Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.

Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine.

Venlafaxine is a clinically effective antidepressant. Caffeine is a metabolic probe for the quantitative measurement of CYP1A2 activity in vivo. This open-label study evaluated the effect of steady-state venlafaxine on CYP1A2-dependent metabolism, as measured by the pharmacokinetic disposition of caffeine, and urinary caffeine metabolite ratios (CMRs). Sixteen healthy subjects received 200 mg of caffeine orally before (Day 1) and after (Day 8) venlafaxine was titrated to steady-state (37.5 mg every 12 hours on Days 2-4, then 75 mg every 12 hours on Days 5-8). Samples were collected before and for 24 hours after caffeine dosing for the determination of caffeine in plasma and 1,7-dimethylxanthine, 3,7-dimethylxanthine, 1,7-dimethyluric acid (17U), 1-methylxanthine (1X) and 1-methyluric acid (1U), and 5-acetylamino-6-amino-3-methyluracil (AAMU) in urine. Blood samples were obtained before venlafaxine doses on Days 7 and 8 (morning dose only) for the determination of trough venlafaxine and O-desmethylvenlafaxine levels. Venlafaxine did not significantly alter the pharmacokinetics of caffeine and its metabolites. Plasma caffeine AUC was unchanged and remained within the bioequivalence criteria (90% confidence interval: 87.9%-102%) in the presence of venlafaxine. Urine metabolite data showed variable increases and decreases in the CMR [(AAMU + 1U + 1X)/17U] for individual subjects. However, the mean CMR was altered by < 10% in the presence of venlafaxine. This in vivo study demonstrated that venlafaxine did not alter the pharmacokinetic profile of caffeine and confirms in vitro data that venlafaxine does not inhibit CYP1A2 metabolism. Therefore, venlafaxine appears to have a relatively low potential for drug interactions based on CYP1A2 inhibition.

Effect of venlafaxine on the pharmacokinetics of risperidone.

An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risperidone before and after venlafaxine dosing to steady state. No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety. However, venlafaxine weakly altered the pharmacokinetics of risperidone. Oral clearance decreased 38%, and the volume of distribution decreased 17%, resulting in a 32% increase in the AUC for risperidone. Renal clearance of 9-hydroxyrisperidone also decreased by 20% in the presence of venlafaxine. Safety profiles of both drugs were not altered. This study demonstrated that venlafaxine did not affect the pharmacokinetic profile of 9-hydroxyrisperidone or the total active moiety, although it weakly inhibited the metabolism of risperidone. These results show that venlafaxine is unlikely to be involved in a pharmacokinetic interaction with concomitant risperidone.

Effect of venlafaxine on the pharmacokinetics of terfenadine.

The effect of steady-state venlafaxine administration on the single-dose pharmacokinetic profile of terfenadine, a cytochrome pigment (P450) isoenzyme CYP3A4 substrate, and its active acid metabolite (fexofenadine) was evaluated in an open-label, nonrandomized study. Twenty-six healthy subjects were given a 120-mg oral dose of terfenadine before and after venlafaxine was titrated up to steady-state. Blood samples were drawn before terfenadine dosing and at various intervals for 48 hours after dosing to measure plasma concentrations of terfenadine and its acid metabolite. Blood samples were obtained before each venlafaxine dose to measure trough levels of venlafaxine and O-desmethyl-venlafaxine. Single-dose pharmacokinetic parameters of terfenadine did not change significantly in the presence of steady-state venlafaxine. However, terfenadine acid metabolite area under the plasma concentration-time curve decreased by approximately 25 percent; this was not thought to be related to the P450 isoenzyme system. These results are consistent with in vitro studies and in vivo studies with other CYP3A4 substrates, indicating that venlafaxine has a low potential for drug-drug interactions that result from inhibition of the CYP3A4 isoenzyme.

Low-dose venlafaxine treatment in panic disorder.

Venlafaxine, a structurally novel antidepressant that combines mechanisms of action of both the cyclic antidepressants and SSRIs, may be effective in the treatment of panic disorder. Thirteen patients with DSM-IV panic disorder with or without agoraphobia participated in an open-label, fixed-flexible dose treatment study with venlafaxine. All patients who completed the 10-week trial exhibited statistically significant decreases in scores on anxiety symptoms as well as complete cessation of panic attacks at an effective mean daily dose of 47 mg per day. Venlafaxine was well tolerated in all completers. Venlafaxine may be an effective antipanic agent, even at lower than typical antidepressant dosages.

Effect of venlafaxine on the pharmacokinetics of alprazolam.

Potential pharmacokinetic effects of venlafaxine on alprazolam, a substrate of the cytochrome pigment 450 (CYP) isoenzyme CYP3A4, were investigated in 16 healthy volunteers. A single 2-mg oral dose of alprazolam was combined with steady-state levels of venlafaxine administered orally at 75 mg twice daily. The levels of alprazolam in plasma and of alprazolam, alpha-hydroxyalprazolam, and 4-hydroxyalprazolam in urine were determined. Steady-state venlafaxine and O-desmethylvenlafaxine concentrations in plasma were reached before venlafaxine was coadministered with alprazolam. Coadministering venlafaxine increased the apparent oral clearance and volume of distribution of alprazolam by 36 percent and 9 percent, respectively, and decreased the alprazolam area under the concentration-time curve and half-life by 29 percent and 21 percent, respectively. There were small but statistically significant increases in mean baseline scores for the digit-symbol substitution and symbol copying tests, probably reflecting a time-dependent learning effect. The maximum score decrease from baseline for these two tests also increased, possibly representing an additive effect of alprazolam and venlafaxine. Overall, venlafaxine did not inhibit the CYP3A4-mediated metabolism of alprazolam in vivo, which corroborates other in vitro and in vivo data showing a lack of CYP3A4 inhibition with venlafaxine.

Once- versus twice-daily venlafaxine therapy in major depression: a randomized, double-blind study.

BACKGROUND: Psychotropic drug dosing regimens are often based on the pharmacokinetic elimination half-life of the compound. This implies that the pharmacokinetic half-life of the drug may be the critical or sole determinant of pharmacodynamic half-life. In the present study, we examined the safety and efficacy of once- versus twice-daily dosing regimens of the immediate-release formulation of venlafaxine, a serotonin and norepinephrine reuptake site blocker with a short elimination half-life. METHOD: Forty-eight patients with a diagnosis of DSM-IV major depressive episode were randomly assigned to once-daily (N = 25) versus twice-daily (N = 23) venlafaxine. Venlafaxine was started at 37.5 mg daily with specified increments up to 225 mg daily. Efficacy was rated using the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale (CGI). RESULTS: Twenty-one patients in each group completed 6 weeks of treatment. We observed a significant reduction in mean weekly HAM-D and MADRS scores at weeks 1 through 6 for both dosing groups (p < .001). There were no statistically significant differences in mean HAM-D or MADRS scores between dosing groups at any time point. There was, however, a nonsignificant trend for a more rapid reduction in the mean HAM-D score at week 2 (p < .06) and in the mean MADRS score at week 1 (p < .07) and week 2 (p < .09) in the b.i.d. dosing group. Similarly, there was a significant decrease in the CGI score at week 2 (p < .02) in the b.i.d. dosing group. The rate of adverse events was similar between treatment groups; the most common adverse events were transient nausea and headaches. CONCLUSION: These results indicate that the immediate-release formulation of venlafaxine may be safe and effective in some patients when used in a once-daily dose regimen. Moreover, the present results suggest that the short elimination half-life of immediate-release venlafaxine should not be the sole determinant for multiple daily dosing and that antidepressant activity may be more profoundly influenced by a drug's pharmacodynamic half-life than by its pharmacokinetic half-life.

Interview assessment of critically Ill patients regarding resuscitation decisions. A case study in ethics research.

To examine how patients perceive and decide their resuscitation status, we monitored 113 admissions to a coronary care unit. We review the research process, including Institutional Review Board concerns, sampling bias and permission by physicians, informed consent, and the patient interview. In-depth psychiatric interviews on 16 patients demonstrated marked misperceptions about resuscitation procedures. Although standardized psychologic measures indicated distress in some of these critically ill patients, the interview itself induced no detected untoward physiologic or emotional reactions. This pilot study demonstrates the feasibility of assessing patients regarding resuscitation status and also identifies relevant methodologic problems to guide future research of resuscitation decision-making.

A longitudinal account of staff adaptation to AIDS patients on a psychiatric unit.

As more patients with AIDS and AIDS-related syndromes are admitted to psychiatric units, staffs must meet new diagnostic and therapeutic challenges while adapting to the unique stresses of treating these patients. The authors discuss several case vignettes to illustrate how the staff of a voluntary acute-stay psychiatric unit progressed over a two-year period from having difficulty treating AIDS patients within the usual therapeutic milieu to directly confronting the issues raised by the disease both among themselves and in the patient community. The authors believe that the staff's ability to cope with AIDS patients may have strongly influenced the patient community's ability to cope, and that clinical experience and educational programs were major contributors to the staff's adaptation. They conclude with several recommendations for psychiatric staffs beginning to treat AIDS patients.

Determining resuscitation status: a survey of medical professionals.

Regarding the determination of resuscitation status (RS) and the writing of do-not-resuscitate orders, we compared the recent Presidential Guidelines with the attitudes and perceptions of 143 medical professionals in a major medical center. Seventy-four percent of respondents believed that RS was primarily determined by the physician. Only 1% believed the patient decides and a minority (40%) believed the patient should decide; 61% would want to decide for themselves if they were ill. Most respondents agreed that neither patients nor staff were well-informed about the individual patient's RS. When presented case vignettes requiring a decision about RS, the respondents frequently chose a RS contrary to the wishes of a competent patient. The findings of this survey point to the significant differences between the Presidential Commission's guidelines and the actual attitudes and perceived practices of clinicians.

Impact of AIDS-related cases on an inpatient therapeutic milieu.

As more individuals whose lives are affected by acquired immune deficiency syndrome (AIDS) begin to need psychiatric hospitalization, psychiatric staffs must be prepared to handle the strong feelings aroused by the disease. The authors present case vignettes of four patients with AIDS-related problems admitted to a voluntary acute-stay ward of a teaching hospital. They then discuss the largely indifferent reaction of the other ward patients to the AIDS-related patients, the tense and fearful reaction of the staff, and the subsequent interruption of the usual functioning of the therapeutic milieu. To develop an optimal management plan, the authors recommend attention to specific principles of patient and milieu assessment.