Comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers.

BACKGROUND: The goal of this study was to evaluate the impact of cytochrome P450 2D6 extensive metabolizer (EM) or poor metabolizer (PM) status on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate) in healthy adults. METHODS: In an open-label, crossover study, 14 healthy volunteers (aged 18-55 years; 7 EMs and 7 PMs) received, in randomized sequence, single doses of venlafaxine ER 75 mg/d or desvenlafaxine 100 mg/d. Cytochrome P450 2D6 genotyping was performed, and plasma drug levels were measured. The arithmetic means and standard deviation (SD) for area under the plasma concentration-versus-time curve (AUC) and peak plasma concentration (Cmax) were calculated. Comparisons of AUC and Cmax between cytochrome P450 2D6 EMs and PMs were calculated using a Wilcoxon exact test. RESULTS: After administration of venlafaxine ER, mean Cmax and AUC of venlafaxine were significantly greater in PMs compared with EMs, whereas mean Cmax and AUC of its metabolite, desvenlafaxine, were significantly lower for PMs than for EMs (P = 0.001, all comparisons). In contrast, mean Cmax and AUC of desvenlafaxine after administration of desvenlafaxine were comparable between EMs and PMs. CONCLUSIONS: Cytochrome P450 2D6 genetic polymorphisms had no discernible impact on exposure to desvenlafaxine after desvenlafaxine administration; in contrast, compared with an EM phenotype, a PM phenotype had a significant effect on venlafaxine and desvenlafaxine plasma concentrations after venlafaxine ER administration. This reduced pharmacokinetic variability of desvenlafaxine may translate into better uniformity of response for patients receiving desvenlafaxine versus venlafaxine, but additional studies are required to test this hypothesis.

The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults.

The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C(max); 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2-hydroxydesipramine AUC (16% increase) and C(max) (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates.

An analysis of correlations among four outcome scales employed in clinical trials of patients with major depressive disorder.

BACKGROUND: The 17-item Hamilton Depression Rating Scale (HAM-D 17) remains the 'gold standard' for measuring treatment outcomes in clinical trials of depressed patients. The Montgomery Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) scales are also widely used. OBJECTIVE: This analysis of data from 22 double-blind, placebo-controlled clinical studies of venlafaxine in adult patients with major depressive disorder was aimed at assessing correlations among these 4 scales. METHODS: Changes from baseline for MADRS, HAM-D 17 and CGI-S, and end point CGI-I scores and response (>or=50% decrease from baseline HAM-D 17 or MADRS, or CGI-S or CGI-I score

Assessing the efficacy of 2 years of maintenance treatment with venlafaxine extended release 75-225 mg/day in patients with recurrent major depression: a secondary analysis of data from the PREVENT study.

The objective of this study was to evaluate the long-term efficacy of venlafaxine extended release (ER) < or =225 mg/day in patients with recurrent major depressive disorder (MDD). In this double-blind trial, outpatients with recurrent MDD (N=1096) were randomized to 10 weeks of acute-phase treatment with venlafaxine ER (75-300 mg/day) or fluoxetine (20-60 mg/day) followed by a 6-month continuation phase and two consecutive 12-month maintenance phases. At the start of each maintenance period, venlafaxine ER responders were randomized to double-blind venlafaxine ER or placebo. In this analysis, data from responders to acute and continuation treatment were analyzed during the combined maintenance phases while receiving venlafaxine ER < or =225 mg/day. Failure to maintain response was defined as an increase in maintenance dose to 300 mg/day or recurrence. Differences were calculated using Kaplan-Meier methods and compared using log-rank tests. Continuation-phase responders (n=114) receiving venlafaxine ER < or =225 mg/day comprised the analysis population (venlafaxine ER: n=55; placebo: n=59). The estimated probability for remaining well across 24 months of maintenance treatment was 67% for venlafaxine ER and 41% for placebo (P=0.007). Venlafaxine ER effectively maintained response at doses < or =225 mg/day for up to 2.5 years in patients with recurrent MDD. The findings are consistent with those of the full data set.

Analysis of the rate of improvement of specific psychic and somatic symptoms of general anxiety disorder during long-term treatment with venlafaxine ER.

INTRODUCTION: Generalized anxiety disorder (GAD) is a chronic illness with psychic and somatic symptoms that do not respond uniformly in the first weeks of treatment. METHODS: A post-hoc analysis of pooled data from five placebo-controlled, double-blind, randomized studies in non-depressed GAD patients treated with venlafaxine extended release (ER) or placebo was performed to determine the temporal response of psychic and somatic symptoms to treatment over 8 weeks. Two of the studies included extension phases of up to 6 months, the results of which were also analyzed here. RESULTS: The earliest symptoms to respond included both psychic symptoms (anxious mood, tension, behavior at interview) and somatic muscular, cardiovascular, and respiratory symptoms. The last symptoms to respond included the psychic symptoms of insomnia and fear and the somatic sensory, gastrointestinal and autonomic symptoms, perhaps in part because of drug-related side effects. Continuing treatment beyond 8 weeks in venlafaxine ER responders for up to 6 months of total treatment results not only in additional improvement in early-responding symptoms, but also in the improvement of late-responding symptoms, perhaps due in part to the development of tolerance to antidepressant side effects. CONCLUSION: Serious consideration should be given to maintaining partial responders to venlafaxine ER treatment on the same treatment for > or = 3-6 months.

An excitement subscale of the Positive and Negative Syndrome Scale.

BACKGROUND: We sought to develop and validate an excitement subscale from the Positive and Negative Syndrome Scale (PANSS) to allow the investigation of mania-like excitement symptoms in clinical trials of patients with schizophrenia using the PANSS and to provide clinicians with a short assessment tool for these states. METHODS: Baseline PANSS data from six double-blind, randomized registration trials of olanzapine, three in schizophrenia and three in acute bipolar mania, were used in these post-hoc analyses. Schizophrenia study data were pooled and randomly split in half. Exploratory principal component factor analysis was performed on half of the data. Factors were extracted based on minimum eigenvalue criteria (eigenvalue> or =1); loadings were determined using an equamax rotation. Confirmatory principal component factor analysis was performed on the other half of the data, retaining the original number of factors. Principal component factor analysis was also done for the pooled bipolar studies. Change in the new mania-like factor scores was then correlated with Young Mania Rating Scale (Y-MRS) scores in each bipolar study. RESULTS: Exploratory principal components analysis on the pooled schizophrenia data extracted five factors: negative, positive, excitement, cognitive, and depressive factors. The mania-like excitement factor was represented by four items (uncooperativeness, poor impulse control, excitement, and hostility), with only moderate loadings by tension and suspiciousness/persecution. Results were similar in the confirmatory analysis and the pooled bipolar studies. Change from baseline to endpoint for the mania-like factor correlated reasonably well (0.64-0.78) with change in Y-MRS scores in the bipolar studies. At baseline, bipolar patients scored higher than patients with schizophrenia on three of four PANSS mania-like factor items: poor impulse control, excitement, and hostility; the converse was true for most other PANSS items. CONCLUSION: Factor analyses of the PANSS consistently uncovered an excitement factor including uncooperativeness, poor impulse control, excitement, and hostility items. This factor may be useful in examining manic symptoms in studies where the addition of a scale specific to mania would be burdensome and where symptoms of excitement are part of the clinical presentation.

Longitudinal effect of olanzapine on fasting serum lipids: a randomized, prospective, 4-month study.

Our objective was to compare lipid profiles of schizophrenic patients treated with conventional antipsychotics or risperidone to those of patients switched to olanzapine. Our results indicate that in patients switched to olanzapine, fasting serum lipids initially increased then returned to pretreatment levels, and endpoint lipid levels were not significantly different from those in patients remaining on conventional antipsychotics or risperidone.

The Metabolic Syndrome in Patients With Severe Mental Illnesses.

BACKGROUND: Since the introduction of the first atypical antipsychotics in the early 1990s, this class of medication has been increasingly relied upon for the treatment of a variety of patients with psychotic and mood disorders.DATA SOURCES: The following retrospective review was derived from the MEDLINE database using the search terms metabolic syndrome, insulin resistance, obesity, diabetes, severe mental illness, schizophrenia, bipolar disorder, mood disorders, depression, unipolar depression, and prevalence from 1966 to the present. LITERATURE SYNTHESIS: Coincident with the growing usage of these agents, there have been a growing number of literature reports of changes in metabolic homeostasis among patients taking these medications. These changes have led to interest in evaluating whether there is a relationship among these mental illnesses, their psychiatric treatments, and certain physical comorbidities known collectively as the metabolic syndrome. This article reviews the existing literature around the metabolic syndrome in patients with severe mental illnesses. CONCLUSION: Patients with severe mental illnesses, particularly schizophrenia and chronic mood disorders, demonstrate a higher prevalence of metabolic syndrome or its components compared with the general population. Based upon this increased risk in these patients, baseline and periodic medical evaluations should become a standard component in ongoing clinical assessment.

Mood Disorders in Family Practice: Beyond Unipolarity to Bipolarity.

Primary care physicians increasingly have treated depressive disorders over the last decade. Unrecognized bipolar disorder, sometimes misdiagnosed as unipolar depression, may lead to treatment resistance or nonresponse. We describe differences between unipolar and bipolar disorders, focusing on recognition, diagnosis, and treatment of bipolar spectrum disorders such as bipolar I, bipolar II, antidepressant-induced mania, and cyclothymia. Broadening the understanding of these different disorders and their presentation in primary care settings can enable earlier and more targeted treatment. Though 3 mood stabilizers are U.S. Food and Drug Administration-approved for treatment of acute mania, no medications are currently approved for treating bipolar depression.

Onset of activity and time to response on individual CAPS-SX17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis.

This pooled analysis of data from two randomized, placebo-controlled trials of venlafaxine extended release (ER) assessed onset of activity and time to response on the 17 symptoms of post-traumatic stress disorder (PTSD) listed in DSM-IV and measured by the 17-item Clinician-Administered PTSD Scale (CAPS-SX17). The intent-to-treat (ITT) population comprised 687 patients (placebo, n=347; venlafaxine ER, n=340). Significant (p<0.05) separation between venlafaxine ER and placebo was observed on most CAPS-SX17 items, with earliest onset of activity and response (week 2) on items 5 (physiological reactivity on exposure to cues) and 14 (irritability or anger outbursts), and (week 4) items 1 (intrusive recollections) and 4 (psychological distress at exposure to cues). Onset of activity and response occurred later (generally, weeks 6-8) on items 9 (diminished interest/participation in activities), 10 (detachment or estrangement), 11 (restricted range of affect), 12 (sense of foreshortened future), all associated with numbing, 15 (difficulty concentrating), 16 (hypervigilance), 17 (exaggerated startle response), associated with hyperarousal, and 6 (avoidance of thoughts/feelings or conversations). Significant differences between venlafaxine ER and placebo were largely absent throughout the treatment period and at the primary week-12 end-point for items 2 (distressing dreams), 7 (avoidance of activities, places or people), 8 (inability to recall important aspect of trauma) and 13 (difficulty falling/staying asleep). These results indicate that symptoms of physiological reactivity and psychological distress in response to cues, and irritability/anger outbursts show early and robust improvement with venlafaxine ER treatment, while symptoms of numbing and hyperarousal take longer. The early and persistent effect of venlafaxine ER over placebo on anger/irritability is noteworthy in view of the clinical significance of these symptoms in PTSD.

A pooled analysis of gender and trauma-type effects on responsiveness to treatment of PTSD with venlafaxine extended release or placebo.

OBJECTIVE: To examine effects of gender and trauma type on response to treatment with venlafaxine extended release (ER) or placebo in patients with posttraumatic stress disorder (PTSD). METHOD: Data were pooled from 2 flexible-dose, parallel-group, randomized, double-blind, placebo-controlled trials: a 12-week trial conducted in the United States (March 2001 to December 2002) and a 24-week trial conducted in 12 countries outside the United States (October 2001 to December 2003). Six hundred eighty-seven outpatients with DSM-IV-diagnosed PTSD and a 17-item Clinician-Administered PTSD Scale abbreviated 1-week Symptom Status version (CAPS-SX-17) score > or = 60 were randomly assigned to treatment with venlafaxine ER (37.5 mg/day-300 mg/day, N = 340) or placebo (N = 347). The primary efficacy end point was the CAPS-SX-17 total score at week 12. Secondary end points included CAPS-SX-17 cluster scores for reexperiencing, avoidance/numbing, and hyperarousal and scores on the Connor-Davidson Resilience Scale (CD-RISC), Clinical Global Impressions-Severity of Illness scale, Sheehan Disability Scale (SDS), and 17-item Hamilton Rating Scale for Depression (HAM-D-17). Analysis-of-covariance models were used to test for differences by gender and trauma type (accidental injury, combat, nonsexual abuse, adult sexual abuse, childhood sexual abuse, unexpected death, and other), treatment (venlafaxine ER vs. placebo), and the treatment-by-trauma-type interaction. RESULTS: Using last-observation-carried-forward analysis, significant effects of treatment with venlafaxine ER were found on the CAPS-SX-17 total score and on all CAPS-SX-17 cluster scores and most other secondary measures. No significant treatment-by-gender interactions were observed. Trauma type significantly affected treatment responsiveness on symptom-related disability (SDS, p = .0057) and resilience (CD-RISC, p = .0012), with a nearly significant effect on depression (HAM-D-17, p = .0625). CONCLUSION: Overall, there does not appear to be a significant effect of gender on the efficacy of venlafaxine ER in the treatment of PTSD. Trauma type may affect treatment outcome but seems to affect domains such as disability and resilience more than core PTSD symptoms.

The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: Outcomes from the 2-year and combined maintenance phases.

OBJECTIVE: To report second-year results from the 2-year maintenance phase of a long-term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression. METHOD: Outpatients with recurrent unipolar depression (DSM-IV criteria; N = 1096) were randomly assigned in a 3:1 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. Responders (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score or= 50% decrease from baseline) entered a 6-month, double-blind continuation phase on the same medication. Continuation-phase responders were enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo, and fluoxetine responders were continued for each period. The second 12-month maintenance phase compared the time to recurrence of depression with venlafaxine ER (75 to 300 mg/day) versus placebo as the primary efficacy measure. The primary definition of recurrence was a HAM-D(17) total score > 12 and < 50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. The time to recurrence was evaluated using Kaplan-Meier methods and compared between the venlafaxine ER and placebo groups using log-rank tests. Secondary outcome measures included rates of response and remission (defined as HAM-D(17)

The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study: outcomes from the acute and continuation phases.

BACKGROUND: We evaluated the comparative efficacy and safety of venlafaxine extended release (ER) and fluoxetine in the acute and continuation phases of treatment. METHODS: In this multicenter, double-blind study, outpatients with recurrent unipolar major depression were randomly assigned to receive venlafaxine ER (75-300 mg/day; n = 821) or fluoxetine (20-60 mg/day; n = 275). After a 10-week acute treatment phase, responders entered a 6-month continuation phase of ongoing therapy with double-blind venlafaxine ER (n = 530) or fluoxetine (n = 185). In the acute phase, the primary outcome was response, defined as a 17-item Hamilton Depression Rating Scale (HDRS) score < or =12 or > or =50% decrease from baseline; the secondary outcome was remission, defined as a HDRS score < or =7. In the continuation phase, the primary outcome was the proportion of patients who sustained response or remission. Secondary measures included time to onset of sustained response or remission (i.e., meeting criteria at two or more consecutive visits), relapse rates, and quality-of-life measures. RESULTS: At the acute treatment phase end point, response rates were 79% for both venlafaxine ER and fluoxetine; remission rates were 49% and 50% for venlafaxine ER and fluoxetine, respectively. In the continuation phase, response rates were 90% and 92%, and remission rates were 72% and 69% for venlafaxine ER and fluoxetine, respectively. Rates of sustained remission at the end of the continuation phase were 52% and 58% for venlafaxine ER and fluoxetine, respectively. CONCLUSION: Venlafaxine ER and fluoxetine were comparably effective during both acute and continuation phase therapy.

Biomarkers in psychotropic drug development.

The authors review the use of biomarkers in the development of novel psychotropic agents. They briefly review clinical drug development, emphasizing the importance of incorporating biomarkers. For the development of psychotropic agents, biomarkers are particularly useful for assessing central nervous system exposure and effects and for serving as surrogate measures for safety and efficacy. Collectively, biomarkers allow for more accurate estimation of doses for clinical trials as drug development progresses. For drugs that target the pathophysiology of Alzheimer disease, several promising biomarkers are becoming available that may allow improved signal detection in clinical trials. Procedures for developing new drugs are evolving rapidly. Technical advances in the field are making it possible to shift from empirically-based methods to mechanistically-driven schemes. Biomarkers enhance the quality and safety of clinical drug development and reduce its cost and duration.