Effects of clonidine on alprazolam discontinuation in panic patients: a pilot study

Effects of adjunctive clonidine (0.15 to 0.7 mg/day) on symptoms experienced during and for 4 weeks after gradual alprazolam discontinuation were observed in panic disorder patients after 6 weeks of successful treatment. Twelve of 14 entered patients were considered to have had a sufficient period of discontinuation (2 weeks) and clonidine administration (1 week) for effects to be assessed adequately. Nine of these 12 patients reached zero dose of alprazolam in 3 to 4 weeks. However, 10 of 12 patients experienced new withdrawal symptoms and 11 of 12 experienced recurrent panic attacks during tapering. Although a greater proportion of patients were successfully discontinued in a shorter time than in a previous nonclonidine trial, clonidine did not appear to have a specific effect on relapse or withdrawal. A placebo-controlled trial is needed to discriminate between possible contributions of clonidine and other factors (e.g., physician attitude, placebo effect of pill taking) to this improved outcome.     

Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers

The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 µg) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.     

Effects of alprazolam on driving ability, memory functioning and psychomotor performance: a randomized, placebo-controlled study.

Alprazolam is prescribed for the treatment of anxiety and panic disorder. Most users are presumably involved in daily activities such as driving. However, the effects of alprazolam on driving ability have never been investigated. This study was conducted to determine the effects of alprazolam (1 mg) on driving ability, memory and psychomotor performance. Twenty healthy volunteers participated in a randomized, double-blind, placebo-controlled crossover study. One hour after oral administration, subjects performed a standardized driving test on a primary highway during normal traffic. They were instructed to drive with a constant speed (90 km/h) while maintaining a steady lateral position within the right traffic lane. Primary performance measures were the Standard Deviation of Lateral Position (SDLP) and the Standard Deviation of Speed (SDS). After the driving test, subjective driving quality, mental effort, and mental activation during driving were assessed. A laboratory test battery was performed 2.5 h after treatment administration, comprising the Sternberg Memory Scanning Test, a Continuous Tracking Test, and a Divided Attention Test. Relative to placebo, alprazolam caused serious driving impairment, as expressed by a significantly increased SDLP (F(1,19) = 97.3, p <.0001) and SDS (F(1,19) = 30.4, p <.0001). This was confirmed by subjective assessments showing significantly impaired driving quality (F(1,19) = 16.4, p <.001), decreased alertness (F(1,19) = 43.4, p <.0001), decreased mental activation (F(1,19) = 5.7, p <.03) and increased mental effort during driving (F(1,19) = 26.4, p <.0001). Furthermore, alprazolam significantly impaired performance on the laboratory tests. In conclusion, alprazolam users must be warned not to drive an automobile or operate potentially dangerous machinery.     

A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder.

A recently reported multinational, 8-week double-blind, placebo-controlled study assessing the efficacy of alprazolam versus placebo in the treatment of panic disorder indicated significant differences favoring alprazolam. We now report the results of a three-site, 6-week, double-blind, fixed-dose study comparing alprazolam 2 mg, alprazolam 6 mg, and placebo in 94 patients with panic disorder with or without agoraphobia. Both alprazolam treatment groups (6 mg and 2 mg) improved significantly more than did the placebo treatment group on most outcome measures. Only a few statistically significant differences between the 6 mg and 2 mg alprazolam groups were discerned, although the pattern of treatment response across measures suggested a dose effect. Dropouts in the placebo group were primarily due to lack of efficacy and in the alprazolam 6 mg group were due to side effects, which may have contributed to the limited differences between groups at study end. The findings suggest that many patients may require less than 6 mg of alprazolam per day for effective treatment of panic disorder.     

Anxiogenic effects of Sumatriptan in panic disorder: a double-blind, placebo-controlled study.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with panic disorder (PD). Our goal was to further examine central serotonergic function in panic patients using autonomic and subjective responses to the postsynaptic serotonin 5-HT1D receptor agonist Sumatriptan. METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed autonomic and subjective responses to oral Sumatriptan (100 mg) and placebo in 15 patients with PD, free of medication. Subjective responses were measured using the Hamilton Anxiety Rating Scale (HAM-A), National Institute of Mental Health Anxiety Scale (NIMHA), a modified version of the Panic Symptom Inventory (PI), Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: PD patients exhibited significantly enhanced autonomic and subjective responses following challenge with Sumatriptan. We observed an increased pulse rate and augmentation of various parameters measured on different anxiety scales. A constant inclination of aggravation of the measured parameters was detected during the hour post challenge. CONCLUSION: Oral administration of Sumatriptan, a 5-HT1D agonist, has been associated with an anxiogenic effect in PD patients.     

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.     

Nonorganic insomnia in panic Disorder: comparative sleep laboratory studies with normal controls and placebo-controlled trials with alprazolam

Objective and subjective sleep and awakening quality was investigated in 11 drug-free patients (4 females, 7 males) aged 30-55 (mean: 44+/-9) years with nonorganic insomnia (F 51.0) related to panic disorder (F 41.0) as compared with 11 age- and sex-matched normal controls aged 30-58 (mean: 44+/-9) years, utilising polysomnography (PSG) and psychometry. PSG demonstrated decreased sleep efficiency (primary target variable), total sleep time (TST) and S2 as well as increased middle and late insomnia, S1, S3+S4, snoring and PLM in patients. There were no intergroup differences in REM variables. Subjective sleep quality deteriorated, as did drive and fine motor activity in the morning, while concentration increased. Blood pressure in the evening and morning and pulse rate in the evening were elevated. These differences as compared with normals were distinct from those observed in other sleep disorders. In a subsequent acute, placebo-controlled cross-over design study, patients received alprazolam 0.5 mg (Xanor((R));) and placebo. As compared with placebo, alprazolam induced an increase in sleep efficiency (primary target variable), TST and S2, a decrease in wakefulness during the total sleep period, S3+S4 and the oxygen desaturation and PLM indices, and improved subjective sleep quality, somatic complaints, drive, affectivity and drowsiness in the morning. There were no changes in REM variables. Thus, alprazolam induced changes that were opposite to the differences observed between patients and controls before treatment, thereby normalizing sleep and awakening quality. As observed in insomnia related to GAD and subsequent benzodiazepine therapy, the present study also points to a key-lock principle in the treatment of insomnia caused by anxiety disorders and neurophysiologically visualizes processes at the receptor level (e.g. benzodiazepine agonists versus inverse agonists). Copyright 2000 John Wiley & Sons, Ltd.     

Double-blind comparison of alprazolam and adinazolam for panic and phobic disorders

Subjects primarily suffering from DSM-III panic disorders (agoraphobia with panic attacks, 13 subjects; panic disorder, one subject) were tested with two drug treatments after a baseline was established using single-blind placebo capsules three times daily for 1 week. Double-blind, 4-week crossover treatments were given with alprazolam, 0.5-6.0 mg/day, and adinazolam mesylate, 10-120 mg/day. Mean final doses in mg/day were 3.1 for alprazolam and 95.5 for adinazolam mesylate. Both were broadly effective in comparison with the baseline condition. Measures included self-rated symptoms and global impressions, physician-rated global impressions, and two forms of challenges, agoraphobic and noradrenergic. The two active drugs were highly similar in overall efficacy across the sample, but alprazolam was favored globally in six subjects, and adinazolam was favored globally in another six subjects. Only two subjects obtained maximal improvement ratings without side effects with both drugs. No diagnostic or demographic factor correlated with the differential in responses to the two active treatments. No clinically significant laboratory abnormalities occurred with either drug.     

Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind placebo-controlled study

In a double-blind controlled study lasting 8 weeks, 50 anxious psychoneurotic outpatients with a primary diagnosis of generalized anxiety or panic disorder were randomly assigned to alprazolam (n=30), a new benzodiazepine, or placebo (n=20), after a washout period of 1 week. Alprazolam at dosages between 0.25 and 3 mg/day was found to be significantly better than placebo in the treatment of either disorder. The finding that alprazolam was effective in the treatment of panic disorder is of interest as this diagnostic category is usually treated with tricyclic antidepressants or MAO inhibitors.     

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.     

Effects of alprazolam on respiratory drive, anxiety, and dyspnea in chronic airflow obstruction: a case study

Alprazolam, an anxiolytic benzodiazepine, has a pharmacologic profile similar to that of diazepam. An intermediate half-life of 10-12 hours and a comparatively brief duration of activity relative to other anxiolytic benzodiazepines justified evaluation of a 0.5-mg test dose in an anxious patient with chronic obstructive lung disease. Subjective indexes, breath-by-breath respiratory drive response to hypercapnia, and blood alprazolam concentrations were determined before and after dosing. Subjective testing included a visual analog dyspnea scale, the state anxiety inventory, and subjective feelings visual analog scales (represented by alertness, calmness, and level of contentment). After dosing, the patient was better able to tolerate the rebreathing study technique. Statistically significant improvements in dyspnea (t - 10.20; p 0.0005), anxiety (t - 45.85; p less than 0.0001), alertness (t - 13.04; p less than 0.0001), cententedness (t - 12.27; p less than 0.0001), and calmness (t - 8.05; p less than 0.0001) occurred after alprazolam administration. Drive to breathe, as determined by mouth occlusion pressure and minute ventilation, was not statistically different before and after dosing. No adverse effects were reported or observed. Further study is warranted.     

A placebo-controlled, randomized withdrawal study of sertraline for panic disorder in Japan

The objective of this double-blind, placebo-controlled randomized withdrawal study was to evaluate the efficacy and safety of sertraline for 8 weeks in treating Japanese patients with DSM-IV panic disorder. Patients (n=394) were initially treated with 8 weeks of open-label sertraline followed by 8 weeks of double-blind treatment with either sertraline (50-100 mg/day) or placebo. Responders during the open-label phase were eligible to be entered into the double-blind phase. Two hundred and forty patients were entered to the double-blind phase and randomly assigned to receive sertraline (n=119) or placebo (n=121). On the primary efficacy measure (relapse), there was no significant difference between the two treatment groups (sertraline 10.1%; placebo 13.2%). However, the frequency of panic attacks was significantly (P=0.012) lower for sertraline compared to placebo. The proportion of sertraline-treated patients who met response criteria (Clinical Global Impression-Improvement Scale score of 1 or 2) at the end of double-blind phase treatment was also significantly (P=0.003) higher for sertraline (89.9%) compared to placebo (74.4%). Panic Disorder Severity Scale total score was significantly (P=0.012) lower in the sertraline group compared to the placebo group. Adverse events during acute treatment were consistent with the known adverse event profile of sertraline, and the incidence of adverse events during the double-blind phase treatment was not different between sertraline and placebo.     

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.     

Effects of alprazolam on the activity of rat cerebellar purkinje neurons: Evidence for mediation by norepinephrine

Acute administration of alprazolam causes a dose-dependent slowing of the spontaneous discharge of cerebellar Purkinje neurons. This effect is reversed by treatment with propranolol. There is also significantly less slowing in animals in which cerebellar neuronal circuitry has been destroyed by pretreatment with 6-hydroxydopamine. These data suggest that some of the depressant effects of alprazolam may be mediated by an interaction with norepinephrine.     

Treatment of social phobia with gabapentin: a placebo-controlled study.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.     

Antidepressant activity of alprazolam in a reserpine-induced model of depression

The effect of chronic (14–21 day) administration of reserpine (0.1 mg/kg/day), imipramine (10 mg/kg/day), alprazolam (5, 10 and 15 mg/kg/day), and diazepam (10 and 30 mg/kg/day) on beta-adrenergic receptors in the cerebral cortex and body weight has been reported in this study. Chronic treatment with both imipramine and alprazolam significantly blocked reserpine-induced increases in beta-adrenergic receptors and loss in body weight. However, diazepam under similar conditions had no significant effect.