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At least 19 recordsLinked to original sources
PubMed1987

Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients.

The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.

Adolescent↗
PubMed1992

Mechanism of immunosuppressive effect of alprazolam: alprazolam suppresses T-cell proliferation by selectively inhibiting the production of IL2 but not acquisition of IL2 receptor.

The purpose of this study was to elucidate the mechanism of action of alprazolam on concanavalin A (Con A)-induced murine T-cell proliferation. Splenic cells of BALB/c mice were first cultured with an optimum dose of Con A in the presence or absence of varying doses of alprazolam to assess effects of alprazolam on T-cell proliferation, interleukin 2 (IL2) production and IL2 receptor (IL2R) expression. Then, Con A-induced T-blast cells from BALB/c mice were cultured with an excess dose of human recombinant IL2 (rIL2) or crude rat IL2 supernate in the presence or absence of alprazolam to assess the effects of alprazolam on the interaction of IL2 and IL2R. The results of these studies clearly demonstrated that alprazolam can inhibit the T-cell proliferation in response to Con A but not to IL2. Alprazolam also reduced the production of IL2 by splenic T-cells, but did not alter the expression of IL2R on Con A-induced T-blast cells. Furthermore, the results also showed that (a) alprazolam did not inhibit the proliferative response of splenic T-cells to a combination of phorbol 12-myristate-13-acetate (PMA) and ionomycin, and (b) the addition of exogenous IL2 reversed the inhibitory effect of alprazolam on T-cell proliferation. Finally, the addition of alprazolam produced a time-dependent inhibiting effect on T-cell proliferation. However, this inhibitory effect of alprazolam was abolished when the drug was added to the cultures of competent cells that fully expressed IL2R. Taken together, these results suggest that alprazolam inhibits murine T-cell proliferation by affecting the mitogenic receptor-mediated events (initiation) rather than the IL2R-mediated events (progression) of ligand-activated T-cells through the cell cycle.

Alprazolam↗
PubMed2002

Suppression of monocyte chemoattractant protein 1, but not IL-8, by alprazolam: effect of alprazolam on c-Rel/p65 and c-Rel/p50 binding to the monocyte chemoattractant protein 1 promoter region.

Alprazolam is a hypnotic/tranquilizer that has been shown to specifically inhibit the platelet-activating factor (PAF)-induced aggregation of human platelets. The goal of this study was to elucidate whether alprazolam modulates IL-1alpha-initiated responses. For this purpose we investigated the effects of alprazolam on the IL-1alpha-induced production of inflammatory cytokines (IL-8 and monocyte chemoattractant protein 1 (MCP-1)) in a human glioblastoma cell line, T98G, and explored the signaling pathways involved. We found that alprazolam inhibited IL-1alpha-elicited MCP-1 production within a range of 0.1-3 micro M. In contrast, it did not inhibit IL-1alpha-induced IL-8 production. Although NF-kappaB is involved in regulating the IL-1alpha-induced expression of MCP-1 and IL-8, the degradation of IkappaB-alpha stimulated by IL-1alpha was not inhibited by alprazolam. Alprazolam prevented NF-kappaB from binding to the MCP-1 promoter region (the A2 and A1 oligonucleotide probes), but binding of NF-kappaB to IL-8/NF-kappaB was not inhibited. Moreover, alprazolam inhibited c-Rel/p50 binding to the A2 oligonucleotide probe, but not p50/p65 from binding to the IL-8/NF-kappaB site. While AP-1 is involved in regulating the IL-1alpha-induced expression of IL-8, but not MCP-1, alprazolam potentiated the binding of c-Jun/c-Fos to the AP-1 oligonucleotide probe. These results show that the inhibition of IL-1alpha-mediated MCP-1 production by alprazolam is mainly due to inhibition of c-Rel/p65 and c-Rel/p50 binding to the MCP-1 promoter region, since alprazolam did not affect the IL-1alpha-mediated activation of NF-kappaB (p50/p65) or AP-1 (c-Jun/c-Fos) binding to the IL-8 promoter region. In conclusion, a new action of alprazolam was elucidated, as shown in the inhibition of c-Rel/p65- and c-Rel/p50-regulated transcription.

Alprazolam↗
PubMed1992

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.

Adolescent↗
PubMed1996

A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism.

OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo. METHOD: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. CONCLUSION: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.

Administration, Oral↗
PubMed2002

Isolation and structural elucidation of degradation products of alprazolam: photostability studies of alprazolam tablets.

Accelerated thermal, hydrolytic, and photochemical degradations of alprazolam were performed under several reaction conditions. The stress studies revealed the photolability of the drug as the most adverse stability factor; the main photodegradation products were isolated and properly characterized as: triazolaminoquinoleine; 5-chloro-[5"-methyl-4H-1,2,4-triazol-4-yl]benzophenone, and 1-methyl-6-phenyl-4H-s-triazo-[4,3-alpha][1,4]benzodiazepinone. Accelerated pH-dependent studies show that the photoinstability increases as the pH decreases; at pH 9.0, photodegradation does not occur, therefore, the photochemical degradation of alprazolam was performed in buffered solutions at pH 2.0 and 3.6. The higher rate of reaction was observed at pH = 2.0; consequently, acidic conditions should be avoided and appropriate light protection is recommended during the drug-development process, storage, and handling. The main degradation route for alprazolam tablets is also photochemical.

Alprazolam↗
PubMed1994

A double-blind, placebo-controlled, multicenter study with alprazolam and extended-release alprazolam in the treatment of panic disorder.

This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).

Adult↗
PubMed1993

Clinical pharmacokinetics of alprazolam. Therapeutic implications.

Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 micrograms/L for each daily dosage change of 1 mg/day. Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women. Coadministration of cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin. Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 micrograms/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Alprazolam absorption kinetics affects abuse liability.

OBJECTIVE: To evaluate the behavioral, subjective, and reinforcing effects of immediate-release (IR) alprazolam and extended-release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability. METHODS: Fourteen healthy men with histories of sedative abuse participated as subjects in a double-blind crossover study. All subjects received placebo, 1 and 2 mg immediate-release alprazolam, and 2 and 3 mg extended-release alprazolam in random order. Behavioral performance, subjective effects, and alprazolam plasma concentrations were assessed repeatedly 1/2 hour before and 1/2, 1, 3, 5, 7, 9, 12, and 24 hours after drug administration. RESULTS: Mean peak alprazolam plasma concentrations occurred 1.7 and 9.2 hours after immediate-release alprazolam and extended-release alprazolam, respectively. Compared to placebo, 2 mg immediate-release alprazolam impaired all measures of psychomotor and cognitive performance (Digit Symbol Substitution Test), motor coordination (circular lights and balance), and memory (digit entry and recall); 2 mg extended-release alprazolam did not affect any of these measures and 3 mg extended-release alprazolam impaired circular lights only. Immediate-release alprazolam, 2 mg, increased all six measures of positive drug effects (e.g., ratings of liking or good effects); none of these measures were increased by 2 mg extended-release alprazolam and only three of the six measures were increased by 3 mg extended-release alprazolam. A drug versus money multiple-choice procedure designed to assess the relative reinforcing effects of each condition was administered 24 hour after the drug. The amount of money subjects were willing to "pay" to take the drug was significantly greater than placebo for both doses of immediate-release alprazolam but for neither dose of extended-release alprazolam. CONCLUSIONS: These data indicate that extended-release alprazolam has less potential for abuse than immediate-release alprazolam.

Adult↗
PubMed1995

Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam.

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and alprazolam after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for alprazolam, 4OH, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam Cmax and AUCtau values significantly increased approximately twofold and 4OH Cmax and AUCtau values significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or dione after the coadministration of alprazolam and nefazodone. However, the mean steady-state mCPP Cmax and AUCtau significantly increased by approximately threefold and t1/2 values significantly increased by approximately twofold after the coadministration of alprazolam and nefazodone in comparison to those when nefazodone was given alone. Competitive inhibition between alprazolam and nefazodone metabolism at cytochrome P450 3A4 may be responsible for the pharmacokinetic interaction when alprazolam and nefazodone were coadministered. No adjustment of nefazodone dosage is required when nefazodone and alprazolam are coadministered. Because alprazolam concentrations in plasma are increased in the presence of nefazodone, a reduction in alprazolam dosage is recommended when the two agents are coadministered.

Adult↗
PubMed1981

[Behavioral and electroencephalographic effects of alprazolam and its metabolites (author's transl)].

The behavioral and electroencephalographic effects of alprazolam and its metabolites were investigated in mice, rats and rabbits, and compared with the data on diazepam, lorazepam and nitrazepam. Locomotor activity of mice in an open-field situation was increased with smaller doses of alprazolam and nitrazepam but not with diazepam and lorazepam. Alprazolam increased the hyperactivity induced by methamphetamine in mice. The anticonflict effects of alprazolam in rats were more potent than those of diazepam and lorazepam. In suppressing hyperemotionality and muricide of olfactory bulbectomized rats, alprazolam was more potent than diazepam and fairly equal to that of lorazepam. Muricide of raphe-lesioned rats was markedly inhibited by alprazolam. Mescaline-induced head-twitches in mice were more markedly increased with alprazolam than with nitrazepam and diazepam. Alprazolam, diazepam and lorazepam prevented both maximal electroshock and pentetrazol convulsions in mice. Alprazolam was more potent than diazepam and lorazepam in potentiating thiopental, ether and ethanol anesthesia in mice. In the impaired rotarod performance, alprazolam was more potent than diazepam and lorazepam in mice, but was much less potent than diazepam and lorazepam in mice, but was much less potent than lorazepam in rats. In conscious rabbits with chronically implanted electrodes, alprazolam induced a drowsy EEG pattern and depressed the EEG arousal response not only to auditory stimulation but also to mesencephalic reticular stimulation. The EEG effect of alprazolam was approx. twice that of diazepam. The pharmacological activity of alpha-hydroxyalprazolam was approx. one third that of alprazolam. However, 5-chloro-2-(3-hydromethyl-5-methyl-4H-1, 2,4-triazolo-4-yl) benzophenone showed no pharmacological activity. These results indicate that alprazolam possesses pharmacologic properties characteristic to benzodiazepines and that the activity is more potent than diazepam. In addition, alprazolam seems to have a specific effect on the central serotonergic mechanisms.

Aggression↗
PubMed2004

Lack of pharmacologic interaction between paroxetine and alprazolam at steady state in healthy volunteers.

This investigation aimed to provide evidence on the lack of pharmacokinetic interaction of paroxetine (20 mg/d) and alprazolam (1 mg/d) in combined therapy. In addition, the central effects of both drugs when administered alone and in combination were assessed to rule out any relevant synergistic depressant central effect. Twenty-five healthy young adult volunteers participated in a double-blind, double-dummy, placebo-controlled, repeated dose (15 days), 4-period crossover study. Each subject received each of 4 treatment sequences (ie, paroxetine-alprazolam placebo, alprazolam-paroxetine placebo, paroxetine-alprazolam, and paroxetine placebo-alprazolam placebo) in randomized order. The ratios for area under the curve within a dosing interval and maximum plasma concentration of the paroxetine plus alprazolam sequence to single agent paroxetine were 1.07 (90% confidence interval = 0.99 to 1.16) and 1.05 (90% confidence interval = 0.97 to 1.13), respectively, with no statistically significant differences between the 2 treatments. Similarly, for alprazolam, ratios for the combined to the single treatment sequence were 0.99 (90% confidence interval = 0.93 to 1.05) and 1.00 (90% confidence interval = 0.94 to 1.07) for area under the curve within a dosing interval and maximum plasma concentration, respectively, showing no evidence for interaction. Comparative pharmacodynamics on the combination was assessed using 6 Psychomotor Performance Tests and 5 Visual Analogue Scales focused on mood variables. Alprazolam and paroxetine plus alprazolam induced similar and significant performance impairment and sedation after both single and repeated dose administration, being less evident on day 15. After dosing, paroxetine plus alprazolam showed a lower recovery pattern than alprazolam alone, especially on day 15. No treatment sequence showed cumulative effects after repeated dose administration. Psychomotor Performance Tests and Visual Analogue Scales data suggested lack of pharmacodynamic interactions. Accordingly, study results showed no evidence for pharmacologic interactions between paroxetine and alprazolam at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence under both single and combined alprazolam treatments.

Adult↗
PubMed1990

In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications.

We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety. As a comparison, we also assessed the effects of diazepam on in vitro CRH release, because in contrast to alprazolam, diazepam is effective in anxiety states but not in depression. Alprazolam (0.01-0.3 mg/kg, iv) produced a dose-dependent inhibition of both plasma ACTH and cortisol secretion in non-restrained adult male rhesus monkeys. Our in vitro studies showed that alprazolam significantly inhibited serotonin (5HT)-induced CRH release in a dose-dependent fashion (10(-10)-10(-5) M). Diazepam also inhibited 5HT-induced CRH release, but was 40 times less potent than alprazolam. Alprazolam was ineffective in blocking basal or CRH-induced ACTH release from rat dispersed anterior pituicytes, suggesting that its in vivo effects are through inhibition of CRH secretion. As expected, the inactive benzodiazepine ligand Ro 15-1788 inhibited the effects of alprazolam on 5HT-induced CRH release, but this occurred only at doses below 10(-7) M. Interestingly, when incubated alone in higher doses with our rat hypothalamic organ culture, Ro 15-1788, like alprazolam, produced a dose-dependent inhibition of 5HT-induced CRH release (10(-7)-10(-5) M), suggesting an agonistic action of Ro 15-1788 at the benzodiazepine receptor at higher concentrations. We conclude that alprazolam is capable of suppressing the primate pituitary-adrenal axis, and that this suppression most likely reflects suppression of the CRH neuron rather than of the pituitary corticotroph cell. We speculate that the enhanced capacity of alprazolam to suppress the CRH neuron relative to other benzodiazepines may contribute to its unique efficacy among this class of drugs in the treatment of major depression. The capacity of Ro 15-1788 to reverse alprazolam-induced suppression of the CRH neuron indicates that the effects of alprazolam are mediated at least in part via its interaction with the benzodiazepine component of the gamma-aminobutyric acidA macromolecular complex.

Adrenocorticotropic Hormone↗
PubMed2004

Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature.

Alprazolam is a benzodiazepine derivative that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered. An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated. In addition to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clinical studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car.

Alprazolam↗
PubMed1995

The effect of alprazolam on serum cortisol and luteinizing hormone pulsatility in normal women and in women with stress-related anovulation.

Alprazolam, a benzodiazepine derivative, stimulates specific gamma-aminobutyric acidA receptors and has been found to inhibit CRH activity in the brain. This study examined the effect of alprazolam on serum cortisol and LH pulsatility in six women in the early follicular phase (EFP), six women in the midluteal phase (MLP), and six women with stress-related anovulation (SRA) of normal weight, but with a previous history of anorexia nervosa. Subjects were given alprazolam (2 mg, orally) or an identical placebo capsule at 0900 h, and blood samples were collected through an indwelling venous catheter every 10 min for 8 h in the SRA women and 10 h in EFP and MLP women. Women with SRA were also given clomiphene (100 mg/day) for 5 days before a further 8-h blood sampling session. As expected, there was a diurnal decline in serum levels of cortisol, which was significantly less in women with SRA (55 +/- 4%) than those in both EFP (76 +/- 4%) and MLP women (75 +/- 3%; P < 0.005). The food-related rise of cortisol that follows lunch in normal women was absent in women with SRA. Alprazolam accentuated the decline in serum cortisol, and in all three groups, the mean serum cortisol level after alprazolam treatment was significantly less (P < 0.05) than that after placebo. In SRA women, alprazolam restored visible LH pulses in all women and increased the mean LH pulse frequency (P < 0.02) and pulse amplitude (P < 0.05). This was associated with an increase in mean serum LH from 1.3 +/- 0.3 to 3.0 +/- 0.06 IU/L (P < 0.02). In EFP women, alprazolam reduced the frequency of LH pulsatility from a mean of 5.8 +/- 0.7 to 3.2 +/- 0.5 pulses/10 h (P < 0.02) and increased the mean pulse amplitude from 2.4 +/- 0.5 to 5.0 +/- 1.1 IU/L (P < 0.0005). Alprazolam had no significant effect on LH pulsatility or amplitude in MLP women. To explain this variation in response to alprazolam, we propose that alprazolam accelerates the GnRH pacemaker in SRA women by inhibiting excessive CRH activity, which blocks the GnRH pacemaker in these women. In normal women, we hypothesize that tonic inhibition of the GnRH pacemaker by CRH is minimal, and the reduced pulsatility of LH after alprazolam treatment in EFP women results from inhibition of stimulatory noradrenergic neurons. In MLP women, we propose that preexisting opioid inhibition of noradrenergic neurons by progesterone blocks this effect of alprazolam.

Adolescent↗
PubMed1989

Intravenous alprazolam challenge in normal subjects. Biochemical, cardiovascular, and behavioral effects.

Alprazolam, a novel benzodiazepine derivative is thought to be effective in the treatment of anxiety, panic, and depressive disorders. There is considerable interest in alprazolam's mechanism of action, particularly whether its profile of actions might resemble that of the alpha 2 adrenoreceptor agonist, clonidine. The present study assessed the biochemical, cardiovascular, and behavioral responses of healthy volunteers to acute intravenous infusions of alprazolam and placebo. Alprazolam reduced ACTH and cortisol while increasing growth hormone. There was a transient reduction in plasma norepinephrine and only modest effects on cardiovascular parameters. Subjects became quite sedated after intravenous alprazolam. This pharmacodynamic profile resembles that previously reported for traditional benzodiazepines, although alprazolam may be a more potent stimulator of growth hormone release. Alprazolam's effects on growth hormone resemble those of clonidine, but unlike clonidine, alprazolam has relatively little effect on plasma catecholamine and cardiovascular parameters. This suggests that alpha 2 mechanisms do not play a primary role in alprazolam's mode of action. Since alprazolam infusion affects three different measures (ACTH/cortisol, growth hormone, and plasma norepinephrine) thought to be dysregulated in depression, challenge with intravenous alprazolam may prove to be a useful "probe" in affective disorders.

Adrenocorticotropic Hormone↗
PubMed1997

Independent interaction of alprazolam and caffeine under chronic dose regimens on differential reinforcement of low-rate (DRL 45-s) performance.

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.

Alprazolam↗