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Objective: To explore the relations between personality traits using the Big Five model and presence of agoraphobia, clinical severity and short-term outcome in an unbiased clinical sample of never-treated panic disorder patients., Method: Panic disorder (PD) patients (n = 103) in the first stages of their illness were evaluated using the Neuroticism-Extraversion-Openness Five Factor Inventory of Personality (NEO-FFI) and were compared with a sample of healthy subjects. Severity was assessed by the Panic Disorder Severity Scale and the Clinical Global Impression Scales. Patients were evaluated after 8 weeks of naturalistic pharmacologic treatment with Selective Serotonin Reuptake Inhibitors., Results: Panic disorder patients show more neuroticism than healthy subjects. Patients suffering from agoraphobia are more introverted than controls. Extraversion, in addition to gender and distress, during panic attacks allows to correctly classifying 72% of the cases of agoraphobia., Conclusion: Low scores in extraversion contribute to explain the presence of agoraphobia in panic disorder. Personality traits are neither related to clinical severity nor to short-term response to pharmacological treatment.

Objective: To examine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of patients with panic disorder., Method: In an open-label, fixed-flexible dose study, 18 patients with panic disorder with or without agoraphobia (DSM-IV diagnostic criteria) were treated with levetiracetam for 12 weeks. Outcome was assessed with standard rating instruments (Clinical Global Impressions-Severity of Illness scale [CGI-S], Clinical Global Impressions-Improvement scale [CGI-I], and the 14-item Hamilton Rating Scale for Anxiety [HAM-A]) and by the number of panic attacks during the previous week. The study was conducted in 2 outpatient clinics in New York City from January 2004 through July 2005., Results: Of the 13 patients completing the study, 11 were rated "very much" or "much" improved on the CGI-I. Panic attack frequency, anxiety (HAM-A), and global severity (CGI-S) ratings also demonstrated significant improvement (all p < .00). For most patients, clinical benefits were apparent after only 1 to 2 weeks of treatment. Levetiracetam was well tolerated with minimal side effects., Conclusion: Given its favorable pharmacokinetics, side effect profile, and, if confirmed, early onset of action and efficacy, levetiracetam might represent significant progress in the pharmacologic management of panic disorder.

Introduction: The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT)., Methods: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response., Results: Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide., Conclusion: Both SSRI's and RIMA's decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.

Pregabalin, a compound with a novel mechanism of action (MOA), has demonstrated efficacy as an adjunctive treatment for epilepsy and in several neuropathic pain models. Multiple generalized anxiety disorder (GAD) clinical trials have shown that pregabalin has efficacy similar to the benzodiazepines and venlafaxine. Onset of anxiolytic effect was observed as early as Week 1 of treatment, and efficacy was seen in treating both psychic and somatic anxiety symptoms. Pregabalin binds potently and selectively to the alpha-2-delta subunit of "hyper-excited" voltage-gated calcium channels (VGCCs). The binding of pregabalin to VGCCs changes their conformation, reducing calcium influx at nerve terminals. Pregabalin only modulates the release of excitatory neurotransmitters in "hyper-excited" neurons, restoring them to normal physiological state. This newly defined MOA is believed to confer on pregabalin its anxiolytic, analgesic, and anticonvulsant properties. Thus, pregabalin may offer physicians an effective and well-tolerated therapy for GAD, which differs from existing treatments.

Generalized anxiety disorder (GAD) frequently occurs comorbidly with other conditions, including depression and somatic complaints. Comorbid GAD sufferers have increased psychologic and social impairment, request additional treatment, and have an extended course and poorer outcome than those with GAD alone; therapy should alleviate both the psychic and somatic symptoms of GAD without negatively affecting the comorbid condition. The ideal treatment would provide relief from both GAD and the comorbid condition, reducing the need for polypharmacy. Physicians need suitable tools to assist them in the detection and monitoring of GAD patients-the GADI, a new, self-rating scale, may meet this requirement. Clinical data have shown that various neurobiologic irregularities (e.g., in the GABA and serotonin systems) are associated with the development of anxiety. Prescribing physicians must take into account these abnormalities when choosing a drug. Effective diagnosis and treatment should improve patients' quality of life and their prognosis for recovery.

The main therapy for the symptomatic management of generalized anxiety disorder (GAD) is pharmacotherapy, although comprehensive management methods also include psychotherapeutic interventions. Traditionally, treatments including anxiolytics and antidepressants have been used in GAD management, but prescribing physicians have more recently moved towards using selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). Indeed, newer medicines have been shown to be as effective as older treatments, but with improved safety and tolerability. Although the best way to treat GAD has yet to be established, these patients clearly need long-term supervision. Ideally, physicians should prescribe treatment with the purpose of ultimately eliminating symptoms and re-establishing normal function. To achieve this goal, physicians need a more effective, faster acting, safer, and better tolerated drug than the many existing GAD treatments.

Objective: Gender differences in clinical presentation and response to sertraline treatment were examined for patients diagnosed with DSM-III-R panic disorder with or without agoraphobia., Method: Data was pooled from 4 double-blind, placebo-controlled outpatient studies (males, N = 335; females, N = 338). Two were 12-week fixed-dose studies (sertraline 50 mg vs. 100 mg vs. 200 mg) and 2 were 10-week flexible-dose studies (sertraline 50-200 mg). Primary outcome measures consisted of the Clinical Global Impression-Improvement scale (CGI-I) and change in panic attack frequency., Results: The clinical presentation of panic disorder was similar except that men reported an earlier age of onset, shorter duration of illness, and significantly more frequent history of alcohol and/or substance dependence/abuse. Sertraline was significantly more effective than placebo in both women and men on the 2 primary outcome measures. When between-sex efficacy was compared, women achieved significantly greater improvement than men on panic frequency and CGI-I, but had equivalent improvement on all other measures. There was no significant between-sex difference in study completion rates, or in adverse event profiles., Conclusions: There was a modest but consistent trend for women to show superior efficacy at the end of acute sertraline treatment. This gender effect only occasionally achieved significance, and must be confirmed by future treatment research.

Objective: In this naturalistic and prospective study, patients with panic disorder (PD) were treated for one year 1) to verify the rate of patients achieving the resolution of full-symptom attacks, limited-symptom attacks, anticipatory anxiety, phobic avoidance and depression; and 2) to identify the predictors of symptom resolution for each domain., Method: One hundred patients with PD, according to DSM-IV criteria, participated in the study. In all patients, a baseline and a follow-up with monthly evaluations of SCL-90, Ham-A, Ham-D and panic diaries were carried out over a one-year period. All patients were treated with paroxetine or citalopram., Results: Seventy-one patients completed the study, whereas the remaining 29 dropped out. Among completers, remission of full- and limited-symptom panic attacks was observed in 76 % of patients, whereas complete remission (resolution of panic attacks, anticipatory anxiety, phobic anxiety, and depression) was achieved by only 46 % of patients. Predictors of absence of symptom remissions were obsessive-compulsive disorder (OCD) and recurrent major depression (MD) comorbidity (for panic attacks), pre-treatment severity of anxious symptoms (for anticipatory anxiety), phobic anxiety (for phobic avoidance), and depressive symptoms (for depression)., Conclusion: This naturalistic study shows that the high comorbidity of OCD and MD and the greater pre-treatment severity of anxious, phobic and depressive symptoms reduced the likelihood of achieving complete remission of symptoms in PD patients who completed the protocol, even though they were adequately treated with SSRI medication.

Objective: This study is the first to investigate the relative effectiveness of cognitive-behavioral therapy (CBT) compared with a selective serotonin reuptake inhibitor (SSRI; sertraline) in a randomized, controlled trial on the treatment of anxiety disorders in older adults., Method: Eighty-four patients 60 years of age and over with a principal diagnosis of generalized anxiety disorder, panic disorder, agoraphobia, or social phobia were randomly assigned to one of three conditions: 15 sessions of CBT, pharmacologic treatment with an SSRI (sertraline; maximum dosage 150 mg), or a waitlist control group. Participants completed measures of primary outcome (anxiety) and coexistent worry and depressive symptoms at baseline, posttreatment, and at three-month follow up., Results: Attrition rates were high in both treatment groups. Consequently, findings are based on a relatively small sample of completers (N = 52). Although both CBT and sertraline led to significant improvement in anxiety, worry, and depressive symptoms both at posttreatment and at three-month follow up, sertraline showed superior results on worry symptoms. Effect size estimates for CBT were in the small to medium range both at posttreatment (mean d = 0.42) and at three-month follow up (mean d = 0.35), whereas effect sizes for sertraline fell into the large range (posttreatment mean d = 0.94 and three-month follow up mean d = 1.02). The waitlist condition showed virtually no effects (posttreatment mean d = .03)., Conclusions: Our findings strongly suggest that the pharmacologic treatment of late-life anxiety with SSRIs has not been given the proper attention in research to date.

The purpose of our study was to evaluate the efficacy and tolerability of low-dose olanzapine augmentation in selective serotonin reuptake inhibitor (SSRI)-resistant panic disorder (PD) with or without agoraphobia. In this 12-week, open-label study, 31 adult outpatients with treatment-resistant PD who had previously failed to respond to SSRI treatment were treated with fixed dose of olanzapine (5 mg/d) in addition to SSRI. Efficacy was assessed using the Panic Attack and Anticipatory Anxiety Scale (PAAAS), the Agoraphobic Cognitions Questionnaire (ACQ), the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the Global Assessment of Functioning Scale (GAF), and the Clinical Global Impression of Improvement (CGI-I). Twenty-six patients completed the trial period with a dropout rate of 16.1%. At week 12, 21 patients were responders (81.8%), and an overall improvement on all rating scales was observed in all patients both with or without agoraphobia. Fifteen patients (57.7%) achieved remission. Olanzapine was well tolerated and the most frequent adverse effects were mild-to-moderate weight gain and drowsiness. No extrapyramidal symptoms were reported. Olanzapine appears to be effective as augmentation strategy in the treatment of SSRI-resistant PD, but study limitations must be considered and placebo-controlled studies are needed.

Background: Improvements in quality of life (QoL) as well as symptomatic relief are important outcomes for the treatment of panic disorder (PD). The aim of this study is to assess the impact of brief cognitive behavior group therapy (CBGT) for panic disorder on QoL and to identify the clinical features associated with these changes., Methods: Thirty-six patients with PD refractory to pharmacological treatment took part in a treatment protocol consisting of 12 sessions of CBGT. To evaluate the changes in QoL, the WHOQOL-bref was administered before and after treatment., Results: Thirty-two patients completed the treatment. Significant improvement in all domains of QoL was observed (p< 0.001), which was associated with reductions in general and anticipatory anxiety (p = 0.018) and agoraphobic avoidance (p = 0.046). Consistent with previous findings, associations between QoL and panic-free status did not reach significance in this small study (p = 0.094)., Conclusions: CBGT was efficacious in the treatment of PD; the symptoms of anticipatory anxiety and avoidance appear to be more important than episodic panic episodes in affecting QoL.

An acute-phase response (APR), manifested as an increase of acute-phase proteins has been shown in major depression. Panic disorder (PD) may share some aetiopathogenic mechanisms with depression, but APR has not been studied in this disorder. Forty-one panic patients in the first stages of their illness were compared with 32 healthy subjects of comparable sex, age, and body mass index. Clinical diagnosis was established with the mini international neuropsychiatric interview, and severity with the panic disorder severity scale and the CGI scale. Laboratory determinations included four acute phase proteins (APPs) [albumin, gammaglobulins, fibrinogen, C-reactive-protein (CRP)] and basal cortisol level. Patients were studied after 8-wk follow-up taking selective serotonin reuptake inhibitors (SSRIs) to assess the evolution of the APPs. Gammaglobulin levels were lower, and both cortisol and CRP levels were higher in PD patients than in controls. APP did not differ between patients with or without agoraphobia. At follow-up, patients who responded to SSRIs presented a decrease in albumin levels, and a trend towards a decrease in cortisol and CRP compared with levels at intake. The conclusions of this study are that there is an APR in patients suffering from PD, and this APR tends to diminish after a successful treatment with SSRIs.

Objective: To review pregabalin's pharmacology, pharmacokinetics, efficacy, and adverse effects in the treatment of neuropathic pain, epilepsy, and anxiety., Data Sources: A MEDLINE search (1993-October 2005) for peer-reviewed English-language publications was performed. Abstracts from professional meetings were also included. Key terms were anxiety, diabetic neuropathy, epilepsy, neuropathic pain, postherpetic neuralgia, pregabalin, and seizures., Study Selection and Data Extraction: Basic pharmacology data were extracted from animal studies; pharmacokinetic data were extracted from human studies. Multicenter, double-blind, placebo-controlled, parallel-group studies were included to describe the efficacy and adverse effects of pregabalin., Data Synthesis: Pregabalin is a new agent that exerts its pharmacodynamic effect by modulating voltage-gated calcium channels. Pregabalin has a linear pharmacokinetic profile. It is completely absorbed, not bound to plasma proteins, not metabolized, and eliminated unchanged through the kidneys. Doses must be adjusted in patients with renal insufficiency. Clinical trials showed that pregabalin is effective in neuropathic pain associated with postherpetic neuralgia, diabetic peripheral neuropathy, in partial epilepsy as adjunctive therapy, and in generalized and social anxiety disorders. The most common adverse effects were dizziness and somnolence. Few serious adverse effects were reported. Pregabalin should not be discontinued rapidly., Conclusions: Pregabalin is an effective and safe analgesic, antiepileptic, and anxiolytic medicine. It will provide a new treatment option for patients with neuropathic pain and partial epilepsy.

A treatment protocol, called experiential cognitive therapy (ExCT), was developed. It integrated traditional cognitive behavior therapy (CBT) with virtual reality exposure for the treatment of panic disorder with agoraphobia (PDA). The objective of this study was to test the efficacy of short-term (four sessions) ExCT compared with a traditional 12-session panic control program (PCP) for the treatment of PDA. Forty patients diagnosed as having PDA by the diagnostic criteria of DSM-IV were randomly assigned to ExCT and PCP groups of 20 patients each. The treatment effects were measured with self-report questionnaires, including the BDI, STAI, ASI, PBQ, ACQ, and BSQ. The authors also assessed high end-state functioning (HES), including the success rate of stopping or reducing medication at post-treatment and 6-month follow-up. In all ratings, both ExCT and PCP groups showed significant improvement post-treatment compared with pre-treatment scores. There were no significant differences between the two treatment groups in HES and medication discontinuation at post-treatment, but there was a significant difference in medication discontinuation at 6-month follow-up. These results suggested that although short-term effectiveness of ExCT might be comparable to the effectiveness of PCP, long-term effectiveness of ExCT might be relatively inferior to the effectiveness of PCP.

Rationale: There is considerable evidence showing that individuals with generalised anxiety disorder (GAD) selectively process threat-related information, e.g. they have a bias to interpret ambiguous information in a threat-related manner. Cognitive theories of anxiety, which provide the basis of cognitive-behaviour therapy, propose that such processing biases play an important role in causing and maintaining anxiety., Objectives: Given that treatment with selective serotonin re-uptake inhibitors (SSRIs) appears to be effective for GAD, we examined whether it is successful in removing cognitive bias., Methods: The clinical group included 19 patients with a diagnosis of GAD, and the control group consisted of a non-clinical sample of volunteers, matched for age, gender and years in education. The patients were assessed on measures of interpretative bias (homophone task), anxiety and depression before being prescribed an SSRI (paroxetine or citalopram). After 4 weeks, the cognitive task and mood measures were repeated in the patient group., Results: Prior to treatment, the GAD group showed a significantly greater level of threat-related interpretive bias than controls. Following SSRI treatment, there were significant reductions in both interpretive bias and in anxiety levels in the GAD group. Furthermore, individuals who showed greater clinical improvement (e.g. reflected by reduced anxiety scores) showed a correspondingly greater reduction in their cognitive bias., Conclusion: The results suggest that SSRIs are effective in modifying both subjective anxiety levels and threat-related interpretive bias.

Relatively absent from previous studies of the pharmacotherapy for bipolar disorder is examination of the impact of comorbidity on treatment choices. This has occurred despite the presence of high levels of comorbid anxiety and substance use disorders, and the association of these disorders with severity and course markers of bipolar disorder. In this study, we examined comorbid disorders, identified by structured interviews, and the pharmacotherapy reported at study entry by the first 1000 patients entered into a large, multicenter study of bipolar disorder (Systematic Treatment Enhancement Program for Bipolar Disorder). Our study focused on the degree to which comorbid conditions are linked to the reported use of mood stabilizers deemed "minimally adequate" and the association between specific comorbidities and pharmacotherapy treatment, such as the use of anxiolytics in patients with anxiety disorders. Despite the presence of high levels of comorbidity, the presence of these disorders was only minimally associated with pharmacotherapy. Of the sample of bipolar outpatients, only 59% reported pharmacotherapy use meeting criteria for "minimally adequate" mood stabilizer, regardless of comorbid diagnoses, rapid cycling, or bipolar I or II status. Moreover, the cross-sectional use of "comorbidity-specific" pharmacotherapy for anxiety disorders, substance use disorders, and attention deficit disorder in this outpatient sample of patients with bipolar disorders was limited, suggesting that comorbid conditions in patients with bipolar disorder may be undertreated. Our findings highlight the need for greater clinical guidance and treatment options for patients with bipolar disorder and comorbidity.

Pharmacotherapy and cognitive-behavioral therapy (CBT) are efficient treatments for Panic disorder with agoraphobia (PDA) yet they remain expensive. This study aims to compare the cost/effectiveness ratio of a CBT for PDA versus a combined treatment of CBT and pharmacotherapy. Eighty-four people followed a CBT either alone or combined with medication. They have been evaluated before treatment, immediately after, as well as one and two years later. The therapy efficacy is calculated at each assessment according to a "Global Functioning Index". Direct and indirect costs are calculated with the "Health Cost Interview". Results suggest that both treatments are equally effective. However, CBT alone is less expensive than CBT with pharmacotherapy. Thus, it offers a better cost-effectiveness ratio that even increases in the long term.

Objective: We examined the relationships between long-term treatment response, side-effects and drug discontinuation in panic disorder (PD)-agoraphobia., Method: A total of 326 patients were naturalistically treated with antidepressants and followed for a period of 3 years. All patients were evaluated by means of the Panic Disorder/Agoraphobia Interview and the Longitudinal Interview Follow-up Examination (LIFE-UP)., Results: A total of 179 patients interrupted pharmacological treatment. Among them, 26.8% were not traceable; 36.9% had deemed further contact with the psychiatrist unnecessary because of remission. Other reasons for interruption were: ineffectiveness (18.4%), side-effects (10.6%) and personal reasons (7.3%). Patients who interrupted pharmacological treatment because of symptom remission remained in the study for a longer period than those patients who interrupted their treatment because of inefficacy., Conclusion: In the long-term treatment of PD with antidepressants, a high percentage of patients who have achieved symptom remission tend to default from further treatment; adherence to long-term treatment with antidepressants was predicted by severe and long-lasting symptomatology.

Background: This naturalistic open label follow-up study had three objectives: 1) To observe the course of illness in Panic Disorder patients receiving long-term versus intermediate-term paroxetine treatment, 2) To compare the relapse rates and side-effect profile after long-term paroxetine treatment between patients with Panic Disorder and Panic Disorder with Agoraphobia, 3) To observe paroxetine's tolerability over a 24 month period., Methods: 143 patients with panic disorder (PD), with or without agoraphobia, successfully finished a short-term (ie 12 week) trial of paroxetine treatment. All patients then continued to receive paroxetine maintenance therapy for a total of 12 months. At the end of this period, 72 of the patients chose to discontinue paroxetine pharmacotherapy and agreed to be monitored throughout a one year discontinuation follow-up phase. The remaining 71 patients continued on paroxetine for an additional 12 months and then were monitored, as in the first group, for another year while medication-free. The primary limitation of our study is that the subgroups of patients receiving 12 versus 24 months of maintenance paroxetine therapy were selected according to individual patient preference and therefore were not assigned in a randomized manner., Results: Only 21 of 143 patients (14%) relapsed during the one year medication discontinuation follow-up phase. There were no significant differences in relapse rates between the patients who received intermediate-term (up to 12 months) paroxetine and those who chose the long-term course (24 month paroxetine treatment). 43 patients (30.1%) reported sexual dysfunction. The patients exhibited an average weight gain of 5.06 kg. All patients who eventually relapsed demonstrated significantly greater weight increase (7.3 kg) during the treatment phase., Conclusions: The extension of paroxetine maintenance treatment from 12 to 24 months did not seem to further decrease the risk of relapse after medication discontinuation. Twenty-four month paroxetine treatment is accompanied by sexual side effects and weight gain similar to those observed in twelve month treatment.

The purpose of the present paper was to investigate the role of coping behavior in patients with panic disorder (PD). This was done by evaluating three items of coping behavior (seeking of social support, wishful thinking and avoidance) in the Ways of Coping Checklist. The subjects consisted of 30 patients with PD (26 with agoraphobia). Coping behavior and the severity of PD was investigated at baseline and at 24 months (the final outcome). At baseline there were no gender differences in coping behavior. The severity of panic attacks significantly correlated with that of agoraphobia. The baseline severity of PD (panic attacks and agoraphobia) did not correlate with coping behavior. At the outcome assessment there was no significant correlation between the severity of panic attack and coping behavior. The severity of agoraphobia at final outcome and the coping behavior (seeking of social support) at baseline were significantly correlated. In the group that had remission in agoraphobia (the good outcome group), the severity of agoraphobia at baseline was significantly lower and the seeking of social support coping behavior was significantly higher than that of the poor outcome group. No significant difference in panic attack severity was noted between the good and poor outcome groups. Discriminant analysis revealed that seeking of social support coping behavior was a significant discriminant factor of agoraphobia. Although these are preliminary data, special coping behavior might be related to improvement of agoraphobia in patients with PD.

Although Noonan syndrome is quite prevalent, there is a general paucity in the description of psychological and psychiatric aspects. In the present paper a 19-year-old female patient with Noonan syndrome is described who presented with anxiety symptoms. Mutation analysis in PTPN11, the NS1 gene on chromosome 12q24, showed no abnormalities. A diagnosis of panic disorder without agoraphobia was established. Treatment with citalopram resulted in a gradual decline of anxiety symptoms. The psychological profile was characterized by a prominent alexithymia. The main conclusion is that patients with Noonan syndrome might have deficits in emotional adaptative functions. It is hypothesized that alexithymia is a key feature of the behavioural phenotype.

Background: Panic disorder (PD) is generally regarded as a chronic condition with considerable variation in severity of symptoms., Aims: To describe the long-term outcome of naturalistically treated PD., Methods: Fifty-five outpatients with PD, who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study., Results: Complete recovery (no panic attacks and no longer on medication during the last 10 years) was seen in 18% of patients, and an additional 13% recovered but were still on medication. Fifty-one percent experienced recurrent anxiety attacks whereas 18% still met diagnostic criteria for PD. The incidence of agoraphobia decreased from 69% to 20%. Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission, although both groups reported improved daily functioning at follow-up. Maintenance medication was common. No benzodiazepine abuse was reported., Conclusion: PD has a favourable outcome in a substantial proportion of patients. However, the illness is chronic and needs treatment. The short-term treatment given in the drug trial had no influence on the long-term outcome.

Background: The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority., Method: For these guidelines, the CPG team reviewed the treatment outcome literature, consulted with practitioners and patients and conducted a meta-analysis of recent outcome research., Treatment Recommendations: Education for the patient and significant others covering: (i) the nature and course of panic disorder and agoraphobia; (ii) an explanation of the psychopathology of anxiety, panic and agoraphobia; (iii) rationale for the treatment, likelihood of a positive response, and expected time frame. Cognitive behaviour therapy (CBT) is more effective and more cost-effective than medication. Tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors are equal in efficacy and both are to be preferred to benzodiazepines. Treatment choice depends on the skill of the clinician and the patient's circumstances. Drug treatment should be complemented by behaviour therapy. If the response to an adequate trial of a first-line treatment is poor, another evidence-based treatment should be used. A second opinion can be useful. The presence of severe agoraphobia is a negative prognostic indicator, whereas comorbid depression, if properly treated, has no consistent effect on outcome.

Despite the acknowledged favorable side effects profile of selective serotonin reuptake inhibitors (SSRIs), comparative studies have not found significant differences in efficacy between tricyclics (TCAs) such as imipramine and clomipramine, and SSRIs in the treatment of panic disorder. The present study focuses on treatment completers to inform patients who adhere to a recommended course of treatment on the possible differential patterns of improvement and of change in side effects between sertraline and imipramine. From an intent to treat consecutive sample of patients participating in the 24-week open phase protocolized treatment of a long-term controlled maintenance/discontinuation study, 20 imipramine completers and 16 sertraline completers with moderate to severe baseline symptomatology were compared using primarily repeated measures analysis of variance on measures of symptom severity, on 15 side effects systematically elicited using an inventory and on heart rate and weight. The results revealed greater early improvement with imipramine compared to sertraline but no enduring differences beyond week 8 of treatments. Side effects, in particular dry mouth, constipation, tremors, sweating, and cardiovascular complaints increased more in severity and were more frequent and persistent during imipramine than sertraline but, except for the 10 beats/min increase in heart rate, side effects were clinically insignificant at the end of both treatments. Change in sexual complaints and weight did not differ between the treatments. The more favorable side effect profile of SSRIs versus TCAs was demonstrated even in the best case scenario of treatment completers. The more rapid improvement with imipramine needs replication but, tentatively, it may be attributed to the greater motivational effects toward action observed with noradrenergic or dual action antidepressants compared to SSRIs.

Objective: Recently, pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available. The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines., Method: A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project, a prospective longitudinal study of anxiety disorders. These patients were interviewed over the course of 10 years to examine their use of psychotropic medications., Results: Despite efforts aimed at increasing the use of selective serotonin reuptake inhibitors (SSRIs) in patients with panic disorder (e.g., APA's practice guideline for panic disorder, Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder), only a modest increase in their use was found. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder. In comparison, SSRI use throughout the follow-up period has remained low. Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine, nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly., Conclusions: These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed. Factors potentially associated with promoting and ignoring treatment recommendations are discussed.

Blunted neuroendocrine and physiological responses to the selective 5-HT(1A) receptor agonist, ipsapirone, have been observed in patients with panic disorder and/or agoraphobia (PDA). In order to examine whether this hyporesponsiveness to ipsapirone is modified by pharmacological or non-pharmacological therapeutic interventions, challenges with an oral dose of ipsapirone (0.3 mg/kg) and placebo were performed in patients with PDA before and after 10 weeks of treatment with clomipramine, aerobic exercise and placebo. Before treatment, administration of ipsapirone was followed by significant increases of cortisol, anxiety and other psychopathological symptoms in comparison to the placebo challenge. In addition, a significant decrease of body temperature was observed. After the 10-week treatment period, the psychological responses to ipsapirone were significantly reduced in the clomipramine and the exercise group. In contrast, there was a non-significant trend towards higher cortisol responses after clomipramine and exercise treatment. The hypothermic response to ipsapirone was significantly reduced by clomipramine treatment. In conclusion, our results demonstrate that effective treatment of panic disorder has divergent effects on the psychological, neuroendocrine and temperature responses to ipsapirone.

Background: To complement existing data on predictors of treatment response in groups of "pure" panic disorder patients studied in clinical trials or in poorly controlled naturalistic follow-up, we sought to elucidate predictors of treatment response over 1 year in a diagnostically heterogeneous and comorbidly ill group of primary care patients with panic disorder participating in a randomized effectiveness study., Method: Patients with DSM-IV panic disorder (N = 115), mostly without agoraphobia, were recruited from 3 primary care clinics in Seattle, Wash., and randomly assigned to an on-site collaborative care intervention (N = 57), in which psychiatrists provided education, 2 visits, follow-up phone calls, and paroxetine, or to usual care by their primary care physician (N = 58). Predictors of response at 3-month intervals over 1 year were determined using logistic regression analysis., Results: Patients with consistent response over the year (response at the majority of available timepoints) were significantly (p <.05) more likely to be white, employed, in higher income strata, and in the intervention group and had less medical comorbidity and phobia severity, fewer recent hospitalizations and emergency room visits, and higher reported Medical Outcomes Study 36-Item Short Form physical and role functioning. The final regression model indicated that responders were more likely to be in the intervention group, be employed, and lack a recent emergency room visit., Conclusion: While some of the univariate findings partially replicate previous results linking greater illness severity with poorer response, univariate findings linking medical comorbidity and low socioeconomic status with poor response, as well as multivariate findings that unemployment and recent emergency room use are the most potent predictors of poor response, have not been previously reported.

Context: This study makes a comparison between two subtypes of panic disorder regarding the clinical efficacy of clonazepam, a benzodiazepine., Objectives: To evaluate the clinical efficacy of clonazepam in a fixed dosage (2 mg/day), compared to placebo, in the treatment of panic disorder patients and to verify whether there are any differences in the responses to clonazepam between panic disorder patients with the respiratory and non-respiratory subtypes., Type of Study: Randomized study with clonazepam and placebo., Setting: Outpatient Anxiety and Depression Unit of the Institute of Psychiatry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Participants: 34 patients with a diagnosis of panic disorder with agoraphobia, between 18 and 55 years old., Procedures: Administration of clonazepam or placebo for 6 weeks, in panic disorder patients, after they were classified within two subtypes of panic disorder: respiratory and non-respiratory., Main Measurements: Changes in the number of panic attacks in comparison with the period before the beginning of the study; Hamilton Anxiety Scale; Global Clinical Impression Scale; and Patient's Global Impression scale., Results: In the group that received clonazepam, by the end of the 6th week there was a statistically significant clinical improvement, shown by the remission of panic attacks (p < 0.001) and decrease in anxiety (p = 0.024). In the group that received clonazepam there was no significant difference between the respiratory and non-respiratory subtypes of panic disorder, regarding the therapeutic response to clonazepam., Conclusion: Clonazepam was equally effective in the treatment of the respiratory and non-respiratory subtypes of panic disorder, suggesting there is no difference in the therapeutic response between the two subtypes.

Generalized anxiety disorder (GAD) is a prevalent and disabling anxiety disorder, conservatively believed to affect at least 5% of the general population. Cardinal symptoms of GAD include chronic and uncontrollable worry, anxiety, and tension, which result in difficulty fulfilling social, professional, and family roles. Treatment options include benzodiazepines, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine XR. Because of the high comorbidity of GAD with other psychiatric disorders, pharmacologic therapy should possess both anxiolytic and antidepressive properties for best outcomes. The SSRIs are a good treatment option, and paroxetine is the best studied SSRI for GAD and the only SSRI to date approved by the US Food and Drug Administration for this indication. Results of randomized, controlled studies of paroxetine have demonstrated its efficacy in the short-term treatment of GAD, in achieving and sustaining full remission, and in preventing relapse. This article provides an overview of GAD and a discussion of studies of paroxetine treatment in this anxiety disorder.

Background: Many short-term trials suggested that the combination of psychotherapy with medication might be more effective than either treatment alone. However, only few studies examined the long-term effectiveness of this combination., Methods: A private practice sample of consecutive patients with DSM-III-R panic disorder with agoraphobia who achieved remission after drug treatment with or without concurrent cognitive-behavioural psychotherapy were followed up. Patients were assessed before treatment, after treatment and at each follow-up contact with the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Rating Scale, and the Hamilton Depression Rating Scale. Kaplan-Meier survival analysis was performed on the time to panic disorder relapse. Cox regression analysis was used to control for the possible confounding effect of factors other than treatment., Results: Of patients who received medication alone (n = 32), 25 (78.1%) relapsed, prevalently (65.6%) during the first year. The estimated mean survival time was 12 months (95% CI 7-17). Of patients who received integrated treatment (n = 21), only 3 (14.3%) relapsed. The estimated mean survival time was 65 months (95% CI 44-86). Treatment was the only variable associated with the occurrence of relapse, with a hazard ratio of 12.6 (95% CI 2.5-63.3) for patients who received only medication., Conclusions: Some methodological limitations, such as treatment allocation by preference, suggest caution in the interpretation of our results. However, the long-term therapeutic advantage of integrated treatment over medication alone was large and independent from known prognostic factors. The long-term effectiveness of integrated treatment should be tested with a randomised controlled trial., (Copyright 2003 S. Karger AG, Basel)

Experimental evidence suggests that panic disorder is characterized by abnormalities in the balance system function and that these abnormalities might be related to the severity of agoraphobic avoidance. Since the balance system can be modulated by the serotonergic system, we investigated the effect of a 6-week treatment with citalopram on the balance system function in patients with panic disorder. Fifteen patients with panic disorder with/without agoraphobia underwent static posturography on days 0 and 42. Static posturography and clinical assessments were carried out by different investigators who were blind to each other. Static posturography showed high percentages of abnormal scores. Patients with no or low agoraphobic avoidance showed less abnormal posturographic measures than those with moderate to severe agoraphobia. After 6 weeks of treatment with citalopram there was a significant decrease of four out of six posturography measures in eyes-closed and neck extension conditions, whereas no significant effect was found in the eyes-open condition. This is the first report that suggests that the modulation of the serotonergic system can improve the balance system function in patients with panic disorder, particularly when visual information is lacking. In addition, our findings confirm the observation that many patients with panic disorder have abnormalities in their balance system function, supporting the idea that these abnormalities are mainly related to agoraphobic avoidance., (Copyright 2003 Wiley-Liss, Inc.)

Background: In Brazil, treatment of panic disorder is most frequently initiated with pharmacotherapy, but only half of the patients can be expected to be panic free after medication. Studies have suggested that individual or group cognitive-behavior therapy (CBT) is an effective treatment strategy for panic patients who have failed to respond to pharmacotherapy., Methods: Thirty-two patients diagnosed with panic disorder with agoraphobia having residual symptoms despite being on an adequate dose of medication were treated with 12 weeks of group CBT. The outcome was evaluated for panic frequency and severity, generalized anxiety, and global severity. Comorbid conditions, a childhood history of anxiety, and defense mechanism styles were assessed as potential predictors of treatment response., Results: Twenty-nine patients completed the 12-week protocol. Treatment was associated with significant reductions in symptom severity on all outcome measures (p < 0.001). Patients with depression had a poorer outcome of the treatment (p = 0.01) as did patients using more neurotic (p = 0.002) and immature defenses (p = 0.05)., Conclusion: Consistent with previous reports, we found that CBT was effective for our sample of treatment-resistant patients. Among these patients, depression as well as neurotic defense style was associated with a poorer outcome. The use of CBT in Brazil for treatment-resistant and other panic patients is encouraged., (Copyright 2003 S. Karger AG, Basel)

Background and Objective: Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line treatment for panic disorder, although up to 30% of patients either do not respond to SSRIs or withdraw due to adverse events. Reboxetine, a selective norepinephrine reuptake inhibitor (selective NRI), is effective in treating depression and may alleviate depression-related anxiety. This study aimed to investigate the efficacy of reboxetine in the treatment of patients with panic disorder who did not respond to SSRIs., Method: In this 6-week, open-label study, 29 adult outpatients with panic disorder who had previously failed to respond to SSRI treatment received reboxetine 2 mg/day, titrated to a maximum of 8 mg/day over the first 10 days. Efficacy was assessed using the Panic Self-Questionnaire (PSQ), the Hamilton Rating Scale for Anxiety (HAM-A), the 17-item Hamilton Rating Scale for Depression (HRSD) and the Global Assessment of Functioning (GAF) Scale., Results: The 24 patients who completed the study responded well to reboxetine treatment. Significant improvement (p < 0.001) was observed in the number of daily panic attacks, and on the scales measuring anxiety, depression and functioning. Reboxetine was generally well tolerated. Five patients withdrew due to adverse events., Conclusions: Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients and warrants further clinical investigation., (Copyright 2002 John Wiley & Sons, Ltd.)

Background: Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors (SSRIs) have proved to be effective in the treatment of panic disorder. The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone., Method: 161 patients with panic disorder with or without agoraphobia (DSM-IV criteria) underwent a manual-guided cognitive-behavioral therapy of 15 sessions. Forty-three unsuccessfully treated patients from this group were included in a double-blind, placebo-controlled, next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo., Results: Overall, patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior (p < .05) and anxiety discomfort (p < .01), whereas patients in the cognitive-behavioral therapy plus placebo condition did not. Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition, from 0.4 to 1.0., Conclusion: Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality. The importance of timely evaluation of treatment results is emphasized.

This study investigated the chronic use (6.3 +/- 0.5 years; mean +/- SEM) of therapeutic doses of clomipramine (57.0 +/- 8.0 mg/day) by outpatients with panic disorder/agoraphobia who were currently in remission to assess impairment of memory and psychomotor functions. In addition, the association between test performance and serum levels of clomipramine (CMI) and its active metabolite desmethylclomipramine (DCMI) was also assessed. Patients and healthy volunteers matched for sex, age and educational level were submitted to rating scales and to memory and psychomotor tests. There was no significant difference between groups regarding any variable, except for metamemory. Significant associations were found between (i) longer-term clomipramine treatment and poorer performance in the implicit test and (ii) higher serum levels of clomipramine or desmethylclomipramine, or both (CMI + DCMI) and lower performance in central executive tests and metamemory. The results showed that low doses of CMI chronically administered to panic patients are associated with diminished metamemory and impaired priming and working memory. Further investigations are needed to confirm these results and to determine whether the chronic use of higher therapeutic doses of tricyclic antidepressants is associated with more intense deleterious effects on memory and psychomotor functions.

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients. In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22). Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers. In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.

The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder., (Copyright 2002 Elsevier Science Ltd.)

Carbon dioxide (CO2) inhalation induces acute anxiety and panic attacks in patients with Panic Disorder (PD). Anti-panic drugs decrease CO2 reactivity after the first days of treatment; however, the clinical meaning of this finding has not yet been established. This study investigated the effects of treatment with tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs) on CO2 reactivity and compared the relationships between 35% CO2 hyperreactivity modulation and short-term clinical outcome. One hundred twenty-three patients with PD with or without agoraphobia who were hyperreactive to CO2 were randomly assigned to treatment groups with imipramine, clomipramine, paroxetine, sertraline, or fluvoxamine. A double-blind, randomized design was applied. Each patient received the 35% CO2 challenge on days 0, 7, and 30. The severity of clinical symptomatology was measured on days 0 and 30. Decreased hyperreactivity to 35% CO2 in all five treatment groups was already evident after the first week. The decrease in CO2 reactivity at the end of treatment was proportional to the degree of clinical improvement. Multiple regression analyses showed that the decrease in CO2 reactivity after the first week was a significant predictor for good clinical outcome after one month. The results of this study confirm evidence that psychoactive drugs effective in the treatment of PD decrease CO2 hyperreactivity. They also suggest that precocious modulation of CO2 reactivity might fairly reliably predict short-term clinical outcome in patients with "respiratory" PD.

Objective: Quality of life in a treatment-seeking cohort of patients with social anxiety disorder was compared with that of patients with panic disorder who were matched for age, comorbid illnesses, and gender and with population-based norms., Methods: The study participants were 33 patients with social anxiety disorder and 33 patients with panic disorder who had participated in clinical trials and who had completed the Medical Outcomes Study Short-Form-36 (SF-36) as part of a baseline evaluation. The patients did not have significant comorbid psychiatric disorders. Paired t tests were used to compare baseline scores on subscales of the SF-36 between the two cohorts. One-sample t tests were used to compare scores on subscales of the SF-36 with expectation scores based on 2,474 persons from the general population., Results: Compared with the general population, the patients with social anxiety disorder had significantly greater impairment as measured by the SF-36 social functioning and mental health subscales. Subscale scores also indicated poorer emotional role functioning, but the difference was not significant. However, they were significantly less impaired than the patients with panic disorder in terms of physical functioning, physical role, and mental health., Conclusions: Patients with social anxiety disorder who do not have significant comorbid depression or anxiety are substantially impaired in quality of life, but to a lesser extent than patients with panic disorder, who suffer from both mental and physical impairments in quality of life.

It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse. This study further explores the relationship between relapse and duration of imipramine treatment in this population.Fifty-one patients, all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and randomized to double-blind maintenance or placebo substitution, discontinued imipramine treatment eventually and were followed over a 12-month risk period: 27 during first year placebo substitution, 7 after 12 months of imipramine maintenance in placebo substitution, and 17 after variable durations of imipramine maintenance in open discontinuation. There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation. Duration of imipramine treatment, the method of discontinuation (open versus placebo substitution), or any of the 9 variables from the demographic, clinical, and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse. The rate of relapse after only 6 months of treatment (10 out of 27, 37%) was identical to the rate of relapse after 12 to 30 months of treatment (9 out of 24, 37.5%). The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients. Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction.

In a recent study, the authors suggested that tachycardia, dry mouth, and sweating continued to burden patients with panic disorder with agoraphobia who have shown marked and stable response to 6 months of imipramine treatment at the fixed, weight-adjusted dose of 2.25 mg/kg/day. Although sexual dysfunction and weight gain were not a significant burden in that study, they are important problems in long-term treatment with antidepressant drugs. In the present study, in the context of a randomized, double-blind, placebo-controlled, 1-year discontinuation and maintenance study of 53 patients with panic disorder with agoraphobia who respond to imipramine, the authors examine the extent and the specificity of these five side effects of imipramine maintenance using data at pretreatment, at the end of 24 weeks of open imipramine treatment (or month 0 of randomization), and at months 2, 4, 6, 8, 10, and 12 of randomized treatment. Hierarchical linear modeling and repeated measures of analyses of variance in subsamples of completers confirmed that dry mouth, sweating, and increased heart rate constitute a significant and specific enduring burden of imipramine maintenance treatment. The data also revealed that weight gain is a significant and specific side effect of 1-year imipramine maintenance treatment; however, the likelihood of reporting sexual dysfunction decreased over time, with no difference between the placebo and imipramine maintenance conditions. The results are discussed in the context of previous studies of imipramine side effects in the management of depression and the available literature of sexual and weight side effects of antidepressant medications in the treatment of anxiety disorders.

Using spectral analysis of heart rate, several studies have shown that panic disorder patients are characterized by a reduced heart rate variability (HRV), indicative of abnormalities in autonomous nervous system (ANS) function. We recently reported that patients with panic disorder, who did not respond to pharmacotherapy, were characterized at baseline by a higher heart rate. In this study, ANS functioning is investigated as a possible predictor of nonresponse to pharmacotherapy. Twenty-eight medication-free panic disorder patients entered a 12-week open-label treatment study with mirtazapine. Five-minute HRV recordings were obtained before treatment and were analysed using spectral analysis. The data of 17 patients could be used. The total spectrum and low frequency power of responders to mirtazapine were significantly higher than those of nonresponders. Our findings suggest that nonresponders to short-term mirtazapine treatment are characterized at baseline by a lowered output of the ANS. The results are preliminary in view of the small sample studied.

The omnipresent worry and anxiety that are characteristic of generalized anxiety disorder (GAD) significantly reduce social and occupational functioning. Yet many clinical investigations of GAD fail to evaluate treatment-related changes in function. As a consequence, many patients who respond to pharmacologic treatment (defined as having a > or = 50% reduction in symptoms) still exhibit subsyndromal symptoms that predispose to relapse. This is particularly true for patients with GAD who have comorbid psychiatric or medical conditions. In recent years, the goal of treatment for anxiety disorders has been set toward the achievement of full remission--that is, a virtually asymptomatic state. Remission indicates an improvement not only of symptoms but also of functionality. Benzodiazepines, azapirones, and antidepressants are the three main classes of agents currently used in the treatment of GAD. Some antidepressants have been shown to better facilitate remission. This article will summarize evidence for the clinical utility of pharmacotherapeutic agents commonly used in the treatment of GAD.

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.

This study investigated the relationship between panic symptoms during remission and subsequent relapse of panic disorder. Research subjects were 169 individuals, enrolled in the Harvard/Brown Anxiety Research Project, who were in episodes of panic disorder at intake and remitted during the 8-year follow-up period. Panic symptoms during remission were examined as predictors of panic disorder relapse. For the relapses that did occur, we report the level of symptomatology during the previous 4 weeks. Depending on symptom severity and whether or not the relapse included agoraphobia, panic symptoms during remission were associated with an approximate two- to threefold increased risk of relapse. However, on examination of symptoms during the 4 weeks before relapse, we found that the majority of relapses were preceded by no panic symptoms. Thus, although panic symptoms during remission may indicate an increased risk of subsequent relapse, the absence of symptoms during remission does not indicate that relapse is unlikely.