Doses Of Alprazolam Research Articles

Effects of alprazolam on capture stress-related serum cortisol responses in Korean raccoon dogs (Nyctereutes procyonoides koreensis)

The purpose of this study was to evaluate the effect of alprazolam on the stress that Korean raccoon dogs (Nyctereutes procyonoides koreensis) may experience while caught in a live trap by measuring their serum cortisol response. The animals were placed in a live trap with or without being pretreated with oral doses of alprazolam. In both groups, pre-trap blood samples were initially collected without anesthesia before the animals were positioned in the live trap; then post-trap blood samples were collected after the animals had remained in the live trap for 2 h. Changes in cortisol levels were observed using a chemiluminescent immunoassay. The level of cortisol increased in the control group and decreased in the alprazolam-pretreatment group (p < 0.05). In this study, we demonstrated that alprazolam pretreatment reduced stress during live trap capture.

A Case of Suicidal Thoughts With Alprazolam

To the Editor: This is the first report, to our knowledge, of suicidal thoughts emerging after a dose of alprazolam. Case report. Ms A, a woman in her late 20s, presented for the first time in 2008 and was diagnosed with obsessive-compulsive disorder with panic attacks (DSM-IV criteria) and was prescribed fluoxetine 20 mg in the morning and alprazolam 0.25 mg 3 times a day as needed. She was not depressed and had not experienced suicidal thoughts in the past. After a single dose of both alprazolam 0.25 mg and fluoxetine 20 mg, she experienced grogginess and sleepiness that lasted for 24 hours. She continued taking only fluoxetine for the next 2 weeks without any side effects. However, as she still experienced panic-like symptoms, she tried taking half the initial dose of alprazolam (half a tablet of alprazolam 0.25 mg) together with fluoxetine 20 mg. This time, she described the “grogginess and sleepiness” as less severe than the first time with alprazolam 0.25 mg. The next morning, she repeated the same doses of alprazolam with fluoxetine and reported “feeling worse in a different way.” She had thoughts of jumping down from her apartment. These thoughts lasted “till the effects wore off,” referring to the grogginess and sleepiness. Subsequent to this, she has stopped taking alprazolam completely and continued with fluoxetine without experiencing similar symptoms. The product literature on alprazolam does not report suicidal thoughts or ideation.1 A meta-analysis of controlled trials of alprazolam in treatment of depression does not suggest that alprazolam is associated with increased risk of suicidality.2 The majority of those treated with alprazolam experienced improvement of suicidal ideation, and that rate of improvement was significantly greater for those taking alprazolam compared to those taking placebo (71.9% vs 57.7%). However, there are reports indicating that all benzodiazepines have been associated with the emergence or worsening of depression3,4; whether they were causative is unknown. Benzodiazepines have also been observed to precipitate suicide in already depressed patients.5 The American Psychiatric Association report on benzodiazepines warns, in discussing toxicity, that benzodiazepines have been reported to cause or exacerbate symptoms of depression. This is not a frequent side effect, but depressive symptoms can be potentially serious.6 The United Kingdom's Committee on Safety of Medicines recommends that benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients.7 In another report,8 there were 6 patients, previously emotionally stable, who experienced suicidal ideation with a cluster of other symptoms; however, all of these patients had taken greater than maximally recommended doses of diazepam (above 40 mg a day) primarily for medical conditions.8 Coadministered fluoxetine can increase serum alprazolam concentrations.9,10 The interaction effect is an increased risk of alprazolam toxicity with symptoms such as somnolence, dizziness, ataxia, slurred speech, hypotension, and psychomotor impairment. In the study by Greenblatt et al,9 12 healthy male volunteers were given fluoxetine 20 mg twice a day or placebo and a single dose of alprazolam 1 mg on days 3 and 24 of the 31-day, double-blind, crossover study. Fluoxetine significantly increased the half-life of alprazolam from 17 hours to 20 hours and significantly decreased its clearance from 61 mL/min to 48 mL/min. The mechanism of action is thought to be through inhibition of the cytochrome P450 3A4 isoenzyme, which is responsible for alprazolam metabolism. Whether alprazolam actually triggered the suicidal thoughts or whether these were in relation to the side effects this patient experienced cannot be clearly determined. However, there is high probability, given the risks associated with benzodiazepine use, that alprazolam contributed to the emergence of suicidal thoughts in this patient. The combination of fluoxetine with alprazolam should be used with caution in patients with anxiety disorders.

Pre‐medication and renal pre‐conditioning: a role for alprazolam, atropine, morphine and promethazine

Four pre-medication drugs are used to relieve pain, allay anxiety, reduce secretion and enhance hypnosis, were evaluated for their effects on ischemia reperfusion (I/R) injury which is one of the major complications of vascular and transplantation surgery. Right kidney was removed from female rats (210-250 g) 3 weeks before surgical procedure. Different doses of morphine (0.5, 2 and 5 mg/kg), promethazine (1, 2 and 5 mg/kg), atropine (0.1, 0.3 and 0.5 mg/kg) and alprazolam (0.08, 0.32 and 0.64 mg/kg) were administered subcutaneously 30 min before left renal artery occlusion and 6 h reperfusion. Left kidneys were processed for histological evaluations. Creatinine and BUN were measured in serum samples. Morphine, promethazine, atropine and alprazolam at all evaluated doses significantly decreased serum creatinine and BUN levels and histopathological scores. The effects of promethazine (1 mg/kg) and all doses of alprazolam were more potent than other pre-medication drugs and doses. This study suggested a protective effect of these pre-medication drugs on I/R injury. Although obvious studies are required, these findings may lead to effective therapies against I/R injury.

Selective effects of benzodiazepines on the acquisition of conditioned taste aversion compared to attenuation of neophobia in C57BL/6 mice

The effects of pre-conditioning administration of anxiolytic benzodiazepines on the acquisition of a conditioned taste aversion (CTA) and on the acquisition of attenuation of neophobia (AN) were investigated in C57BL/6 mice. A CTA was induced by injecting lithium chloride (LiCl; 6 mEq x kg(-1)) 30 min after the animal had imbibed a novel 0.5% saccharin solution. In other animals, neophobia was attenuated by a single access to the novel 0.5% saccharin solution, followed only by injection of saline. Pre-conditioning administration of chlordiazepoxide (CDZ; 6-24 mg x kg(-1), i.p.) and alprazolam (0.3-1 mg x kg(-1), p.o.) resulted in a CTA that did not differ initially from that observed in vehicle-treated controls, but which showed faster extinction. The acquisition of AN was impaired only after the higher doses of CDZ (12-24 mg x kg(-1), i.p.) or alprazolam (1 mg x kg(-1), i.p.). The results show that in this test, altered acquisition of an aversive CTA memory by anxiolytic benzodiazepines is reflected in more rapid extinction. Moreover, at low doses, these drugs showed selectivity for weakening CTA learning compared to AN learning. Evidence is discussed that selective weakening of aversive memory formation is a clinically relevant effect of anxiolytic benzodiazepines.

EFFICIENCY OF ALPRAZOLAM AT CARDIALGIA SYNDROME CAUSED BY THE CERVICOTHORACIC OSTEOCHONDROSIS AND CORONARY HEART DISEASE

The purpose of work was the analysis of efficiency of application alprazolam in treatment of psychoautonomic infringements at cardialgia syndrome caused by a cervicothoracic osteochondrosis and coronary heart disease. Use of a low dose of alprazolam (0,75 mg day in 3 receptions) reduces the raised level of anxiety at patients with cardialgia syndrome.

An evaluation of data for 10 children born to mothers who attempted suicide by taking large doses of alprazolam during pregnancy

FDA has identified alprazolam, a new type of benzodiazepine, as pregnancy category D. The objective of this study was to evaluate the effects on fetal development of very large doses of alprazolam that were used for suicide attempts during pregnancy. Pregnant women were identified among the patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who were admitted as self-poisoned subjects from a total population of the three million people of Budapest and its surrounding region. Rates of congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status were compared between children born to mothers who attempted suicide during pregnancy using alprazolam alone or in combination with other drugs and in their sib controls. Between 1984 and 1993, 559 pregnant women attempted suicide during pregnancy with drugs: 30 of these women self-poisoned with alprazolam, 10 delivered live-born infants who were examined. Doses of alprazolam used were between 7.5 and 100 mg, with a mean of 30 mg. Six of the 10 exposed children were born to mothers who attempted suicide between the 6th and 12th postconceptional weeks. Of the 10 exposed children, two had congenital abnormalities. One had a multiple congenital abnormality that included atypical gastroschisis and minor anomalies; an association of this defect and the 30 mg alprazolam used for self-poisoning in the 14th postconceptional week cannot be excluded. Another exposed child had mild pectus excavatum, but the times of the suicide attempt and the critical period for producing this defect did not overlap. Of 12 sibs, one had a multiple congenital abnormality. Thus, the rate of congenital abnormalities did not significantly differ between exposed children and their sibs. Mean birth weight was higher for babies born to mothers who attempted suicide by alprazolam during pregnancy than in their sib controls. Cognitive status and behavioral scale of the exposed children did not indicate fetotoxic effects, including neurotoxic effects, of large doses of alprazolam. The large doses of alprazolam used for self-poisoning during pregnancy did not result in a significantly higher rate of congenital abnormalities; however, there were only 10 self-poisoned pregnant women, and an association of one multiple congenital abnormality with a large dose of alprazolam cannot be excluded. The findings in this study did not identify fetotoxicity, including neurotoxicity, of very large doses of alprazolam. Our study shows that the self-poisoning model is feasible and provides beneficial information for use in estimating human teratogenic and fetotoxic risks of drugs.

The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam—induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an β1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

The effect of sympathetic antagonists on the antidepressant action of alprazolam.

Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

Protective effect of alprazolam against sleep deprivation-induced behavior alterations and oxidative damage in mice

Sleep deprivation is considered as a risk factor for various diseases. Sleep deprivation leads to behavioral, hormonal, neurochemical and biochemical alterations in the animals. The present study was designed to explore the possible involvement of GABAergic mechanism in protective effect of alprazolam against 72 h sleep deprivation-induced behavior alterations and oxidative damage in mice. In the present study, sleep deprivation caused anxiety-like behavior, weight loss, impaired ambulatory movements and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep-deprived mice brain. Treatment with alprazolam (0.25 and 0.5 mg/kg, ip) significantly improved behavioral alterations. Biochemically, alprazolam treatment significantly restored depleted reduced glutathione, catalase activity, reversed raised lipid peroxidation and nitrite level. Combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of alprazolam (0.25 mg/kg) significantly antagonized protective effect of alprazolam. However, combination of muscimol (0.05 mg/kg) with alprazolam (0.25 mg/kg, ip) potentiated protective effect of alprazolam. On the basis of these results, it might be suggested that alprazolam might produce protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.

Relative influences of adjunctive topiramate and adjunctive lamotrigine on scanning and the effective field of view

A subsample of 67 adult patients with partial seizures participating in a randomized, double-blind study comparing the cognitive effects of adjunctive lamotrigine (LTG) and adjunctive topiramate (TPM) was administered Performance On-Line (POL) in addition to a battery of neuropsychological tests at baseline, week 8 and week 16 of treatment. The POL is a self-administered computer task that measures scanning, divided-attention, and the effective field of view. Although the POL does not measure driving performance, POL scores are correlated with driving performance. The results show that adjunctive TPM, but not adjunctive LTG, negatively impacted cognition. Both simple target identification and divided-attention performance on POL were compromised in the TPM group but not in the LTG group. The relative POL impairment associated with chronic TPM treatment was similar to that observed with the acute effects of alcohol with a breath level of .045% or a low dose of alprazolam (0.5mg). Thus, driving-related visual and cognitive skills were compromised by adjunctive TPM treatment. Therapeutic doses of adjunctive TPM pose a potential risk of impaired scanning and divided-attention skills.

Cognitive style, alprazolam plasma levels, and treatment response in panic disorder

This study investigated an anxiety-prone cognitive style (measured by the Anxious Thoughts and Tendencies Questionnaire, AT&T) as a predictor of the acute response to increasing alprazolam plasma levels in panic disorder. Panic disorder patients (n=26) were treated with escalating doses of alprazolam for 4 weeks, then a fixed dose of 1 mg four times a day for 4 weeks. At 0, 1, 2, 3, 4, 6, and 8 weeks, trough alprazolam plasma levels; clinical, self-report, and performance measures; and vital signs were assessed. Panic attack data were from daily diaries. The repeated response measures were analyzed in relation to alprazolam plasma levels using SAS GENMOD, with patients classified as high or low on the baseline AT&T. Panic attacks, anticipatory anxiety, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, and clinicians' global ratings improved with increasing alprazolam plasma levels. Hopkins Symptom Checklist-90 Anger-Hostility; Profile of Mood States Vigor, Confusion, and Friendliness; and speed and accuracy of performance worsened. Patients with high AT&T scores were worse throughout the study on situational panics, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, the Hamilton Rating Scale for Depression, and Clinical Global Improvement; most Hopkins Symptom Checklist-90 clusters; Profile of Mood States Anxiety, Depression, and Confusion; and Continuous Performance Task omissions. We conclude that in panic disorder: (1) alprazolam has a broad spectrum of clinical activity related to plasma levels in individual patients; (2) sedation, disinhibition, and performance deficits may persist for at least a month after dose escalation ends; (3) marked anxiety-prone cognitions predict more symptoms throughout treatment, but do not modify the response to alprazolam and therefore should not influence the choice of alprazolam as treatment.

Sleep-Related Hypomanic Symptoms as a Predictor of Bipolar Spectrum Disorders

Sir: Deciding whether to prescribe antidepressants for the depressed patients with bipolar spectrum disorders remains a challenge for clinicians. Two most-feared potential consequences of using antidepressants in patients with bipolar spectrum disorders are triggering a manic switch and/or generating a rapid cycling course of the disease.1 Experts have long tried to recognize the depressed patients who are at a greater risk for switching to mania; thus, several symptoms have been suggested as “soft signs” of bipolarity, including hypersomnia, psychomotor retardation, young age at onset of depression, family history of bipolar disorder, drug-induced hypomania, seasonality of the episodes, and diurnal variation of the symptoms.2 However, the list is not yet complete, and many cases still cannot be correctly predicted. As a result, clinical findings that could be used as new predictors of bipolar spectrum disorders could be helpful for future interventions. Case report. Ms. A was a 27-year-old married woman who experienced an aggravation of depressive and anxiety symptoms for 6 months beginning in August 2005. Symptoms included depressed mood, loss of interest, repeated crying spells, loss of concentration, insomnia, decreased appetite, irritability, worry, and preoccupation with death. Past history revealed no significant finding other than mild depressive and anxiety symptoms in the previous 4 years and no episodes of mania or hypomania. She had no suggestive symptoms for a bipolar spectrum disorder except for very brief periods (about 30 seconds) of euphoria and inflated self-esteem, which occurred just before falling asleep, in a semiconscious state between wakefulness and sleep. During these periods, she experienced an exuberant sense of power, and she believed that she was able to “move mountains.” Family history for bipolar disorder was negative. The patient met the criteria for major depressive disorder based on DSM-IV-TR and received 5 mg/day of citalopram (February 2006), and after 5 days, the dose was increased to 10 mg/day, in addition to 1.25 mg/day of alprazolam, in 3 divided doses. One week later, the patient showed significant improvement. In addition, alprazolam had reduced the sleep latency, and the patient did not experience or remember any sleep-related hypomanic symptoms. Instead, she reported having distinct periods of euphoria and talkativeness 15 to 20 minutes after taking each dose of alprazolam. These periods would happen after all doses of alprazolam and would completely resolve after about 10 minutes, and the patient would return to her depressed baseline. The patient did not experience any other side effects other than a mild sedation during the day. The alprazolam dose was reduced to 0.75 mg/day to decrease sedation and then tapered to complete cessation in the next 3 weeks, and citalopram was continued. Sleep-related hypomanic symptoms did not recur after reducing or discontinuing alprazolam. The patient was followed for 6 more months and remained euthymic (August 2006). Recent studies suggest that the lifetime prevalence of bipolar spectrum disorders in the general population is more than 6%,3 that is, much higher than what was previously speculated.2 It is also reported that about 12.5% of the patients initially diagnosed as having depression will be reclassified as having a bipolar spectrum disorder in their course of illness.4 This patient reported experiencing distinct brief periods of euphoria and inflated self-esteem before sleep onset, which could potentially be related to bipolar spectrum disorders. Even though we did not have enough evidence to accept it as a new soft sign of bipolar spectrum disorders before starting the medications, transient hypomanic symptoms induced by taking al-prazolam suggested that “sleep-related periods of euphoria” could be assumed as one of the predictors of bipolar spectrum disorders. We are aware that had the patient been followed without decreasing the dose of alprazolam, she might not have developed a bipolar disorder. Obviously, this could not be performed because of ethical considerations. Future studies could tell more about the diagnostic value and effect of each of the soft signs on the long-term course of the disease.

Combining alprazolam with systematic desensitization therapy for dental injection phobia

To determine whether a benzodiazepine facilitates systematic desensitization, 144 subjects with dental injection phobia received systematic desensitization in combination with placebo or one of two doses of alprazolam (0.5 mg or 0.75 mg). Systematic desensitization therapy included computer-controlled presentation of digitized video segments followed by in vivo exposure segments, culminating in an actual dental injection. Subjects advanced to the next hierarchy segment when low anxiety was reported during a segment. Alprazolam and placebo groups progressed at the same rate. The 0.75 mg group had elevated heart rates while watching video segments compared with placebo. In a subsequent behavioral avoidance test (during which subjects were randomized to a new drug condition), there was no indication that state-dependent learning had occurred. Dental fear was reduced similarly in all groups for 1 year after study completion. No advantage was found to combining alprazolam with systematic desensitization for dental injection phobia.

Anxiolytic-like effect of 5-HT 2 ligands and benzodiazepines co-administration: Comparison of two animal models of anxiety (the four-plate test and the elevated plus maze)

Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT 2A/2C agonist DOI and the 5-HT 2B agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT 2 ligands in the FPT and the EPM. Indeed, close distribution of GABA A and 5-HT 2 receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT 2A ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.

Pharmacokinetics of an Extended Release Formulation of Alprazolam (Xanax XR) in Healthy Normal Adolescent and Adult Volunteers

The purpose of this study was to estimate pharmacokinetics, safety, and tolerability of single doses of an extended release formulation of alprazolam (Xanax XR) in adolescent and adult healthy volunteers. This was a randomized, open-label, single-dose, 2-period crossover study. Twelve adolescent healthy volunteers (13-17 years) and 12 adult healthy volunteers (20-45 years) received single doses of Xanax XR 1 mg or 3 mg tablets. Blood samples were obtained predose and for 48 hours postdose. Plasma samples were assayed for alprazolam and its two active metabolites alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam using a validated LC-MS/MS method. Safety assessments included clinical laboratory tests, vital signs, and adverse event monitoring. At both dose levels, mean plasma concentration-time profiles of alprazolam, alpha-hydroxy-alprazolam, and 4-hydroxy-alprazolam were similar in adolescent and adult subjects. The ratios of estimated geometric means for AUC(0-infinity) and Cmax between adolescents and adults for both dose levels were 115% (95% CI: [93, 143]) and 111% (95% CI: [95, 129]), respectively. An assessment of dose proportionality between the 3 mg and 1 mg alprazolam doses within both age groups indicated that the AUC(0-infinity) and Cmax were both within 80-125% equivalence limits. Parent-metabolite ratios were similar in both age groups and were consistent with those previously reported. Alprazolam was well tolerated by both age groups. The most common adverse event was somnolence, which occurred in a dose-related manner. Based on the similar pharmacokinetic profiles, dosing of Xanax XR should be similar in adolescents and adults.

Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects

Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.

Application of a computational decision model to examine acute drug effects on human risk taking.

In 3 previous experiments, high doses of alcohol, marijuana, and alprazolam acutely increased risky decision making by adult humans in a 2-choice (risky vs. nonrisky) laboratory task. In this study, a computational modeling analysis known as the expectancy valence model (J. R. Busemeyer & J. C. Stout, 2002) was applied to individual-participant data from these studies, for the highest administered dose of all 3 drugs and corresponding placebo doses, to determine changes in decision-making processes that may be uniquely engendered by each drug. The model includes 3 parameters: responsiveness to rewards and losses (valence or motivation); the rate of updating expectancies about the value of risky alternatives (learning/memory); and the consistency with which trial-by-trial choices match expected outcomes (sensitivity). Parameter estimates revealed 3 key outcomes: Alcohol increased responsiveness to risky rewards and decreased responsiveness to risky losses (motivation) but did not alter expectancy updating (learning/memory); both marijuana and alprazolam produced increases in risk taking that were related to learning/memory but not motivation; and alcohol and marijuana (but not alprazolam) produced more random response patterns that were less consistently related to expected outcomes on the 2 choices. No significant main effects of gender or dose by gender interactions were obtained, but 2 dose by gender interactions approached significance. These outcomes underscore the utility of using a computational modeling approach to deconstruct decision-making processes and thus better understand drug effects on risky decision making in humans.

Intra-ventral tegmental area heroin-induced place preferences in rats are potentiated by peripherally administered alprazolam

The present experiment was designed to replicate and extend previous results of an opiate + benzodiazepine interaction in which peripherally administered alprazolam was observed to modulate behavior resulting from intravenous injections of heroin. As a first step in determining the role of central sites in this drug interaction, changes in drug reward (measured by conditioned place preference; CPP) were assessed in rats given systemic administration of alprazolam coupled with intracranially infused heroin (into the ventral tegmental area; VTA). Sprague–Dawley rats were implanted with guide cannula targeting the VTA, after which a heroin-induced CPP dose–response curve was determined (2.5–40 ng administered bilaterally in 0.5 μl/side). In other animals, intra-VTA heroin-induced place preferences were challenged with systemically applied alprazolam (0.125 mg/kg IP). The data confirm that rats dose-dependently develop reliable place preferences for a distinct environment paired with bilateral VTA-infusions of heroin. Additionally, when a non-rewarding dose of alprazolam was combined with a non-rewarding bilateral intra-VTA heroin dose (5 ng), a significant CPP was produced. These data extend earlier results by demonstrating that a systemically applied benzodiazepine can enhance the rewarding effects produced by central opiate administration. The results suggest that the VTA might be a site where this opiate + benzodiazepine interaction occurs.

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance

There is evidence of more widespread use and abuse of benzodiazepines (BZPs) among elderly women. However, factors underlying this observation are poorly understood but could be related to more intense withdrawal reactions, which are a major risk factor for continued BZP use. We previously reported elevations in interdose morning plasma cortisol levels in healthy elderly individuals after chronic treatment with alprazolam, possibly consistent with increased hypothalamic-pituitary-adrenal (HPA) axis activity and drug withdrawal. In this study, we examined sex-related differences in this population. Twenty-five cognitively intact healthy elderly (13 women and 12 men) participated in a parallel, double-blind, placebo-controlled study that included a group that received acute and chronic (3 weeks) treatment with alprazolam (0.5 mg b.i.d.). Elderly women, but not men, experienced significant elevations in interdose morning plasma cortisol levels over 3 weeks of chronic treatment with alprazolam (0.5 mg b.i.d.) compared to placebo. In addition, higher morning plasma cortisol levels were significantly associated with better cognitive performance but not with higher plasma drug levels or greater degree of tolerance development to an acute alprazolam challenge. Elderly females experienced a greater interdose activation of the HPA axis during treatment with therapeutic doses of alprazolam than men, which could be related to drug withdrawal.

A method for determining the magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of two different doses alprazolam

While there is no doubt that benzodiazepine administration leads to transient cognitive impairment in healthy adults, the nature and magnitude of such impairment has not been well described. The cognitive effects of a single dose of alprazolam 0.5 and 1 mg were therefore assessed in 36 healthy adults on measures of psychomotor function, visual attention, working memory, planning and learning in a double-blind parallel-groups study. Measures of these different cognitive functions were selected on the basis of their brevity and because they yielded distributions of performance data that were without skew, floor or ceiling effects of range restriction (i.e. normal distributions). With data satisfying the assumptions for parametric analysis, measures of effect size could be computed in addition to significance testing, thus allowing for direct and meaningful comparison between the different performance measures used. Alprazolam 0.5 mg reduced only the speed of attentional performance although the magnitude of this reduction was large (d = 0.8). At 1.0 mg, impairments in psychomotor function, equivalent to that seen for attentional function at the lower dose, were observed. In addition, moderate (d approx = 0.5) impairments in working memory, and learning also became obvious. When considered together, these results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also become impaired, and it is likely that the combination of these led to the observed moderate impairments in higher level executive and memory processes. The current study also illustrates a method for directly comparing the magnitude of change in cognitive function between measures with different performance metrics.