes. Limitations: It is a retrospective data description based on a naturalistic treatment. The sample has a small size and the some data could be different in a large sample. Conclusion: PD–BI patients have demographic, clinical and therapeutic features similar to BI and the data support its validation as a special severe bipolar I disorder subgroup. © 2007 Elsevier B.V. All rights reserved.

Benzodiazepines are efficacious and well tolerated in clinical use. Besides the anxiolytic effects, they present sedative, muscle relaxant and anticonvulsive properties. Concerns regarding their use rely on drug dependence after prolonged used and difficult to manage withdrawal symptoms during drug discontinuation. Studies show that treatment duration up to 12 weeks is insufficient to reach maximal possible therapeutic effect and relapse during or shortly after drug discontinuation is frequent. Rebound and intolerable adverse events during drug discontinuation can be avoided in most cases if the dose is slowly down titrated in small decrements over a prolonged period of time. Most recent treatment guidelines recommend selective serotonin reuptake inhibitors (SSRI) as the first choice for the treatment of PD and the benzodiazepines have the reputation to cause dependence, especially if they are taken for long-term and in high doses. However these recommendations are mainly based on expert opinions mainly supported by a large number of clinical trials with SSRI since evidence coming from direct drug comparisons in PD is sparse. The SSRI have side effects and need a gradual tapering out too. There is no doubt that every substance must be prescribed with clinical concerns and indications. The benzodiazepines are efficacious in PD and the physician can manage the concern about dependence and withdrawal. It is very important to include this class of drugs in the armamentarium for treating PD.

Research into panic disorder (PD) has long indicated the possibility of distinct PD subtypes, such as respiratory, cardiovascular or gastrointestinal, based on the symptoms experienced during a panic attack (PA). In this chapter, we will elaborate on the new developments concerning the respiratory subtype (RS) of panic disorder (PD) since its first description, presenting psychopathological features, diagnostic criteria, genetic and physiopathological hypotheses, as well as therapeutic and prognostic characteristics. Evidence drawn from the available literature indicates a greater incidence of family history of PD, as well as higher comorbidity rates for disorders of anxiety and depression, among RS patients in comparison with patients of the non-respiratory subtype (NRS). RS patients were also more sensitive to CO2, hyperventilation and caffeine. These patients were clearly distinguished from the NRS patients by certain characteristics, such as the heightened sensitivity to CO2 and the higher incidence of a family history of PD. Nonetheless, it was not possible to demonstrate differential responses to pharmacological treatment and cognitive behavioral therapy 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.

Until now, little information exists about pharmacological strategies to follow in the treatment of panic disorder (PD) patients with unsatisfactory response to first line medications. Furthermore, there is no consensus about the definition of concept and management of treatment-resistant PD. The physiopathology of panic disorder is related to serotoninergic, noradrenergic and GABAergic systems. Based on this knowledge, antidepressants, anxiolytics, atypical antipsychotics and anticonvulsants have been studied in PD treatment. Besides selective serotonin re-uptake inhibitors, tricyclics, benzodiazepines and venlafaxine, there is limited scientific evidence on the effectiveness of other medications. More studies are needed for a better elucidation of the effectiveness and tolerability of medications in PD, especially atypical antipsychotics, anticonvulsants and other new drugs. For the moment, it is important to use existing scientific evidences regarding effectiveness, tolerability and safety, combined with clinical experience, to plan a rational treatment sequence for PD patients.

Panic attacks may present with conspicuous respiratory symptoms, which may also occur between attacks. Patients with panic attacks and respiratory symptoms have increased susceptibility to respiratory panicogenic challenges than patients without respiratory symptoms. Highly stressful situations, which may trigger a severe anxiety state such as panic attacks are characterized by a prothrombotic phenotype that increases the risk of thromboembolic events. Although episodes of pulmonary embolism might be accompanied by panic attacks, pulmonary embolism is seldom suspected when anxiety is the most likely alternative diagnosis. Given that recurrent thromboembolic disease may complicate with pulmonary artery hypertension and death, the diagnosis of pulmonary thromboembolism is fundamental. The diagnosis of pulmonary thromboembolism requires a high index of suspicion, because showers of microemboli are often asymptomatic or they may present with dyspnea, cough and wheezing, mimicking asthma. Notably, many patients with pulmonary thromboembolism have a relatively clear chest X-rays while severely hypoxemic. Confirmation of diagnosis usually depends on ventilation/perfusion lung scan or invasive imaging studies, such as computed tomographic pulmonary angiography. This paper discusses the characteristics of panic attacks that invite the suspicion of pulmonary embolism. It also suggests some diagnostic algorithms that help rule out thromboembolic disorders in the setting of panic attacks.

Panic disorder was described in several literary reports and folklore. Perhaps one of the oldest examples lies in Greek mythology, in which the Pan god was responsible for the term panic. Before 1850, the symptoms for anxiety were still usually associated with signs and symptoms of depression. In the second half of the nineteenth century, a progressive change began to take place in the field of anxiety symptoms. Henry Maudsley, in 1879, described a melancholic panic, and this was the first time the term panic was technically used in psychiatry. Jacob Mendes DaCosta, during the American Civil War described the irritable heart. At 1894, Sigmund Freud described the angstneurose (anxiety neurosis) and was impressed with the symptoms and associated phobias. In 1954, Mayer-Gross, associated anxiety disorders to hereditary, organic and psychological factors, dividing them in simple anxious states and phobic anxious states. In 1964, Donald Klein, published that patients with these disorders responded favorably to imipramine, a tricyclic antidepressant. His observations and descriptions influenced the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, 1980), in which the term panic disorder appears for the first time in an official classification. In 1993, Donald Klein described the “False Suffocation Alarm Theory”. This theory has been widely accepted, based on laboratory studies of respiratory, cognitive and biochemical tests. In the last 50 years, the mysteries of panic disorder have been revealed through basic and clinical research.

INTRODUÇÃO: Estudos indicam que há uma associação entre tabagismo e transtorno do pânico, e alguns autores sugerem que o tabagismo aumenta o risco de ataques de pânico e transtorno do pânico. Este estudo analisa a hipótese de que pacientes fumantes com esse transtorno apresentam um quadro clínico mais grave. MÉTODO: Sessenta e quatro pacientes em tratamento no Laboratório do Pânico e Respiração (Instituto de Psiquiatria da Universidade Federal do Rio de Janeiro), com transtorno do pânico, segundo critérios do Manual de Diagnóstico e Estatística das Perturbações Mentais (DSM, 4ª edição), foram divididos em grupos de tabagistas e não-tabagistas. Os grupos foram avaliados quanto a características sociodemográficas, comorbidades e gravidade do quadro clínico. RESULTADOS: Não houve diferença significativa em relação à gravidade do transtorno do pânico; no entanto, tabagistas tiveram prevalência de depressão significativamente maior (p = 0,014) do que não-tabagistas. CONCLUSÃO: Este estudo não evidenciou que o transtorno do pânico em tabagistas é mais grave, porém indicou que esses pacientes têm mais comorbidade com depressão. INTRODUCTION: Several studies indicate that panic disorder and tobacco smoking are associated, and some authors hypothesize that smoking increases the risk of panic attacks and panic disorder. The objective of this study is to investigate whether smokers have a more severe form of panic disorder than non-smokers. METHOD: Sixty-four patients already in treatment at the Laboratory of Panic and Respiration (Instituto de Psiquiatria da Universidade Federal do Rio de Janeiro) with panic disorder as established by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, were divided into groups of smokers and non-smokers. Both groups were compared regarding sociodemographic data, comorbidities and clinical status severity. RESULTS: There was no statistically significant difference between the two groups regarding severity; however, prevalence of depression was significantly higher in the smoker group than in non-smokers (p = 0.014). CONCLUSION: This study did not indicate that smokers have a more severe form of panic disorder, but smoking and comorbid depression were associated.

OBJECTIVE: Our aim was to identify the personality traits in patients with panics disorder, major depression and with both disorders (comorbidity). METHOD: Diagnoses were made with the Structured Clinical Interview for DSM-IV before the treatment, and the personality evaluation with the Maudsley Personality Inventory was made during the follow-up. Four groups were analyzed: a control group (n = 30), a major depression without panic disorder group (n = 45); a panic disorder without major depression group (n = 56) and a comorbidity group (n = 21), with major depression and panic disorder, simultaneously. RESULTS: All disorder groups had significantly higher neuroticism means when compared to the control group. The highest mean was in the comorbidity group, followed by the major depression group and the panic disorder group. The difference of neuroticism means between the comorbidity group and the panic disorder group also reached statistical significance. The lowest extraversion mean was in the comorbidity group, followed by the major depression group, the panic disorder group, and the control group. Compared to normal controls, extraversion was significantly low in the comorbidity and major depression groups. CONCLUSION: In our sample, there was a continuum of personality traits between panic disorder and major depression and, the co-occurrence of these disorders was associated with accentuated personality traits. OBJETIVO: Identificar os traços de personalidade presentes em pacientes com transtorno do pânico, depressão maior e comorbidade. MÉTODO: Os diagnósticos foram feitos com o Structured Clinical Interview para o DSM-IV antes do início do tratamento, e a avaliação dos traços de personalidade com o Maudsley Personality Inventory foi feita durante o acompanhamento desses pacientes. Quatro grupos foram comparados: um grupo controle (n = 30), um grupo de depressão maior sem transtorno do pânico (n = 45); um grupo de transtorno do pânico sem depressão maior (n = 56) e um grupo de comorbidade (n = 21), com transtorno do pânico e depressão maior, simultaneamente. RESULTADOS: Todos os grupos de pacientes tiveram médias de neuroticismo significativamente maiores quando comparados ao grupo controle. A maior média foi no grupo de comorbidade, seguida pelas dos grupos de depressão maior e transtorno do pânico. A diferença de neuroticismo entre o grupo de comorbidade e de transtorno do pânico também foi estatisticamente significativa. Entre os grupos de pacientes, a menor média de extroversão foi a do grupo de comorbidade, seguida pelas de depressão maior e transtorno do pânico. Quando comparados ao grupo controle, apenas os grupos de comorbidade e depressão maior tiveram extroversão significativamente mais baixa. CONCLUSÃO: Na nossa amostra, houve uma continuidade de traços de personalidade entre o transtorno do pânico e a depressão maior, e a sobreposição de sintomas de pânico-agorafobia e de depressão estava associada a traços de personalidade acentuados.

Our aim was to compare the demographic and clinical features of panic disorder (PD) patients with agoraphobia-DSM-IV-who had a panic attack after both an oral caffeine and the 35% carbon dioxide (CO2) challenge tests (responsive group) and compare them with PD patients who did not have a panic attack after both tests (non-responsive group). We examined 83 PD patients submitted to a 35% CO2 test and to an oral caffeine (480 mg) intake within 1 week interval. A panic attack was induced in 51 (61.4%) patients during the CO2 test (chi2=31.67, df=1, p

The prevalence of panic disorder (PD) in the population is high and these patients have work impairment, high unemployment rates, seek medical treatment more frequently and have more hospitalizations than people without panic symptoms. Despite the availability of pharmacological, psychological and combined treatments, approximately one-third of all PD patients have persistent panic attacks and other PD symptoms after treatment.MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases were searched for clinical trials in treatment-resistant PD. Only studies published between 1980 and 2015, in English, with human subjects, considered "journal articles" and clinical trial were included. We included trials recruiting only adult subjects with treatment-resistant PD, consistent with criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, case series, retrospective studies or studies with10 PD subjects were not included.Only 11 articles were included in this review. There were few quality studies, only two were randomized, controlled and double blind. Augmentation of the pharmacological treatment with cognitive-behavioral therapy demonstrated some short-term efficacy in treatment-resistant PD. There were also preliminary evidences of efficacy for monotherapy with reboxetine and olanzapine, and augmentation with pindolol, divalproex sodium, aripiprazole and olanzapine in short-term treatment.

Our aim was to describe the clinical features of 35% CO2-induced panic attacks in patients with panic disorder (PD) (Diagnostic and Statistical Manual and Mental Disorders, Fourth Edition) and compare them with the last spontaneous panic attack in patients with PD who had not had a panic attack after the 35% CO2 challenge test. We examined 91 patients with PD submitted to the CO2 challenge test. The test consisted of exhaling as fully as possible, took a fast vital capacity breath, held their breath for 8 seconds, exhaled, and then repeated the fast vital capacity breath, again holding for 8 seconds. The patients inhaled the 35% CO2/65% O2 mixture or atmospheric compressed air, randomly selected in a double-blind design. Scales were applied before and after the test. A total of 68.1% (n = 62) patients with PD had a panic attack (responders) after the CO2 test (chi2(1) = 25.87, P = .031). The last spontaneous panic attack and the symptom profile from the patients with PD who had not had a panic attack after the test (n = 29, 31.9%) were described to compare. The responders had more respiratory symptoms (chi2(1) = 19.21, P.001), fulfilling the criteria for respiratory PD subtype (80.6%); the disorder started earlier (Mann-Whitney, P.001), had a higher familial prevalence of PD (chi2(1) = 20.45, P = .028), and had more previous depressive episodes (chi2(1) = 27.98, P.001). Our data suggest that there is an association between respiratory PD subtype and hyperreactivity to a CO2 respiratory challenge test. The responders may be a subgroup of respiratory PD subtype with future diagnostic and therapeutic implications.

Background Schizobipolar disorder is considered related to both schizophrenia and bipolar disorder. We aimed to describe with retrospective methodology the demographic, clinical, and treatment features in a group of schizobipolar disorder patients who have been treated for at least a 5-year period and compare them with bipolar I and schizophrenic patients who were treated during the same period. Method We compared the demographic and clinical data of 61 schizobipolar, 57 bipolar I, and 55 schizophrenic outpatients who were diagnosed and treated for at least 5 years in the outpatient clinic in the Federal University of Rio de Janeiro. Results The schizobipolar disorder patients had a profile similar to the bipolar I patients but are significantly different from schizophrenic patients in educational level, marital status, occupation, drug and alcohol abuse episodes, presence of depressive, mixed and maniac episodes, family history of bipolar I and mood disorders, and use of medications. Only the age of onset, suicide attempts, and family history of suicide are not significantly different among the groups. The schizophrenic patients used antipsychotics for more days and the schizobipolar and bipolar I used more antidepressants and mood stabilizers. 37 (60.6%) schizobipolar patients had their diagnosis changed to bipolar disorder by their physician in different periods during the period studied. Limitations It is a retrospective data description based on a naturalistic treatment. The family history was collected from the patient and whenever possible from one first-degree relative. Conclusion Schizobipolar disorder patients have demographic, clinical and therapeutic features similar to bipolar I patients and data support its definite inclusion in the bipolar spectrum group.

The demographic, clinical and therapeutic features of the respiratory subtype of panic disorder (PD) versus the non-respiratory subtype were studied in a prospective design. Sixty-seven PD outpatients (DSM-IV), who had previously been categorized into respiratory ( n =35) and non-respiratory ( n =32) subgroups, were openly treated with clonazepam for a 3-year period. The principal measure of efficacy was the number of panic attacks, obtained from the Sheehan Panic and Anticipatory Anxiety Scale. In the first 8 weeks of treatment (acute phase), the respiratory subtype group had a significantly faster response to clonazepam. During the follow-up (weeks 12-156), the two subgroups did not differ significantly in the number of panic attacks experienced from baseline to end point. Patients in the respiratory subtype were characterized by a later onset of disorder and a family history of PD. Patients in the non-respiratory subgroup had a significantly higher number of past depressive episodes than those in the respiratory subgroup. The respiratory subgroup had a faster response after 8 weeks of treatment and an equivalent response in the 3-year follow-up period. Clonazepam had a sustained therapeutic effect over the entire treatment period.

Panic disorder patients are hypervigilant to danger cues and highly sensitive to unpredictable aversive events, what leads to anticipatory anxiety, that is one key component of the disorder maintenance. Prefrontal cortex seems to be involved in these processes and beta band activity may be related to the involvement of top-down processing, whose function is supposed to be disrupted in pathological anxiety. The objective of this study was to measure frontal absolute beta-power (ABP) with qEEG in panic disorder and agoraphobia (PDA) patients compared to healthy controls. Methods: qEEG data were acquired while participants (24 PDA patients and 21 controls) watched a computer simulation (CS), 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. The statistical analysis was performed by means of a repeated measure analysis of variance (two-way ANOVA) and ABP was the dependent variable of interest. The main hypothesis was that a higher ABP in PDA patients would be found related to controls. Moreover, in HAM the ABP would be different than in LAM. Results: the main finding was an interaction between the moment and group for the electrodes F7, F8, Fp1 and Fp2. We observed a higher ABP in PDA patients when compared to controls while watching the CS. The higher beta-power in the frontal cortex for the PDA group may reflect a state of high excitability, together with anticipatory anxiety and maintenance of hypervigilant cognitive state. Conclusions: our results suggest a possible deficiency in top-down processing reflected by a higher ABP in the PDA group while watching the CS and they highlight the recruitment of prefrontal regions during the exposure to anxiogenic stimuli. Limitations: the small sample, the wide age range of participants and the use of psychotropic medications by most of the PDA patients.