Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Therapeutic effects and effects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients.

Two groups of 12 outpatients each (six men and six women) with generalized anxiety disorder, participated in this study. Each patient was treated single-blind with placebo during the first 7 days (baseline), followed by a double-blind drug treatment period of 4 consecutive weeks (active) and ending again with 7 days single-blind placebo treatment (washout). One group received buspirone 5 mg three times a day in the first week and continued with 10 mg in the morning, 5 mg in the afternoon, and 5 mg in the evening during the second, third, and fourth weeks. The other group received diazepam 5 mg three times a day in all 4 weeks. On the evening of the seventh day of each treatment week the Hamilton Rating Scale for Anxiety and the Symptom Check List (90 items) were applied to assess the therapeutic effects, followed by an on-the-road driving test that started 1.5 hours after the last drug or placebo intake. The test consisted of operating an instrumented vehicle over a 100 kilometer highway circuit while attempting to maintain a constant speed and a steady lateral position within the right traffic lane. Two patients in the diazepam group were unable to complete their test after the first and second treatment week, respectively, because of serious sedative reactions. Both buspirone and diazepam were equally effective in reducing overall anxiety symptoms. The specific profiles showed that buspirone also reduced concomitant depressive symptoms and symptoms of interpersonal sensitivity and anger-hostility. In contrast, diazepam was found to be slightly more effective in reducing somatic symptoms and to positively affect sleep disturbances. Moreover, abrupt discontinuation of diazepam resulted in a relapse of psychic anxiety symptoms comparable with the placebo-baseline level and a partial relapse of somatic anxiety symptoms. Chronic treatment with buspirone had no significant effects on lateral position and speed control. In contrast, diazepam significantly impaired control of lateral position in the first 3 weeks of treatment. There was no significant impairment in the fourth treatment week and the placebo-washout week. Speed control was significantly impaired only in the first week. The relevance of the trend toward decreasing performance impairment during chronic treatment remains to be established.     

Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome

Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19 ± 17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1–2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (χ² = 7.34; df 2; P < 0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches. Received: 27 March 1997/Final version: 9 June 1998     

Statistical interpretation of the antisecretory effect of famotidine measured by intragastric pH-metry

Objective: Intragastric pH-metry is widely used to evaluate the efficacy of antisecretory drugs, but statistical interpretation of the measurements has not yet been standardised. Methods: The effects of single morning (N = 9) or evening (N = 7) doses of the H₂-receptor antagonist famotidine, 20 mg (QUAMATEL^R, Gedeon Richter, Hungary) were compared by 24-hour intragastric pH-metry in hyperacid patients, in a prospective, controlled clinicopharmacological study. Intragastric pH was repeatedly measured with or without administration of famotidine, and {1} the minute to minute median pH values were calculated. Results: {2} Both treatments significantly reduced gastric acidity according to the “traditional” parameters of the time at pH ≥ 3, or median pH in the first 12 hours. Famotidine treatment in the evening was more effective than in the morning (634 vs 463 min or 5.22 vs 3.10). The morning and evening treatment groups did not differ from each other in these parameters when compared on the days without famotidine. {3} After demonstration of the significant differences between the treatment vs control days, and morning vs evening administrations we applied the Pattern Recognition by Independent Multicategory Analysis (PRIMA) method to select the most sensitive parameters for evaluation of the H₂-receptor antagonist drug effect. The PRIMA method was developed to determine the sensitivity of each statistical parameter analysed in a comparison of different groups (discriminating power), and to determine the separability of groups using several parameters concomitantly (separation of groups). The mean pH, the period at pH ≥ 3, and the duration of pH-increase ≥ 1 on the day of treatment compared to the control day were found to be the most sensitive parameters both in demonstrating H₂-receptor antagonist effect and in differentiation of morning and evening doses. {4} High separability of morning and evening treatment groups was achieved using these three parameters concomitantly according to the PRIMA method. Conclusion: This method may be of value in other clinical or clinicopharmacological trials to standardise the statistical analysis of data by selection of the most sensitive parameters for comparison of the patient groups. In subsequent studies it might also increase the sensitivity of discrimination by concomitant analysis of different parameters using the smallest appropriate number of patients. Received: 22 July 1995/Accepted in revised form: 23 February 1996     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

Abstinence symptoms following oral THC administration to humans

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ⁹-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use. Received: 13 April 1998/Final version: 1 July 1998     

Plasma serotonin level after 1 day of fluoxetine treatment: a biological predictor for antidepressant response?

Rationale: Antidepressant treatments present a delayed onset of action. Objective: The present study investigated whether plasma or serum serotonin, 5-hydroxytryptamine (5-HT), could predict clinical improvement. Methods: Biological parameters were determined after a 4-week drug-free period (day 0) and 1, 14 and 28 days after the beginning of the treatment with fluoxetine 20 mg daily in depressed patients. Clinical evaluations were assessed on days 0, 14 and 28. Results: One day after a single dose, the mean values of plasma 5-HT (5.4 ± 2.6 nmol/l) and serum 5-HT (484 ± 215 nmol/l) were not statistically different from basal mean values (4.5 ± 2.5 nmol/l and 523 ± 263 nmol/l, respectively). The repeated treatment significantly reduced serum 5-HT to 34% (P = 0.002) and 17% (P = 0.0004) of pretreatment values after 14 and 28 days of treatment, respectively; plasma 5-HT was also reduced significantly to 28% and 15% of pretreatment values (P < 0.05 in both cases). At day 28, four of the eight patients responded by showing a reduction in MADRS score of at least 50% of the baseline score. No correlation was found between pretreatment values of serum or plasma 5-HT and clinical evolution, even if a tendency (P < 0.07) to lower serum 5-HT pretreatment values was observed in responders. Plasma 5-HT after 1 day of treatment was significantly different between responders and non-responders: the plasma 5-HT concentration in responders was 3.4 ± 1.7 nmol/l versus 7.4 ± 1.6 nmol/l in non-responders (P = 0.02). Moreover, plasma 5-HT levels after 1 day of treatment were positively correlated to the final MADRS score (r = +0.89, n = 8, P = 0.003) and inversely correlated to its change from the initial score (r = −0.76, n = 8, P = 0.02). Conclusion: These preliminary data show that fluoxetine and norfluoxetine might influence 5-HT peripheral venous blood parameters and that plasma 5-HT after 1 day of treatment might be a biological predictor for antidepressant response. Received: 10 July 1998/Final version: 12 October 1998     

Ritanserin in the treatment of alcohol dependence – a multi-center clinical trial

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT₂ receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects’ QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence. Received: 30 April 1996/Final version: 3 July 1996     

Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial

A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S, BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (≥30% reduction) and the CGI improvement (score ≤2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden. Received: 5 November 1997/Final version: 16 March 1998     

Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder

The effects of flesinoxan, a potent and selective 5-HT_1A agonist, were studied in two pilot studies in panic disorder patients to explore the role of 5-HT_1A receptors in the mechanism of action of antipanic agents. This paper reports on the results of these two studies with flesinoxan. In study I, using a single-blind crossover design, five patients were treated for 1 week with placebo, 4 weeks with flesinoxan (up to 2.4 mg per day), and 2 weeks with placebo. In study II, 15 patients were enrolled in a double-blind, three-armed study with placebo and two dosages of flesinoxan. After a single-blind placebo run-in phase of 1 week, patients were treated for 8 weeks with placebo, 0.6 or 1.2 mg/day flesinoxan. In pilot study I patients’ condition worsened during the 4-week flesinoxan treatment period. Anxiety was frequently reported as an adverse event. Symptoms returned to the pre-treatment level during the 2-week placebo washout period. In pilot study II, no treatment effects in either group were observed. Anxiety as an adverse event was less prominent than in the first pilot study. A lowering of mood was seen in some patients. The sample sizes of these two pilot studies are too small to draw firm conclusions on the efficacy of flesinoxan in panic disorder, but the present data are not encouraging in this respect. The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients.     

Influence of nicotine on simulator flight performance in non-smokers

In a placebo-controlled study, we investigated the influence of nicotine on late-day aviation performance in 15 non-smoking subjects. In a within-subjects design, subjects were tested on 2 days, each lasting 8 h and consisting of three 75-min simulator flights (late-afternoon practice, evening test, night test). Prior to each test, subjects received either nicotine polacrilex 2 mg or placebo gum. As expected, overall performance was significantly better after nicotine, compared to placebo (P < 0.01). Post-hoc analysis of individual flight tasks showed that nicotine improved scores on approach to landing, a task which appears to require sustained attention. We conclude that nicotine may improve late-day flight performance in non-smoking aviators. Received: 15 September 1997/Final version: 11 March 1998     

Extended Release Quetiapine Fumarate (Quetiapine XR) as Adjunct Therapy in Patients with Generalized Anxiety Disorder and a History of Inadequate Treatment Response: A Randomized,Double-Blind Study

Objective

To evaluate the efficacy and tolerability of adjunct extended release quetiapine fumarate (quetiapine XR) in patients with generalized anxiety disorder (GAD) and inadequate response to selective serotonin reuptake inhibitors/ serotonin norepinephrine reuptake inhibitors (SSRI/SNRIs).

Methods

11-week (1-week single-blind placebo run-in; 8-week randomized treatment; 2-week post-treatment period), double-blind, placebo-controlled study. Patients were randomized to quetiapine XR or placebo adjunct to SSRI/SNRI. 50 mg initial dose; 150 mg/day, Day 3; 300 mg/day, Weeks × and 4 if indicated (Clinical Global Impressions-Severity of Illness [CGI-S] ≥ 4; 150 mg/day tolerated). Primary endpoint: change from randomization to Week 8 in HAM-A total score. Secondary variables: Hamilton Rating Scale for Anxiety (HAM-A) psychic/somatic clusters, response and remission; and CGI-S.

Results

409 patients were randomized to quetiapine XR (n = 209) or placebo (n = 200); 41% and 55% of patients, respectively, had dose increases (300 mg/day). Week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (–10.74; p = 0.079) versus placebo (–9.61). Secondary variables were generally consistent with the primary analysis, except a significant reduction in HAM-A total score at Week 1 (–6.45, quetiapine XR versus –4.47, placebo; p < 0.001); significant improvements in HAM-A psychic cluster (p < 0.05) and CGI-S total (p < 0.05) scores at Week 8. Adverse events (.10% either group) were dry mouth, somnolence, sedation, headache, and dizziness.

Conclusions

In patients with GAD and inadequate response to SSRI/SNRI, adjunct quetiapine XR did not show a statistically significant effect for the primary endpoint at Week 8, although some secondary endpoints were statistically significant versus placebo. Quetiapine XR was generally well tolerated.     

The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia

A 24-week, double-blind, randomized trial was performed to compare the efficacy and tolerability of venlafaxine and paroxetine in patients with major depression or dysthymia. Outpatients aged 18-70 years with a baseline score of 17 on the 21-item Hamilton Depression Rating Scale (HAM-D) were eligible. Patients were randomly assigned to venlafaxine, 37.5 mg, in the morning and evening or paroxetine, 20 mg, in the morning and placebo in the evening, which could be increased to venlafaxine, 75 mg twice daily, or paroxetine, 20 mg twice daily, after 4 weeks. Efficacy was assessed with the 21-item HAM-D, the Montgomery-Asberg Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impressions Scale. Forty-one patients were randomized to venlafaxine and 43 to paroxetine. At week 6, a response was observed in 55% of patients on venlafaxine and 29% on paroxetine (P = 0.03). At week 12, significantly (P = 0.011) more patients in the venlafaxine group had a HAM-D remission score of 8 or less (59% versus 31%). Discontinuation for any reason occurred in 16 (39%) patients on venlafaxine and 11 (26%) on paroxetine. The most common adverse events were nausea (28%), headache (18%) and dry mouth (15%) with venlafaxine and headache (40%) and constipation (16%) with paroxetine. Venlafaxine was effective and well tolerated for the treatment of patients with mild to moderate depression or dysthymia. A consistently higher proportion of patients had a response or remission on venlafaxine than on paroxetine.     

Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans

Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., “I feel a good drug effect,”“I feel high”), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs. Received: 20 May 1997/Final version: 13 November 1998     

Hypnotic and hypothermic action of daytime-administered melatonin

Six healthy male volunteers (average age = 22.5 years) received orally melatonin (MLT; 3 mg or 9 mg) or placebo at 0930 hours in a randomized, single-blind, cross-over study. Both doses of exogenously administered melatonin (ex-MLT) induced transient, significant suppression of core body temperature (BT) compared to the placebo condition. There was no significant difference in the degree of BT suppression among the two MLT conditions in spite of significantly higher levels of serum MLT with the close of 9 mg, suggesting that there may be a threshold level of ex-MLT inducing the hypothermic action. Daytime administered ex-MLT also induced a significant sleep-inducing effect only in the 9 mg condition, while 3 mg ex-MLT failed to produce statistical significance. These findings suggest that the sleep-inducing action of ex-MLT occurs only at relatively high doses, and this action is probably not due to its BT lowering action. The present study led us to assume that ex-MLT produce its therapeutic effect for circadian rhythm sleep disorders through induction of circadian phase-shifting preceded by an acute, transient hypothermic action rather than light entrainment after setting sleep time by induction of sleep propensity. Received: 29 October 1996/Final version: 8 April 1997     

Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks

Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT) system. There is increasing evidence that the cholecystokinin-4 (CCK₄) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1) to validate this model further and 2) to shed more light on the putative CCK\5-HT interaction. To this end, we studied the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK₄-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 μg CCK₄. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK₄ while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when rechallenged with CCK₄, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the validity of the CCK₄ test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin are implicated in the regulation of anxiety. Received: 15 April 1996/Final version: 27 September 1996     

A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety

Pooled data were analyzed for 367 female patients enrolled in a double-blind, placebo-controlled, multi-centre trial comparing buspirone, a non-benzodiazepine anxiolytic, and diazepam in the treatment of generalized anxiety disorder. After a 4 to 7-day wash-out period, patients were allocated at random to receive one or other of the trial medications or placebo over a 4-week period. Mean daily dosages were 24.5 mg for buspirone and 20.8 mg for diazepam (range 10 mg to 60 mg for both drugs). Patients were assessed on entry and at weekly intervals using the Hamilton Anxiety Rating Scale, and at the end of treatment both patients and physicians gave an overall opinion of response to treatment. Details of adverse events were also recorded. The results showed that both buspirone and diazepam were approximately equal in efficacy and superior to placebo. Menstruation and the occurrence of premenstrual tension did not alter the anxiolytic activity of either drug. Patients taking diazepam had significantly more adverse effects, i.e. drowsiness, weakness, fatigue, inco-ordination and depression, than did those in the buspirone group. In a separate commentary, the anxiety disorder and the data from the study are reviewed to place them in the overall perspective of gynaecological care.     

Gepirone in anxiety: a pilot study

Ten patients suffering from generalized anxiety disorder were treated, after a single-blind placebo washout week, with the nonbenzodiazepine anxiolytic gepirone in a 6-week open label trial. Mean Hamilton Anxiety scores improved from 24.8 to 7.1 (p less than 0.01). Other physician- and patient-rated scales showed comparable improvement on a mean maximal dose of 41 mg of gepirone. The medication appeared to be nonsedating and well tolerated. The anxiolytic effect of the medication was very marked in several cases, and gepirone appears to have promise as an anxiolytic agent.     

Duration of benzodiazepine clinical activity: Lack of direct relationship with plasma half-life

The anxiolytic activity and tolerance of two dosage schedules of prazepam, a long plasma half-life benzodiazepine, were compared under double-blind conditions in two groups of 10 inpatients each who met Research Diagnostic Criteria for Generalized Anxiety Disorder and presented chronic and severe symptomatology. Patients received prazepam 40 mg per day on one of two dosage schedules: 1) divided dosage (DD) - 10 mg in the morning and at noon and 20 mg in the evening; or 2) single dosage (SD) - 40 mg in the evening. The 3 weeks of therapy were preceded and followed by 1 week of wash-out for baseline and follow-up assessments, which were performed weekly with the Hamilton Anxiety Scale, Clinical Global Impression, rating of morning drowsiness and evening worsening of symptoms, and patient self-rating of anxiety by means of a visual analogue scale performed both in the morning and in the afternoon. The results showed a clear superiority of the DD over the SD schedule: better anxiolytic efficacy on the Hamilton Anxiety Scale (P<0.0005) and on both morning and afternoon visual analogue scales (P<0.01 andP<0.0002); less morning drowsiness (P<0.0001); and steadier anxiolytic effect during the daytime, as globally rated by the investigator (P<0.0001) or measured by morning-afternoon differences on the visual analogue scale (P<0.005). These results suggest that plasma pharmacokinetics alone may not be sufficient to predict the duration of benzodiazepine anxiolytic activity.