Short‐term and long‐term evaluation of selective serotonin reuptake inhibitors in the treatment of panic disorder: fluoxetine vs citalopram

This double‐blind study evaluates the efficacy and tolerability of fluoxetine and citalopram in the acute and long‐term treatment of panic disorder in 42 patients meeting DSM‐IV criteria for panic disorder with or without agoraphobia. Fluoxetine and citalopram showed similar efficacy in the treatment of panic disorder patients. On the basis of HRSA and PASS mean score evaluation, fluoxetine was more rapid than citalopram in reducing generalized anxiety symptoms, spontaneous panic attacks and anticipatory anxiety. Fluoxetine appeared to be effective at a dosage of 10 mg/day, while citalopram reached the same efficacy at a dosage of 30 mg/day. Long‐term evaluation has demonstrated high rates of persistent full remission with both drugs. Copyright © 1999 John Wiley & Sons, Ltd.     

Clomipramine. An overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder

During the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focused on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder. Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity. In patients with panic disorder with or without agoraphobia (DSM-IIIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks' treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety. Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug's anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine less than or equal to 250 mg/day and 2.1% of patients receiving greater than or equal to 300 mg/day. In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically.     

Spotlight on paroxetine in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or = 60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.     

Paroxetine: an update of its use in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or =60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.     

Fluoxetine treatment of depressed patients with comorbid anxiety disorders

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared to major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in severity of both depressive and anxiety symptoms in outpatients with major depression with comorbid anxiety disorder following fluoxetine treatment. We enrolled 123 outpatients (mean age 38.9 +/- 10.8 years; 49% women) with major depressive disorder accompanied by one or more current comorbid anxiety disorders in our study. Patients were treated openly with fluoxetine 20 mg/day for 8 weeks. Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D) and the patient-rated Symptom Questionnaire (SQ) Scales for Depression and Anxiety. The mood and anxiety disorder modules of the Structured Clinical Interview for DSM-III-R were administered at screen and endpoint. We used 'intent-to-treat' analysis in examining all patients assigned to treatment and completing the baseline visit. The mean number of comorbid anxiety disorders per patient was 1.5 +/- 0.68. The mean HAM-D-17 score and mean Clinical Global Impressions-Severity scores decreased significantly from baseline to endpoint (week 8) following fluoxetine treatment (p < 0.0001). There were significant decreases in all four SQ scale scores, from baseline to endpoint: depression, anxiety, somatic symptoms and anger-hostility (p < 0.0001). Fifty-three percent of patients (n = 65) were depression responders (i.e. > or = 50% decrease in HAM-D-17 score at endpoint) and 46% (n = 57) were remitters (HAM-D-17 < or = 7 at endpoint). Patients with panic disorder had significantly higher baseline HAM-D-17 scores compared to those without panic disorder (p < 0.01). Patients with comorbid obsessive-compulsive disorder (OCD) were significantly less likely to be responders to fluoxetine at endpoint (> or = 50% decrease in HAM-D-17) and to be remitters (HAM-D-17 score of s 7 at endpoint) compared to patients without comorbid OCD (p < 0.01). Of the 41 patients on whom endpoint Structured Clinical Interview for DSM-III-R modules for anxiety disorders were available, 49% (n = 20) no longer met criteria for one or more of their anxiety disorder diagnoses at endpoint. Our preliminary findings suggest that fluoxetine is effective in treating outpatients with major depression with comorbid anxiety disorders, with a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are required in larger samples to confirm our findings.     

High-dose fluoxetine: efficacy and activating-sedating effects in agitated and retarded depression

The effects of high-dose fluoxetine (median 80 mg/day), standard-dose imipramine (median 200 mg/day), and placebo were studied in 706 outpatients meeting DSM-III criteria for major depressive disorder. Baseline psychomotor activity of each patient was prospectively categorized as agitated, retarded, or neither. Rates of occurrence of total and significant (leading to discontinuation) activating adverse events (insomnia, agitation, anxiety, nervousness) and sedating events (somnolence, asthenia) were compared between treatments on an overall basis and within categories of baseline psychomotor activity. Additionally, these rates were compared across baseline psychomotor activity for each treatment. Efficacy was evaluated on an overall basis and with respect to baseline psychomotor activity. There was more total activation with fluoxetine than placebo (p = 0.008), but total activation with fluoxetine (28%) showed only a trend (p = 0.092) for being greater than with imipramine (21%). Discontinuations for activation with fluoxetine (5%) did not differ from imipramine (5%). Sedation and discontinuations for sedation with both fluoxetine and imipramine significantly exceeded placebo. The only drug-drug difference in discontinuations was for sedation where imipramine (11%) exceeded fluoxetine (5%; p = 0.008). Only for the occurrence of sedation with imipramine (47% among patients retarded at baseline) was there a significant association with baseline psychomotor activity (p = 0.021). Both fluoxetine and imipramine were superior to placebo and equal in efficacy in decreasing total Hamilton Rating Scale for Depression (HAM-D), the sleep disturbance HAM-D factor, and the anxiety/somatization HAM-D factor scores. These improvements were independent of baseline psychomotor activity.     

Do antidepressants selectively suppress spontaneous (unexpected) panic attacks? A replication

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.     

Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial.

A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.     

Clomipramine, a better reference drug for panic/agoraphobia. I. Effectiveness comparison with imipramine

An 8-week, double-blind, flexible-dose trial comparing low doses of clomipramine (mean=50 mg) with moderate doses of imipramine (mean=113.8 mg and propanteline (active placebo), was carried out in 60 out-patients with panic disorder with or without agoraphobia. Efficacy evaluation included global, anxiety and depression rating scales, and the determination of rates of relapse over up to 10 weeks of single-blind placebo follow-up. Both tricyclics were significantly more effective than propanteline, but clomipramine tended to act faster and more consistently than imipramine on most measures. Given the degree of blindness achieved and the significantly lower doses of clomipramine, this seems a better reference drug than imipramine for clinical trials in panic/agoraphobia.     

Drug Treatment of Panic Disorder

Abstract: Drug treatment of panic disorder is reviewed with focus on recent controlled studies. The efficacy of alprazolam, a triazolobenzodiazepine, and imipramine, a tricyclic antidepressant, has consistently been demonstrated, but there is reasonable evidence that other benzodiazepines or antidepressants might also be effective if equipotent doses are used. Most controlled studies demonstrate drug efficacy on several psychopathological symptoms, including the core symptom panic attacks. Limited evidence indicates that alprazolam may be more efficacious in treating panic attacks than avoidance behaviour, and the reverse when imipramine is concerned. Drug efficacy appears to be most consistently documented in moderately to severely ill panic patients. The benzodiazepines are better tolerated than antidepressants in terms of patient acceptance, and the improvement sets in faster with benzodiazepines. In the presence of depressive symptoms considered secondary to panic attacks and/or agoraphobia, both types of drugs appear efficacious. Difficulty discontinuing high-dose benzodiazepine treatment remains the most important side effect of the treatment but sedation can, like anticholinergic side effects of the tricyclic antidepressants, be troublesome, thereby diminishing patient compliance. The role of newly developed antidepressants with a more specific mode of action and milder side effects awaits evaluation in controlled trials.     

Cardiovascular and symptomatic reduction effects of alprazolam and imipramine in patients with panic disorder: results of a double-blind, placebo-controlled trial

Seventy-nine patients with panic disorder were randomized to an 8-week double-blind treatment with alprazolam, imipramine, or placebo. Patients kept daily records of panic attacks, activity, anxiety, sleep, and medication use. Weekly measures of anxiety, depression, somatic symptoms, fears, avoidance, disability, and improvement were obtained. All patients underwent a symptom-limited exercise treadmill and other cardiovascular measures. By physician and patient global assessment, patients receiving alprazolam or imipramine were significantly better than patients on placebo. The alprazolam effects were apparent by week 1; the imipramine effects by week 4. All groups showed significant reductions in anxiety, depression, somatic measures, and panic attack frequency. At 8 weeks, patients in the alprazolam group reported significantly less fear than patients in the other two groups. Subjects in the imipramine group showed a significant increase in heart rate and blood pressure.     

Interactive model of therapeutic response in panic disorder: moclobemide,a case in point

It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments (interaction between treatment and baseline score). Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks, but not for the frequency of situational panic attacks or measures of agoraphobia. This report presents similar analyses of data from a study using moclobemide. Patients (N = 452) with panic disorder were randomized to placebo or a fixed dose of moclobemide (75, 150, 300, 600, or 900 mg/day). They were treated double-blindly and evaluated at baseline and 1, 2, 3, 4, 6, and 8 weeks later. The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary, and fear and avoidance ratings based on the patient's main phobia using baseline (pre) and end-point (post) values for all randomized patients. Adjoining dose groups were combined. Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes. Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms. This study replicates the authors' earlier findings, except for situational panic attacks, which probably were not reliably identified. Antidepressants selectively suppress panic attacks, especially unexpected attacks, but not agoraphobia. The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinically separable biologic and cognitive components that respond differentially to treatment. Antidepressants benefit primarily patients with many unexpected panic attacks. Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means (analysis of covariance).     

Modeling anxiety-like states: pharmacological characterization of the chick separation stress paradigm

While previous research has sought to validate the chick separation stress paradigm as an anxiolytic screening assay, it is unknown whether the paradigm better models a nonspecific anxiety-like state or something similar to panic disorder or generalized anxiety disorder. To characterize the anxiety model pharmacologically, cockerels were administered drug probes that were either: (1) only effective for treating panic disorder (phenelzine 3.125-25.0 mg/kg), (2) effective for treating both panic disorder and generalized anxiety disorder (alprazolam 0.065-0.5 mg/kg; clonidine 0.1-0.25 mg/kg; imipramine 1.0-15.0 mg/kg), (3) only effective for treating generalized anxiety disorder (buspirone 2.5-10.0 mg/kg; trazodone 0.1-3.0 mg/kg) or (4) capable of exacerbating symptoms of panic disorder in humans (yohimbine 0.1-3.0 mg/kg). At 7 days after hatch, chicks received either vehicle or drug probe intramuscularly 15 min prior to social separation under a mirror (low-stress) or no-mirror (high-stress) condition for a 180-s observation period. Dependent measures were distress vocalizations to index separation stress and sleep-onset latency to index sedation. Phenelzine, alprazolam, imipramine and clonidine were able to attenuate distress vocalizations (at doses without significant sedation) whereas buspirone and trazodone did not. Paradoxically, yohimbine modestly attenuated distress vocalizations. These results suggest that the chick separation stress paradigm better models panic disorder than generalized anxiety disorder as an anxiolytic screen.     

Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluoxetine is a new antidepressant which enhances serotoninergic neurotransmission through potent and selective inhibition of neuronal reuptake of serotonin. Metabolism by N-desmethylation occurs in man yielding desmethylfluoxetine, which also inhibits serotonin reuptake. Both the parent compound and metabolite possess elimination half-lives of several days facilitating the maintenance of steady-state plasma concentrations during long term treatment. Fluoxetine has overall therapeutic efficacy comparable with imipramine, amitriptyline and doxepin in patients with unipolar depression treated for 5 to 6 weeks, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients. Geriatric patients also responded as well to fluoxetine as to doxepin. The symptomatic improvement in patients with unipolar depression during short term fluoxetine treatment has been satisfactorily maintained when therapy was extended for at least 6 months: the relapse rate was low and similar to that of imipramine. Preliminary data have shown that patients with bipolar depression gained similar therapeutic benefit from fluoxetine or imipramine. Other preliminary trials have indicated that fluoxetine may be useful in obsessive-compulsive disorders. Usual doses of fluoxetine cause significantly fewer anticholinergic-type side effects than tricyclic antidepressants. Nausea, nervousness and insomnia are the most frequently reported fluoxetine-related adverse effects, but these have usually not been severe. Therapeutic doses of fluoxetine do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease and fluoxetine has been relatively safe in the small number of patients who have taken overdoses. It has not been clearly established whether some types of depression may respond more readily to fluoxetine than other antidepressants, and its overall therapeutic efficacy has not been compared with other second generation antidepressants. Thus, with its different and perhaps improved side effect profile compared with older tricyclic antidepressants, fluoxetine offers properties that could be used to advantage in many patients with depression.     

Differential modulation of antipredator defensive behavior in Swiss-Webster mice following acute or chronic administration of imipramine and fluoxetine

The Mouse Defense Test Battery (MDTB) has been designed to assess defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat. Primary measures taken before, during and after predator confrontation comprise escape attempts, predator assessment, defensive attack and flight. Previous reports from this laboratory have shown that the panic-promoting drug yohimbine potentiated flight behavior, while long-term treatment with the panicolytic agent alprazolam reduced this response. In order to evaluate further the possibility that the MDTB may represent an effective animal model of panic attacks, the present study investigated the behavioral effect of imipramine and fluoxetine, two serotonin reuptake inhibitors (SRIs) known to alleviate panic symptoms when given on a repeated basis. Both drugs were administered acutely and chronically (one daily IP injection for 21 days) at 5, 10 and 15 mg/kg. Our results showed that a single dose of imipramine or fluoxetine strongly potentiated flight reactions in response to an approaching predator and increased defensive attack toward the rat. This was in contrast to chronic treatment with each drug which dramatically decreased flight responses and defensive attack behaviors. In addition, long-term administration with both SRIs produced a reliable attenuation of predator assessment activities. Taken together, these findings suggest an acute anxiogenic-like effect of imipramine and fluoxetine followed by a fear/anxiety reducing effect after repeated administrations. These results support clinical observations revealing an acute anxiogenic effect of SRIs followed by an anxiolytic and/or panicolytic effect after chronic use, and support previous results suggesting that the MDTB may be useful for the investigation of panic-modulating agents.     

Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects

The present reference drugs for the treatment of panic disorder and agoraphobia are imipramine and alprazolam. The latter decreases performance and cognitive functioning. No study of such functions in panic/agoraphobia is available. Fifty four out-patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia (PAG), taking part in a parallel groups controlled trial of imipramine (mean dose ±SEM 114±9 mg), clomipramine (50±4 mg) and propanteline (active placebo) over 8 weeks, were studied. A test battery of psychomotor and memory tests was administered at baseline, and after 1, 4 and 8 weeks of treatment. Their results were compared (at baseline and at the end of the trial) with those of a control group of 57 normal untreated subjects. There was no difference between treatments, and no drug effect on any test at any time. No consistent difference between patients and controls was detected. Given its apparently higher potency, and the absence of deleterious effects on cognitive measures known to be affected by benzodiazepines, we conclude that clomipramine is better than imipramine or alprazolam as a reference drug for panic/agoraphobia.     

The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder

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

Clinical evaluation of alprazolam in patients with panic disorder: A double-blind comparison with imipramine

The antipanic effect and tolerability of alprazolam and imipramine were compared during 9 weeks in 55 inpatients with panic disorder with or without agoraphobia. Both drugs decreased significantly the frequency of panic attacks, alprazolam as early as 3 weeks of treatment. The symptoms of generalized anxiety and depression decreased similarly in both groups. The tolerability of alprazolam appeared slightly better than that of imipramine. Drug-induced anticholinergic side-effects were more frequent in the imipramine group, whereas sedation, impotency, and myoclonic jerks appeared more often in the alprazolam group.     

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders

Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.     

Imipramine in panic disorder. 1. Clinical response and pharmacological changes

Clinical and biochemical variables were monitored in 18 patients with panic disorder before and during treatment with imipramine over 16 weeks. Imipramine dosage was slowly increased from a starting dose of 10 mg daily, to prevent early treatment drop-outs. All patients were effectively treated for at least 6 weeks, and only two patients dropped out before the end of the study. There were substantial reductions in panic attack frequency, ratings of depression and avoidance behaviour, but only small reductions in ratings of state and general anxiety. Plasma levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl- ethylene glycol initially fell after starting imipramine, but returned to pre-treatment levels by week 8 of treatment. Plasma imipramine and/or desipramine concentrations were very variable and did not correlate with either psychological or biochemical changes during treatment.