Do suicidal thoughts or behaviors recur during a second antidepressant treatment trial?

OBJECTIVE: A subset of patients undergoing initial antidepressant treatment experience worsening of symptoms, including thoughts of suicide or suicidal behavior. The present study explores whether this subset of patients is also more likely to experience recurrence or worsening of these symptoms during a second treatment trial with a different antidepressant. METHOD: We examined data collected between July 2001 and September 2006 from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter effectiveness study of outpatients with major depressive disorder diagnosed by a DSM-IV checklist. In that study, subjects who did not remit with citalopram treatment were randomized among next-step treatment options. The main outcome measure for this post hoc analysis, presence of suicidal thoughts and behaviors, was assessed using the suicide item on the 16-item Quick Inventory of Depressive Symptomatology--Self-Rated. Logistic regression was used to examine association between emergence or worsening of these symptoms with the first-step (level 1) citalopram treatment and emergence or worsening with next-step (level 2) pharmacologic or psychosocial treatment, including augmentation with bupropion or buspirone; switch to sertraline, venlafaxine, or bupropion; or addition of or switch to cognitive therapy. RESULTS: Of 1,240 subjects entering level 2 with a score less than 3 on the suicide item, 102 (8.2%) experienced emergence or worsening of suicidal thoughts or behaviors. Emergence or worsening at level 1 was strongly associated with reemergence or worsening at level 2 (crude OR = 4.00 [95% CI, 2.45-6.51], adjusted OR = 2.95 [95% CI, 1.76-4.96]). Overall magnitude of risk was similar among next-step pharmacologic augmentation versus switching. CONCLUSIONS: These results suggest that individuals who experience emergence or worsening of suicidal thoughts or behaviors with one antidepressant treatment may warrant closer follow-up during the next-step treatment, as these symptoms may recur regardless of which modality is selected.

Treatment with duloxetine in adults and the incidence of cardiovascular events.

BACKGROUND: Cardiovascular events are inconclusively associated with duloxetine use in clinical trials and spontaneous reports. This analysis of cardiovascular events in relation to duloxetine use within a large health insurance database provides further data on the association. METHODS: This cohort study was conducted within a population with commercial health insurance. Adults with depression who initiated duloxetine were matched to separate cohorts of initiators of venlafaxine, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), along with untreated patients with depression, and enrollees without depression. The cohorts were followed for cardiovascular events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization), which were identified through health insurance claims and confirmed upon review of underlying medical records. Proportional hazards and Poisson regression models were used for comparisons. RESULTS: There were approximately 64,000 person-years of follow-up among all cohorts (including 17,386 person-years among 21,457 duloxetine initiators), yielding 279 cardiovascular events. Relative to duloxetine initiators, those without depression had lower rates of combined events (incidence rate ratio [IRR], 0.51; 95% confidence interval [CI], 0.32-0.81) and coronary revascularizations (IRR, 0.51; 95% CI 0.29-0.89). The IR of each of the cardiovascular outcomes did not differ across the other cohorts, even accounting for time since last duloxetine dispensing. CONCLUSION: The incidence of cardiovascular events did not differ among duloxetine initiators relative to other antidepressant comparators or those with untreated depression but was higher than those without depression, suggesting that depression itself (or associated morbidities) may affect the risk of cardiovascular events.

Cost effectiveness of escitalopram versus SNRIs in second-step treatment of major depressive disorder in Sweden.

OBJECTIVES: Escitalopram is the S-enantiomer of citalopram and is the most discriminating of the selective serotonin reuptake inhibitors (SSRI). The aim of the current analysis was to assess the cost effectiveness of escitalopram versus the serotonin norepinephrine reuptake inhibitors (SNRI) duloxetine and generic venlafaxine as second-step treatment of major depressive disorder. METHODS: The analysis was based on a decision analytic model. Effectiveness outcomes were quality-adjusted life-years (QALYs) and remission rates; cost outcomes were direct medical costs, including impact of treating adverse events, and indirect costs associated with lost productivity. The analysis was performed from the societal perspective in Sweden over a 6-month timeframe. RESULTS: Estimated remission rates showed an incremental effectiveness in favour of escitalopram of 16.4 percentage points compared with both SNRI comparators. The escitalopram strategy was associated with a 0.025 increase in QALYs. Sensitivity analyses demonstrated that the model is robust and that escitalopram remains a cost-effective option when considering future predicted price reductions of generic venlafaxine. LIMITATIONS: The main limitation in this study was the lack of data available for second-step treatment. The remission rates, which are a key input to the model, were obtained from a relatively small sample of patients on second-step treatment and there are no published relapse rates for second-step treatment. The model also assumed that there was no difference in the adverse event (AE) rates between treatments after the first 8 weeks. CONCLUSIONS: This cost-effectiveness analysis indicates that, at a willingness-to-pay threshold of £30,000, escitalopram is the most cost-effective second-step treatment option for MDD in Sweden in over 85% cases compared with both venlafaxine and with duloxetine. Benefits for escitalopram included both increased effectiveness and reduced overall costs. The major contributing costs were those associated with productivity loss. The model was shown to have internal validity and robustness through the use of stochastic simulations and sensitivity analyses, which were conducted around the key efficacy parameters.

Desvenlafaxine: application withdrawal. Desvenlafaxine: withdrawal of marketing application for depression also.

A welcome move! This psychoactive agent has an unfavourable risk-benefit balance in both hot flushes and depression.

Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study.

BACKGROUND: Generic drugs are lower-cost versions of patent-expired brand-name medications. Bioequivalence is decreed when the 90% confidence intervals for the ratios of the generic to the reference compound for the area under the curve and maximum plasma concentration (C(max)) fall within a 0.80 to 1.25 range. The aim of the present pilot study was to compare the pharmacokinetic profiles of brand-name and generic formulations of citalopram and extended-release venlafaxine. METHOD: Effexor XR/Novo-venlafaxine XR 75 mg and Celexa/Gen-citalopram 40 mg were studied in a randomized crossover design. Healthy male volunteers took either Effexor XR or Novo-venlafaxine XR for 4 days, a 4-day washout was allowed, and then participants took the other venlafaxine formulation for 4 days. This was followed by a washout of at least 7 days. The participants then took Celexa or Gen-citalopram for 8 days, a 14-day washout was allowed, and then participants took the other citalopram formulation for 8 days. In each of the study phases, the sequence of treatment (brand-name x generic) was randomly assigned. Plasma levels of drugs were measured at fixed intervals after participants took the drugs and at steady state. The study was conducted from November 2007 through July 2008. RESULTS: Twelve participants completed the venlafaxine study. Nine of the participants, plus 3 new participants, were then enrolled in the citalopram study, to maintain a total of 12. The plasma levels of citalopram were similar after ingestion of the brand-name and generic drugs. After ingestion of venlafaxine, the C(max) values were 36 +/- 6 ng/mL and 52 +/- 8 ng/mL in the brand-name and generic groups, respectively. The ratio of the log-transformed values of C(max) was 150% and, therefore, not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-desmethyl-venlafaxine [ODV]) was also significantly increased in the generic group (+43% higher in the generic group at 3 h; +48% higher at 5 h; p < .05). No differences were seen at steady state for either ODV or venlafaxine. Participants taking Novo-venlafaxine reported 3 times more side effects than those taking Effexor XR. Pill contents were identical in the 2 groups, but extraction of venlafaxine occurred more readily with the generic formulation than with the brand-name formulation, which required an additional sonication. CONCLUSION: Gen-citalopram appeared to be bioequivalent to Celexa, whereas Novo-venlafaxine XR was not bioequivalent to Effexor XR. Consequently, the Novo-venlafaxine formulation released its active ingredient more rapidly and outside the acceptable norm. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00676039.

An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

Desvenlafaxine: another "me too" drug?

OBJECTIVE: To compare desvenlafaxine with its parent drug, venlafaxine, to determine the usefulness of this new medication. DATA SOURCES: Information was obtained through a MEDLINE search (1966-June 2008) and from published abstracts. Search terms included desvenlafaxine, O-desmethylvenlafaxine, Pristiq, major depressive disorder, and venlafaxine. STUDY SELECTION AND DATA EXTRACTION: All English-language studies and abstracts pertaining to desvenlafaxine and venlafaxine were considered for inclusion. Preference was given to human data. DATA SYNTHESIS: Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor and is the active metabolite of the antidepressant venlafaxine. The recommended dose is 50 mg daily, based on the efficacy and safety data of 50, 100, 150, 200, and 400 mg of desvenlafaxine. The response and remission rates of depression at 8 weeks for the 50-mg dose are 51-63% and 31-45%, respectively. These rates are comparable with those seen with venlafaxine (58% and 45%, respectively). Adverse effects are also similar to those of venlafaxine, with the most common being insomnia, somnolence, dizziness, and nausea. The decreased potential of CYP2D6 activity with desvenlafaxine compared with the parent drug may be a potential advantage in patients on other medications metabolized via this enzymatic pathway. Also, desvenlafaxine tablets are less expensive than extended-release (XR) venlafaxine, which may decrease healthcare costs in the short term. However, venlafaxine XR is expected to go off patent in 2010. CONCLUSIONS: With the overall similarity between these 2 drugs and the potential lack of cost savings, the need for desvenlafaxine and its ultimate utility in treating major depressive disorder appears to be insignificant.

Adequacy of venlafaxine dose prescribing in major depression and hospital resources implications.

Venlafaxine, a dual serotonin and noradrenaline re-uptake inhibitor, has been found to be effective at doses below 375 mg daily, but for patients with major depression higher doses can be required. In this retrospective naturalistic study, we investigated the effectiveness and resource implications of prescribing higher than standard doses of venlafaxine (tablet preparation). Ninety-six outpatients fulfilling DSM-IV criteria for major depressive disorder were assigned to two demographically matched cohorts: cohort A, receiving high doses (n = 38; doses > or =375 mg/day) and cohort B, receiving standard doses (n = 58; doses <375 mg/day). Data on hospital resources, drugs and medical profiles were extracted from patients' records. Information on cohort A was also obtained before their high-dose regime, while taking standard doses. A within-group analysis of cohort A showed that patients spent fewer days in hospital (P = 0.03) and had fewer outpatients visits (P < 0.01) when on high doses than when on standard doses. A between-group analysis found that cohort A, while on higher doses, had fewer outpatient visits compared with cohort B (P < 0.01). Patients in both groups had satisfactory drug tolerability and efficacy profiles. There were no differences between cohorts with regard to baseline characteristics, a part from the more intensive use of additional medications made by cohort A. Our preliminary investigation suggests that higher doses of venlafaxine may be cost-saving in relation to selected hospital resources. However, one cannot firmly conclude that the change in service use is due to the higher-dose regime, and we recommend further research to ascertain the cost-effectiveness of adequate dose prescribing in patients with poor symptom resolution at lower doses of venlafaxine.

Venlafaxine hyponatraemia: incidence, mechanism and management.

OBJECTIVE: This prospective study was performed on patients aged >65 years commencing therapy with venlafaxine, in order to determine the incidence of hyponatraemia induced by the drug, to investigate the underlying pathophysiological mechanisms, and to evaluate a simple approach to management of this condition. METHOD: All patients aged >65 years seen by one author (MR) from all referral sources were entered into the study. Baseline biochemical tests were ordered, and if hyponatraemia developed (plasma Na <130 mmol L(-1)) additional tests were performed to ascertain the mechanism, while the patient continued on venlafaxine and fluid restriction was instituted. RESULTS: A total of 58 patients were seen, of whom 10 developed hyponatraemia, giving an incidence of 17.2%. Of these 10 patients, five were excluded from prolonged observation because of either severe medical illness, side-effects from the antidepressant or being lost to follow up. When hyponatraemia developed, it invariably did so within a few days of starting venlafaxine, and was associated with non-suppression of antidiuretic hormone in the face of a low serum osmolality. Fluid restriction (800 mL day(-1)) was effective in raising the plasma sodium to the normal range within 2 weeks, after which the fluid restriction could be relaxed without relapse occurring. These patients remained well for the follow-up period of up to 6 months. CONCLUSIONS: Patients >65 years of age should have their electrolytes measured 3-5 days after starting venlafaxine therapy. If hyponatraemia develops, it can be managed with modest fluid restriction without discontinuing drug treatment, subject to close continued clinical observation and biochemical monitoring.

Global benefit-risk assessment of antidepressants: venlafaxine XR and fluoxetine.

BACKGROUND: Quantifying efficacy and safety differences between drugs is difficult because rigorous statistical methods to assess benefit and risk simultaneously are lacking. METHODS: Global benefit-risk (GBR) analysis of clinical trial data was used retrospectively to compare venlafaxine extended release (XR) and fluoxetine. Of 301 outpatients with moderate to severe depression given venlafaxine XR 75-225 mg/day (n=100), fluoxetine 20-60 mg/day (n=103), or placebo (n=98) for up to 8 weeks, 295 qualified for analysis. Primary efficacy variables were Hamilton Rating Scale for Depression (HAM-D) remission (final on-therapy score risk category were 2.1 (1.1-4.0) and 2.2 (1.1-4.3) for venlafaxine XR vs. fluoxetine and placebo, respectively. For CGI response, relative gains of venlafaxine XR were 1.39 (P<0.01) and 1.45 (P<0.01) vs. fluoxetine and placebo; benefit exceeded risk in 66, 53, and 52% of patients given venlafaxine XR, fluoxetine, and placebo (P=0.041 vs. venlafaxine XR), respectively. CONCLUSIONS: GBR analysis can be applied to a wide array of efficacy and safety data to form statistical tests of clinically meaningful treatment comparisons. In this comparison, the GBR assessments on response and remission significantly favored venlafaxine XR.

A benefit-risk analysis of once-daily venlafaxine extended release (XR) and venlafaxine immediate release (IR) in outpatients with major depression.

The traditional analysis of clinical trial data for antidepressants separately evaluates the results of efficacy and tolerability. The present analysis simultaneously evaluated these outcome criteria in a double-blind, placebo-controlled study of outpatients with major depression. Patients received either once-daily extended release (XR) venlafaxine or immediate release (IR) venlafaxine. Individual patient data on efficacy and treatment-emergent study events (TESE) for venlafaxine XR and venlafaxine IR were grouped into five categories. Efficacy was defined as a final on-therapy Clinical Global Impressions improvement score of 1 (very much improved) or 2 (much improved). A TESE was defined as any new adverse event or any adverse event that existed at baseline and increased in severity during treatment. Benefit/risk was evaluated using a linear measure and a ratio measure for dizziness, Insomnia, nausea, nervousness, somnolence, and a composite of anticholinergic events. This analysis demonstrated a superior benefit/risk ratio for the once-daily venlafaxine XR compared with venlafaxine IR, and a statistically significant benefit-to-risk ratio of at least 2:1 for venlafaxine XR over venlafaxine IR was demonstrated for nausea and dizziness. This approach to the statistical analysis of clinical trial data represents an advancement in addressing treatment outcome by incorporating clinically relevant measures of both efficacy and safety.

Subchronic antidepressant treatment with venlafaxine or imipramine and effects on blood pressure and heart rate: assessment by automatic 24-hour monitoring.

Venlafaxine is a new nontricyclic antidepressant inhibiting the reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine without antagonizing cholinergic, histaminergic, or noradrenergic receptors. Significantly, in a first placebo-controlled safety and efficacy study, high doses of venlafaxine increased blood pressure in some study subjects. In order to investigate further the effect of subchronic antidepressant drug treatment on blood pressure and heart rate, the effects of a conventional tricyclic (imipramine) and a structurally different phenethylamine antidepressant (venlafaxine) were compared. Sixteen inpatients with major depression (melancholic type) were treated for six weeks with imipramine or venlafaxine in a randomized parallel double-blind design. Blood pressure was monitored for 24 hours before treatment and at days 14 and 28 by means of a portable, automatic blood-pressure monitoring system. Both compounds lowered systolic blood pressure by about 5% on average, while diastolic pressure was influenced neither by imipramine nor by venlafaxine. Imipramine treatment resulted in a significant 15% increase in heart rate on both day 14 and day 28, whereas heart rate tended to decrease under venlafaxine. When the data of individual patients were evaluated, a clinically significant increase in blood pressure was apparent in one venlafaxine-treated patient; a marked increase in blood pressure in one patient treated with imipramine proved to be reversible with continued treatment. Due to the relatively small sample sizes, the present data do not allow a definitive judgement as to whether venlafaxine may cause differential blood pressure alterations in comparison with imipramine. However, our results demonstrate that the blood pressure-increasing effect reported for venlafaxine from first clinical studies might be clinically significant in individual patients. Furthermore, our study shows that 24-hour monitoring of blood pressure and heart rate is a powerful tool in safety evaluations of new drugs, even in relatively small samples.