Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers.

BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. METHODS: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. FINDINGS/RESULTS: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. IMPLICATIONS/CONCLUSIONS: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder.

Comparative Ethanol-Induced Potentiation of Stimulatory Responses to Dexmethylphenidate Versus Methylphenidate.

The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the time course of maximal drug exposure after a single dose. In a 4-way, randomized, crossover study design, 12 men and 12 women normal volunteers received d-MPH (0.15 mg/kg) or dl-MPH (0.3 mg/kg) with or without ethanol (0.6 g/kg). Serial visual analog scales were used as surrogates for drug abuse liability ("high," "good," "like," "stimulated," and "any drug effect"). Combining pure d-MPH with ethanol significantly (P < 0.005) increased the area under the effect curves (AUC(0-5.25h)) of all 5 subscales. The dl-MPH-ethanol combination significantly (P < 0.05) increased these AUCs with the exception of like (P = 0.08). Effects of the pure d-MPH-ethanol combination exhibited delayed potentiation relative to dl-MPH-ethanol. A pharmacokinetic interaction between the l-isomer of dl-MPH and ethanol has previously been shown to increase early exposure to d-MPH. Administration of the pure isomer d-MPH precludes this absorption phase pharmacokinetic interaction with ethanol. This notwithstanding, the pure d-MPH-ethanol combination resulted in comparable, if not greater, cumulative stimulant potentiation than the dl-MPH-ethanol combination. These findings provide evidence of a pharmacodynamic component to d-MPH-ethanol synergistic interactions and carry implications for the rational drug individualization in the treatment of attention-deficit/hyperactivity disorder.

The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity.

Milk thistle (Silybum marianum) extracts are widely used as a complementary and alternative treatment of various hepatic conditions and a host of other diseases/disorders. The active constituents of milk thistle supplements are believed to be the flavonolignans contained within the extracts. In vitro studies have suggested that some milk thistle components may significantly inhibit specific cytochrome P450 (P450) enzymes. However, determining the potential for clinically significant drug interactions with milk thistle products has been complicated by inconsistencies between in vitro and in vivo study results. The aim of the present study was to determine the effect of a standardized milk thistle supplement on major P450 drug-metabolizing enzymes after a 14-day exposure period. CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5 activities were measured by simultaneously administering the four probe drugs, caffeine, tolbutamide, dextromethorphan, and midazolam, to nine healthy volunteers before and after exposure to a standardized milk thistle extract given thrice daily for 14 days. The three most abundant falvonolignans found in plasma, following exposure to milk thistle extracts, were silybin A, silybin B, and isosilybin B. The concentrations of these three major constituents were individually measured in study subjects as potential perpetrators. The peak concentrations and areas under the time-concentration curves of the four probe drugs were determined with the milk thistle administration. Exposure to milk thistle extract produced no significant influence on CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 activities.

An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: a dose escalation study.

Milk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans have been only partially investigated in humans. Furthermore, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study evaluated the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses of either one (175 mg), two (350 mg), or three (525 mg) milk thistle capsule(s) on three separate study visits. Additionally, the steady-state pharmacokinetic parameters were determined after the subjects were administered one capsule three times daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3 ± 0.9 versus 0.8 ± 0.9 ng/mg creatinine) but failed to reach statistical significance (P = 0.076).

Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans.

Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.

A randomized controlled trial comparing the memory effects of continuation electroconvulsive therapy versus continuation pharmacotherapy: results from the Consortium for Research in ECT (CORE) study.

OBJECTIVE: To compare the memory effects of continuation electroconvulsive therapy (C-ECT) versus continuation pharmacologic intervention (C-PHARM) at 12 and 24 weeks after completion of acute electroconvulsive therapy (ECT). METHOD: Eighty-five patients with Structured Clinical Interview for DSM-IV-diagnosed unipolar major depressive disorder, enrolled in a multisite, randomized, parallel-design trial conducted at 5 academic medical centers from 1997 to 2004, who had remitted with an acute course of bilateral ECT and remained unrelapsed through 24 weeks of continuation therapy, were included in this analysis. They were randomly assigned to C-ECT (10 treatments) or nortriptyline plus lithium (monitored by serum blood levels) for 24 weeks. Objective neuropsychological measures of retrograde and anterograde memory and subjective assessment of memory were obtained at baseline, 12 weeks, and 24 weeks. The Rey Auditory-Verbal Learning Test and the Autobiographical Memory Interview were the primary outcome measures. RESULTS: The C-PHARM group showed a greater group difference (P < .01) for baseline to 12-week change for the Autobiographical Memory Interview. No other memory measures showed group differences for change scores from baseline to 12 weeks. Groups showed no baseline to 24-week change-score differences on any of the memory measures. For both groups, 12-week objective anterograde memory scores (eg, Auditory-Verbal Learning Test percent retention P = .0001; Rey-Osterrieth Complex Figure or Taylor Figure percent retention P < .002) and 24-week subjective memory scores were significantly improved (Squire Subjective Memory Questionnaire P < .02) over baseline. This result reflects the apparent resolution of a presumed decrement in anterograde memory associated with acute ECT preceding this study. CONCLUSIONS: The finding of no memory outcome differences between unrelapsed recipients of C-ECT and C-PHARM is consistent with clinical experience. Memory effects have only a small role in the choice between C-ECT and C-PHARM.

Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE).

BACKGROUND: Although electroconvulsive therapy (ECT) has been shown to be extremely effective for the acute treatment of major depression, it has never been systematically assessed as a strategy for relapse prevention. OBJECTIVE: To evaluate the comparative efficacy of continuation ECT (C-ECT) and the combination of lithium carbonate plus nortriptyline hydrochloride (C-Pharm) in the prevention of depressive relapse. DESIGN: Multisite, randomized, parallel design, 6-month trial performed from 1997 to 2004. SETTING: Five academic medical centers and their outpatient psychiatry clinics. PATIENTS: Two hundred one patients with Structured Clinical Interview for DSM-IV-diagnosed unipolar depression who had remitted with a course of bilateral ECT. INTERVENTIONS: Random assignment to 2 treatment groups receiving either C-ECT (10 treatments) or C-Pharm for 6 months. MAIN OUTCOME MEASURE: Relapse of depression, compared between the C-ECT and C-Pharm groups. RESULTS: In the C-ECT group, 37.1% experienced disease relapse, 46.1% continued to have disease remission at the study end, and 16.8% dropped out of the study. In the C-Pharm group, 31.6% experienced disease relapse, 46.3% continued to have disease remission, and 22.1% dropped out of the study. Both Kaplan-Meier and Cox proportional hazards regression analyses indicated no statistically significant differences in overall survival curves and time to relapse for the groups. Mean +/- SD time to relapse for the C-ECT group was 9.1 +/- 7.0 weeks compared with 6.7 +/- 4.6 weeks for the C-Pharm group (P = .13). Both groups had relapse proportions significantly lower than a historical placebo control from a similarly designed study. CONCLUSIONS: Both C-ECT and C-Pharm were shown to be superior to a historical placebo control, but both had limited efficacy, with more than half of patients either experiencing disease relapse or dropping out of the study. Even more effective strategies for relapse prevention in mood disorders are urgently needed.

Lexical and metrical stress in word recognition: lexical or pre-lexical influences?

The influence of lexical stress and/or metrical stress on spoken word recognition was examined. Two experiments were designed to determine whether response times in lexical decision or shadowing tasks are influenced when primes and targets share lexical stress patterns (JUVenile-BIBlical [Syllables printed in capital letters indicate those syllables receiving primary lexical stress.]). The results did not support an effect of lexical stress on the organization of lexical memory. In Experiment 3 primes and targets whose first syllables shared lexical stress only (MUDdy-PASta), metrical stress only (alTHOUGH-PASta), both cues (LECtern-PASta), or neither cue (conTROL-PASta) revealed no priming effect. However, targets whose first syllables were strong were responded to faster than targets whose first syllables were weak. Experiment 4 manipulated the metrical stress patterns of bi-syllabic primes and targets. Targets with strong-weak metrical stress patterns were responded to more quickly than those with strong-strong or weak-strong patterns. Although the priming paradigm did not reveal an influence of lexical and metrical stress on the organization of lexical memory, the data do support an influence of strong syllables on the processing of auditorily presented words.

Relief of expressed suicidal intent by ECT: a consortium for research in ECT study.

OBJECTIVE: This study assessed the incidence, severity, and course of expressed suicidal intent in depressed patients who were treated with ECT. The data are from the first phase of an ongoing, collaborative multicenter study, the overall aim of which was to compare continuation ECT with pharmacotherapy in the prevention of relapse after a successful course of ECT. METHOD: Suicidal intent, as expressed by patients during an interview, was scored at baseline and before each ECT session with item 3 on the 24-item Hamilton Depression Rating Scale in 444 patients with unipolar depression. RESULTS: One hundred thirty-one patients (29.5%) reported suicidal thoughts and acts (score of 3 or 4) at baseline. Scores decreased to 0 after 1 week (three ECT sessions) in 38.2% of the patients, after 2 weeks (six ECT sessions) in 61.1%, and in 80.9% at the end of the course of treatment. CONCLUSIONS: Expressed suicidal intent in depressed patients was rapidly relieved with ECT. Evidence-based treatment algorithms for major depressive mood disorders should include dichotomization according to suicide risk, as assessed by interview. For patients at risk, ECT should be considered earlier than at its conventional "last resort" position.

Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report.

BACKGROUND: Remission of illness in patients with major depressive disorder (MDD) is achieved in less than half of patients initially treated with medication. Electroconvulsive therapy (ECT) is another treatment option. We report the speed of response and remission rates in a cohort of depressed patients who received a course of acute-phase ECT in the initial phase of an ongoing multicenter randomized trial of continuation ECT versus pharmacotherapy. METHOD: Patients with MDD according to DSM-IV criteria received bilateral ECT 3 times weekly. Prior to each treatment, a 24-item Hamilton Rating Scale for Depression (HAM-D-24) score was obtained by a clinical rater. Sustained response was defined as a > or = 50% reduction in baseline HAM-D-24 score for at least 2 and all subsequent measurement occasions. Remission was defined as HAM-D-24 scores of < or = 10 for at least the last 2 consecutive assessments. Data were collected from May 1997 through November 2000. RESULTS: Of the 253 patients who entered the study, 86% (N = 217) completed the acute course of ECT. Sustained response occurred in 79% of the sample, and remission occurred in 75% of the sample (N = 253); 34% (85/253) of patients achieved remission at or before ECT #6 (week 2), and 65% (164/253) achieved remission at or before ECT #10 (weeks 3-4). Over half (54%; 136/253) had an initial first response by ECT #3 (end of week 1). CONCLUSION: ECT was associated with rapid response and remission in a high percentage of patients. ECT warrants early consideration in treatment algorithms for patients with MDD.

Relationship between somatization and remission with ECT.

Patients treated with electroconvulsive therapy (ECT) were divided into those with less severe depression and those with more severe depression. In the less severely depressed group, high somatic anxiety and hypochondriasis predicted a low likelihood of sustained remission with ECT. In the more severely depressed group, these traits were not predictive of ECT outcome.

Combined ECT and Antidepressant Drug Therapy.

The current literature on the interaction between antidepressant drugs and electroconvulsive therapy (ECT) is reviewed. Tricyclic antidepressants, atypical antidepressants, and monoamine oxidase inhibitors are discussed. The efficacy of combinations and possible adverse effects (mainly cardiovascular and seizure threshold effects) are considered. Many previous studies on the efficacy of combinations used inadequate methods, and the safety data consist largely of anecdotes and small case series. Additional studies are needed to assess the safety and efficacy of the combined use of antidepressants and ECT.

Weekly ECT in Geriatric Depression.

Fifteen elderly depressed psychiatric inpatients were randomly assigned to receive either standard three-times-weekly electroconvulsive therapy (ECT) or once-weekly ECT. Outcome measures included cognitive assessment and antidepressant response. Although both groups improved with treatment, the three-times-weekly group improved substantially more quickly. There was no difference in cognitive effect between the two groups. We conclude that the traditional three-times-weekly schedule of ECT may optimally balance speed of antidepressant response and cognitive impairment.