Agoraphobia and panic attacks complicated by primary aldosteronism improved by treatment with eplerenone: a case report.

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.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial.

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 (ß = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (ß = -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.

Generaliseerunud ärevushäire ja paanikahäire (agorafoobiaga või ilma) käsitlus perearstiabis / Management of generalized anxiety disorder and panic disorder (with or without agoraphobia) in family practice

The update of the treatment manual "Management of generalized anxiety disorder and panic disorder (with or without agoraphobia) in family medicine" was initiated because more than five years had passed since the publication of the original manual in 2014. The procedure for updating treatment manuals is written in the "Estonian manual for the preparation of treatment manuals" (2020). At the first meeting, the working group of the treatment guideline reviewed the questions raised during the preparation of the original guideline and found that some clinical questions concerning the pharmacological treatment of generalized anxiety disorder may have added evidence over time, which may change the originally given recommendation. They also wanted to review the recommendations regarding healthcare management given in the original guide. Based on the audit of the Estonian Health Insurance Fund (1) published in 2018, it was revealed that the diagnosis, treatment and monitoring of anxiety disorders varies in Estonia. One of the observations was the incomplete completion of treatment documentation, which made it difficult to assess and understand the justification of various actions and the doctor's thinking in the treatment of a patient with an anxiety disorder. The audit showed that most of the patients were prescribed treatment at the initial visit: a third were recommended psychotherapy, a third were prescribed antidepressant treatment, and a third were treated with a benzodiazepine. However, recommendations on self-help techniques are mostly not shared. The auditors recommended developing evidence-based material on self-help techniques that can be given to the patient (with him). The audit also noted that sufficient opportunities must be ensured to refer patients to psychotherapy. Mental health nurses are needed, who would help monitor and support patients. In order to ensure the best treatment for the patient, it is important that the family doctor can easily consult with a psychiatrist during the treatment process. The purpose of updating the treatment manual was to ensure contemporary evidence-based treatment of patients with anxiety disorders in family medicine care in Estonia. When updating the guide, the focus was on the (re)opened questions of the working group and the bottlenecks in the treatment of patients with anxiety disorders revealed by the audit.

Ravijuhendi "Generaliseerunud ärevushäire ja paanikahäire (agorafoobiaga või ilma) käsitlus perearstiabis" ajakohastamine algatati, kuna algse juhendi ilmu- misest 2014. aastal oli möödunud üle viie aasta. Ravijuhendite uuendamise kord on kirjas "Eesti ravijuhendite koostamise käsiraamatus" (2020). Ravijuhendi töörühm vaatas esimesel koosolekul läbi algse juhendi koostamisel esitatud küsi- mused ja leidis, et mõningate generaliseerunud ärevushäire farmakoloogilist ravi puudutavate kliiniliste küsimuste kohta võib aja jooksul olla lisandunud tõen- dusmaterjali, mis võib algselt antud soovitust muuta. Samuti sooviti üle vaadata algses juhendis antud tervishoiukorraldust puudutavad soovitused. 2018. aastal ilmunud Eesti Haigekassa auditi (1) põhjal selgus, et ärevushäirete diagnoosimine, ravi ja jälgimine Eestis varieerub. Üks tähelepanekuid oli puudu- lik ravidokumentatsiooni täitmine, mistõttu oli raske hinnata ja aru saada eri tege- vuste põhjendatusest ja arsti mõttekäigust ärevushäirega patsiendi käsitluses. Au- dit näitas, et esmasel visiidil määrati enamikule patsientidest ravi: kolmandikule soovitati psühhoteraapiat, kolmandikule määrati antidepressantravi ja kolmandik sai raviks bensodiasepiini. Soovitusi eneseabivõtete kohta enamasti aga ei jaga- tud. Auditeerijad soovitasid välja töötada tõenduspõhise materjali eneseabivõte- te kohta, mille saab patsiendile (kaasa) anda. Veel märgiti auditis, et patsientide psühhoteraapiale suunamiseks tuleb tagada piisavad võimalused. Juurde on vaja vaimse tervise õdesid, kes aitaksid patsiente jälgida ja toetaksid neid. Patsiendile parima ravi tagamiseks on oluline, et raviprotsessis saaks perearst vajadusel hõlp- sasti psühhiaatriga konsulteerida. Ravijuhendi ajakohastamise eesmärk oli tagada ärevushäirega patsientide nüü- disaegne tõenduspõhine käsitlus perearstiabis Eestis. Juhendi ajakohastamisel keskenduti töörühma (taas)avatud küsimustele ja auditist selgunud ärevushäirega patsiendi käsitluse kitsaskohtadele.

Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder with or without agoraphobia. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Embase, Medline, and ClinicalTrials.gov from inception to 17 June 2021. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials that included adults aged ≥18 years with a diagnosis of panic disorder, compared drugs used to treat the panic disorder, and measured the outcomes of interest, including remissions, dropouts, and adverse events. METHODS: Risk of bias in the included studies was assessed using the revised Cochrane risk of bias tool for randomised trials. Direct meta-analyses were performed using random effects models. A two stage network meta-analysis with surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of drug classes and individual SSRIs. RESULTS: 87 studies including a total of 12 800 participants and 12 drug classes were eligible for inclusion. Almost all the studies (86/87) had some concern or were at high risk of bias. Network meta-analysis of remission with consistent results indicated that tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs) were associated with significantly higher remission rates than placebo, with risk ratios of 1.39 (95% confidence interval 1.26 to 1.54), 1.47 (1.36 to 1.60), 1.30 (1.00 to 1.69), 1.38 (1.26 to 1.50), and 1.27 (1.12 to 1.45), respectively. SUCRAs identified benzodiazepines (84.5%, mean rank=2.4), tricyclic antidepressants (68.7%, 3.8), and SSRIs (66.4%, 4.0) as the top three best treatments for remission. However, tricyclic antidepressants, benzodiazepines, and SSRIs were also significantly associated with increased risk of adverse events compared with placebo, with risk ratios of 1.79 (1.47 to 2.19), 1.76 (1.50 to 2.06), and 1.19 (1.01 to 1.41), respectively. Consistency assumption of adverse events was upheld but could still be present on removal of studies with high percentages of women participants and those with agoraphobia. A SUCRA cluster ranking plot considering both remission and adverse events among all drug classes indicated that SSRIs were associated with high remission and low risk of adverse events. Among individual SSRIs, sertraline and escitalopram provided high remission with an acceptable risk of adverse events. CONCLUSION: The findings suggest that SSRIs provide high rates of remission with low risk of adverse events for the treatment of panic disorder. Among SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events. The findings were, however, based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020180638.

Stepped-care versus treatment as usual in panic disorder: A randomized controlled trial.

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.

Role of Benzodiazepines in Anxiety Disorders.

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.

Benzodiazepines versus placebo for panic disorder in adults.

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.

Antidepressants versus placebo for panic disorder in adults.

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.

Patients' characteristics and their influence on course of fear during agoraphobic symptom provocation: may SS(N)RI treatment compensate unfavorable individual preconditions?

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.

No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia: A Double-Blind, Randomized Controlled Trial.

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.

Facing the fear--clinical and neural effects of cognitive behavioural and pharmacotherapy in panic disorder with agoraphobia.

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.

Intensive behavioral therapy for agoraphobia.

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.

Azapirones versus placebo for panic disorder in adults.

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.

The common traits of the ACC and PFC in anxiety disorders in the DSM-5: meta-analysis of voxel-based morphometry studies.

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.

Phosphate levels as a possible state marker in panic disorder: preliminary study of a feasible laboratory measure for routine clinical practice.

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.

Brain-derived neurotrophic factor in generalized anxiety disorder: results from a duloxetine clinical trial.

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.