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BACKGROUND Obstructive sleep apnea (OSA) is frequently comorbid with late-life depression. The purpose of this project was to determine, using a sample of older adults with major depressive disorder, whether patient-reported diagnosis of OSA was associated with rate of response to venlafaxine. METHODS Participants from this multisite study were adults ≥60 years old (n = 468) with major depressive disorder and a Montgomery Asberg Depression Rating Scale (MADRS) score of ≥15. Depression response was the outcome variable, defined as a MADRS score of ≤10 for two consecutive assessments at the end of 12 weeks of open-label treatment with venlafaxine 300 mg/day. To assess OSA, participants were asked if they had been diagnosed with OSA using polysomnography. RESULTS Eighty participants (17.1%) reported a diagnosis of OSA prior to baseline. Participants with OSA were more likely to be male, report greater impairment on measures of health, experience a longer duration of the index episode, and receive an adequate antidepressant trial prior to entering the study. During the 12 weeks of treatment, 40.8% responded to treatment with venlafaxine (43.6%, n = 169/388 of the no OSA group, and 27.5%, n = 22/80 of the OSA group). Participants without OSA were 1.79 times more likely to respond to treatment (HR: 1.79 [95%CI: 1.13-2.86], P < .05) compared to those with OSA. CONCLUSIONS OSA may impair response to antidepressant pharmacotherapy in depressed older adults. Future studies of antidepressant response rates among depressed older adults with OSA should both prospectively diagnose OSA and monitor adherence to treatments such as continuous positive airway pressure.

Background The 12-item Concise Health Risk Tracking Self-Report (CHRT-SR12 ) is a brief, self-report measure that systematically assesses both suicidal thinking and associated thoughts that may indicate the propensity for suicidal acts. It can be used as a tool to both assess risk and guide treatment interventions targeting associated cognitions. Methods This report used acute treatment data from a clinically representative sample of outpatients with nonpsychotic major depressive disorder (N = 665) participating in the Combining Medications to Enhance Depression Outcomes trial, who received up to 12 weeks of escitalopram, escitalopram plus bupropion SR, or venlafaxine XR plus mirtazapine. Outcome assessors and patients were masked to treatment. Results Factor analysis of CHRT-SR12 confirmed that the 12 items have higher order structure with two subscales (Propensity, Suicidal Thoughts) and a total score. Internal consistencies were acceptable for both subscales and total score. All three scales were modestly correlated with overall depression severity (r = 0.54 to r = 0.21) and highly discriminating among patients grouped by suicide item ratings on three different depressive symptom ratings. The three scales also distinguished change over the acute phase treatment for those with different levels of baseline suicidal ideation (measured by 30-item Inventory of Depressive Symptomatology (item 18) and for those with change in suicidal ideation (baseline to last visit). Conclusions The CHRT-SR12 has good to excellent psychometric properties and is sensitive to change in suicidal thinking and propensity toward suicidal behavior in outpatients with major depressive disorder. It allows for the monitoring of thoughts and feelings associated with increased suicidal risk as well as levels of thoughts about suicide.

BACKGROUND: There is a need to identify biomarkers of treatment outcomes for Major Depressive Disorder (MDD) that can be disseminated. We investigated the predictive utility of pre-treatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pre-treatment anxious depression as a hypothesized moderator of HRV effects. METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment-in Depression; iSPOT-D) in patients with current nonpsychotic MDD (N=1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pre-treatment, patients were defined as having anxious (N=309) versus nonanxious (N=413) depression and their resting high-frequency HRV (root mean square of successive differences; RMSSD) was assessed. Patients’ usual treating clinicians managed medication. At 8 weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. RESULTS: Pre-treatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach. TRIAL REGISTRATION: International Study to Predict Optimized Treatment-in Depression; NCT00693849; https://clinicaltrials.gov/ct2/show/NCT00693849

We explored whether clinical outcomes differ by treatment strategy following initial antidepressant treatment failure among patients with and without clinically relevant symptom clusters.The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was used to examine depression remission and response in patients with coexisting anxiety, atypical features, insomnia, and low energy. We applied propensity scoring to control for selection bias that precluded comparisons between augmentation and switch strategies in the original trial. Binomial regressions compared the likelihood of remission or response among patients with and without symptom clusters for switch versus augmentation strategies (n = 269 per arm); augmentation strategy type (n = 565); and switch strategy type (n = 727).We found no statistically significant difference in remission or response rates between augmentation or switch strategies. However, symptom clusters did distinguish among augmentation and switch strategies, respectively. For patients with low energy, augmentation with buspirone was less likely to produce remission than augmentation with bupropion (remission Risk Ratio (RR): 0.54, 95% CI: 0.35-0.85, response RR: 0.67, 95% CI: 0.43, 1.03). Also, for patients with low energy, switching to venlafaxine or bupropion was less likely to produce remission than switching to sertraline (RR: 0.59, 95% CI: 0.36-0.97; RR: 0.63, 95% CI: 0.38-1.06, respectively).Remission and response rates following initial antidepressant treatment failure did not differ by treatment strategy for patients with coexisting atypical symptoms or insomnia. However, some second-step treatments for depression may be more effective than others in the presence of coexisting low energy. Subsequent prospective testing is necessary to confirm these initial findings.

Generalized anxiety disorder (GAD) is a highly prevalent and disabling condition. Escitalopram and venlafaxine extended release (XR) both are indicated for the treatment of GAD. Outpatients (ages 18-65 years) with DSM-IV-defined GAD (Hamilton Anxiety Scale [HAMA] >or=20) were eligible to participate in this randomized, double-blind, placebo-controlled, multicenter, flexible-dose trial. Following randomization, patients received 8 weeks of double-blind treatment with escitalopram (10-20 mg/day; N=127), venlafaxine XR (75-225 mg/day; N=129), or placebo (N=136). The primary efficacy parameter was mean change from baseline at week 8 in HAMA total score, using the Last Observation Carried Forward (LOCF) approach. Secondary efficacy parameters were HAMA psychic anxiety subscale, Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-I) scales. Treatment was completed by 77% of patients. The least square mean difference for change from baseline at week 8 in HAMA total score for escitalopram and venlafaxine XR versus placebo were -1.52 (P=.09) and -2.27 (P=.01), respectively, for LOCF, and -1.92 (P=.033) and -3.02 (P=.001), respectively, for Observed Cases (OC). On all secondary parameters, both active treatments were significantly superior to placebo on the LOCF and OC analyses. Discontinuation due to adverse events was not different for escitalopram versus placebo (7 versus 5%, P=.61), but was significantly greater for venlafaxine XR (13%) versus placebo (P=.03). Venlafaxine XR, but not escitalopram, separated from placebo on the primary efficacy measure, using the LOCF approach. However, overall efficacy analyses suggest that escitalopram and venlafaxine XR are both effective treatments for GAD. Escitalopram was better tolerated.

Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking.Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment.Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant.Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed.

We evaluated the relative efficacy of venlafaxine XR on the psychic versus somatic symptoms of anxiety in patients with generalized anxiety disorder as determined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Data were pooled and analyzed from 1,841 patients with generalized anxiety disorder who participated in five short-term (8-week) double-blind, multicenter, placebo-controlled studies, two of which had long-term (6-month) extensions. Somatic and psychic anxieties were studied using the Hamilton rating scale for anxiety (HAM-A) factor scores. We examined response rates (> or =50% improvement over baseline severity score) in the overall population and in patients with mainly somatic symptomatology at baseline (somatizers). Venlafaxine XR significantly reduced factor scores for both psychic and somatic HAM-A factors compared with placebo, from the first and second weeks of treatment, respectively. Patients treated with venlafaxine XR had significantly higher rates of response than patients receiving placebo on the psychic (58% vs. 38%, P

Venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), produces significantly higher remission rates in depressed patients than do the selective serotonin reuptake inhibitors (SSRIs). In this analysis of pooled data, we explored the relationship between differences in treatment efficacy, early improvement of symptoms, and severity of baseline anxiety in depressed patients treated with either venlafaxine or fluoxetine. A pooled analysis was performed on data from 1,454 outpatients with major depression from five double-blind, randomized studies comparing the 6-week efficacy of venlafaxine (542 patients) with fluoxetine (555 patients). The Hamilton rating scale for depression (HAM-D) total and item scores were analyzed at different treatment times up to 6 weeks. Venlafaxine and fluoxetine both produced statistically significant higher response and remission rates compared with placebo starting from week 2 for response and weeks 3 to 4 for remission. Venlafaxine was statistically significantly superior to fluoxetine from week 3 until week 6 in respect of response rate, and from week 2 until week 6 for remission rate. After 1 week of treatment, greater improvement in individual symptoms was observed in the depressed mood, suicide, and psychic anxiety items of the HAM-D scale for both venlafaxine- and fluoxetine-treated patients compared with placebo. Improvement in psychic anxiety was statistically significantly greater with venlafaxine than with fluoxetine. The presence of baseline psychic anxiety correlated significantly to treatment outcome when analyzing the remission rates. In depressed patients with moderate anxiety (HAM-D psychic anxiety scoreor = 2), venlafaxine statistically significantly increased remission rates compared with placebo from week 4 until week 6, while a significant effect of fluoxetine on remission rates was observed starting at week 6. Remission rates in the severely anxious depressed patients (score2) were statistically significantly higher with venlafaxine than placebo starting from week 3 until the end of the study period, but no difference could be observed between fluoxetine and placebo. Baseline severity of psychic anxiety had a significant impact on remission rates after treatment of patients diagnosed with depression. Venlafaxine's superior remission rates in the more severely anxious patients and its ability to improve psychic anxiety as early as week 1 compared with fluoxetine suggest that venlafaxine's early efficacy on anxiety symptoms may be the basis for its superior efficacy in depression.

Objective This review critically evaluates recent information on the cytochrome P450 system, with an emphasis on drug interactions involving antidepressant medications, particularly venlafaxine, nefazodone, and mirtazapine. Methods: International literature on the cytochrome P450 system and related drug interactions from 1995–1997 were critically examined. Results: Venlafaxine, nefazodone, and mirtazapine have different effects on the cytochrome P450 system. In vitro, venlafaxine is a weaker CYP2D6 inhibitor than most of the selective serotonin reuptake inhibitors (SSRIs) by a factor of 1–3 orders of magnitude. In vivo drug interaction studies generally confirm in vitro results. However, some exceptions exist. The clinical significance of such interactions remains unknown. Venlafaxine had minimal or no demonstratable inhibition of CYP1A2, CYP3A4, or CYP2C. Nefazodone is a potent inhibitor of CYP3A4 and is therefore absolutely contraindicated with concurrent administration of terfenadine, astemizole, and cisapride. It is a weak inhibitor of CYP1A2, 3A4, and 2D6. A metabolite of nefazodone, mCPP, is a weak and probably clinically insignificant inhibitor of CYP2D6. Mirtazapine has minimal inhibitory effects on CYP1A2, CYP3A4, and CYP2D6 in vitro. Little is known about its interactions with other drugs. Conclusions: With the addition of the latest antidepressant medications, the clinician may now choose antidepressants with little liability for drug–drug interactions. Venlafaxine and mirtazapine are associated with a lower risk of clinically significant drug interactions than SSRIs. Nefazodone is a potent inhibitor of CYP3A4 and therefore may not be suitable for all patient populations. It is, however, a much weaker CYP2D6 inhibitor than the SSRIs. More studies are needed to assess more accurately and precisely the risk of such untoward drug–drug interactions with these novel antidepressants, particularly in more diverse ethnic patient populations. Depression and Anxiety, Volume 7, Supplement 1:24–32, 1998. © 1998 Wiley-Liss, Inc.

A number of studies have shown that elevated levels of inflammatory cytokines may promote depression and suicidal ideation and that neuroprotective peptides may decrease the response to stress and depression. In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor α (TNFα)) and two putative "resiliency" neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY)) were compared between patients with depression and healthy controls.Eighteen patients with major depression and 25 healthy controls underwent a lumbar puncture; CSF samples were withdrawn and assayed for IL-1, IL-6, TNFα, BDNF, and NPY levels. Patients with depression were then entered into an 8-week treatment protocol and had repeated lumbar puncture procedures post-treatment.Contrary to prediction, we found that at baseline depressed patients had higher CSF NPY concentration compared to the normal comparison group. Within the depressed patients, we found several statistically significant correlations between elevated CSF cytokine levels and clinical severity.Despite the small sample size, given the challenges in obtaining CSF from patients with depression these data are of interest in confirming some aspects of the inflammatory hypothesis of depression.

Background: The Depression and Somatic Symptoms Scale (DSSS) is a self-administered scale developed for monitoring both depression and somatic symptoms. The aims of this study were to establish the criterion-related validity of the DSSS by testing the correlation between the DSSS and the Short Form 36 (SF-36) scale and to compare the ability of the DSSS and two other scales in predicting the outcome of the SF-36. Methods: The study enrolled 135 outpatients with a major depressive episode, 95 of whom received treatment for 1 month. Four scales were administered and evaluated: the DSSS, the SF-36, the Hospital Anxiety and Depression Scale, and the Hamilton Depression Rating Scale. Pearson correlation was used to test correlations among scales. Multiple linear regressions were used to find the scales most effective in predicting the SF-36. Results: The three scales were significantly correlated with most of the SF-36 subscales. The depression and somatic subscales of the DSSS significantly correlated with the mental and physical subscales of the SF-36, respectively. The DSSS and the Hospital Anxiety and Depression Scale were better able to predict physical and mental subscales of the SF-36, respectively. The Hamilton Depression Rating Scale had a good ability to predict functional impairment. Conclusions: Psychometric scales with appropriate somatic symptoms might be more compatible with both physical and mental dimensions of the SF-36. DSSS proved to be a valid scale for monitoring both depression and somatic symptoms in patients with depression. Future studies should test whether the DSSS is better at predicting the treatment and prognosis of depression than conventional scales for depression. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc.

Because of reported efficacy of combining classes of antidepressants, 25 patients were treated with bupropion in combination with SRI's and venlafaxine. Fifteen patients inadequately responsive to monotherapy received combination treatment; ten patients without residual symptoms received adjunctive bupropion to treat SRI- or venlafaxine-induced side effects. Fourteen subjects (56%) responded, 11 (44%) did not. Twelve of 15 subjects receiving combination treatment to boost the effects of monotherapy responded, while only 2 of 10 subjects receiving combination treatment for side effects responded. Combination therapy was well tolerated even by geriatric and "medically frail" patients.

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

Based on preliminary evidence of its usefulness in treatment-resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12-week double-blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open-label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double-blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery-Asberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =-7.2, baseline =29.6), in comparison to olanzapine (-4.8, P=.03), fluoxetine (-4.7, P=.03), or venlafaxine (-3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (-14.1 vs. -7.7, P

Serotonin–norepinephrine reuptake inhibitors (SNRIs) may be used as an alternative treatment for depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant. This randomized, open-label, multicenter study compared the effectiveness of the SNRI venlafaxine extended release (VXR) with that of conventional antidepressants (CA) in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a CA in a primary care setting. Patients with a Hamilton Depression Rating Scale (HAM-D17) score ≥17 were randomly assigned to treatment with an alternative CA or VXR. Remission was defined as a score ≤7 on the HAM-D17. Efficacy analyses were carried out on 3,097 patients from the intent-to-treat (ITT) population (1,632 VXR; 1,465 CA). The antidepressants prescribed most frequently in the CA group were paroxetine (21.3%), citalopram (20.1%), sertraline (19.1%), fluoxetine (17.0%), and mirtazapine (7.9%). After 24 weeks of treatment, the VXR group demonstrated a significantly higher remission rate than did the CA group (59.3% VXR; 51.5% CA; P

Perimenopause is often marked by vasomotor symptoms and dysphoria. Antidepressant studies have demonstrated decreased frequency and severity of hot flashes in breast cancer survivors and menopausal women. We hypothesized that venlafaxine would relieve both depressive and vasomotor symptoms in depressed perimenopausal women. Sixteen women fulfilling clinical criteria for climacteric phase and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for a depressive episode were enrolled in an open-label 8-week trial of extended-release venlafaxine. Depressive and climacteric symptoms were monitored using the Hamilton Rating Scales for Depression (Ham-D) and Anxiety (Ham-A), Clinical Global Impression (CGI) scale, and Greene Climacteric Scale (GCS). Serum follicular stimulating hormone (FSH) and estradiol concentrations were monitored. Significant decreases in Ham-D and Ham-A scores and the GCS psychiatric subscale were seen after 2 weeks of treatment. In an intention-to-treat analysis, 81% of the subjects demonstrated a therapeutic antidepressant response (>50% decline in Ham-D score) and 75% achieved clinical remission (Ham-D score < or =7) after 8 weeks of venlafaxine therapy (75-225 mg/day). Total GCS scores declined 60%, and GCS vasomotor subscores decreased among those with vasomotor symptoms at baseline. These data suggest that venlafaxine treatment improves overall well-being, reduces depressive symptoms, and may diminish baseline vasomotor symptoms in depressed perimenopausal women. Further studies are warranted to investigate the utility of venlafaxine in perimenopausal depression.

Treatment-resistant depression (TRD) is an important clinical problem. This paper briefly reviews the definition of TRD and summarizes methodological issues that pertain to treatment research. Recent studies of venlafaxine treatment for TRD also are reviewed. It is concluded that venlafaxine at higher doses is a reasonably well-tolerated and an effective alternative for patients with TRD and typically should be used before tricyclic antidepressants or monoamine oxidase inhibitors. Further research is needed to confirm the prediction that switching a SSRI nonresponder to venlafaxine is a more effective strategy than switching to a second SSRI. The relative merits of switching from a SSRI to venlafaxine versus adding a norepinephrine reuptake inhibitor also warrant careful study.

Pediatric psychopharmacology is hindered by the relative lack of controlled, empirical clinical trials [Shatzberg and Nemeroff, 1998: Washington, D.C.: The American Psychiatric Press, Inc. p 301-306]. Psychiatric disorders in children and adolescents carry considerable morbidity, impede development, and carry a significant mortality by suicide. Therefore, there is a need for studies of antidepressants and other psychotropics in children and adolescents. This article reviews the preliminary evidence that venlafaxine (Effexor), a novel antidepressant, may be useful in children and adolescents with a variety of psychiatric disorders.

Although the efficacy of available antidepressants has been well established in the treatment of mild to moderate depression, clinical research literature on severe depression is more limited, due to lack of a standardized definition for the condition and the resulting inconsistent data. Given the heterogeneous nature of severe depression, reports suggesting noradrenergic as well as serotonergic system involvement in depressive disorders, and the substantive capability of both clomipramine and TCA-SSRI combination to treat severe depression, investigation of dual-action antidepressant agent efficacy in the treatment of severe depression is warranted. The merit of one such combined-action agent, venlafaxine, is reviewed. Efficacy findings from the limited number of comparative clinical trials conducted in the severely depressed patient population suggest that, while venlafaxine has been evaluated in a broad range of depressed patients, this compound may be particularly effective for the severely ill. Pharmacological features of venlafaxine, which may benefit the patient with severe depression, include the possibility of a rapid onset of action and a dose-response curve. Based upon studies comparing venlafaxine with both placebo and other first-line antidepressants, it is concluded that venlafaxine is safe, tolerable, and effective for the treatment of severe depression.

Generalized anxiety disorder (GAD) is a common and chronic disorder with a low rate of spontaneous remission. A complication in treatment selection is the high rates of co-morbid major depressive disorder in this population. A number of treatments exist to treat GAD. The most recent medication to gain an indication for GAD is venlafaxine XR, a serotonin/norepinephrine reuptake inhibitor that is also approved for the treatment of major depressive disorder. More than 2,000 patients with GAD have been studied in outpatient trials of venlafaxine XR with demonstrated efficacy, tolerability and safety of this compound. This article reviews these studies, both short term and longer (6 month) continuation trials. The response to venlafaxine XR in this population, combined with good tolerability, makes this agent an appropriate first-line medication for GAD. In general, treatment with antidepressants, though associated with a longer onset of action than benzodiazepines, does not produce physiological dependency, and is useful in a patient population with a high prevalence of mood disorders.

Venlafaxine is a medication available by prescription in the U.S. both in an immediate release and an extended release formulation. Preclinical studies indicate it has the effect of potently blocking the serotonin and norepinephrine transporters. Venlafaxine is approved by the FDA for the treatment of major depressive disorder and generalized anxiety disorder. Suggestive evidence, mostly from open label case series, indicates efficacy of venlafaxine in several other conditions including panic disorder, social anxiety disorder, obsessive compulsive disorder, trichotillomania, ADHD, chronic pain, and fibromyalgia. The limited evidence supporting efficacy in these conditions is reviewed. Additional randomized clinical trials with placebo controls are indicated.

Newer antidepressants are more expensive in terms of acquisition costs than older drugs. However, cost effectiveness simulations and retrospective analyses of administrative databases of newer antidepressants, including venlafaxine, suggest that the higher acquisition costs may be offset or more than offset by savings of other treatment costs. Because simulations and retrospective studies are vulnerable to multiple methodologic uncertainties, large scale randomized "real-world" cost effectiveness experiments are needed. If venlafaxine in actual practice is more effective or has a more rapid onset of action than SSRIs as suggested by efficacy studies and existing meta-analyses, these effects could translate into pharmacoeconomic advantages.

Venlafaxine (Effexor) is an effective antidepressant and has also been approved for the treatment of generalized anxiety disorder. Venlafaxine was initially characterized as an inhibitor of both serotonin (5HT) and norepinephrine (NE) uptake and was therefore termed a "dual uptake inhibitor." This chapter reviews data from both in vitro and in vivo studies regarding its effects on 5HT and NE neurotransmission. In addition, the effects of venlafaxine on other systems that may play a role in its therapeutic efficacy effects are described. The data indicate that venlafaxine is a relatively weak inhibitor of NE transport in vitro. In vivo studies indicate that venlafaxine selectively inhibits 5HT uptake at low therapeutic doses and inhibits both 5HT and NE uptake at higher therapeutic doses. This chapter concludes with a discussion of the effects of venlafaxine on various aspects of physiology.

Improving outcomes for patients with depression involves selecting the best possible drug therapy. Considerations relevant to drug product selection include: 1) pharmacokinetic issues such as half-life and time to steady-state, and protein binding; 2) pharmacodynamic drug-drug interactions; and 3) drug metabolism-related drug interactions. A comparison of selected antidepressants with an emphasis on venlafaxine's similarities and differences is presented. Based on these parameters, selecting an antidepressant medication, such as venlafaxine, that has a low potential for drug interactions at the Cytochrome P450 (CYP) enzyme system, and is easy to monitor and dose, facilitate successful treatment of patients. Venlafaxine has been evaluated in clinical studies that demonstrate low to negligible drug interaction potential at CYP2D6, CYP1A2, CYP2C19, and CYP3A4. Its short half-life and time to steady-state, when coupled with the extended release characteristics of the preferred dosage formulation allow for once daily dosing and rapid attainment of therapeutic effects. The CYP3A4 system is involved in both first-pass metabolism and systemic clearance of medications. Drug interactions at this isoenzyme have proven to be of high clinical relevance ranging from cardiovascular toxicity and death with commonly used drugs such as cisapride, to subtherapeutic levels of cyclosporine or protease inhibitors leading to transplant rejection or HIV relapse. Reasons for the under detection and reporting of drug interaction mediated adverse events include healthcare system structure, the poor return to follow up of non-adherent patients, the need for greater education and training of clinicians to recognize drug-related adverse events, and the reluctance of patients to spontaneously communicate about the unpleasant effects of their medication.

Venlafaxine is a unique antidepressant medication with well documented efficacy and safety in the acute treatment of major depressive disorder. Reports suggest that it may also be effective in the treatment of dysthymic disorder and bipolar II depression, but the available data for these conditions are more limited compared to major depressive disorder. Several studies suggest that there may be a more rapid onset of action for venlafaxine in the treatment of major depression compared to other antidepressant pharmacotherapies, but this has not been fully established. Venlafaxine is also effective in the important long term continuation and maintenance phases of the treatment of depression.

Geriatric patients with major depression present clinical challenges not encountered in younger individuals, including a greater incidence of medical comorbidity, higher rates of multiple medication use, changes in drug metabolism due to age or physical illness, and increased sensitivity to antidepressant side effects. Nevertheless, successful treatment of depressive disorders in the elderly improves mental and physical functioning, decreases morbidity and perhaps mortality, and enhances quality of life. Recent research indicates that newer antidepressants are effective for late life depression and safer for older individuals. Among newer antidepressants, venlafaxine has a pharmacological profile that makes it an attractive choice for geriatric patients. It has limited potential to interact with other medications because it only weakly inhibits the cytochrome P450 system and binds to plasma proteins at a low level. Dosing may have to be adjusted for patients with renal failure, but typically not for those with liver disease or other medical conditions. Data from three double-blind and four open clinical trials support the safety and efficacy of venlafaxine for geriatric depression. Patients may experience transient, generally tolerable side effects such as insomnia, nausea, agitation, or dry mouth early in treatment, but more serious problems such as falls or cardiac rhythm disturbances seem to be rare. Treatment emergent hypertension occurs in a small percentage of older patients, generally at doses above 150 mg/day. Finally, emerging data suggest that venlafaxine may be effective for conditions such as stroke, anxiety, and neuropathic pain that frequently accompany depressive disorders in the elderly.

There is a longstanding belief that personality represents a structure that is stable over time, and changes, if at all, very slowly. Nonetheless, clinical and empirical evidence suggests that in patients with some Axis I disorders, the rate of personality disorders using DSM criteria decreases after treatment, suggesting that personality as assessed by phenomenological systems is state-dependent. An alternative to the DSM phenomenological system of conceptualizing personality is the dynamic concept of character, that is, a predictable pattern of both adaptive and pathological defense mechanisms, and personality organization comprised of object relations, ego strengths, and superego development. Data from this study address the hypothesis that defense mechanisms and personality organization remain relatively stable in patients treated for Axis I disorders, irrespective of clinical improvement. Patients meeting DSM-IV criteria for major depressive disorder (MDD) entered randomized, controlled medication trials. Defensive functioning was evaluated with the Defense Style Questionnaire (DSQ) [Bond et al., 1983: Arch Gen Psychiatry 40:333-338], and personality organization was assessed with the Inventory of Personality Organization (IPO; Clarkin et al., unpublished), both at baseline and at the completion of the clinical trial. Data were analyzed for whether an individual's pattern of defense mechanisms and personality organization were stable over time regardless of response to treatment of MDD. The question was also asked whether a predominant pattern of defense mechanisms or level of personality organization predicts response to treatment or dropout rate. Among treatment responders, nonresponders and drop-outs, baseline DSQ scores were similar except for "image-distorting" defenses, which were significantly more prevalent among drop-outs compared to responders (P = .016). Post-treatment DSQ values revealed a significant decrease in "maladaptive" defenses (P = .01) in the entire sample, while intermediate and "adaptive" defenses remained unchanged. This same pattern was found to hold true in treatment responders. When comparing treatment responders and nonresponders at the end of the trial, medication responders used significantly less "maladaptive" defenses than did nonresponders (P = .003), and had a significantly higher, or healthier level of "overall defensive functioning" (P = .04). Baseline and post-treatment IPO values did not show significant differences. Results of the study address the question of whether there are personality characteristics that are enduring and that can be appreciated irrespective of an Axis I disorder.

Because of reported efficacy of combining classes of antidepressants, 25 patients were treated with bupropion in combination with SRI's and venlafaxine. Fifteen patients inadequately responsive to monotherapy received combination treatment; ten patients without residual symptoms received adjunctive bupropion to treat SRI- or venlafaxine-induced side effects. Fourteen subjects (56%) responded, 11 (44%) did not. Twelve of 15 subjects receiving combination treatment to boost the effects of monotherapy responded, while only 2 of 10 subjects receiving combination treatment for side effects responded. Combination therapy was well tolerated even by geriatric and "medically frail" patients.