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Background: Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder. The introduction of SSRIs has enabled a greater understanding of the role of serotonin in the etiology of panic disorder; however, the role of norepinephrine has been more challenging to ascertain. The aim of this study was to determine the efficacy and tolerability of reboxetine, a novel selective norepinephrine reuptake inhibitor, in patients with panic disorder with and without agoraphobia., Method: Eighty-two patients (aged 18-65 years) with DSM-III-R panic disorder, with or without agoraphobia, were randomly assigned to receive 6 to 8 mg/day of reboxetine (42 patients) or placebo (40 patients) for 8 weeks in this placebo-controlled, parallel-group, double-blind clinical trial., Results: Of the 82 patients enrolled in the trial, 75 were considered in the analysis (37 patients in the reboxetine group and 38 patients in the placebo group). At last assessment, there was a significant reduction in the mean number of panic attacks (range, 9.3-1.2) and phobic symptoms (range, 8.1-3.2) in the reboxetine group compared with the placebo group (ranges, 8.5-5.8 and 7.7-5.2, respectively; p < .05). Improvement in Hamilton Rating Scale for Depression, Hopkins Symptom Checklist-90, and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group. Adverse events reported more frequently with reboxetine than placebo included dry mouth (36% vs. 16%), constipation (27% vs. 22%), and insomnia (26% vs. 22%)., Conclusion: Reboxetine was effective and well tolerated in the treatment of panic disorder.

Objective: Previous studies have shown that neuroactive steroids modulate anxiety and stress reactivity. However, no data on the possible role of these gamma-aminobutyric acid(A) (GABA(A)) receptor-modulating neuroactive steroids in patients with anxiety disorders are available., Method: The concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta-THP, 3beta,5alpha-THP, and their precursors were studied in the plasma of 10 patients with panic disorder and 10 matched healthy comparison subjects. In addition, the effects of paroxetine treatment on neuroactive steroid concentrations were studied in the panic disorder patients over a 24-week period., Results: Unexpectedly, patients with panic disorder had significantly greater concentrations of the positive allosteric modulators 3alpha,5alpha-THP and 3alpha,5beta-THP and significantly lower concentrations of 3beta,5alpha-THP (a functional antagonist for GABA(A) agonistic steroids), which might result in greater GABA(A) receptor-mediated neuronal activity. Paroxetine treatment did not affect neuroactive steroid concentrations, which were highly stable over 24 weeks., Conclusions: Differences in neuroactive steroid composition in patients with panic disorder were the opposite of those seen in patients with major depression and may reflect counterregulative mechanisms against the occurrence of spontaneous panic attacks.

Benzodiazepines (BZs) are commonly used in conjunction with cognitive behavioral therapy (CBT) in the treatment of panic disorder with agoraphobia (PDA). However, empirical evidence provides little support for the utility of this combined treatment approach over CBT alone. Westra and Stewart [Clin. Psychol. Rev. 18 (1998) 307] have proposed that pm or as-needed use of BZs may inhibit positive CBT outcome to a greater extent than regularly scheduled BZ use. Using a naturalistic design, the present study investigated the impact of manner of BZ use on treatment outcome from CBT in 43 patients with PDA. Among various BZ parameters (chronicity, frequency, dose, and frequency of prn use), pm use of BZs for coping with anxiety symptoms was a significant negative predictor of degree of change in both anxiety sensitivity and anxious arousal from pre- to post-CBT. Although no significant between-group differences were evident in pre-treatment symptomatology, unmedicated subjects demonstrated the most positive overall CBT outcome, while pm BZ users evidenced the fewest gains. Regular BZ users were generally not significantly differentiated from unmedicated subjects in CBT outcome and both tended to obtain post-treatment scores in the nonclinical range. Implications of these findings for clinical management of BZ use throughout CBT for PDA are discussed.

Objective: To investigate the long-term efficacy, prevention of relapse and safety of sertraline in the treatment of panic disorder., Method: This study consisted of 52 weeks of open-label sertraline treatment (n=398) followed by a 28 weeks of a double-blind, placebo-controlled discontinuation trial (n=183)., Results: Ninety-three patients were randomized to sertraline and 90 were randomized to placebo. Discontinuation due to insufficient clinical response occurred in 23.6% of placebo-treated patients and 12.0% of sertraline-treated patients (log-rank test, P=0.040). Thirty-three per cent of placebo-treated patients had an exacerbation of panic symptomatology, versus 13% of sertraline-treated patients (log-rank test, P=0.005). Abrupt cessation of sertraline resulted in dizziness (4.3% sertraline vs. 16.9% placebo; P=0.007) and insomnia (4.3% sertraline vs. 15.7% placebo; P=0.013) occurring at significantly higher rates., Conclusion: Long-term sertraline treatment was effective in preventing relapse of panic disorder, well tolerated and associated with minimal discontinuation symptoms.

Pagoclone is a cyclopyrrolone that is believed to act as a partial agonist at the gamma-aminobutyric acid (GABA)-A/benzodiazepine (BDZ) receptor. In theory, such partial agonists should be anxiolytic but lack the adverse side-effects of sedation, tolerance and withdrawal associated with full GABA-A/BDZ agonists. The objective of the randomized double-blind crossover study was to assess whether pagoclone was an effective anti-panic agent and also to assess its side-effect profile. Patients recruited had a diagnosis of Panic Disorder (DSM-IV) with at least one panic attack per week. Following a 2-week screening period, patients entered a 6-week trial consisting of two 2-week treatment periods, each followed by a 1-week washout. Patients were randomly assigned to receive either pagoclone 0.1 mg t.d.s. or placebo on their first treatment period and the converse on their second. The primary measure was daily panic attack dairy. Fourteen patients completed the study, the mean number of panic attacks during screening was 5.8+/-0.8 (SEM), this fell to 3.6+/-0.5 during treatment with pagoclone (p = 0.05) and 4.3+/-0.8 with placebo (p = 0.14). There was no significant difference on direct comparison of pagoclone with placebo or in any of the secondary measures (including Rickels withdrawal scale) or the adverse event profiles. The study provides preliminary evidence that pagoclone has anxiolytic properties in the absence of typical BDZ side-effects. This is consistent with its theoretical mode of action as a partial agonist at the GABA(A)/BDZ receptor.

In this report we describe the outcome of eight outpatients with panic disorder and agoraphobia who discontinued their treatment with a selective serotonin reuptake inhibitor (SSRI) in the context of a structured, group program of cognitive-behavior therapy. All patients successfully discontinued their SSRI medication while demonstrating clinical improvement. These results were maintained at 3-month follow-up. This case series suggests that manualized CBT for discontinuation of benzodiazepine treatment for panic disorder may be successfully applied to SSRI discontinuation as well.

Pfizer is developing pregabalin, a follow-up compound to its GABA agonist gabapentin, for the potential treatment of several central nervous system (CNS) disorders including epilepsy, neuropathic pain, anxiety and social phobia [286425]. By December 2000, Pfizer anticipated filing an NDA for pregabalin for seven major indications (beginning with neuropathic pain and add-on epilepsy), with the FDA by the end of 2001. Filings for generalized anxiety disorder (GAD), social anxiety disorder and fibromyalgia are expected to take place in 2002, and filings for epilepsy monotherapy and panic disorders are expected to take place in early- and late-2003, respectively [336918], [393182], [399956]. By January 2001, pregabalin was in phase II development in Japan for the potential treatment of neuropathic pain, with an anticipated approval date of 2005 [394827]. However, following analysis by the FDA of a mouse study that showed incidence of a specific tumor type, Pfizer announced in February 2001, that it is restricting the use of pregablin in some clinical patients [398726] and it has frozen trials for neuropathic pain [398785]. In April 2001, Morgan Stanley Dean Witter predicted potential sales of $350 million in 2002, rising to $1750 million in 2006, with peak sales in excess of $2000 million [406923].

Background: The results from our 1 year placebo-controlled maintenance/discontinuation study in remitted panic disorder with agoraphobia patients confirmed the significant prophylactic effectiveness of imipramine maintenance treatment but suggested that this may be necessary in only 37% of the patients who relapse following discontinuation of 6 months acute imipramine treatment. This paper presents pilot data from a second year extension of the above-mentioned study with the aim of exploring the putative protective effects of maintenance imipramine therapy beyond the 1st year., Method: Eighteen patients from the 30 who survived, in stable remission, the first 12 months of the maintenance/discontinuation study gave written consent to participate in a double-blind 2nd year extension phase with the knowledge that those on placebo will continue on the same condition (N = 7, PBO-PBO) and those on imipramine (N = 11) will be rerandomized to 2nd year maintenance (N = 4, IMI-IMI) or placebo substitution (N = 7, IMI-PBO). The procedures continued unchanged from that of the 1st year of the study and patients were followed with planned assessments every 2 months over the second 12-month experimental period of the study., Results: None of the IMI-IMI patients relapsed, two (28.5%) of the IMI-PBO patients relapsed, and two (28.5%) of PBO-PBO patients relapsed. The mean estimated time without relapse was 10 months and 9 months for IMI-PBO and PBO-PBO, respectively. The estimated probability of not relapsing was .64 for IMI-PBO and .60 for PBO-PBO (Mantel-cox test chi2 =.84, p = .77)., Conclusion: These interlocking controlled observations tentatively suggest that a substantial degree of prophylactic efficacy continues and that a substantial need for continued prophylaxis exists beyond the 1st year of maintenance imipramine treatment in panic disorder with agoraphobia patients.

The effect of a short treatment (7 days) with citalopram on the reactivity to inhalations of 35% CO2 and 65% oxygen and on clinical symptomatology was investigated in 15 patients with panic disorder who had a positive response to 35% CO2 inhalation. An open study design was applied. On day 0, before starting drug treatment, and after 1 week of treatment, each patient underwent the 35% CO2 challenge, and clinical symptomatology was evaluated with psychometric scales. The results showed a significant reduction of CO2 reactivity and of scores on the anticipatory anxiety subscale of Panic Associated Symptoms Scale. These results confirm that the serotonergic system plays an important role in the modulation of CO2 hyperreactivity and suggest an early anxiolytic effect of citalopram in patients who have panic disorder and are hyperreactive to CO2.

Antidepressants have a much broader range of indication than the name suggests. The efficacy of antidepressant treatment of nervous and stress-related disorders has been documented in several controlled trials, both in comparison with placebo and with other antidepressants. Most studies have included testing in panic disorder, with or without agoraphobia, and obsessive compulsive disorder, but there is empirical evidence for the efficacy of the drugs in most anxiety disorders. Antidepressants with a preference for serotonergic neurotransmission (i.e. clomipramine and SSRIs (serotonin specific reuptake inhibitors) are particularly effective in the treatment of panic disorder and obsessive compulsive disorder. Owing to their more favourable side effect profile as compared with classical antidepressants, the SSRIs are considered to be the drugs of first choice, except for generalised anxiety disorder, where the efficacy of venlafaxine has been most thoroughly documented. Studies comparing different antidepressant are warranted. So are studies elucidating the relative benefits of drug treatment and psychotherapy, but, with the concept of modern anxiety treatment, there is no principal objection to combining the two treatment methods.

Objective: To assess the effectiveness of clonazepam, in a fixed dose (2 mg/day), compared with placebo in the treatment of panic disorder patients., Method: 24 panic disorder patients with agoraphobia were randomly selected. The diagnosis was obtained using the structured clinical interview for DSM-IV. All twenty-four subjects were randomly assigned to either treatment with clonazepam (2 mg/day) or placebo, during 6 weeks. Efficacy assessments included: change from baseline in the number of panic attacks; CGI scores for panic disorder; Hamilton rating scale for anxiety; and panic associated symptoms scale., Results: At the therapeutic endpoint, only one of 9 placebo patients (11.1%) were free of panic attacks, compared with 8 of 13 (61.5%) clonazepam patients (Fisher exact test; p=0,031)., Conclusion: the results provide evidence for the efficacy of clonazepam in panic disorder patients.

Background: More than one third of panic disorder patients have a chronic and/or recurrent form of the disorder, accounting for much of the individual and societal cost associated with the illness. Six clinical variables have been most consistently identified as high-risk predictors of poor outcome: (1) panic severity, (2) presence of agoraphobia, (3) comorbid depression, (4) comorbid personality disorder, (5) duration of illness, and (6) female sex. No published research has systematically examined the differential antipanic efficacy of selective serotonin reuptake inhibitors in patients at high risk for poor outcome., Method: Data were pooled (N = 664) from 4 double-blind, placebo-controlled studies of the efficacy of sertraline for the treatment of DSM-III-R panic disorder. Two of the studies were 12-week fixed-dose studies with starting daily doses of sertraline, 50 mg, and 2 were 10-week flexible-dose studies with starting daily doses of sertraline, 25 mg. All other study design features were the same, except for the exclusion of women of childbearing potential in the 2 fixed-dose studies. Exclusion of patients with marked personality disorders and depression meant that only 4 of the poor-outcome variables could be evaluated., Results: Clinical improvement was similar for patients treated with sertraline whether or not they carried an agoraphobia diagnosis, had a duration of illness > 2 years, or were female. Patients with high baseline panic severity had significantly (p = .01) less improvement on the endpoint Clinical Global Impressions-Improvement (CGI-I) scale than patients with moderate severity, although the Clinical Global Impressions-Severity of Illness scale change score was higher in the patients with high severity (-2.00 vs. -1.31). For patients with 3 or more high-risk variables, there was a modest, but statistically significant, tendency for reduced global improvement (endpoint CGI-I score of 2.7 for the high-risk vs. 2.4 for the non-high-risk group; p = .017), although the high-risk group actually had a similar endpoint reduction in frequency of panic attacks (82%) compared with the non-high-risk group (78%)., Conclusion: Treatment of panic disorder with sertraline was generally effective, even in the presence of baseline clinical variables that have been associated with poor treatment response. The main limitations of the analysis were the reliance on pooled data from 4 studies (even if the designs were similar) and our inability to examine the impact of depression and personality disorders on response to treatment because of the exclusion criteria of the clinical trials.

The purpose of this study was to test the following interrelated hypotheses in a larger sample by attempting to replicate supportive results from a small therapeutic study: (1) the pathogenesis of panic disorder includes at least two identifiable components: a biological component represented by spontaneous (unexpected) panic attacks, and a cognitive component represented by situational attacks and especially by phobias; (2) these components respond differently to treatment; (3) many biological processes respond to an effective intervention in proportion to their deviance from "normal" prior to treatment ("Law of Initial Value"); and (4) the response of spontaneous panic attacks to an effective treatment conforms to that model. Previously, the authors reanalyzed an 8-week therapeutic study of panic disorder that included groups treated with placebo and with imipramine (225 mg daily). The criteria of response were spontaneous panic attacks (biological component), situational panic attacks (both components), and agoraphobia ratings (cognitive component). The analyses compared the regression lines for posttreatment status on pretreatment status in the imipramine and placebo groups. The effect of imipramine on spontaneous panic attacks fitted the hypothesized model: the pre-post slope in the placebo group was approximately 1 (45 degrees), whereas the slope in the imipramine group was approximately 0. There was no significant difference in pre-post slopes between the imipramine and placebo groups for situational panic attacks or agoraphobia ratings. For this report, the authors applied the same approach to another larger data set from a study using a similar design, but a different antidepressant. In this multicenter, double-blind study, patients with panic disorder were randomly assigned to receive 10 weeks of treatment with placebo (N = 78) or fluoxetine 10 mg (N = 84) or 20 mg (N = 81) daily. Spontaneous and situational panic attacks were registered in a daily diary, and agoraphobia was rated at each visit. Using baseline and endpoint data, fluoxetine had a statistically significant, dose-dependent, suppressive effect on spontaneous panic attacks, as measured by the pre-post slopes in the three treatment groups. The placebo group showed some response (slope = 0.69). There were no significant drug effects on situational panic attacks. On ratings of agoraphobia, the slopes in the placebo and the fluoxetine 20 mg groups did not differ, but the slope in the fluoxetine 10 mg group was significantly less than that in the placebo group, suggesting a therapeutic drug effect on agoraphobia only at the lower dose. These results are consistent with the stated hypotheses. They suggest that the therapeutic effects of antidepressants on panic disorder may be due primarily to the specific suppression of spontaneous panic attacks among patients with high baseline pathologic findings. Implications of these results for concepts of pathogenesis, clinical practice, and therapeutic research regarding panic disorder are discussed.

In a recent study, the authors gauged the net effectiveness of imipramine to be 53%; that is, of 110 patients having panic disorder with agoraphobia who started a course of imipramine at a fixed, targeted, weight-adjusted dose of 2.25 mg x kg(-1) x day(-1), 59 adhered to the regimen and showed a marked and stable response. The present study investigated in detail the side effects burden of imipramine treatment in the same sample using hierarchical linear modeling in a short-term perspective, based on data at baseline (N = 110) and at weeks 1, 2, 4, 6, and 8 (N = 77) of treatment, and a long-term perspective, based on data at baseline and at weeks 8, 16 (N = 66), and 24 (N = 59). Deviations from the general pattern were explored by considering only severe side effects or only completers of treatment to better gauge the clinical significance of the findings. The results revealed that of 15 complaints systematically elicited using a side effects inventory, only 3--dry mouth, sweating, and constipation--continued as a substantial burden at the end of 6 months of treatment. On most other items, the initial increase was followed by a decrease to lower than baseline at the end of treatment. In the case of nausea, vomiting, increased energy, headache, and sexual disorders, the complaints were at their worst before treatment started and improved over the course of treatment. A sustained heart rate elevation between 10 and 15 beats per minute was found, but there were no significant effects on blood pressure or weight. The discussion underscores the need for more methodologically improved comparative studies with selective serotonin reuptake inhibitors in the treatment of panic disorder.

Advances in the neurobiology of post-traumatic stress disorder (PTSD) and the availability of modern psychotropics have led to renewed interest in the pharmacotherapy of this disorder. In this paper we focus on trials of the selective serotonin reuptake inhibitors (SSRIs) in PTSD. Studies of the pharmacotherapy of PTSD were identified using methods developed by the Cochrane collaboration. Although a range of open trials of different SSRIs in PTSD show promise, there are few controlled pharmacotherapy studies in this disorder. Nevertheless, pharmacotherapy for PTSD appears to have reasonably robust effects, with odds ratios for responder status, defined as 'much improved' or 'very much improved' on the Clinical Global Impression Scale (CGI), on drug versus placebo varying from 2.2 to 5.6 in randomized controlled trials of different agents. The SSRIs appear both safe and effective for this indication. Additional research with these agents is necessary to clarify many questions, including predictors of response, duration of treatment, comparison with other agents, and integration with psychotherapy. In the interim, however, the SSRIs can be recommended as a first-line medication for the treatment of PTSD.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score > or = 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder.

This review article summarizes comparator-controlled, short-term studies with currently available selective serotonin reuptake inhibitors (SSRIs) in the treatment of panic disorder and agoraphobia. Fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram have all been proven to be superior to pill-placebo in the treatment of panic disorder, agoraphobia and associated symptoms such as depression. Direct comparisons with other antidepressants, benzodiazepines, cognitive-behavioural therapies or combinations of SSRIs with psychotherapeutic interventions are scarce. The majority of studies have reported on fluvoxamine whereas, to date, sertraline and citalopram have been compared only with placebo. Meta-analyses have suggested that combining an antidepressant with exposure in vivo produces the greatest treatment gains. Since this procedure is already commonly used in everyday clinical practice, it is recommended that future research in the treatment of panic disorder be directed towards the investigation of a combination of SSRIs with exposure therapy.

Objective: How far the results of randomized controlled studies apply to everyday care cannot be judged without regular measurements of outcomes in daily practice. We report on systematic data from a 3-year naturalistic prospective study on panic disorder-agoraphobic (PDA) patients treated with antidepressants in a setting of routine clinical practice. Our aim is to describe the evolution of PDA in relation to the treatments employed, and to explore demographic and clinical characteristics that might be predictive of outcome., Methods: 326 DSM-III-R PDA patients treated with antidepressants in a setting of routine clinical practice were included in a 3-year naturalistic prospective study. We utilized structured and semi-structures instruments, including the Structured Clinical Interview for Diagnosis and the Longitudinal Interview Follow-up Examination. The main antidepressants used were imipramine (39%), clomipramine (28.5%) and paroxetine (23.3%); only 9% of patients received other antidepressants., Results: 147 patients (45.1%) stayed on medication throughout the entire period of the follow-up. Of those who interrupted the treatment, 38% stayed in remission. The probability of achieving at least one remission during the 3-year follow-up period was 96.5% for PD and 95.9% for Agoraphobia. Relapses after a period of at least 2 months of complete remission were also common, and the probability of presenting at least one relapse during the 3-years follow-up period was 67.1% for PD and 39% for Agoraphobia. The longest period of remission of PD is associated with low severity, medium-lasting course in patients with an onset of the illness in young adulthood. Less severe agoraphobia associated with moderately severe panic attacks appears to confer a better control of phobic behavior. All three major drugs were reasonably well tolerated (only 9% dropped out because of side effects), with sexual dysfunction and increased appetite being the most common side effects at the last evaluation; in the first phase of the treatment anticholinergic effects and jitteriness were more common with TCAs., Conclusion: Both classical antidepressants and paroxetine emerge as a useful treatment in the long-term management of PDA; paroxetine appears particularly useful in PDA patients because it was significantly less likely to induce jitteriness, thereby reducing barriers to compliance.

The inhalation of 35% carbon dioxide has consistently been shown to provoke panic attacks in panic disorder patients. We aim to determine if an acute dose of clonazepam (2 mg) attenuates the panic attacks induced by an inhalation of 35% carbon dioxide in panic disorder. Twenty-two panic disorder patients who had been drug-free for 1 week participated in a carbon dioxide challenge test 1 h after a dose of either 2 mg of clonazepam or placebo with a randomized double-blind method. Also in a double-blind design during the tests the patients inhaled either atmospheric compressed air ('placebo control') or the carbon dioxide mixture. All patients participated in both tests which were done with a 20-min interval. Immediately before and after the inhalation, the anxiety levels and the symptoms of panic were always assessed. In the clonazepam group (n=11) two patients (18.2%) had a mild panic attack and in the placebo group (n=11) nine patients (81.8%) had a moderate to severe panic attack in the CO(2) challenge test. No patient had panic attacks during inhalation of atmospheric compressed air although anticipatory anxiety levels tended to be higher than in the CO(2) tests. After the CO(2) test anxiety levels were significantly greater in the CO(2) group (three-way ANOVA with Geisser-Greenhouse adjustments, F(31.92,1.86)=17.15, d.f.=7, P=0.013). Although a small sample was studied, the findings suggest the efficacy of an acute dose of clonazepam in attenuating panic attacks induced by carbon dioxide inhalation.

Objective: To compare the relative efficacy and safety of lesopitron 4-80 mg/d versus lorazepam 2-4 mg/d and placebo in a subgroup of patients with anxiety history taken from a larger study of patients with a primary diagnosis of generalized anxiety disorder (GAD)., Design: Six-week, randomized, double-blind, parallel, placebo and lorazepam-controlled, Phase II, single-center, outpatient study., Setting: Outpatient clinic., Patients: One hundred sixty-one patients with GAD were randomized in the main study; 68 with a documented history of GAD or anxiety disorder not otherwise specified were included in the subgroup., Methods: After a one-week placebo lead-in, patients were randomized to receive placebo, lesopitron, or lorazepam twice daily for six weeks, followed by a one-week taper period. Efficacy was assessed using the Hamilton Rating Scale for Anxiety (HAM-A) and the Clinical Global Impressions scale. Safety was assessed through physical examinations, monitoring of vital signs, 12-lead electrocardiograms, laboratory analyses, and adverse event monitoring., Results: An overall mean improvement in the HAM-A total score between baseline and end point for all three treatment groups was seen, with mean changes of 3.4 (95% CI 2.0 to 4.8), 6.1 (95% CI 4.1 to 8.1), and 6.1 (95% CI 4.6 to 7.6) for the placebo, lesopitron, and lorazepam groups, respectively (omnibus p = 0.044, uncorrected). Positive treatment effects were also observed in the subgroup population on several other measures and suggest that additional therapeutic trials may be warranted. Future trials could be stratified on the basis of referral status (symptomatic volunteer vs. clinical patient with preexisting illness) or previous exposure to anxiolytics, and use a fixed-dose rather than flexible-fixed-dose design., Conclusions: The subgroup analysis represents a comparison of treatment outcome in GAD patients presenting with a history of previous episodes of GAD or anxiety disorder not otherwise specified compared with those who were experiencing their first episode of GAD and reported no anxiety history. Although the overall study analysis was equivocal, for the approximately 40% of patients with recurrent anxiety disorder, beneficial effects for both lesopitron and lorazepam are suggested.

Aim: To determine clinical efficiency and tolerance of paxil (paroxetin) in the treatment of panic disorders., Material and Methods: An open, non-comparative 7 week study entered 60 patients (mean age 36.6 +/- 3.22 years) with panic disorders and agoraphobias with panic disorders. Paroxetin was given in a single daily dose 20-60 mg/day in the morning. The results were assessed by Hamilton and Sihan scales, scale of clinical impression, by reduction of panic attacks., Results: In 72.2% of patients panic attacks ceased or occurred less frequently (by 50%). Anxiety relieved by 67 +/- 4.6%. The number of the responders was greater while the effect occurred faster in patients with panic disorders. The drug was well tolerated, side effects occurred in 43.3% of cases. They were mild or moderate., Conclusion: Paroxetin has a prominent anxiolytic and antiphobic action, is well tolerated and is effective in panic disorders and agoraphobia with panic disorders.

Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) were measured in 10 outpatients with panic disorder, twice (at a 48-h interval) before and twice on days 30-32 of treatment with alprazolam (2-2.5 mg/day), and twice in 10 age- and sex-matched healthy controls. TNF-alpha concentrations did not differ in patients and control subjects, either before therapy or at days 30-32 of therapy. In five patients before therapy, and in three of them after therapy, TNF-alpha values were higher than the maximal concentrations of the cytokine in controls.

Background: This 12-week, placebo-controlled study was carried out to compare the relative efficacy of paroxetine, clomipramine, and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia., Method: After a 3-week single-blind, placebo run-in period, 131 patients were randomly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression scale, the Patient Global Evaluation, the Hamilton Rating Scale for Anxiety, the Marks-Sheehan Phobia Scale, the Montgomery-Asberg Depression Rating Scale, and the Sheehan Disability Scale., Results: Comparisons with placebo revealed significant superiority of paroxetine (20-60 mg/day) and clomipramine (50-150 mg/day) on nearly all outcome measures. On most measures, paroxetine also showed higher efficacy than cognitive therapy. With few exceptions, cognitive therapy did not differ significantly from placebo. The number of subjects becoming panic-free (66%) was higher and the onset of action was faster in the paroxetine-treated group. Treatment with cognitive therapy yielded the highest drop-out rate (26%)., Conclusion: In this short-term study assessing treatment of panic disorder and agoraphobia, paroxetine and clomipramine were consistently superior to pill placebo, whereas cognitive therapy was superior on only a few measures.

Background: There has been little systematic work done regarding the long-term treatment of panic disorders. The aim of the present study was to assess the 12-month cumulative risk of relapse specifically due to discontinuation of imipramine and to test the hypothesis that maintenance treatment with imipramine protects patients with panic disorder and agoraphobia from such reversals., Method: Following an acute-phase open trial with imipramine (2.25 mg/kg per day) involving 110 patients for 6 months, the 56 patients who were in stable remission, did not require additional treatment, and consented to be randomly assigned to double-blind maintenance (n = 29) or discontinuation (n = 27) conditions were followed up with planned assessments every 2 months during a 1-year period. There were no behaviorally oriented interventions or instructions at any time during the 18 months of the study., Results: Maintenance treatment (1 relapse) and discontinuation (10 relapses) conditions had significantly different survival curves (Mantel-Cox statistic chi(2)1 = 10.47, P = .001). None of the additional 10 variables from demographic, clinical, and open-treatment domains considered in the proportional hazard model disrupted the significant relationship between experimental drug condition and relapse; other things being equal, a patient receiving imipramine maintenance was 92.5% lower in the hazard rate of relapse than a patient receiving placebo., Conclusion: The results confirm the very high degree of prophylactic effectiveness of maintenance imipramine treatment and demonstrate that relapse, although substantial, occurs in a minority of patients with panic disorder and agoraphobia who are in stable remission prior to treatment discontinuation.

Background: The purpose of this multicenter, double-blind, placebo-controlled study was to evaluate the efficacy and safety of optimized dosages of clonazepam for the treatment of panic disorder and assess the tolerability of a schedule for gradual discontinuation., Method: Adult patients with panic disorder with or without agoraphobia (DSM-III-R criteria) were randomly assigned to receive either placebo or clonazepam in individually adjusted doses over 3 weeks to approximate an optimal dosage, which was then maintained for an additional 3 weeks, amounting to a 6-week therapeutic phase. The daily dose range was 0.25 to 4.0 mg administered in 2 divided doses. In the following 7-week discontinuance phase, the doses were tapered gradually to cessation., Results: At the therapeutic endpoint, clonazepam (N = 222) proved clinically and statistically superior to placebo (N = 216) in change in the number of panic attacks and in Clinical Global Impressions-Severity of Illness (CGI-S) and CGI-Change scores, Patient's Global Impression of Change scores, amount of fear and avoidance associated with phobic symptoms, and duration of anticipatory anxiety. The gradual tapering of clonazepam was not associated with symptoms suggestive of withdrawal syndrome. Although patients taking clonazepam experienced some clinical worsening compared with the status achieved at endpoint, particularly in terms of number of panic attacks, no deterioration was observed using their condition at baseline as point of reference. No overall evidence of rebound was found. All regimens were generally well tolerated. Somnolence was the main adverse event associated with clonazepam therapy. The percentage of patients who reported adverse events was higher in the clonazepam group than in the placebo group, as was the mean number of adverse events per patient., Conclusion: In this placebo-controlled trial, clonazepam was an efficacious and safe shortterm treatment of the symptoms of panic disorder. Discontinuance during and after slow tapering was well tolerated.

Background: Fluoxetine and its active metabolite norfluoxetine have long half-lives of 4-6 days and 4-16 days, respectively. We postulated that, owing to the long elimination half-life, patients diagnosed with panic disorder might be maintained on fluoxetine taken once a week, after being treated initially with daily doses of fluoxetine., Method: Ten patients with DSM-III-R panic disorder were treated openly with fluoxetine, 20-40 mg daily. Once panic free, these patients were switched to once-weekly dosing of fluoxetine, and dosage was titrated as needed., Results: All 10 patients successfully switched to once-weekly dosing. One patient reported recurrence of panic attacks 18 months after the switch. After a brief treatment for 4 weeks with benzodiazepines and daily fluoxetine, the patient was once again maintained on once-weekly dosing when rechallenged. Patients have been maintained in a panic-free state for up to 26 months with a single weekly dose of fluoxetine ranging from 10 to 60 mg. The medication was well tolerated., Conclusion: Fluoxetine at doses ranging from 10 to 60 mg administered once weekly appears to be effective maintenance treatment for patients with panic disorder who were initially treated successfully with daily fluoxetine. A once-weekly regimen may allow for considerable cost savings and may serve as a convenient alternative method for treating panic disorder.

The coincidence between panic disorder and depression is a well known phenomenon. However, only few studies investigated the coincidence of panic disorder with schizophrenia. This may in part be explained by the fact that both positive and negative symptoms of schizophrenia may mask the clinical symptoms of a panic disorder. We report on a female patient suffering both from agoraphobia with panic disorder and paranoid schizophrenia according to ICD-10. The productive psychotic symptoms responded well to treatment with a low dose of zotepine, whereas the panic disorder was effectively treated with a combined therapy with imipramine and cognitive behavioral therapy. Although it has to be questioned whether the coincidence between panic disorder and schizophrenia reflects two different diagnostic entities, the occurrence of symptoms of a panic disorder in schizophrenia deserve further attention because these may be treated efficiently by a specific pharmacotherapy and psychotherapy.

Background: In the treatment of panic disorder with agoraphobia, the efficacy of pharmacological, psychological and combined treatments has been established. Unanswered questions concern the relative efficacy of such treatments., Aims: To demonstrate that moclobemide and cognitive-behavioural therapy (CBT) are effective singly and more effective in combination., Method: Fifty-five patients were randomly assigned to an eight-week treatment of: moclobemide plus CBT; moclobemide plus clinical management ('psychological placebo'); placebo plus CBT; or placebo plus clinical management., Results: Comparisons between treatments revealed strong effects for CBT. Moclobemide with clinical management was not superior to placebo. The combination of moclobemide with CBT did not yield significantly better short-term results than CBI with placebo. The CBT results remained stable during a six-month follow-up, although a substantial proportion of patients treated with placebo plus CBT needed additional treatment., Conclusions: CBT was highly effective in the treatment of panic disorder with agoraphobia and reduced agoraphobia to levels that were comparable to those of non-clinical controls.

Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.

Background: Benzodiazepines (BZs) can impair explicit memory after a single dose and also when taken repeatedly for treatment of anxiety disorders. A previous study with agoraphobia/panic patients found that the BZ alprazolam impaired memory during an 8-week treatment and residual impairments were still manifest several weeks after drug withdrawal (Curran et al. 1994). The present study followed up the same group of patients 3.5 years after treatment to determine whether those memory impairments persisted., Method: Thirty-one patients, 15 who had originally been treated with alprazolam and 16 with placebo, were assessed on a battery of psychometric tests and self-rating scales., Results: Ex-alprazolam patients performed at the same levels as ex-placebo patients on the memory task and on other objective tests. Performance levels of both groups were similar to pre-treatment baselines, however there were differences in subjective ratings whereby ex-alprazolam patients rated themselves as less attentive and clear headed and more incompetent and clumsy than ex-placebo patients., Conclusions: Explicit memory impairments found while patients were taking alprazolam and weeks after drug withdrawal did not persist 3.5 years later. We suggest that the memory impairments observed in our previous study weeks after withdrawal of alprazolam were not residual effects of alprazolam but rather were due to the drug's interference with practice effects on the tests and habituation of anxiety over repeated exposure to the test situation.

Rational treatment of panic disorders with antidepressants rests on decisions of drug choice, dosage, and duration of treatment. In this paper, we selectively review the author's research with the standard antidepressant, imipramine, in the treatment of panic disorder with agoraphobia as it relates to practical issues. We develop general guidelines for treatment, suggest researchable ways of increasing the net effectiveness of treatment with this class of drugs, and discuss limited generalizations to the extant literature on selective serotonin reuptake inhibitors in panic disorders.

Cognitive behavior therapy (CBT) has been combined with pharmacotherapy in the treatment of panic disorder in three ways: (1) to treat agoraphobic symptoms in the condition of panic with agoraphobia; (2) to reduce withdrawal effects during drug taper; and (3) to treat panic attacks. Exposure treatment and pharmacotherapy have a modest additive effect, although more patients drop out of exposure therapy combined with imipramine treatment compared with exposure therapy alone. CBT reduces symptoms of withdrawal from alprazolam and other benzodiazepines and improves the outcome of drug treatment. At present, sufficient data are not available to determine whether the effects of CBT combined with drug therapy are additive in treating panic disorder. The results of a large trial are awaited. Current CBT consists of 12 sessions and is not widely offered to patients because of cost considerations. Efforts are being made to decrease the number of sessions necessary by improving cognitive techniques. One of these models is the subject of an ongoing trial. Finally, efforts to educate and counsel patients in the clinical setting regarding the psychopathology of panic attacks may improve the outcome of pharmacotherapy.

Background: The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder. We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder., Methods: One hundred seventy-six nondepressed outpatients with panic disorder, with or without agoraphobia, from 10 sites followed identical protocols that used a flexible-dose design. After 2 weeks of single-blind placebo, patients were randomly assigned to 10 weeks of double-blind, flexible-dose treatment with either sertraline hydrochloride (50-200 mg/d) or placebo., Results: Sertraline-treated patients exhibited significantly greater improvement (P=.01) at end point than did patients treated with placebo for the primary outcome variable, panic attack frequency. Significant differences between groups were also evident for clinician and patient assessments of improvement as measured by the Clinical Global Impression Improvement (P=.01) and Severity (P=.009) Scales, Panic Disorder Severity Scale ratings (P=.03), high end-state function assessment (P=.03), Patient Global Evaluation rating (P=.01), and quality of life scores (P=.003). Adverse events, generally characterized as either mild or moderate, were not significantly different in overall incidence between the sertraline and placebo groups., Conclusion: Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder.

In psychiatric studies, treatment efficacy is usually measured by rating scales. These scales have ordinal (rank) level and the statistical evaluation of the scale scores should be performed with nonparametric rather than parametric tests. In recent years, nonparametric statistical procedures for repeated measures have been developed for the evaluation of clinical trials in psychiatry. To assess the frequency of application of nonparametric tests in psychiatric trials, an analysis was performed on all treatment studies with panic disorder patients (DSM-III/III-R) that could be traced in the literature. This survey revealed that nonparametric tests were used in only 16.7% of all studies.

Objective: This study determined the efficacy and safety of sertraline in the treatment of patients with panic disorder., Method: The study was a randomized, double-blind, parallel-group, flexible-dose comparison of sertraline and placebo in outpatients with a DSM-III-R diagnosis of panic disorder with or without agoraphobia. After a 2-week single-blind placebo lead-in, 168 patients entered a 10-week double-blind phase in which they were randomly assigned to treatment with either sertraline or placebo., Results: Sertraline was significantly more effective than placebo in decreasing the number of full and limited-symptom panic attacks. Among patients who completed the study, the mean number of panic attacks per week dropped by 88% in the sertraline-treated patients and 53% in the placebo-treated patients. Sertraline-treated patients also had significantly more improvement than placebo-treated patients in scores on the Quality of Life Enjoyment and Satisfaction Questionnaire, patient global evaluation, and Clinical Global Impression severity of illness and global improvement scales. Overall, patients tolerated sertraline well, and only 9% terminated treatment because of side effects., Conclusions: Sertraline is an effective and well-tolerated treatment for patients with panic disorder.

We conducted a meta-analysis to update the knowledge of long-term efficacy of different treatments in panic disorder with or without agoraphobia. Included were 68 studies pertaining to 106 treatment conditions and 1346 patients. Effect sizes Cohen's d were calculated within the treatment conditions at posttest and at follow-up for panic and agoraphobia. A comparison was made between six treatments: high-potency benzodiazepines, antidepressants, psychological panic management, exposure in vivo, antidepressants combined with exposure, and psychological panic management combined with exposure in vivo. The mean (+/- SD) duration of the follow-up period was 62 +/- 89 weeks. In the majority of the studies (84%), follow-up had a naturalistic character. The lack of information about treatments received between posttest and follow-up limits the interpretation of the results. For all conditions, the treatment gains at posttest were maintained during the follow-up period. The mean (+/- SD) d for panic was 1.11 +/- 0.70 at posttest and 1.28 +/- 0.61 at follow-up; for agoraphobia, the mean d at posttest was 1.36 +/- 1.10 and at follow-up it was 1.41 +/- 0.82. Significant differences were found in efficacy on agoraphobic measures at follow-up between the combination of antidepressants and exposure in vivo versus psychological panic management, exposure in vivo, and the combination of psychological panic management and exposure. Overall, the data suggest that different treatment options for panic disorder with or without agoraphobia are effective at both posttest and follow-up. Research on long-term treatment, discontinuation of therapies, and interventions between posttest and follow-up need more attention, for pharmacotherapy as well as psychotherapy.

Background: Imipramine has proven efficacy for panic disorder. This study assesses the net effectiveness of systematic, open imipramine treatment in a homogenous sample of panic disorder patients with agoraphobia., Methods: One hundred and ten consecutive patients with DSM-III-R moderate to severe panic disorder with agoraphobia were treated with a fixed regimen of imipramine 2.25 mg/kg/day for 24 weeks. No instructions or encouragement for self-directed exposure to phobic situations or other coping strategies with panic or fear were given. Assessments were conducted at the end of the 2-week placebo run-in and at weeks 8, 16, and 24 of treatment., Results: Overall, 53% had a marked and stable response. Most measures revealed that substantial improvement continued beyond week 8 of treatment. Treatment success was accompanied with significant improvements in anxiety sensitivity, dysphoric mood, and functional well-being., Conclusions: These results provide a clinically relevant reference with which to compare the effectiveness of alternative treatments in providing nearly complete symptom remission in patients with primary panic disorder with agoraphobia.

Objective: The purpose of this study was to compare the therapeutic effect of exercise for patients with panic disorder to a drug treatment of proven efficacy and to placebo., Method: Forty-six outpatients suffering from moderate to severe panic disorder with or without agoraphobia (DSM-III-R criteria) were randomly assigned to a 10-week treatment protocol of regular aerobic exercise (running), clomipramine (112.5 mg/day), or placebo pills., Results: The dropout rate was 31% for the exercise group, 27% for the placebo group, and 0% for the clomipramine group. In comparison with placebo, both exercise and clomipramine led to a significant decrease in symptoms according to all main efficacy measures (analysis of variance, last-observation-carried-forward method and completer analysis). A direct comparison of exercise and clomipramine revealed that the drug treatment improved anxiety symptoms significantly earlier and more effectively. Depressive symptoms were also significantly improved by exercise and clomipramine treatment., Conclusions: These results suggest that regular aerobic exercise alone, in comparison with placebo, is associated with significant clinical improvement in patients suffering from panic disorder, but that it is less effective than treatment with clomipramine.

Objective: To determine the efficacy of divalproex sodium in the treatment of psychiatric outpatients with treatment refractory panic disorder and comorbid mood instability., Method: This was an 8-week, open-trial, flexible-dose outcome study conducted at a tertiary care referral centre. Individuals with panic disorder who failed to respond to a cognitive behavioural treatment program and standard antipanic medication, who also suffered from mood instability, were chosen to participate in the study. Divalproex sodium was administered at a flexible dose to reach serum levels of 300 to 600 mumol/L (45 to 90 ug/ml) unless limited by tolerance. Patients were rated by self- and rater-administered questionnaires that measured the number of panic attacks, the degree of agoraphobic avoidance, the levels of depression, anxiety, and mood swings, and the perceived sense of well being., Results: Thirteen subjects were enrolled in the study, and 10 subjects completed it. Two dropped out early because of the medication's side effects, and 1 was lost within the first month of follow-up. All 10 subjects showed significant improvement in depressive and anxiety symptoms and mood instability. There was also a statistically and clinically significant improvement in panic attacks and measures of quality of life., Conclusions: These findings suggest that divalproex sodium is useful in the treatment of patients with panic disorder and concomitant mood instability, who are refractory to conventional treatment. Double-blind trials will be required to verify these findings.

A new scale for assessing severity in PDA (Panic Disorder with/without Agoraphobia) has recently been developed: the Panic and Agoraphobia Scale [P & A (Bandelow, 1995)]. The objective of this study was to test whether the scale is sensitive to changes during a treatment trial. Thirty-seven patients (mean age, 32.7; S.D., 6.3) with PDA were treated with imipramine (75-150 mg/day) for 8 weeks in an open prospective trial. Patients with concurrent agoraphobia were instructed in practising self-exposure to agoraphobic situations. The total scores on the P & A, the Hamilton Anxiety Scale (HAMA) and the Clinical Global Impression Scale (CGI) were used as the main efficacy criteria. Treatment results were excellent, as could be shown by a decrease in the average severity scores of the P & A observer-rated version from 28.9 (S.D., 8.1) to 13.3 (S.D., 11.8; rank statistic T(N) = 6.7; P < 0.0001). The largest effect size r(w) of all clinician-rated scales was seen with the observer-rated version of the P & A, although closely followed by the CGI and the HAMA. Among the self-rated scales, the P & A (self-rated version) also showed the largest effect size. All five subscores of the P & A showed significant improvements. The highest treatment effect sizes could be seen in the 'panic attacks' subscore, followed by the 'anticipatory anxiety' subscore. The new Panic and Agoraphobia Scale (P & A) is a useful tool for measuring treatment efficacy in panic disorder trials.

Objective: This study was designed to determine the minimum paroxetine dose effective for treating panic disorder., Method: Of 425 patients with DSM-III-R panic disorder with or without agoraphobia who underwent a 2-week drug-free screening period, 278 patients were randomly assigned to double-blind treatment with a 10-week course of placebo or paroxetine at a dose of 10, 20, or 40 mg/day., Results: At 40 mg/day, paroxetine was superior to placebo across the majority of outcome measures. Despite a mean of 9.5 to 11.6 full panic attacks during the screening period, 86.0% of the patients taking 40 mg of paroxetine, 65.2% of those taking 20 mg, 67.4% of those taking 10 mg, and 50.0% of the placebo-treated patients were free of full panic attacks during the 2 weeks ending at week 10. The 40-mg paroxetine group experienced significantly greater global improvement than the placebo group and significantly greater improvement in frequency of full and limited-symptom panic attacks, intensity of full panic attacks, phobic fear, anxiety, and depressive symptoms, usually evident by week 4. All doses of paroxetine were well tolerated, and adverse effects were consistent with those associated with selective serotonin reuptake inhibitors., Conclusions: Paroxetine is an effective and well-tolerated short-term treatment of panic disorder. The minimum dose demonstrated to be significantly superior to placebo was 40 mg/day, although some patients did respond at lower doses.

Previously untreated symptomatic volunteers with generalized anxiety disorder (GAD) performed the Temperament and Character Inventory at baseline and after 4 to 6 months of paroxetine treatment. Scores from 29 volunteers were analyzed with paired t-tests. A marked reduction was noted in Harm Avoidance and a marked increase was noted in Self-Directedness. Smaller changes were noted in Cooperativeness and Novelty Seeking. Overall, treatment was associated with a reduction in maladaptive personality traits.

Background: This study reports the outcome of depression and anxiety disorders in older people., Methods: Follow-up of 165 subjects age 65 or over, initially identified in a community study in inner London as depressed or having an anxiety disorder., Results: 117 subjects still living in the area; 25 had died. Death was predicted only by activity limitation at first interview and not by other demographic or morbidity variables. Eighty-six subjects reinterviewed; 21 males, 65 females. Of the depressed, 34% had recovered, 39% were depressed and 27% were dead. Predictors from initial interview of continuing depression were female gender and more severe depression. Of those with phobic anxiety, 16% had recovered, 18% died and 66% were still phobic. Predictors of continuing phobic anxiety from initial interview were female gender and "stand-alone" phobic anxiety, i.e., not being depressed at initial interview. Sixty percent of those with early onset phobias had specific phobias; 82% of those with late-onset phobias had agoraphobia. Twenty-two subjects were prescribed psychotropics. The only significant predictor of psychotropic prescription was having sleep disturbance at initial interview. A low score on life satisfaction was significantly correlated with depression but not with phobic disorder. A high score was correlated with not having a current psychiatric disorder., Limitations: Some subjects were lost to follow-up. Those on psychotropics were particularly likely to refuse an interview., Conclusion and Clinical Relevance: In older people, neither depression nor the anxiety disorders generally remit spontaneously. Those with a particularly poor prognosis are women and those with a more severe depression. Agoraphobia may be precipitated in older people by stressful events and interferes with life satisfaction. There is potential for increased pharmacological treatment of older people with affective disorders.

In this multicenter, parallel-group, placebo-controlled, fixed-dose study, the efficacy, safety, dosing characteristics, and discontinuation of clonazepam were analyzed in patients with panic disorder. Four hundred thirteen patients were randomly assigned to receive placebo or one of five fixed daily doses of clonazepam (0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, and 4.0 mg). After 3 weeks of dose escalation, the fixed dose was given for 6 weeks (the dose-maintenance phase) and then was tapered during a 7-week discontinuance phase. The completion rates for the dose-maintenance phase ranged from 59 to 85% for the clonazepam groups (74% for the placebo group). Efficacy measurements at the end of the dose-maintenance phase indicated clinical improvement in all treatment groups but with a clear differentiation of the four higher doses of clonazepam from the 0.5-mg dose and placebo. The minimum effective dosage, as determined by the Williams' test, was 1.0 mg daily. Dose-response analysis showed that daily dosages of 1.0 mg and higher were equally efficacious in reducing the number of panic attacks. All treatments were well tolerated. Somnolence and ataxia were reported more often by patients in the 3.0- and 4.0-mg groups; depression, dizziness, fatigue, and irritability, although not showing dose-relatedness, were reported by more patients taking clonazepam than placebo. During the discontinuance phase, most patients worsened from their condition at the end of the dose-maintenance phase but did not revert to that at baseline. In addition, with the tapering schedule chosen for this study, patients in all treatment groups tolerated the discontinuance of clonazepam. Daily doses of 1.0 to 2.0 mg of clonazepam offered the best balance of therapeutic benefit and tolerability.

Background: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance., Method: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day., Results: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment., Conclusion: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.