Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3).

BACKGROUND: The endogenous opioid system is a fundamental regulator of mood in humans. Previously reported clinical trials have demonstrated the efficacy of the investigational agent buprenorphine/samidorphan (BUP/SAM) combination, an opioid-system modulator, for the adjunctive treatment of major depressive disorder. We present here a third phase III study of different design. METHODS: Adult patients with major depressive disorder and inadequate response to antidepressant therapy were enrolled in this double-blind, placebo-controlled, placebo run-in study to evaluate the efficacy, safety, and tolerability of adjunctive BUP/SAM 2 mg/2 mg. Patients with baseline Hamilton Depression Rating Scale score $20 received double-blind placebo in addition to background antidepressant therapy for 4 weeks. Nonresponders were randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period. RESULTS: Least-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], P=0.782). There were no differences in MADRS-based response or remission rates. Overall, 42.9% of the BUP/SAM 2 mg/2 mg group and 34.5% of the placebo group experienced at least one treatment-emergent adverse event during the 6-week treatment period, most of which were mild or moderate in severity. There were no clinically important changes in laboratory parameters, weight, or vital signs and no evidence of abuse potential during treatment or opiate-withdrawal symptoms post treatment. CONCLUSION: Efficacy results in FORWARD-3 measured by change in MADRS-10 score did not meet the primary end point, but postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was consistent with that seen in previously reported trials. BUP/SAM 2 mg/2 mg was well tolerated.

A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality.

OBJECTIVE: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. METHOD: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. RESULTS: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). CONCLUSIONS: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study.

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study.

OBJECTIVE: To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg. METHOD: Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks. Subjects were enrolled between September 2006 and February 2010. Efficacy outcomes included predefined criteria for response, remission, recovery, relapse, and recurrence. Subjects treated with adjunctive L-methylfolate 15 mg were included in the efficacy analysis. RESULTS: Of 68 subjects who met criteria for the 12-month open-label phase, 38% (n = 26) achieved full recovery, and none experienced a recurrence of MDD. For subjects entering the open-label phase in remission (n = 11), 91% (n = 10) achieved full recovery with L-methylfolate 15 mg, and none experienced a relapse or recurrence. Among 57 subjects who entered the open-label phase as nonremitted, 61% (n = 35) achieved remission. Of subjects who entered the open-label phase with a response without remission (n = 4), 50% (n = 2) had full recovery, and of subjects entering the open-label phase with no response (n = 53), 26% (n = 14) met recovery criteria. CONCLUSIONS: Adjunctive L-methylfolate 15 mg/d may be an early option in patients who fail to adequately respond to antidepressant monotherapy, with preliminary evidence demonstrating sustained remission and sustained recovery. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00321152.

Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs.

OBJECTIVE: Adjunctive treatment with L-methylfolate calcium significantly improved treatment outcomes in patients with major depressive disorder (MDD) and an inadequate response to antidepressants. This post hoc exploratory analysis evaluated baseline concentrations of cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, and IL-17; tumor necrosis factor α [TNF-α]; and interferon γ [IFN-γ]), high-sensitivity C-reactive protein (hsCRP), insulin, adiponectin and leptin and body mass index (BMI [kg/m2]) on L-methylfolate calcium treatment response. METHOD: Adults with DSM-IV MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) were eligible. Patients were randomized 3:3:2 according to the sequential parallel comparison design to placebo versus placebo, placebo versus L-methylfolate calcium (15 mg/d), or L-methylfolate calcium versus L-methylfolate calcium (15 mg/d) during two 30-day phases. The primary outcome was change on the 17-item Hamilton Depression Rating Scale (HDRS-17). Treatment effect with 95% CIs was estimated from baseline concentrations of individual biomarkers and combinations. Cytokines were measured by immunoassay; adiponectin, insulin, and leptin by radioimmunoassay; and hsCRP by a standard turbidimetric assay. The effects of baseline biomarker levels (above and below the median) on outcome were analyzed. The first participant was enrolled July 14, 2009, and the last participant completed April 28, 2011. RESULTS: Mean change on HDRS-17 from baseline was significantly improved with L-methylfolate calcium versus placebo (pooled treatment effect, -2.74; 95% CI, -4.99 to -0.48; P = .017) overall and for those with baseline BMI ≥ 30 (pooled treatment effect, -4.66; 95% CI, -7.22 to -1.98; P = .001) but not BMI < 30. Pooled mean changes in depression across treatment for baseline levels of individual markers above median were significant (L-methylfolate calcium vs placebo) for TNF-α, IL-8, hsCRP, and leptin (pooled treatment effects, -4.33 to -3.94 [P ≤ .02]) and for combinations of BMI ≥ 30 with elevated levels of TNF-α, IL-6, IL-8, hsCRP, and leptin (pooled treatment effects, -6.31 to -3.98 [P ≤ .05]). CONCLUSIONS: In this exploratory analysis, inflammatory and obesity-related factors were associated with greater symptom improvement with L-methylfolate calcium. Combinations of BMI ≥ 30 with elevated IL-6, IL-8, hsCRP, TNF-α, and leptin predicted improved response to L-methylfolate calcium in MDD patients with an inadequate antidepressant response. Further studies are necessary to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955.

Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.

OBJECTIVE: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). METHOD: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011. RESULTS: Seventy-five patients were enrolled. Patients with specific biological (body mass index ≥ 30 kg/m², elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo. CONCLUSIONS: Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955.

Residual symptoms and relapse: mood, cognitive symptoms, and sleep disturbances.

Remission is the standard of care in major depressive disorder (MDD). However, even in patients who respond to treatment and achieve remission, residual symptoms significantly inhibit functionality and increase the risk of relapse and recurrence. The most common residual symptoms are fatigue, sleep problems, and cognitive dysfunction. Clinicians should be cognizant of these potential residual symptoms and the unique ways in which they present in patients with MDD. Treating these symptoms as target symptoms from baseline increases the patient's chances of an asymptomatic remission. Making use of clinically practical screening instruments and monitoring these target symptoms throughout the course of treatment can improve patients' functional recovery.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.

OBJECTIVE: The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD: In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS: In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

A 12-week, randomized, double-blind, placebo-controlled, sequential parallel comparison trial of ziprasidone as monotherapy for major depressive disorder.

OBJECTIVE: To study ziprasidone monotherapy for major depressive disorder, defined according to the DSM-IV. METHOD: One hundred twenty outpatients were enrolled between June 2008 and September 2010 in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 fashion to receive ziprasidone for 12 weeks, placebo for 6 weeks followed by ziprasidone for 6 weeks, or placebo for 12 weeks. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17), with the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR), and Clinical Global Impressions-Severity of Illness scale (CGI-S) serving as the study secondary measures. RESULTS: One hundred twenty patients (53 women [44.1%]) were randomized to treatment. The mean (SD) age of these patients was 43.7 (11.0) years. Mean (SD) baseline HDRS-17, CGI-S, and QIDS-SR scores were 19.9 (5.0), 4.3 (0.6), and 15.6 (3.0), respectively. There was no statistically significant difference in reduction of depressive symptoms, response rates, or remission rates between ziprasidone- or placebo-treated patients. This was true for both the study primary as well as secondary outcome scales. CONCLUSIONS: In conclusion, treatment with ziprasidone monotherapy was not associated with any statistically significant advantage in efficacy over placebo. Although studies involving larger sample size would be required to have adequate statistical power to detect treatment differences smaller than 2.5 points on the HDRS-17, such differences would be of questionable clinical relevance. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00555997.

Evidence for the use of l-methylfolate combined with antidepressants in MDD.

Helping patients with major depressive disorder achieve symptom-free remission with antidepressant therapy remains challenging. In this activity, 3 investigators discuss the results of a 2-trial, multicenter, randomized, double-blind, placebo-controlled study of adjunctive l-methylfolate, the bioavailable form of folate, in patients who had inadequately responded to an SSRI. The efficacy of doses of 7.5 mg/d versus 15 mg/d is examined, and the safety and tolerability of l-methylfolate are compared with those of other adjunctive treatments. Different types of folate are explained, and the characteristics of patients who might benefit from adjunctive l-methylfolate are proposed.

Psychosocial outcomes in patients with recurrent major depressive disorder during 2 years of maintenance treatment with venlafaxine extended release.

BACKGROUND: Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated. METHODS: Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q), Life Enjoyment Scale-Short Version (LES-S), Social Adjustment Scale-Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE). RESULTS: At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40) on SF-36 vitality and role function-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05). LIMITATIONS: Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind. CONCLUSIONS: For patients with recurrent MDD, 2 years' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo.

Assessing rates and predictors of tachyphylaxis during the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study.

BACKGROUND: Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment. METHODS: Data were collected from a multiphase, doubleblind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) score

Augmentation strategies to increase antidepressant tolerability.

The goal of antidepressant treatment is full remission, but adverse events prevent many patients from reaching and sustaining this goal. Differential diagnosis should be made between antidepressant side effects and adverse events that are related to other causes. Antidepressant side effects may be transient or persistent and may occur early or later in treatment. Pharmacologic and nonpharmacologic strategies can be used to improve the tolerability of antidepressants, resulting in a greater probability of achieving and sustaining remission.

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

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

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

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

Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study.

OBJECTIVES: To test the long-term efficacy and safety of venlafaxine extended-release (ER) in preventing recurrence in patients with major depression. METHOD: This multiple-phase study, entitled "Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years" (PREVENT), was conducted from December 2000 through July 2005 in patients with recurrent unipolar depression (DSM-IV) who were initially randomly assigned to double-blind treatment with venlafaxine ER (75 mg/day to 300 mg/day) or fluoxetine (20 mg/day to 60 mg/day) for 10 weeks of acute treatment. Responders then received 6 months of continuation treatment. Those who remained responders were then enrolled into a 12-month maintenance period. Venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo. Fluoxetine responders were not randomly assigned but continued taking fluoxetine in order to maintain the blind during the maintenance study. Time to recurrence of depression (17-item Hamilton Rating Scale for Depression total score > 12 and < 50% reduction from acute phase baseline) with venlafaxine ER versus that of placebo were compared. RESULTS: The efficacy evaluable sample consisted of 129 patients in each group. The mean daily dose of venlafaxine ER was 224.7 mg (SD = 66.7). The cumulative probability of recurrence through 12 months, based on the primary definition, was 23.1% (95% CI = 15.3 to 30.9) for venlafaxine ER and 42.0% (95% CI = 31.8 to 52.2) for placebo (p = .005, log-rank test). CONCLUSION: Patients who had been successfully treated with venlafaxine ER during acute and continuation therapy were significantly less likely to experience recurrence with venlafaxine ER than with placebo over a 12-month maintenance treatment period. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00046020.

Preventing recurrent depression: long-term treatment for major depressive disorder.

In contrast to continuation therapy, a treatment aimed at suppressing symptoms during a current depressive episode, maintenance therapy is designed to prevent the development of a new episode. Candidates for maintenance therapy include patients who have achieved remission and have had 2 or more lifetime episodes, especially if they have comorbid disorders, ongoing psychosocial stressors, poor symptom control, or severe depressive episodes. Maintenance pharmacotherapy data strongly support the use of antidepressants at the dosage that helped the patient achieve remission. Other maintenance treatment interventions include psychotherapy, especially cognitive-behavioral therapy, and in some extreme cases, electroconvulsive therapy. Maintenance therapy considerations for clinicians include assessing treatment guidelines, addressing nonadherent patients, and measuring medication treatment response.

Calming the bipolar storm: treating acute mania and mixed episodes in patients with bipolar disorder.

Bipolar disorder is a seriously debilitating psychiatric disorder that greatly affects patients and their loved ones. Although bipolar disorder is one of the most frequently occurring mental disorders worldwide, many patients, particularly those with mixed mania, remain misdiagnosed. Compared to pure mania, mixed episodes of bipolar disorder present with symptoms that can be more challenging to treat. However, proper diagnosis and early treatment can usually alter the course of the illness, and remission is certainly possible. This expert roundtable supplement reviews the differences between acute manic and mixed episodes in patients with bipolar disorder, explains proper dosing and the advantages of different dosage formulations, and identifies the rationale for monotherapy and combination therapy in these patient populations. The aim is to educate clinicians about ways to diagnose and treat the mood state aggressively and safely, especially in light of the many new treatment options available.

High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of high-dose sertraline for patients with obsessive-compulsive disorder (OCD) who failed to respond to standard sertraline acute treatment. METHOD: Sixty-six nonresponders to 16 weeks of sertraline treatment who met DSM-III-R criteria for current OCD were randomly assigned, in a double-blind continuation phase of a multicenter trial, either to continue on 200 mg/day of sertraline or to increase their dose to between 250 and 400 mg/day for 12 additional weeks. Efficacy measures included the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH Global OC Scale), and the Clinical Global Impressions-Severity of Illness and -Improvement (CGI-I) scales. Data were collected from July 26, 1994, to October 26, 1995. RESULTS: The high-dose (250-400 mg/day, mean final dose = 357, SD = 60, N = 30) group showed significantly greater symptom improvement than the 200-mg/day group (N = 36) as measured by the YBOCS (p = .033), NIMH Global OC Scale (p = .003), and CGI-I (p = .011). Responder rates (decrease in YBOCS score of > or = 25% and a CGI-I rating < or = 3) were not significantly different for the 200-mg/day versus the high-dose sertraline group, either on completer analysis, 34% versus 52%, or on endpoint analysis, 33% versus 40%. Both treatments showed similar adverse event rates. CONCLUSION: Greater symptom improvement was seen in the high-dose sertraline group compared to the 200-mg/day dose group during continuation treatment. Both dosages yielded similar safety profiles. Administration of higher than labeled doses of selective serotonin reuptake inhibitors may be a treatment option for certain OCD patients who fail to respond to standard acute treatment.