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Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and dose-corrected plasma concentrations (C/D). A database containing concentrations of VEN and ODVEN including 737 of 1594 eligible patients was analyzed. Analyses included sex, body weight, and BMI as well as concentrations of VEN, ODVEN, AM, and C/D. A positive correlation was detected between body weight and daily dosage (rs=0.168, P

Objective The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample. Methods Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V-0 (n = 905), and a group of patients co-medicated with trimipramine, V-TRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05. Results Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the V-TRIM group (1.15 vs. 2.37, P = 0.012). Conclusion Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.

Effects of baseline anxiety on the efficacy of venlafaxine extended release versus placebo were examined in a post hoc pooled subgroup analysis of 1573 patients enrolled in eight short-term studies of major depressive disorder. Anxiety subgroups were defined based on baseline 17-item Hamilton Rating Scale for Depression Item 10 score = 3 (high). Change from baseline to final visit in Montgomery-Asberg Depression Rating Scale total score and Montgomery-Asberg Depression Rating Scale response and remission rates were analyzed. Change from baseline in Montgomery-Asberg Depression Rating Scale total score and response and remission rates was significantly greater for venlafaxine extended release versus placebo in both low and high anxiety subgroups (all P < 0.0001). A statistically significant baseline anxiety by treatment interaction was observed for Montgomery-Asberg Depression Rating Scale total score only (P = 0.0152). The adjusted mean change from baseline in Montgomery-Asberg Depression Rating Scale total score was significantly greater in the high anxiety subgroup versus low anxiety subgroup for patients treated with venlafaxine extended release (-6.27 versus -3.89; P = 0.0440) but not placebo. These results support the efficacy of venlafaxine extended release for major depressive disorder treatment in patients with anxiety symptoms. Copyright (C) 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

The aim of this study was to quantify the risk of hair loss with different antidepressants. A retrospective cohort study design using a large health claims database in the USA from 2006 to 2014 was utilized. A cohort of new user and mutually exclusive users of fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion were followed to the first diagnosis of alopecia. The cohort was comprised of 1 025 140 new users of fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion, with sertraline the most commonly prescribed (N=190 227) and fluvoxamine (N=3010) the least prescribed. Compared with bupropion, all other antidepressants had a lower risk of hair loss, with fluoxetine and paroxetine having the lowest risk [hazard ratio (HR)=0.68, 95% confidence interval (CI): 0.63-0.74, HR=0.68, 95% CI: 0.62-0.74, respectively] and fluvoxamine having the highest risk (HR=0.93, 95% CI: 0.64-1.37). Compared with fluoxetine, bupropion had the highest risk of hair loss (HR=1.46, 95% CI: 1.35-1.58, number needed to harm=242 for 2 years) and paroxetine had the lowest risk (HR=0.99, 95% CI: 0.90-1.09). The results of this large population-based cohort study suggest an increase in the risk of hair loss with bupropion compared with selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, whereas paroxetine had the lowest risk.

This post-hoc analysis evaluated long-term psychosocial outcomes in patients with recurrent major depressive disorder treated with venlafaxine extended release (ER) 75-225 mg/day or placebo. Patients who responded to 10-week venlafaxine ER 75-300 mg/day treatment and maintained response through a 6-month continuation treatment were assigned randomly to venlafaxine ER or placebo maintenance-phase treatment. Data from responders to acute and continuation venlafaxine ER 75-225 mg/day treatment were analyzed during 12-month maintenance treatment while receiving venlafaxine ER of up to 225 mg/day. Failure to maintain improvement in psychosocial functioning, on the basis of the Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey, was defined as loss of at least 50% of the improvement from acute-phase baseline achieved during acute and continuation treatment or dose escalation of more than 225 mg/day. The probability of remaining well (no failure to maintain improvement in functioning) was significantly higher through 12-month maintenance treatment for patients treated with venlafaxine ER 75-225 mg/day versus placebo Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey component summary scores (all P≤0.0351). Effects of up to 20 months of treatment with venlafaxine ER 75-225 mg/day on psychosocial functioning were consistent with the results for venlafaxine ER 75-300 mg/day.

This study evaluated the efficacy of adjunctive pregabalin versus placebo for treatment of patients with generalized anxiety disorder (GAD) who had not optimally responded to previous or prospective monotherapies. This was a phase 3, randomized, double-blind, placebo-controlled study. Patients diagnosed with GAD who had a historical and current lack of response to pharmacotherapy [Hamilton Anxiety Rating Scale (HAM-A) of ≥ 22 at screening] were randomized to adjunctive treatment with either pregabalin (150-600 mg/day) or placebo. The primary outcome measure was the change in HAM-A total scores after 8 weeks of combination treatment. Adverse events were regularly monitored. Randomized patients (N=356) were treated with pregabalin (n=180) or placebo (n=176). Mean baseline HAM-A scores were 20.7 and 21.4, respectively. After treatment, the mean change in HAM-A was significantly greater for pregabalin compared with placebo (-7.6 vs. -6.4, respectively; P

Patients with Huntington's disease (HD) often suffer from psychiatric symptoms including affective disorder, psychosis, irritability, and apathy, which may be present in all stages of the disease. However--despite the obvious likelihood that these symptoms may be reduced by antidepressive treatments--to date, the effectiveness of such treatments in HD has only ever been examined in case studies. Twenty-six HD patients (17 men), with a diagnosis of major depression, were studied. The symptoms of HD and depression were systematically measured using the Beck Depression Inventory and the Hamilton Rating Scale for Depression both at baseline and after 4 weeks of treatment with venlafaxine XR. After 4 weeks of venlafaxine XR treatment, the symptoms of depression in HD patients decreased significantly relative to baseline. However, approximately one in five patients developed significant venlafaxine-related side effects (nausea and irritability). Venlafaxine XR is highly effective in the treatment of depression in HD, although it may produce unpleasant side effects. Further studies are required to establish the most suitable treatment for depression in HD.

Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a scoreor =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total scoreor =31 and31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scoresor =31 or31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total scoreor =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.

It is estimated that up to 45% of patients with depression do not have an adequate response to a first trial of antidepressant therapy with even higher reported rates for the elderly patients. To compare the efficacy and the tolerability of venlafaxine vs. paroxetine in elderly patients suffering from resistant major depression, who did not respond to at least two previous adequate trials of antidepressants. Patients entered an 8-week single-blind study. Patients were rated using the Clinical Global Impression Scale, Hamilton Rating Scale for Depression, and the Geriatric Depression Scale. Assessments were performed at baseline and on days 7,14, 21, 28,42 and 56. Side effects were recorded in a systemic manner. Thirty patients were included in the study, (17 women, 13 men; mean age = 75.9 years, range: 68-83) and all had completed the 6-week trial. Mean dose of venlafaxine used was 165 mg/day (SD = 73.8; range 75-300 mg). Mean dose of paroxetine used was 26mg/day (SD= 15.04; range 10-60 mg). Nine patients treated with venlafaxine (60%) and five patients treated with paroxetine (33%) remitted after 8 weeks of treatment. Four patients treated with venlafaxine and eight patients treated with paroxetine failed to respond. Significant improvement in Hamilton Rating Scale for Depression scores between baseline and endpoint were observed in both groups of patients. The mean Hamilton Rating Scale for Depression change for paroxetine was -12.5 and for venlafaxine -19.1 (P

This study examined the efficacy and tolerability of duloxetine 60-120 mg/day for the treatment of patients with generalized anxiety disorder. This was a multicenter, randomized, double-blind, flexible-dose, placebo and active-controlled (venlafaxine extended-release 75-225 mg/day) trial designed to assess duloxetine 60-120 mg/day during 10 weeks of treatment in adults with Diagnostic and statistical manual of mental disorders-IV-defined generalized anxiety disorder. The primary efficacy outcome measure was mean change from baseline to endpoint in the Hamilton Anxiety Rating Scale total score assessed using analysis of covariance. A total of 487 patients were randomly assigned to duloxetine (n=162), venlafaxine XR (n=164), or placebo (n=161). Significantly greater improvement on the Hamilton Anxiety Rating Scale total score occurred in the duloxetine (P=0.007) and venlafaxine XR (P

The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75-225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (-10.76; P=0.031), but not in the flexible-dose (-10.37; P=0.106) group compared with placebo (-9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible-dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan.

In this study, we evaluated the efficacy and safety of kava kava (Piper methysticum) in generalized anxiety disorder. Data were analyzed from three randomized, double-blind, placebo-controlled trials of kava, including one study with an active comparator (venlafaxine), in adult outpatients with DSM-IV generalized anxiety disorder. The pooled sample (n=64) included the following number of participants: kava, n=28; placebo, n=30; and venlafaxine, n=6. Given the comparability of the study designs, the data comparing kava and placebo were then pooled for further efficacy and safety analyses. No significant differences were observed between the treatment groups in any of the trials. In the pooled analyses, no effects were found for kava, while a significant effect in favor of placebo was observed in participants with higher anxiety at baseline. No evidence of hepatotoxicity was found with kava, and all of the treatments were well tolerated. Findings from these three controlled trials do not support the use of kava in DSM-IV generalized anxiety disorder.

Recent studies have shown that the use of subscales derived from the Hamilton Depression (HAM-D) rating scale are just as reliable and enhance sensitivity for detecting response and remission after antidepressant treatment. The purpose of the present study was to determine if the responses on two items of the HAM-D scale, Depressed Mood (item 1) and Psychic Anxiety (item 10), were predictive of remission of depression in placebo-controlled studies following treatment with venlafaxine or selective serotonin reuptake inhibitors (SSRIs). Data from eight active- and placebo-controlled studies consisting of 2027 subjects who met the DSM-III-R/-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine (n =843), SSRI (either fluoxetine, paroxetine or fluvoxamine, n=743) and placebo (n=441). Treatment duration was 6-8 weeks. Patients who scored zero on the depressed mood and the psychic anxiety items of the HAM-D17 scale were designated as responders. These two scores were also combined to create an Absence of Depressive and Anxious Mood (ADAM) score. Between-group rate comparisons in outcome measures were carried out using Fisher's exact test and logistic regression models. Venlafaxine treatment improved depressed mood, psychic anxiety and ADAM scores after 2 weeks with greater efficacy than treatment with SSRIs or placebo. ADAM scores could also predict the odds ratio of a patient achieving a clinical remission (defined as total HAM-D17 score

Social dysfunction is often associated with depressive disorders and its evaluation is an important measure of treatment outcome. The aim of this study was to assess the effect of two treatments, venlafaxine and amitriptyline, on the social functioning of depressed patients. Twenty-eight outpatients, meeting criteria for recurrent or single major depressive episodes, took part in a double-blind, 8-week trial with amitriptyline or venlafaxine (maximum of 150 mg/day) and were assessed by the Self-Report Social Adjustment Scale (SAS-SR) before and at the end of treatment. The scale was also applied to a carefully selected non-psychiatric sample. Both drugs showed the same efficacy on a clinical scale, but venlafaxine improved social functioning more than amitriptyline as only venlafaxine-treated patients reached SAS-SR values estimated for normal subjects. This effect might be linked to the higher rate of side-effects observed with amitriptyline.

Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P

Predicting differential antidepressant efficacy remains an elusive goal in major depressive disorder (MDD). The aims of this study were three-fold. Firstly, to examine if psychomotor retardation symptoms (item 8 on the 17-item Hamilton Depression Rating Scale) improve preferentially to venlafaxine (VEN) over escitalopram (ESC) treatment. Secondly, whether the 18 item CORE psychomotor signs scale predicted antidepressant remission. Finally, to investigate the role of two norepinephrine transporter gene (NET) polymorphisms (rs2242446 and rs5569) on antidepressant efficacy. Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. MDD (n=113) were treated with ESC or VEN prospectively for 8 weeks and rated serially with the Hamilton Depression Rating Scale. In a subsample (n=51) of patients from one of the three recruitment sites, the CORE psychomotor signs scale was also administered at baseline. Participants treated with VEN had significantly greater reduction in psychomotor retardation symptoms than those treated with ESC. The CORE scale did not predict antidepressant response or remission. Neither NET polymorphism moderated antidepressant efficacy. Findings suggest possible preferential utility of a selective serotonin and noradrenaline reuptake inhibitor in cases of MDD presenting with greater psychomotor retardation. The moderate to small sample size makes a type II error risk possible, and the negative findings need to be interpreted with caution. The positive finding of preferential efficacy of VEN for psychomotor retardation symptoms has potential translational utility.

Venlafaxine has been shown in clinical trials to be safe and well tolerated in patients with major depression. Data were pooled from 19 studies in which 2181 patients were given venlafaxine, 451 were given placebo and 591 were given a reference antidepressant (imipramine, trazodone, clomipramine, maprotiline, dothiepin or amineptine). Long-term safety was evaluated in 422 patients who were given venlafaxine for at least 1 year; as well, a total of 229 elderly patients have been treated with venlafaxine, including 66 who were given it for at least 1 year. The adverse events that occurred during short-term treatment in > or = 10% of patients were nausea, headache, insomnia, somnolence, dry mouth, dizziness, constipation, asthenia, sweating and nervousness. In comparator-controlled trials, the frequency of anticholinergic events with the reference agents was approximately twice that with venlafaxine. The safety profile and patient acceptability of venlafaxine are comparable to those of third-generation antidepressants, and possibly better than those of first-generation agents.

Venlafaxine is a structurally novel phenylethylamine agent with antidepressant properties. The preclinical profile suggests that it will be as effective as the tricyclic antidepressants (TCAs) with few significant effects on the neuroreceptors that mediate many of the side effects common with the TCAs. Venlafaxine has been studied in more than 2500 patients in clinical trials; its efficacy has been evaluated in more than 700 venlafaxine-treated patients in six placebo-controlled trials (five in out-patients and one in in-patients). These studies used a wide range of doses (25-375 mg/day) and different dose regimens (t.i.d. and b.i.d). The results of these studies clearly establish that venlafaxine is significantly more effective than placebo. In the two studies that used doses of 375 mg/day, a significant difference from placebo was observed on the Montgomery- Asberg Depression Rating Scale (MADRS) at the earliest time points assessed, after 4 days of treatment in the in-patient study and after 1 week of treatment in the out-patient study. Venlafaxine also appears to be as effective as some reference antidepressants. A positive dose-response effect has been demonstrated with doses of up to 375 mg/day, with a minimum effective dose of 75 mg/day.

The antidepressant efficacy and short-term safety of venlafaxine and fluoxetine were compared in 68 patients hospitalized with major depression and melancholia. Venlafaxine was superior in efficacy to fluoxetine; total scores for both the MADRS and the HAM-D were significantly (p < or = 0.05) lower in the venlafaxine group than in the fluoxetine group at Weeks 4 and 6. Overall tolerance was similar for the two treatments.

Specific serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment in major depressive disorder (MDD). There is evidence that venlafaxine may be more effective than several antidepressants in the treatment of MDD. This meta-analysis includes all published, randomized, double-blind, head-to-head trials, which compared venlafaxine and an SSRI in the treatment of MDD in adults. Twenty-six trials comparing venlafaxine with an SSRI were included (total participants: 5858). Meta-analysis using a random effect model showed that venlafaxine was superior to SSRIs in achieving remission [odds ratio (OR)=1.13, 95% confidence interval (CI)=1.0-1.28, P=0.05] and response (OR=1.17, 95% CI=1.03-1.34, P=0.02). Subgroup analysis found that venlafaxine had a significantly better response rate than fluoxetine (OR=1.28, 95% CI=1.05-1.55, P=0.01). There were no significant differences in response or remission between venlafaxine and other individual SSRIs. There was no significant difference in all cause discontinuation between venlafaxine and SSRIs (OR=1.10, 95% CI=0.97-1.25, P=0.15). Venlafaxine had significantly higher discontinuation due to adverse events compared with SSRIs (OR=1.41, 95% CI=1.10-1.79, P=0.006). The superior efficacy of venlafaxine over SSRIs is of clinical importance. However, higher rates of discontinuation due to adverse events for venlafaxine compared with SSRIs are a disadvantage. Findings of this meta-analysis that included only published studies were similar to those from meta-analysis that included unpublished data.

The objective of this study was to evaluate the efficacy and tolerability of escitalopram versus serotonin and noradrenaline reuptake inhibitors (SNRIs) as second step treatment (defined operationally as poor response or intolerability to an antidepressant) for major depressive disorder (MDD). Results from all eligible head-to-head clinical trials of MDD (which excluded patients who earlier failed two or more antidepressants) sponsored by Lundbeck or Forest comparing escitalopram and SNRIs (venlafaxine and duloxetine) were pooled. A second step treatment subgroup was identified, defined as patients treated earlier with any antidepressant in the 6-month period before baseline. Data from three clinical trials were included in the analysis; 132 patients were identified in the second step treatment subgroup (66 in each of the escitalopram and SNRI groups). The primary efficacy analysis showed that the patients subsequently treated with escitalopram had significantly lower Montgomery Asberg Depression Rating Scale total scores after 8 weeks compared with those subsequently treated with SNRIs (difference = -6.4, P< 0.0001). Escitalopram treatment was also associated with higher clinical response (73 vs. 44%, P= 0 . 0004 ) and remission rates (62 vs. 41%, P=0.0083) compared with subsequent treatment with SNRIs. Escitalopram showed a better tolerability profile with lower all-cause withdrawals from study (9 vs. 23%, P

The objective of this study was to compare venlafaxine and fluoxetine with placebo in treating major depressive disorder with melancholic features. Adult inpatients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder with melancholia and 21-item Hamilton Depression Rating Scale (HAM-D₂₁) scores > or =24 (n=289) were randomized to receive (double-blind) venlafaxine 225-375 mg/day, fluoxetine 60-80 mg/day, or placebo for 6 weeks. The primary outcome measures were HAM-D₂₁ total score, HAM-D depressed mood item, Montgomery Asberg Depression Rating Scale total score and the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scores. Last observation carried forward (LOCF) was the primary analysis method. In the LOCF analysis, venlafaxine was statistically superior to placebo on the CGI-S (venlafaxine -1.7, placebo -1.1; P=0.003) and the HAM-D depressed mood item (venlafaxine -1.6, placebo -1.1; P=0.010); and to fluoxetine on the CGI-S (-1.2; P=0.012). No significant differences were observed on the other 12 LOCF primary efficacy comparisons. Increases in pulse and blood pressure, dry mouth, constipation, and lightheadedness were significantly more common with venlafaxine than fluoxetine. Venlafaxine was statistically superior to placebo on two of five primary and two of five secondary outcome measures and to fluoxetine on one primary and one secondary outcome measure (LOCF). Venlafaxine was not superior to fluoxetine or placebo in providing remission.

The aim was to evaluate the efficacy of venlafaxine extended release (ER) on characteristics of resilience, measured by the Connor-Davidson Resilience Scale, in patients with posttraumatic stress disorder (PTSD). Data were evaluated from a randomized, 6-month, international, multicenter study of adult outpatients with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD for >or=6 months, and 17-item Clinician-Administered PTSD Scale score >or=60. Patients were assigned randomly to treatment with flexible-dose venlafaxine ER (37.5-300 mg/day) or placebo. Changes from baseline scores and effect sizes of response to treatment with venlafaxine ER compared with placebo were computed for each item, as well as for the newly developed 2-item and 10-item subscales. Effect sizes across items ranged from 0.41 (moderate) to 0.08 (very weak). The effect size for the Resilience Scale-2 (2-item subscale) was 0.32, which was comparable to the effect sizes of 0.35 for the 25-item full scale and 0.34 for the 10-item subscale. Venlafaxine ER improved resilience on individual Connor-Davidson Resilience Scale items that reflect four factors (hardiness, persistence/tenacity, social support, and faith in a benevolent or meaningful world), to varying degrees in patients with PTSD. The findings suggest that assessment of treatment response might be enhanced by routine evaluation of resilience.

The objective of this study was to assess the efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) 50 and 100 mg/day for major depressive disorder (MDD). A multicenter, randomized, double-blind, placebo-controlled trial was conducted in Europe and South Africa. Outpatients with MDD received fixed-dose desvenlafaxine (50 or 100 mg/day) or placebo for 8 weeks. The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression total score; secondary measures included Clinical Global Impressions-Improvement scores. The intent-to-treat population included 483 patients: desvenlafaxine 50 mg (n=164), desvenlafaxine 100 mg (n=158), and placebo (n=161). At the last-observation-carried-forward analysis (final evaluation) using analysis of covariance, adjusted mean changes from baseline on the Hamilton Rating Scale for Depression were significantly greater for both desvenlafaxine 50 mg (-13.2; P=0.002) and 100 mg (-13.7; P

This article reanalyses and reviews data from the two published randomized clinical trials comparing escitalopram and venlafaxine XR in the treatment of patients with major depressive disorder. The aim was to further compare the efficacy and tolerability of escitalopram and venlafaxine XR and to assess the impact of the two treatments on the patient's quality of life, as well as the benefit/risk of treatment. A total of 243 escitalopram-treated patients and 240 venlafaxine XR-treated patients were included in this analysis. Comparable treatment efficacy was achieved with respect to the prospectively defined primary efficacy endpoint (mean change from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score at week 8). An analysis of the outcome at the end of study by baseline severity showed that the treatment difference became greater the more severely depressed the patients were at baseline. At the highest permitted doses, in the subgroup of patients who were severely depressed (baseline MADRS > or =30), patients treated with escitalopram had a statistically significantly greater improvement (P

The combined serotonin-norepinephrine reuptake inhibitor, venlafaxine XR, has demonstrated significant response and remission in patients diagnosed with depression when measured with the Hamilton Depression Rating Scale (HAM-D). This pooled analysis of data from five studies compared the sustained remission of depressive symptoms in patients treated with venlafaxine XR, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine or paroxetine, or placebo. Data from 1391 subjects enrolled in five active and placebo-controlled studies who met the DSM-III-R or DSM-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine XR (n = 560), fluoxetine/paroxetine (n = 298) and placebo (n = 496). Mean treatment duration was 8 weeks. Responders were defined as those patients whose HAM-D-21 score decreased byor = 50% from baseline. Remission was defined as a HAM-D-17 scoreor = 7. Sustained remission was defined as maintenance of remission through week 8 or the end of treatment (if before week 8) and foror = 2 weeks. Between-group rate comparisons in outcome measures were carried out using Fisher's exact and log-rank tests. Venlafaxine XR produced significantly higher rates of sustained remission in depressed patients compared to fluoxetine/paroxetine or placebo over this 8-week treatment period. As early as week 2, a significantly greater proportion of patients treated with venlafaxine achieved improved depression scores (remission and response). A significantly greater rate of remission and sustained remission occurred with venlafaxine compared to placebo. Remission was achieved earlier with venlafaxine and lasted throughout the remainder of the study. These results demonstrate that venlafaxine XR is more effective than fluoxetine/paroxetine for sustaining remission of depressive symptoms.

The primary endpoints in this study were the remission rates [final Hamilton Rating Scale for Anxiety (HAM-A) total score ≤ 7] and reduction from baseline in the HAM-A total score in patients with generalized anxiety disorder (GAD) and no associated depression. Patients with GAD (DSM-IV and HAM-A total score >18) were randomly assigned to treatment with venlafaxine XR or placebo for 8 weeks. A 1-week placebo run-in period preceded the double-blind phase. Patients with a >20% drop in their total HAM-A score during the run-in period, were excluded from the double-blind phase. All patients started therapy with 75 mg/day venlafaxine XR or matched placebo. Patients with less than 30% decrease in their HAM-A total score at the end of the second week, doubled their dose. Patients on the 150 mg/day dose underwent a 1 -week taper period. Of the 24 patients in the venlafaxine XR group, 62.5% achieved remission versus 9.1% in the placebo group (P=0.0006). The mean decrease from baseline in HAM-A total score was 19.2 points for the venlafaxine XR group and 10.8 points for the placebo group (P

Although there have been many attempts to find predictors of therapeutic response to antidepressant treatment of obsessive-compulsive disorder (OCD), few reports have evaluated the joint predictive value of a number of clinical characteristics. This study aimed to identify clinical predictors of outcome in OCD, and to develop an easily applicable method to predict response to drug treatment. One hundred and fifty patients with primary OCD according to DSM-IV criteria were randomly assigned in a 12-week, double-blind, comparison trial with a selective serotonin reuptake inhibitor (paroxetine), and a serotonin-noradrenaline reuptake inhibitor (venlafaxine). The primary efficacy parameter was the Yale-Brown obsessive-compulsive scale (Y-BOCS) score, and response to treatment was prospectively defined as a >/= 35% decrease from the beginning. A stepwise multivariate analysis was used to identify predictors. The absence of previous therapies, moderate baseline severity of obsessive-compulsive symptoms (Y-BOCS score < 23), and low Hamilton Depressive Rating Scale scores (6-15) were found to be prognostic determinants of good response to pharmacotherapy. The prognostic ability of the prediction model to discriminate between responders and non-responders was quantified as the area under the receiver operating/operator characteristic curve (ROC area), which was 0.71 (95% confidence interval 0.63-0.8), demonstrating a reasonable discriminatory power. This study is the first to present a model that can estimate by the use of prediction rules the probability of treatment response to antidepressants in patients with OCD.

A 24-week, double-blind, randomized trial was performed to compare the efficacy and tolerability of venlafaxine and paroxetine in patients with major depression or dysthymia. Outpatients aged 18-70 years with a baseline score of 17 on the 21-item Hamilton Depression Rating Scale (HAM-D) were eligible. Patients were randomly assigned to venlafaxine, 37.5 mg, in the morning and evening or paroxetine, 20 mg, in the morning and placebo in the evening, which could be increased to venlafaxine, 75 mg twice daily, or paroxetine, 20 mg twice daily, after 4 weeks. Efficacy was assessed with the 21-item HAM-D, the Montgomery-Asberg Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impressions Scale. Forty-one patients were randomized to venlafaxine and 43 to paroxetine. At week 6, a response was observed in 55% of patients on venlafaxine and 29% on paroxetine (P = 0.03). At week 12, significantly (P = 0.011) more patients in the venlafaxine group had a HAM-D remission score of 8 or less (59% versus 31%). Discontinuation for any reason occurred in 16 (39%) patients on venlafaxine and 11 (26%) on paroxetine. The most common adverse events were nausea (28%), headache (18%) and dry mouth (15%) with venlafaxine and headache (40%) and constipation (16%) with paroxetine. Venlafaxine was effective and well tolerated for the treatment of patients with mild to moderate depression or dysthymia. A consistently higher proportion of patients had a response or remission on venlafaxine than on paroxetine.

The study aimed to evaluate the clinical response to venlafaxine in social phobia in 12 patients who were non-responders to selective serotonin reuptake inhibitors, and to assess how the response could be influenced by the comorbidity in Axis II with avoidant personality disorder (APD). The duration of the study was of 15 weeks using open flexible doses regimen in individuals with or without concomitant APD. The venlafaxine dose ranged from 112.5 mg/day to 187.5 mg/day. Venlafaxine improves social phobia and/or APD symptomatology, as demonstrated by decreasing Liebowitz Social Anxiety Scale total scores (P < 0.05). In fact, venlafaxine significantly reduced the avoidant behaviour and specific sociophobic aspects, while notably improving the depression dimension and the basic anxiety symptoms. With regard to tolerability, the profile of venlafaxine was satisfactory with the main side-effects being nausea, headache and anxiety.

The onset of extrapyramidal symptoms has been traditionally linked to the prescription of neuroleptic treatment: there are some reports in the international literature describing extrapyramidal effects related to antidepressant. In this paper we present a case under multiple pharmacologic treatment in whom extrapyramidal symptoms developed shortly after the adjunct of nortriptyline to a combination of venlafaxine and valproic acid administered for several months. We describe here the clinical history of this patient, affected by Bipolar Disorder, type II, and the progressive pharmacologic path in his treatment. Possible hypothesis to explain this evidence are discussed.

Post-traumatic stress disorder (PTSD) is frequently treated with antidepressant medications, especially the newer selective serotonergic antidepressants which have documented efficacy in PTSD. Analagous to depression, however, some PTSD patients may not have a satisfactory response to these agents. This case report describes a PTSD patient who did not respond to several serotonergic antidepressants, but did improve with venlafaxine which has both noradrenergic and serotonergic properties.

The objective of this analysis was to determine the efficacy of venlafaxine in comparison with that of placebo during long-term treatment. A pooled analysis of relapse rates in outpatients with major depression continuing long-term treatment (up to 12 months) after responding to short-term treatment (6 weeks) was performed combining the data from four randomized, double-blind, placebo-controlled clinical trials. Relapses were defined as two consecutive Clinical Global Impression (CGI) severity scores greater than 3 (mildly ill), as a CGI severity score greater than 3 at withdrawal regardless of the reason for withdrawal, or as withdrawal due to lack of efficacy. Data from 304 patients (185 venlafaxine, 119 placebo) well balanced for baseline characteristics were included in the pooled analysis. Percentages of patients completing the long-term phase were 38% venlafaxine and 26% placebo (p = 0.034). Cumulative relapse rates by 6 months of long-term treatment were 11% venlafaxine and 23% placebo (p = 0.019). Cumulative relapse curves for the venlafaxine and placebo groups over the 1-year long-term treatment differed significantly (p = 0.022). The results from this analysis indicate that long-term treatment with venlafaxine in patients with major depressive disorder is effective in maintaining the initial response compared with placebo and suggest that venlafaxine will be effective in the prevention of relapse.

It is important to evaluate a new antidepressant in terms of its efficacy in relation to that of reference agents such as the tricyclics and monoamine oxidase inhibitors. Newer antidepressants have not been shown to be more effective than the reference agents, either in the proportion of patients in whom they produce a therapeutic response or in their speed of onset of antidepressant activity. The serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine appears to offer some advantages in both of these areas. In a number of short-term placebo- and comparator-controlled trials, venlafaxine was shown to be as effective as, and in some cases more effective than, the reference antidepressants. These findings were also substantiated in meta-analyses of both short-term and long-term comparator-controlled studies. In terms of its onset of activity, venlafaxine was shown to produce statistically significant differences from placebo as early as Day 4 in a study in severely depressed in-patients with melancholia and by Week 1 in a study in out-patients with major depression. A rationale is presented to define the clinical relevance of these findings.

The newer antidepressants have clearly shown themselves to be safer and to have a more acceptable side effect profile than the traditional antidepressants. Greater patient acceptability has important consequences in relation to efficacy, in that compliance is likely to be better in the long term. One of the newest antidepressants, the serotonin- noradrenaline reuptake inhibitor venlafaxine, has neurobiologic properties that recommend it for clinical use by both the psychiatrist and the general practitioner. Controlled studies have confirmed the overall utility of this agent in treating a range of depressive subtypes, such as moderate depression and severe endogenous depression, with a low risk of serious adverse events and an excellent tolerability profile. In addition, venlafaxine has shown a dose-response relationship for efficacy, offering the possibility of a wide dose range, which may be suitably employed in different clinical situations.

The antidepressant efficacy and short-term safety of venlafaxine and fluoxetine were compared in 68 patients hospitalized with major depression and melancholia. Venlafaxine was superior in efficacy to fluoxetine; total scores for both the MADRS and the HAM-D were significantly (por = 0.05) lower in the venlafaxine group than in the fluoxetine group at Weeks 4 and 6. Overall tolerance was similar for the two treatments.