Alprazolam placebo-controlled studies

Schweizer E, Patterson W, Rickels K, et al Double-blind, placebo-controlled study of a once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Am J Psychiatry 150 1210-1215, 1993 Seivewright N Benzodiazepine misuse by illicit drug misusers. Addiction 96 333—334, 2001... 

Zwanzger P, Eser D, Aicher S, Schule C, Baghai TC (2003) Effects of alprazolam on chole-cystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity a placebo-controlled study. Neuropsychopharmacology 28 979-984... 

Several controlled studies of IMI involved less homogeneous samples of anxious children. Neither IMI nor alprazolam (a BZ) was superior to placebo in an 8-week study of 24 children (ages 7-18 years) with school refusal, which included subjects with anxiety and depression (Bernstein et ah, 1990). A more recent placebo-controlled study of IMI -I- CBT for 47 adolescents (ages 12-18 years) with school refusal, anxiety, and/or depression was designed to address the limitations of previous studies of TCA treatment for pediatric anxiety disorders (Bernstein et ah, 2000). Accordingly, sample size was based on proposed power analysis IMI dose and serum level were monitored to ensure adequate exposure (mean IMI dose 180 mg/day mean serum IMI180 pg/L and mean IMI -I- DMI 250 pg/L at week 3 and week 8) and CBT was manual based and closely monitored. Fifty-four percent of subjects treated with IMI -I- CBT met remission criteria (defined as > 75% school attendance at the end of the study), compared to 17% of subjects treated with placebo -I- CBT. No between-group differences were noted... 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Several open trials have reported significant improvement or remission of panic attacks in patients given clonazepam ( 60, 61, 62, 63, 64, 65 and 66). One double-blind, placebo-controlled study comparing the efficacy of alprazolam, clonazepam, and placebo found both drugs superior to placebo and comparable with each other (67). Because favorable response to clonazepam usually occurs early in treatment, lack of initial improvement may predict treatment failure ( 42, 61, 68). Interdose and morning rebound anxiety have not been reported. Clonazepam is not approved by the FDA for panic attacks, and because there are only a few controlled studies, there is only limited knowledge about its efficacy for this indication. 

Chouinard G, Annable L, Fontaine R, et al. Alprazolam in the treatment of generalized anxiety and panic disorders a double-blind, placebo-controlled study. Psychopharmacology 1982 77 229-233. 

In a double-bhnd, crossover, placebo-controlled study in 12 healthy men of the impact of alprazolam 0.25 and 1.00 mg on aspects of action monitoring, i.e. the monitoring of response conflict and the detection and correction of errors by means of neurophysiological measures, alprazolam significantly reduced the amplitude of the error-related negativity (ERN) and therefore affected brain correlates of error detection (18). It increased reaction... 

Sertraline (50-150 mg/day) had no effects on alprazolam metabolism in a randomized, double-blind, placebo-controlled study in 10 healthy volunteers (33). 

In another study, Malsch and Kieser (2001) investigated the anxiolytic effects of WS 1490 compared to placebo in patients previously treated with a benzodiazepine. They evaluated the potential of the kava preparation as a replacement for the benzodiazepine, as well as the ability of the kava preparation to reduce benzodiazepine withdrawal symptoms. This was a five-week randomized, double blind placebo-controlled study in outpatients with non-psychotic anxiety (e.g., generalized anxiety disorder, social phobia, and simple phobia). Forty patients were included, and all had been on benzodiazepines (i.e., lorazepam, bromazepam, oxazepam, or alprazolam) for a mean duration of 20 months prior to entering the study. Of the 40 patients, 25 were males, and the mean age of the total sample was 40 years (range 21—75 years). 

Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy for PTSD. Efficacy for fluoxetine, paroxetine, and sertraline has been demonstrated in well-designed double-blind placebo-controlled studies to reduce all symptom domains (intrusive recollection, avoidance/numbness, and hyperarousal). - Other treatment options include the tricyclic antidepressants (TCAs) amitriptyline and imipramine and the irreversible monoamine oxidase inhibitor (MAOl) phenelzine, which have been shown to reduce re-experiencing. However, in comparison with SSRIs, TCAs and phenelzine are associated with a higher incidence of side-effects, risk of overdose, and poor compliance. Alprazolam has demonstrated anecdotal efficacy however, regular use of benzodiazepines is not recommended. Benzodiazepines can be used on an as-needed basis for specific symptoms (e.g. sleep disturbances). CBT has shown beneficial effects in relatively well-controlled studies, while the results with exposure therapy are... 

A placebo-controlled study in 12 healthy subjects found that nefazodone 200 mg twice daily caused an almost twofold increase in the plasma levels of alprazolam 1 mg twice daily taken for 7 days. Another study found that impairment of psychomotor performance and increased sedation occurred when nefazodone was given with alprazolam. A case report describes benzodiazepine withdrawal symptoms in a woman taking alprazolam after nefazodone was withdrawn following several years of concurrent use. She needed an alprazolam dosage increase from 500 micrograms to 4 mg daily to control her symptoms. ... 

No important changes in the pharmacokinetics of paroxetine were seen when 12 healthy subjects given paroxetine 30 mg daily were also given diazepam 5 mg three times a day. Adverse events were not inereased by the combination. In another study it was foimd that paroxetine did not increase the impairment of a number of psychomotor tests eaused by oxazepam.In vitro studies using human liver mierosomal enzymes have shown that paroxetine is a relatively weak inhibitor of alprazolam metabolism mediated by the cytochrome P450 subfamily CYP3A. Furthermore, a randomised, placebo-controlled study in 22 healthy subjeets reported no evidence for a pharmacokinetic or pharmacological interaction between paroxetine and alprazolam. ... 

Psychological In a double-blind, randomized, placebo-controlled study of the effects of alprazolam on human social behavior in... 

Richelson E, Nelson A Antagonism by neuroleptics of neurotransmitter receptors of normal brain in vitro. Eur J Pharmacol 103 197-204, 1984 Rickels K, Schweizer E The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry 54 [suppl) 20-23, 1993 Rickels K, Weisman K, Norstad N, et al Buspirone and diazepam in anxiety a controlled study. J Chn Psychiatry 43(12 pt 2) 81-86, 1982 Rickels K, Feighner JP, Smith WT Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42 134-141, 1985 Rickels K, Schweizer E, Weiss S, et al Maintenance drug treatment for panic disorder, 11 short- and long-term outcome after drug taper. Arch Gen Psychiatry 50 61-68, 1993... 

Although behavioral treatments for social phobia have been well studied, there are very limited data on its pharmacological management, b- Blockers (propranolol, atenolol) have been recommended, but available evidence indicates their effect may be no different than that of placebo ( 78). In a controlled study, the monoamine oxidase inhibitor (MAOl) phenelzine has been shown to be more effective than placebo (78, 79). Anecdotal reports have also described efficacy with alprazolam, clonidine, and fluoxetine, but systematic data are lacking (80, 81, 82 and 83). 

Berger CP, Presser B. Alprazolam in the treatment of two subsamples of patients with late luteal phase dysphoric disorder a double-blind, placebo-controlled crossover study. Obstet Gynecol 1994 84 379-385. 

Gardner and Cowdry (1985) found an increase in dyscontrol in borderline patients taking alprazolam in a double-blind, placebo-controlled cross-over study. The dyscontrol included the following Overdose, severe Overdose, moderate Deep neck cuts Transverse wrist cuts Tried to break own arm Threw chair at child and Arm and head banging jumped in front of car. ... 

The potential interaction of paroxetine 20 mg/day and alprazolam 1 mg/day for 15 days on polysomnographic sleep and subjective sleep and awakening quality has been evaluated in a randomized, double-blind, doubledummy, placebo-controlled, repeated-dose, four-period, crossover study in 22 young subjects with no history of sleep disturbances (29). There were subjective withdrawal symptoms after abrupt discontinuation of alprazolam, including increased subjective sleep latency and reduced subjective sleep efficiency. 

Electroencephalography (EEG) In a placebo-controlled crossover clinical trial, the pharmacological effect of a single dose of alprazolam 1 mg on EEG of nine healthy volxmteers was studied Nonlinear couplings assessed by... 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

---