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Background: Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist., Case Presentation: The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks., Conclusions: There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered., (© 2023. The Author(s).)

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens., Competing Interests: Declaration of Competing Interest All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Stepped-care (SC) models for anxiety disorders are implemented on a large scale and are assumed to be as effective for the greater majority of patients as more intensive treatment schemes. To compare the outcomes of SC and international guideline-based treatment (Treatment as Usual: TAU) for panic disorder, a total of 128 patients were randomized to either SC or TAU (ratio 2: 1, respectively) using a computer generated algorithm. They were treated in four mental health care centres in the Netherlands after therapists had been trained in SC by a senior expert therapist. SC comprised 10-week guided self-help (pen-and-paper version) followed, if indicated, by 13-week manualized face-to-face cognitive behavioural therapy (CBT), with medication- if prescribed- kept constant. TAU consisted of 23-week regular face-to-face CBT (RCBT) with medication -when prescribed- also kept constant. The means of the attended sessions in the SC condition was 5.9 (SD = 4.8) for ITT and 9.6 (SD = 9.6) for the RCBT condition. The difference in the number of attended sessions between the conditions was significant (t(126) = -3.87, p < .001). Remission rates between treatment conditions did not differ significantly (SC: 44.5%; RCBT: 53.3%) and symptom reduction was similar. Stepping up SC treatment to face-to-face CBT showed a minimal additional effect. Importantly, drop-out rates differed significantly for the two conditions (SC: 48.2%; RCBT: 26.7%). SC was effective in the treatment of panic disorder in terms of symptom reduction and remission rate, but dropout rates were twice as high as those seen in RCBT, with the second phase of SC not substantially improving treatment response. However, SC required significantly less therapist contact time compared to RCBT, and more research is needed to explore predictors of success for guided self-help interventions to allow treatment intensity to be tailored to patients' needs and preferences., Competing Interests: Although at the time of the study one of the authors (MV) was a member of the board HSK Groep as well as an employee of the Behavioural Science Institute of Radboud University, his affiliation with HSK Groep does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.

This chapter reviews the role of benzodiazepines (BZs) in the treatment of anxiety disorders, specifically panic disorder with or without agoraphobia, generalized anxiety disorder, and social anxiety disorder (social phobia). BZs pharmacology, classification, efficacy, adverse effects, withdrawal symptoms, possible dependence, and abuse; their positioning among pharmacological treatment; and guidance on how to use them are discussed.

Background: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action., Objectives: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults., Search Methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data., Selection Criteria: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo., Data Collection and Analysis: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability., Main Results: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence)., Authors' Conclusions: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

Background: Patients' characteristics and antidepressants are discussed to be relevant in the context of phobic exposure., Aims: To identify patients characteristics associated with a differential course of fear during disorder-specific symptom provocation as well as to elucidate the effect of selective serotonin-(noradrenalin-) reuptake inhibitors [SS(N)RI] on development of fear in the context of re-exposure to the phobic stimuli., Methods: Twenty-eight clinically well-characterized patients with panic disorder and agoraphobia (PD/AG) were classified into subjects who show a reduction of fear ('Fear-') during a symptom provocation via a picture-based paradigm (T1) and those who did not ('Fear+'). Subsequently, SS(N)RI treatment was administered to all patients and subjects were re-exposed to the feared stimuli after 8 weeks of treatment (T2). Moreover, brain activity within the 'fear network' was measured via functional magnetic resonance imaging (fMRI) at T1 and T2., Results: Fear - were significantly younger and demonstrated increased exposure-related fear as well as stronger activity in several fear-related brain areas than Fear+. We found significant improvements in all clinical parameters after pharmacological intervention for the whole sample (T1-T2; all measures p < .02). However, reduction of fear as well as activation in (para)limbic structures during symptom provocation were now attenuated in Fear - but increased in Fear+., Conclusions: Advanced age may predict a therapeutically unfavorable course of fear during agoraphobic symptom provocation. Since we found no negative impact of medication on fear development at all, there was some evidence that SS(N)RI treatment might improve the individual ability to get involved with the agoraphobic stimuli while conducting disorder-specific exposure.

Background: Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition., Objectives: To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo., Search Methods: We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews., Selection Criteria: All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo., Data Collection and Analysis: Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference., Authors' Conclusions: The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Purpose/background: D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the effectiveness of adding 125 mg of DCS to exposure therapy (before or directly after the first 6 treatment sessions) in patients with panic disorder with agoraphobia and (2) the effectiveness of DCS augmentation preceding exposure relative to DCS augmentation directly postexposure., Methods/procedures: Fifty-seven patients were allocated to 1 of 3 medication conditions (placebo and pre-exposure and postexposure DCS) as an addition to 6 exposure sessions within a 12-session exposure and response prevention protocol. The primary outcome measure was the mean score on the "alone" subscale of the Mobility Inventory (MI)., Findings/results: No differences were found in treatment outcome between DCS and placebo, administered either pre-exposure or postexposure therapy, although at 3-month follow-up, the DCS postexposure group compared with DCS pre-exposure, exhibited greater symptom reduction on the MI-alone subscale. Ancillary analyses in specific subgroups (responders vs nonresponders, early vs late responders, severely vs mildly affected patients) did not reveal any between-group DCS versus placebo differences. Finally, the study did not find an effect of DCS relative to placebo to be specific for successful exposure sessions., Implications/conclusions: This study does not find an effect of augmentation with DCS in patients with severe panic disorder and agoraphobia administered either pretreatment or directly posttreatment sessions. Moreover, no preferential effects are revealed in specific subgroups nor in successful exposure sessions. Yet, a small effect of DCS administration postexposure therapy cannot be ruled out, given the relatively small sample size of this study.

Introduction: Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates., Experimental Procedures: We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29)., Results: Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups., Discussion: This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala's involvement in the fear system's sensitivity to treatment., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: We investigated the efficacy of an intensive 1-week behavioral therapy program focusing on agoraphobia for panic disorder patients with agoraphobia (PDA)., Design and Methods: The study design was a case-control study. Main outcome measure was the agoraphobia score of the Fear Questionnaire (FQ-AGO). The outcomes on the FQ-AGO of a 1-week intensive therapy (96 patients) and a twice-weekly therapy (98 patients) were compared., Results: Agoraphobia improved significantly in both groups, 1 week and 3 months after therapy. Effect size for changes in the 1-week intensive therapy on the FQ-AGO was 0.75., Limitations: Limitations are use of antidepressants, no placebo group, and no long term follow-up., Conclusion: Behavioral therapy for agoraphobia can be shortened significantly if intensified without affecting therapy outcome, thus allowing patients a more rapid return to work and resumption of daily activities., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Panic disorder is common in the general population. It is often associated with other psychiatric disorders, such as drug dependence, major depression, bipolar disorder, social phobia, specific phobia and generalised anxiety disorder. Azapirones are a class of drugs used as anxiolytics. They are associated with less drowsiness, psychomotor impairment, alcohol potentiation and potential for addiction or abuse than benzodiazepines. However, azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear. It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder., Objectives: To assess the effects of azapirones on panic disorder in adults, specifically:1. to determine the efficacy of azapirones in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison with placebo;2. to review the acceptability of azapirones in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate adverse effects of azapirones in panic disorder with or without agoraphobia, including general prevalence of adverse effects, compared with placebo., Search Methods: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, search date: 10th January 2014), which includes relevant randomised controlled trials from The Cochrane Library (all years), MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-)., Selection Criteria: Randomised controlled trials that compared azapirones with placebo for panic disorder in adults., Data Collection and Analysis: Three review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information., Main Results: Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses., Authors' Conclusions: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder.

Background: The core domains of social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD) with and without agoraphobia (GA), and specific phobia (SP) are cognitive and physical symptoms that are related to the experience of fear and anxiety. It remains unclear whether these highly comorbid conditions that constitute the anxiety disorder subgroups of the Diagnostic and Statistical Manual for Mental Disorders--Fifth Edition (DSM-5) represent distinct disorders or alternative presentations of a single underlying pathology., Methods: A systematic search of voxel-based morphometry (VBM) studies of SAD, GAD, PD, GA, and SP was performed with an effect-size signed differential mapping (ES-SDM) meta-analysis to estimate the clusters of significant gray matter differences between patients and controls., Results: Twenty-four studies were eligible for inclusion in the meta-analysis. Reductions in the right anterior cingulate gyrus and the left inferior frontal gyrus gray matter volumes (GMVs) were noted in patients with anxiety disorders when potential confounders, such as comorbid major depressive disorder (MDD), age, and antidepressant use were controlled for. We also demonstrated increased GMVs in the right dorsolateral prefrontal cortex (DLPFC) in comorbid depression-anxiety (CDA), drug-naïve and adult patients. Furthermore, we identified a reduced left middle temporal gyrus and right precentral gyrus in anxiety patients without comorbid MDD., Conclusion: Our findings indicate that a reduced volume of the right ventral anterior cingulate gyrus and left inferior frontal gyrus is common in anxiety disorders and is independent of comorbid depression, medication use, and age. This generic effect supports the notion that the four types of anxiety disorders have a clear degree of overlap that may reflect shared etiological mechanisms. The results are consistent with neuroanatomical DLPFC models of physiological responses, such as worry and fear, and the importance of the ventral anterior cingulate (ACC)/medial prefrontal cortex (mPFC) in mediating anxiety symptoms.

Objective: Low serum phosphate level is considered one of the metabolic adaptations to the respiratory alkalosis induced by hyperventilation associated with panic disorder. The aim of this study was to assess phosphatemia as a possible state marker for panic disorder., Methods: Sixteen panic disorder patients underwent clinical assessment with a semi-structured interview, a set of rating scales and the self-rated State and Trait Anxiety Inventory (STAI), as well as extraction of venous blood samples at baseline and after 12 weeks of pharmacological treatment. Ten healthy volunteers of similar sex, age and educational level filled out the STAI and gave blood samples at baseline and 12 weeks later., Results: The median (25th-75th percentiles) of phosphate levels (mg/dl) was 2.68 (2.22-3.18) among patients and 4.13 (3.74-4.70) among healthy volunteers respectively (P < 0.001). Seven (44%) patients and no healthy volunteers presented low serum phosphate (<2.50 mg/dl) at baseline; this patient abnormality was corrected in all cases after successful treatment. At baseline, the age-adjusted correlation between phosphate levels and state-anxiety was -0.66 (P < 0.001) among all 26 participants and -0.51 (P = 0.05) among the 16 panic disorder patients., Conclusions: Measurement of phosphate levels could be easily introduced into clinical practice as a possible marker for chronic hyperventilation in panic disorder, although further investigations with larger sample sizes are necessary to characterize panic disorder patients with low versus normal phosphate levels., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and anxiety, but has not been examined systematically in generalized anxiety disorder (GAD). The objective of this study was to examine the relationship between baseline BDNF level and treatment response in patients with GAD., Methods: Patients (N=168) were from China, met criteria for DSM-IV GAD, had a Hospital Anxiety and Depression Rating Anxiety (HADS-A) subscale score ≥10, and a Sheehan Disability Scale (SDS) global functioning total score ≥12 at baseline. Study design was double-blind therapy for 15 weeks with duloxetine 60-120 mg or placebo. Efficacy measures included the HADS-A and Hamilton Anxiety Rating Scale (HAMA) total score. Change from baseline to endpoint for BDNF by treatment group was analyzed using ANCOVA models with baseline BDNF level as a covariate., Results: No significant association was found between baseline plasma BDNF levels and anxiety illness severity. Patients who received duloxetine (n=88) had a significantly greater mean increase in plasma BDNF level (957.80 picograms/ml) compared with patients who received placebo (n=80; 469.93 pg/mL) (P=.007). Patients who met response and remission criteria (with either treatment) had greater mean increases in BDNF at endpoint from baseline (P≤.05) but when compared with nonresponders and nonremitters, respectively, the differences in mean increase were not statistically significant between groups., Conclusions: BDNF levels significantly increased with duloxetine treatment for GAD, but response and remission outcomes were not clearly related to an increase in plasma BDNF level., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We aimed to examine whether anxiety sensitivity and agoraphobic fear could affect the time taken to remission after 24 weeks of open-label escitalopram treatment of patients with panic disorder (PD). We recruited 158 patients, and 101 patients completed the study. Clinical severity and psychological characteristics were assessed at baseline and 4, 12, and 24 weeks after the treatment, using the Clinical Global Impression-Severity (CGI-S), the Hamilton Rating Scales for Anxiety and Depression, the Anxiety Sensitivity Index-Revised (ASI-R), the Albany Panic and Phobia Questionnaire (APPQ), and the Panic Disorder Severity Scale (PDSS). Remission was defined as the absence of full panic attacks and PDSS scores of 7 or less. Completing patients were stratified according to the time taken to remit: early (n=20) and late (n=58) remission and non-remission groups (n=23). There were no significant differences among the three groups at baseline on the CGI-S and the PDSS mean scores. However, early remitters had significantly lower scores than late remitters and non-remitters on the ASI-R and APPQ. In conclusion, anxiety sensitivity and agoraphobic fear can affect the time to remission after pharmacotherapy, and clinicians should consider the psychological characteristics of PD patients in order to achieve an optimal response to pharmacotherapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Low circulating levels of testosterone have been associated with major depression, but there is more limited evidence for differences in patients with anxiety disorders. The use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants is associated with sexual side effects, warranting testing for interactions with testosterone., Methods: Data are from 722 male and 1380 female participants of The Netherlands Study of Depression and Anxiety (NESDA), who were recruited from the community, general practice care, and specialized mental health care. Depressive and anxiety diagnoses were assessed using the DSM-IV Composite International Diagnostic Interview. To smooth the episodic secretion, the four morning saliva samples per participant and the two evening samples were pooled before testosterone analysis., Results: Morning median testosterone levels were 25.2 pg/ml in men and 16.2 pg/ml in women, with lower evening levels of 18.2 and 14.1 pg/ml, respectively. Significant determinants of testosterone levels were sex, age, time of the day, use of contraceptives, and smoking status. Female patients with a current (1-month) depressive disorder (effect size 0.29; P=0.002), generalized anxiety disorder (0.25; P=0.01), social phobia (0.30; P<0.001), and agoraphobia without panic disorder (0.30; P=0.02) had lower salivary testosterone levels than female controls. Higher testosterone levels were found in male and female participants using SSRIs than in non-users (effect size 0.26; P<0.001)., Conclusion: Salivary testosterone levels are lower in female patients with a depressive disorder, generalized anxiety disorder, social phobia, and agoraphobia as compared to female controls. SSRIs may increase salivary testosterone in men and women., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Efficacy of treatments for panic disorder is well established, but not all patients respond. Adult separation anxiety has been found to predict poorer response to CBT, but its effect on response to medication has not been previously explored., Study Aim: The aim of this study is to investigate if panic-agoraphobic spectrum factors, including 'separation anxiety' factor predict treatment outcome in patients with panic disorder., Study Sample: Participants who met criteria for PD (n=57) completed baseline assessment and 12 months follow-up. Patients were administered the Panic Agoraphobic Spectrum Self-Report (PAS-SR, Lifetime and Last-Month Versions), and the Panic Disorder Severity Scale (PDSS). We examined patients who met the following criteria at baseline: 1) PDSS total score>7; 2) no current Axis I comorbidity with major depression; 3) no lifetime or current bipolar disorder. All patients were treated with evidence-based psychopharmacological treatment for panic disorder during the 12-month observation period., Results: Twenty eight patients (48.1%) achieved remission during the follow-up period. In a logistic regression model, controlling for baseline severity, gender and age, only the last-month PAS-SR 'separation anxiety' factor was associated with a lower likelihood of remission., Conclusions: Signs and symptoms of separation anxiety in adulthood, as assessed with the PAS-SR Last Month version, are predictors of poor treatment outcome in patients with PD. We submit that the assessment of panic-agoraphobic spectrum features, including adult separation anxiety, should become routine of clinical assessment of patients with PD. It is likely that a better psychopathological characterization of patients may inform treatment selection, and result in better treatment outcome., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We performed a meta-analysis of all single- or double-blind, randomized controlled trials comparing alprazolam to another benzodiazepine in the treatment of adult patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Third or Fourth Edition, criteria for panic disorder or agoraphobia with panic attacks. Eight studies met inclusion criteria, describing a total of at least 631 randomized patients. In the pooled results, there were no significant differences in efficacy between alprazolam and the comparator benzodiazepines on any of the prespecified outcomes: improvement in mean panic attack frequency (between-arm weighted mean difference of 0.6 panic attacks per week; 95% confidence interval [CI], -0.3 to 1.6), improvement in Hamilton Anxiety Rating Scale score (weighted mean difference of 0.8 points; 95% CI, -0.5 to 2.1), and proportion of patients free of panic attacks at the final evaluation (pooled relative risk, 1.1; 95% CI, 0.9-1.4). Statistical heterogeneity on prespecified outcomes was not eliminated by stratification on baseline anxiety level. The available evidence fails to demonstrate alprazolam as superior to other benzodiazepines for the treatment of panic disorder.

A 51-year-old woman had panic disorder with agoraphobia and major depressive disorder sequentially. The aforementioned symptoms subsided significantly after treatment with milnacipran, 125 mg, administered daily for 2 months. However, panic attacks with agoraphobia were noted frequently when she tapered down milnacipran to 50 mg daily. She consequently experienced depression that gradually increased in degree, with poor energy, poor sleep, thoughts of helplessness, and ideas of death. After administration of a daily dose of 125 mg of milnacipran for 1 month, her panic attacks with agoraphobia and depressed mood were again alleviated. The present report shows significant effects of milnacipran on the comorbidity of panic disorder with agoraphobia and major depressive disorder.

D-cycloserine (DCS)-augmented exposure therapy has proven efficacy in the treatment of acrophobia, social phobia, panic disorder and OCD. Here we studied whether DCS can also improve the effect of cognitive behavioral therapy (CBT) in patients with agoraphobia and panic disorder. To this end, 39 patients with the diagnoses of agoraphobia and panic disorder were treated with 11 sessions of CBT including three individual in-vivo exposure sessions (flooding), augmented with either 50mg of DCS (N=20) or placebo (N=19) in a randomized double blind design. Primary outcome was the total score of the panic and agoraphobia scale. Both groups profited considerably from therapy and DCS did not significantly improve this outcome (p=0.475; η(2)p = 0.01). However, there was a statistical trend (p=0.075; η(2)p = 0.17) in the more severely ill patients that DCS accelerated symptom reduction in the primary outcome at post-therapy. No serious adverse effects occurred during the trial. We conclude that in patients with agoraphobia and panic disorder, DCS seems to lack an additional benefit to efficient cbt, probably due to a floor effect. Nonetheless, the acceleration of symptom reduction in severely ill patients might represent a valuable treatment option deserving further investigation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The purpose of this study was to evaluate the efficacy and effectiveness of imipramine on the treatment of comorbid chronic dizziness and panic disorder., Method: Nine patients with panic disorder and agoraphobia associated with chronic dizziness underwent otoneurological screening and were treated with a 3-months course of imipramine. Anxiety levels were measured with the Hamilton Anxiety Scale (HAM-A), dizziness levels were evaluated using the Dizziness Handicap Inventory (DHI), and panic severity and treatment outcome were assessed with the Clinical Global Impression Scale (CGI)., Results: At the baseline 33.3% (n=3) had a bilateral peripheral deficit vestibulopathy, the mean scores for HAM-A were 27.2±10.4, for DHI were 51.7±22.7, and for CGI-S were 4.8±0.9. All patients had a significant reduction in their HAM-A (11.1±5.5, p=0.008), DHI (11.5±8.1, p=0.008) and CGI-I (1.8±0.7, p=0.011) levels after 3-months imipramine treatment (mean=72.2±23.2 mg/day)., Conclusion: This study found a decrease in anxiety levels and in the impact of dizziness in the patients' quality of life after a 3-months treatment course with imipramine.

The objective of the present randomized, open-label, naturalistic 8-week study was to compare the efficacy and safety of treatment with clonazepam (N = 63) and paroxetine (N = 57) in patients with panic disorder with or without agoraphobia. Efficacy assessment included number of panic attacks and clinician ratings of the global severity of panic disorders with the clinical global impression (CGI) improvement (CGI-I) and CGI severity (CGI-S) scales. Most patients were females (69.8 and 68.4% in the clonazepam and paroxetine groups, respectively) and age (mean ± SD) was 35.9 ± 9.6 years for the clonazepam group and 33.7 ± 8.8 years for the paroxetine group. Treatment with clonazepam versus paroxetine resulted in fewer weekly panic attacks at week 4 (0.1 vs 0.5, respectively; P < 0.01), and greater clinical improvements at week 8 (CGI-I: 1.6 vs 2.9; P = 0.04). Anxiety severity was significantly reduced with clonazepam versus paroxetine at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine (73 vs 95%; P = 0.001). The most common adverse events were drowsiness/fatigue (57%), memory/concentration difficulties (24%), and sexual dysfunction (11%) in the clonazepam group and drowsiness/fatigue (81%), sexual dysfunction (70%), and nausea/vomiting (61%) in the paroxetine group. This naturalistic study confirms the efficacy and tolerability of clonazepam and paroxetine in the acute treatment of patients with panic disorder.

Objective: Tranylcypromine has been recommend as an option for therapy-resistant depressive and anxiety disorders. In this case report the effectiveness of this medication as a part of a combined therapy-program including pharmacological, behavioural and psychodynamic interventions could be demonstrated on an outpatient with a therapy-resistant depression and agoraphobia., Methods: The development of the illness, clinical symptoms and the 4 year ongoing therapy of a 69-year old patient are described in detail., Results/conclusion: After the failure of 13 antidepressant agents with considerable side effects, a one year sustained remission of depression as well as great improvement of agoraphobia could be achieved with tranylcypromine. In this situation, tranylcypromine showed itself, for the first time, to be a very effective and well tolerated antidepressant., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To examine the effectiveness of paroxetine and cognitive-behavioural therapy (CBT) in elderly patients suffering from panic disorder with or without agoraphobia (PD(A))., Method: Forty-nine patients aged 60+ years with confirmed PD(A) were randomly assigned to 40 mg paroxetine, individual CBT, or to a 14-week waiting list. Outcomes, with avoidance behaviour and agoraphobic cognitions being the primary measures, were assessed at baseline and at weeks 8, 14 (conclusion CBT/waiting list), and at week 26 (treated patients only) and analysed using mixed models., Results: All outcome measures showed that the patients having received CBT and those treated with paroxetine had significantly better improvement compared with those in the waiting-list condition. With one patient (1/20, 5%) in the CBT and three (3/14, 17.6%) in the paroxetine condition dropping out, attrition rates were low., Conclusion: Patients with late-life panic disorder respond well to both paroxetine and CBT. Although promising, the outcomes warrant replication in larger study groups.

Objectives: The most important change of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) is the use of dimensional approach to assess the severity of symptoms across different diagnosis. There are 2 purposes in this study: the first purpose was to identify the proportion of outpatients with panic disorder who have suicidal ideation. The second aim was to examine the relationships among panic, agoraphobic symptoms, and suicidal ideation in patients with panic disorder, adjusting by age, social support, and alcohol use., Methods: Sixty patients with panic disorder were recruited from outpatient psychiatric clinics in southern Taiwan. Suicidal ideation in the preceding 2 weeks was measured. The Panic and Agoraphobic Symptoms Checklist, Social Support Scale, Questionnaire for Adverse Effects of Medication for Panic Disorder, and Social Status Rating Scale were used to understand the severity of panic and agoraphobia, social support, drug adverse effects, and social status. Significant variables from the univariate analysis were included in a forward regression model. Then, we used structural equation modeling to fit the model., Results: We found that 31.7% of outpatients with panic disorder had had suicidal ideation in the preceding 2 weeks. Multiple regression analysis showed that younger age, current alcohol use, more severe panic symptoms, and less social support were associated with suicidal ideation. In addition, the structural equation model illustrated the recursive model from panic to agoraphobia and suicidal ideation. Agoraphobia had no association with suicidal ideation. Panic symptom was a mediator to suicidal ideation but not agoraphobic symptoms., Conclusions: A high proportion of patients with panic disorder had suicidal ideation. We found that panic symptoms, social support, age, and alcohol use affected suicide and could be identified. The 3-level model from panic to agoraphobia revealed that panic was a predictor of agoraphobia and agoraphobia was not a predictor of panic. This verified the evolution of the diagnostic view of the DSM. Panic symptom was a mediator to suicidal ideation. With the dimensional model in DSM-V, panic symptoms can be used as a marker for greater morbidity and severity., (2010 Elsevier Inc. All rights reserved.)

Several anticonvulsants, although as yet not lamotrigine (LTG), have been found useful in the treatment of panic disorder with (PDA) or without agoraphobia. We administered LTG (200 mg/d) to 4 outpatients with PDA, as an augmentation therapy (3 patients with chronic and severe agoraphobia) or monotherapy (1 drug-naive patient with first-onset PDA) in a 14-week trial. The patient under LTG monotherapy improved significantly, whereas PDA symptoms in 2 of the other patients improved to some extent.

Objective: To establish the long-term effectiveness of 3 treatments for DSM-IV panic disorder with or without agoraphobia: cognitive-behavioral therapy (CBT), pharmacotherapy using a selective serotonin reuptake inhibitor (SSRI), or the combination of both (CBT + SSRI). As a secondary objective, the relationship between treatment outcome and 7 predictor variables was investigated., Method: Patients were enrolled between April 2001 and September 2003 and were randomly assigned to treatment. Academic and nonacademic clinical sites participated. Each treatment modality lasted 1 year. Pharmacotherapists were free to choose between 5 SSRIs currently marketed in The Netherlands. Outcome was assessed after 9 months of treatment (posttest 1), after discontinuation of treatment (posttest 2), and 6 and 12 months after treatment discontinuation (follow-up 1 and follow-up 2)., Results: In the sample (N = 150), 48% did not suffer from agoraphobia or suffered from only mild agoraphobia, while 52% suffered from moderate or severe agoraphobia. Patients in each treatment group improved significantly from pretest to posttest 1 on the primary outcome measures of level of anxiety (P < .001), degree of coping (P < .001), and remitter status (P < .001), as well as on the secondary outcome measures of depressive symptomatology (P < .001), and from pretest to posttest 2 for health-related quality of life (P < .001). Gains were preserved from posttest 2 throughout the follow-up period. Some superiority of CBT + SSRI and SSRI as compared with CBT was observed at posttest 1. However, at both follow-ups, differences between treatment modalities proved nonsignificant. Client satisfaction appeared to be high at treatment endpoint, while patients receiving CBT + SSRI appeared slightly (P < .05) more satisfied than those receiving CBT only., Conclusions: No fall-off in gains was observed for either treatment modality after treatment discontinuation. SSRIs were associated with adverse events. Gains produced by CBT were slower to emerge than those produced by CBT + SSRI and SSRI, but CBT ended sooner., Trial Registration: Netherlands Trial Register (www.trialregister.nl) Identifier: ISRCTN8156869., (©Copyright 2010 Physicians Postgraduate Press, Inc.)

Background: Previous research in outpatient samples suggests that panic and agoraphobic comorbidity is related to suicidality in outpatients with major depression. The purpose of the study was to further investigate this relationship specifically in a hospitalized sample., Method: This study examined the severity of current suicidal ideation and behaviors in a psychiatric hospital sample diagnosed with major depressive disorder alone (MDD; n=28) versus MDD plus panic-agoraphobic spectrum disorders (MDD+PAS; n=69)., Results: Members of the MDD+PAS group were significantly more likely to have had a suicide attempt history, higher current depression severity, and higher current suicidal severity compared with individuals in the MDD alone group. The relationship between the current suicidality and comorbid PAS remained significant after controlling for the overall depression severity and other clinical factors., Conclusions: These findings suggest that panic-agoraphobic comorbidity is associated with a greater risk for suicidality in hospitalized patients, which cannot be adequately explained by the level of current depression alone. The clinical and research implications for these findings are discussed., ((c) 2010 Wiley-Liss, Inc.)

Objective: Although the majority of individuals with panic disorder first present to the primary care setting, little is known about the psychiatric treatment that primary care patients with the disorder typically receive. The purpose of this study was to explore characteristics of treatment received by patients with panic disorder with agoraphobia and by those with panic disorder without agoraphobia, examine demographic and clinical predictors of receiving treatment, and explore treatment barriers., Methods: This study used data from the Primary Care Anxiety Project (PCAP), which is a naturalistic, longitudinal study of anxiety disorders among primary care patients. This study presents data for 235 PCAP participants diagnosed at the study intake assessment as having panic disorder with agoraphobia (N=150) or without agoraphobia (N=85)., Results: Many patients with panic disorder were not receiving psychiatric treatment at study intake (38%), with those without agoraphobia being less likely to receive treatment. Psychotropic medications were the treatment of choice, with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors being the most commonly received class of medications (34%). Only 38% of those with panic disorder with agoraphobia and 24% of those with panic disorder without agoraphobia were receiving psychotherapy, and the use of empirically supported interventions was rare. The most common treatment barriers were not believing in using medication or therapy for emotional problems and not receiving a treatment recommendation from one's provider., Conclusions: The findings suggest a need for better treatment dissemination, in addition to making interventions more accessible or adapting them to the particular needs of primary care patients.

The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GI) symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4-6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300-450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.5 mg/day; lorazepam, 6 mg/day). A GI-high subgroup (high GI symptomatology) was defined by a baseline HAM-A item-11 (GI) score of 3 or greater (severe/very severe). At baseline, 301 patients (16.2%) met criteria for the GI-high subgroup. Baseline characteristics were approximately similar for the four study treatments in the GI-high subgroup. For the GI-high subgroup, last observation carried forward (LOCF) endpoint reduction in HAM-A was significantly higher on PGB-300/450 -13.8+/-1.2 and PGB-600 -14.7+/-1.0 compared with PBO -10.1+/-0.9 (P<0.01 for both comparisons); but the difference on PGB-150 did not achieve significance (-13.5+/-1.6; P=0.083). Also in the GI-high subgroup, endpoint reduction in HAM-A item-11 was significantly higher on PGB-300/450 compared with PBO (-1.93+/-0.16 vs. -1.52+/-0.13; P=0.04), but did not achieve significance on PGB-600 mg (-1.89+/-0.14; P=0.06), or PGB-150 mg (-1.90+/-0.23; P=0.16). In the GI-high subgroup, treatment with a benzodiazepine was not associated with significant endpoint reduction in either the HAM-A total score or the HAM-A item-11 score. Patients in the GI-high subgroup had higher discontinuation rates when treated with benzodiazepines, whereas treatment with PGB 300-600 mg/day was not associated with treatment-emergent worsening in GI symptoms compared with placebo. Treatment with PGB improved overall levels of anxiety, as well as specifically improving GI symptoms.

Panic disorder with agoraphobia (PD/AG) is one of the most costly and disabling anxiety disorders with a large range of secondary mental health problems. According to numerous clinical trials, cognitive-behavioural therapy (CBT) represents the most effective psychotherapeutic intervention for PD/AG. Little is known about the exact mechanisms of CBT and their neurobiological effects on the fear network. Within the PANIC-NET a unique, large multilevel and multicenter research project was implemented. By carrying out a randomized controlled clinical trial, different CBT components (exposure vs. cognitive techniques) were investigated in 360 patients in order to identify the core active ingredients of CBT. Furthermore, experimental add-on therapy with D-Cycloserine was tested. In an integrated approach, fear-circuit mechanisms were investigated employing psychophysiological techniques, functional neuro-imaging using 3T-fMRI and molecular genetic approaches.

Background: The self-report version of the Panic Disorder Severity Scale (PDSS-SR) has been developed recently and has demonstrated good psychometric properties. However, there is no cross-cultural evaluation of this scale. The purpose of this study was to confirm the reliability and validity of the PDSS-SR in Korean subjects., Methods: We studied 148 patients with principal DSM-IV diagnoses of panic disorder who underwent formal structured diagnostic assessment and the PDSS interview. The participants completed self-report measures including the PDSS-SR, Anxiety Sensitivity Index-Revised, Albany Panic and Phobia Questionnaire, Beck Depression Inventory, Beck Anxiety Inventory, and Spielberger State-Trait Anxiety Inventory-Trait Version., Results: The PDSS-SR had a single-factor structure, with all seven items having salient loadings. Cronbach's alpha for the PDSS-SR was .88 and intraclass correlation coefficient was .71 between PDSS-SR and PDSS. Also, the scale showed excellent 1-day test-retest reliability and demonstrated significant correlation with other anxiety-related measures. In addition, the PDSS-SR was sensitive to change with pharmacological treatment., Conclusions: The findings of this study strongly support the reliability and validity of the PDSS-SR. It is expected that this scale will be helpful in clinical settings and research protocols in Korea., ((c) 2009 Wiley-Liss, Inc.)

Anxiety disorders frequently affect the general population and have a lifetime prevalence ranging from 13.6% to 28.8%. This paper reviews full articles dealing with the pharmacological treatments of generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder (PD) and post-traumatic stress disorder (PTSD). This review also attempts to evaluate the use of new drugs acting on several neurotransmitters involved in the pathophysiology of anxiety disorders. Major advances include the development of glutamatergic drugs for treating GAD and OCD. Further randomized controlled trials to test the effect of glutamatergic agents in the treatment of OCD and GAD would be warranted.

Objective: To establish whether the combination of cognitive-behavioral therapy (CBT) and pharmacotherapy (SSRI) was more effective in treating panic disorder (PD) than either CBT or SSRI alone, and to evaluate any differential effects between the mono-treatments., Method: Patients with PD (n = 150) with or without agoraphobia received CBT, SSRI or CBT + SSRI. Outcome was assessed after 9 months, before medication taper., Results: CBT + SSRI was clearly superior to CBT in both completer and intent-to-treat analysis (ITT). Completer analysis revealed superiority of CBT + SSRI over SSRI on three measures and no differences between CBT and SSRI. ITT analysis revealed superiority of SSRI over CBT on four measures and no differences between CBT + SSRI and SSRI., Conclusion: Both the mono-treatments (CBT and SSRI) and the combined treatment (CBT + SSRI) proved to be effective treatments for PD. At post-test, CBT + SSRI was clearly superior to CBT, but differences between CBT + SSRI and SSRI, and between SSRI and CBT, were small.

The aim of this investigation was to explore the prevalence and features of discontinuation syndromes ensuing with gradual tapering of selective serotonin reuptake inhibitors (SSRIs), in optimal clinical conditions in patients with panic disorder and agoraphobia. Twenty-six consecutive outpatients met the DSM-IV criteria for panic disorder and agoraphobia while taking SSRIs. Twenty remitted upon behavioural treatment. Antidepressant drugs were then tapered at the slowest possible pace and with appropriate patient education. Patients were assessed with the Discontinuation-Emergent Signs and Symptoms (DESS) checklist 2 wk, 1 month and 1 yr after discontinuation. Nine of the 20 patients (45%) experienced a discontinuation syndrome, which subsided within a month in all but three patients who had been taking paroxetine for a long time. Discontinuation syndromes appeared to be fairly common even when performed with slow tapering and during clinical remission. In some cases disturbances persisted for months after discontinuation.

Objectives: Selective serotonin reuptake inhibitors (SSRIs) are currently considered as the first drug of choice in the treatment of panic disorder (PD). The aim of this long-term, naturalistic comparison study was to compare 4 SSRIs with respect to tolerability and treatment outcome of PD. Outcome measures included relapse rates and adverse effects., Methods: Two hundred patients with PD were enrolled in our study. All subjects met DSM-IV criteria for PD or PD with agoraphobia (PDA). All patients were assigned to receive SSRI monotherapy for 12 months with either citalopram (n = 50), fluoxetine (n = 50), fluvoxamine (n = 50), or paroxetine (n = 50) in a randomized, nonblinded fashion. Both the treating psychiatrist and the patients were not blind to the assigned treatment, but the clinician raters were blind to the study medication. The study design allowed for assignment of a particular SSRI as indicated according to the clinical judgment of the study psychiatrists. The Panic Self-Questionnaire, which is a self-report scale, was administered at baseline and then once per month during the duration of the 12-month study. The visual analog scale and the Clinical Global Impression Scale were administered at baseline and then once per month during the period of the study. Reports of sexual dysfunction were assessed using a nonstructured clinical interview at monthly visits. The body weight of study subjects was measured at baseline, and then at the 12th month visit end point., Results: Of 200 patients who entered the study, 127 patients (63.5%) completed the full 12-month protocol. Retention rates were highest for paroxetine (76% [38/50]), intermediate for citalopram (68% [34/50]) and fluvoxamine (60% [30/50]), and lowest for fluoxetine (50% [25/50]). Patients who completed the 12-month protocol responded favorably to the study treatment. The paroxetine and the citalopram groups had significantly lower rates of panic symptoms as measured at visits on weeks 4 and 8. At visits on months 3, 6, 9, and 12, however, there were no statistically significant differences between the 4 groups in relapse rates (defined as the occurrence of 1 or more panic attacks during the previous week of treatment) (F1,127 = 0.17; P = 0.13 [not statistically significant]). At the 12th month end point, patients in all 4 treatment groups had a statistically significant increase in body weight. Body weight among the study population increased by 6.1 + 4.9 kg from a mean weight of 72.4 + 7.3 kg at the onset of treatment. Reports of sexual adverse effects at the 12th month visit were similar in the citalopram, fluoxetine, and paroxetine groups, but the fluvoxamine patient group reported fewer sexual adverse effects at the 12th month visit., Conclusions: Most of our PD patients responded well to 12-month treatment with either citalopram, fluoxetine, fluvoxamine, or paroxetine, and the overall response rate was equal after the first 4 weeks of treatment. Although patients treated with paroxetine had the lowest dropout rates during the initiation phase, they had the highest rate of adverse effects as measured at the 12th month visit. Conversely, patients in the fluvoxamine group had the highest dropout rate (which was primarily caused by adverse effects in the initiation phase of treatment.); however, patients who were able to tolerate fluvoxamine throughout the full course of the study were observed to have lower rates of sexual dysfunction and weight gain compared with patients treated with the other agents. Overall, when measured at the 12th month visit, monotherapy with paroxetine and citalopram was associated with a higher rate of sexual adverse effects than was treatment with fluoxetine or fluvoxamine. In addition, monotherapy with paroxetine, citalopram, and fluoxetine seemed to cause more weight gain than did treatment with fluvoxamine.

Dizziness is one of the most frequent complaints in both primary and specialized medical care facilities. Many dizzy patients, without a known organic cause, considered as having idiopathic dizziness, may have a psychiatric disorder. Besides, even organic dizziness may cause or exacerbate latent psychiatric alterations. One of the most common disorders associated with dizziness is Panic Disorder with or without Agoraphobia. The aim of this paper is to report a patients case and make a literature review on the subject.

The aim of this study is to evaluate the efficacy of milnacipran in the acute treatment of patients with panic disorder. Thirty-one patients who met Diagnostic and statistical manual of mental disorders-IV criteria for panic disorder with or without agoraphobia were included in the study. Patients were initially treated with milnacipran 25 mg twice daily and then 50 mg twice daily until the 10th week. The treatment outcome and panic disorder severity were determined by the Panic Disorder Severity Scale, Panic Inventory, Clinical Global Impression and Hamilton Anxiety Scale, all of which were applied during every evaluation interview. Quality of life (WHOQOL-bref) was evaluated at baseline and at the end of the study. Missing data were handled by using the last observation carried forward for all participants who had taken at least one dose of study medication. Intention-to-treat was used in the analyses. Pharmacological treatment resulted in a clinically and statistically significant mean reduction in all severity measures. Remission (Clinical Global Impression < or = 2) was obtained in 58.1% of the sample. Regarding WHOQOL, we found a significant improvement (P<0.05) across treatment in all the domains studied. Although results may be influenced by the open design of this pilot study and by the small sample size, our findings suggest that milnacipran may be effective for the treatment of panic disorder and justify further research.

Background: Comorbid substance use and mental illness is prevalent and often results in serious consequences. However, little is known about the efficacy of treatments for patients with dual diagnosis., Methods: This paper reviews both the psychosocial and medication treatments for those diagnosed with a substance-related disorder and one of the following disorders: (a) depression, (b) anxiety disorder, (c) schizophrenia, (d) bipolar disorder, (e) severe mental illness, and (f) nonspecific mental illness. We made no restriction of study design to include all published studies, due to the dearth of studies on treatments of patients with dual diagnosis., Results: Fifty-nine studies were identified (36 randomized-controlled trials; RCT). Limited number of studies, especially RCTs, have been conducted within each comorbid category. This review did not find treatments that had been replicated and consistently showed clear advantages over comparison condition for both substance-related and other psychiatric outcomes., Conclusions: Although no treatment was identified as efficacious for both psychiatric disorders and substance-related disorder, this review finds: (1) existing efficacious treatments for reducing psychiatric symptoms also tend to work in dual-diagnosis patients, (2) existing efficacious treatments for reducing substance use also decrease substance use in dually diagnosed patients, and (3) the efficacy of integrated treatment is still unclear. This review provides a critique of the current state of the literature, identifies the directions for future research on treatment of dual-diagnosis individuals, and calls for urgent attention by researchers and funding agencies to conduct more and more methodologically rigorous research in this area.

Agoraphobia with panic disorder is a phobic-anxious syndrome where patients avoid situations or places in which they fear being embarrassed, or being unable to escape or get help if a panic attack occurs. During the last half-century, agoraphobia has been thought of as being closely linked to the recurring panic attack syndrome, so much so that in most cases it appears to be the typical development or complication of panic disorder. Despite the high prevalence of agoraphobia with panic disorder in patients in primary-care settings, the condition is frequently under-recognised and under-treated by medical providers. Antidepressants have been demonstrated to be effective in preventing panic attacks, and in improving anticipatory anxiety and avoidance behaviour. These drugs are also effective in the treatment of the frequently coexisting depressive symptomatology. Among antidepressant agents, SSRIs are generally well tolerated and effective for both anxious and depressive symptomatology, and these compounds should be considered the first choice for short-, medium- and long-term pharmacological treatment of agoraphobia with panic disorder. The few comparative studies conducted to date with various SSRIs reported no significant differences in terms of efficacy; however, the SSRIs that are less liable to produce withdrawal symptoms after abrupt discontinuation should be considered the treatments of first choice for long-term prophylaxis. Venlafaxine is not sufficiently studied in the long-term treatment of panic disorder, while TCAs may be considered as a second choice of treatment when patients do not seem to respond to or tolerate SSRIs. High-potency benzodiazepines have been shown to display a rapid onset of anti-anxiety effect, having beneficial effects during the first few days of treatment, and are therefore useful options for short-term treatment; however, these drugs are not first-choice medications in the medium and long term because of the frequent development of tolerance and dependence phenomena. Cognitive-behavioural therapy is the best studied non-pharmacological approach and can be applied to many patients, depending on its availability.

This study compares the speed of onset of action of the extended release (XR) formulation of alprazolam with that of the compressed tablet (CT) formulation in a sample of outpatients with DSM-IV panic disorder. Diary records of hourly antianxiety benefit from a 9-week open label switch study of 30-patients stabilized on alprazolam- CT for 3 weeks and then switched to an equivalent dose of alprazolam-XR, were used to examine the timing and magnitude of clinical benefit on both formulations. The magnitude of benefit at the first hour after the first morning dose was similar for both formulations. The peak benefit, over the hours after the first morning dose, was also similar and 90% of peak benefit that was achieved in the first hour on both formulations. Mean time to peak benefit was similar (1.5 h for alprazolam-CT vs. 1.6 h for alprazolam-XR) and the percent of patients achieving peak benefit in the first hour was also similar. Compared to the CT formulation, alprazolam-XR had a much longer duration of therapeutic action (11.3 +/- 4.2 h vs. 5.1 +/- 1.7 h). The results, which may be related to the biotechnology (and resultant pharmacokinetic profile) of the XR preparation, suggest that alprazolam-XR has value as a "rescue" as well as a prophylactic or maintenance treatment in panic disorder. These results must be viewed in the context of the study limitations including its small size, the lack of independence of groups in a switch study, and the limitations of the diary records used.

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

We report the case of a 54-year-old woman who was admitted for benzodiazepine withdrawal. After 6 weeks of carbamazepine treatment (600, then 200 mg) the patient suddenly suffered from a grand mal seizure. Laboratory findings revealed a clinical significant hyponatremia of Na 125 mmol/l (baseline: 143 mmol/l). CCT and ECG were normal. To our knowledge, this is the first description of a seizure related to hyponatremia in an adult carbamazepine-treated patient.