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John M Zajecka,1,2 Arielle D Stanford,3 Asli Memisoglu,4 William F Martin,5 Sanjeev Pathak3 1Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA; 2Psychiatric Medicine Associates, LLC, Skokie, IL, USA; 3Department of Clinical Research, Alkermes, Inc., Waltham, MA, USA; 4Department of Biostatistics, Alkermes, Inc., Waltham, MA, USA; 5Clinical Operations, Alkermes, Inc., Waltham, MA, USA 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. Keywords: buprenorphine, samidorphan, randomized clinical trial, adjunctive therapy, study design, placebo response, opioid system modulator

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. [ABSTRACT FROM AUTHOR]

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.

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.

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., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

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-1β, 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., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

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., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

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.

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., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

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

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.

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)

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.

Background: Whether antidepressants prevent depression during interferon-alpha/ribavirin treatment for hepatitis C virus infection has yet to be established., Aim: To investigate the use of paroxetine in a prospective, double-blind, placebo-controlled study for this indication., Methods: Sixty-one hepatitis C virus-infected patients were randomly assigned to the antidepressant, paroxetine (n = 28), or placebo (n = 33), begun 2 weeks before and continued for 24 weeks during interferon-alpha/ribavirin treatment. Primary endpoints included development of major depression and severity of depressive symptoms measured by the Montgomery Asberg Depression Rating Scale (MADRS)., Results: Rates of major depression during the study were low (17%) and did not differ between groups. Nevertheless, using published MADRS cut-off scores, the percent of subjects who met criteria for mild, moderate or severe depression during interferon-alpha/ribavirin therapy was significantly lower in paroxetine- vs. placebo-treated subjects (P = 0.02, Fisher's exact test). Assignment to paroxetine was also associated with significantly reduced depressive symptom severity. This effect was largely accounted for by participants with depression scores above the median (MADRS > 3) at baseline in whom paroxetine was associated with a maximal reduction in MADRS scores of 10.3 (95% CI: 2.1-18.5) compared with placebo at 20 weeks (P < 0.01). Study limitations included a small sample size and high drop-out rate., Conclusion: This double-blind, placebo-controlled trial provides preliminary data in support of antidepressant pre-treatment in hepatitis C virus patients with elevated depressive symptoms at baseline.

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.

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.

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.

Objective: Sertraline may produce dual neurotransmitter effects similar to the serotonin-norepinephrine reuptake inhibitors (SNRIs); however, it has been tested against an SNRI in only 1 previous study, and never at an optimal dose. The objective of the current multisite study was to compare relatively higher doses of sertraline (i.e., 150 mg/day) and venlafaxine extended release (XR) (225 mg/day) in outpatients with major depressive disorder., Method: Subjects with DSM-IV major depressive disorder were randomly assigned to 8 weeks of double-blind treatment with sertraline (N = 82) or venlafaxine XR (N = 78). The study ran from January 2002 through January 2003. The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Questionnaire; secondary outcome variables included the 17-item Hamilton Rating Scale for Depression., Results: Both treatments led to significant improvement in depressive symptoms and quality-of-life measures. No significant differences were noted between treatment groups for final scores on the primary or secondary measures. The treatment groups did not differ significantly in the percentage of responders (sertraline = 55%, venlafaxine XR = 65%; intent-to-treat [ITT] sample) or remitters (sertra-line = 38%, venlafaxine XR = 49%; ITT sample), although the proportions are similar to those found in earlier selective serotonin reuptake inhibitor (SSRI) vs. venlafaxine meta-analyses. In patients who achieved the maximum dose of drug and maintained it for 3 weeks, response rates were similar to those found at lower doses (sertraline = 59%, venlafaxine XR = 70%); however, remission rates for this sample were comparable for both drug groups (sertraline = 48%, venlafaxine XR = 50%)., Conclusions: The efficacies of sertraline and venlafaxine XR were comparable. Although response and remission rates did not differ statistically, the rates were analogous to those reported in previous meta-analyses. However, at clinically relevant higher doses, the remission rates were very similar., Clinical Trials Registration: ClinicalTrials.gov identifier NCT00179283.

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.

Remission of a patient's index major depressive episode is essential in preventing a recurrent or chronic depressive course. Once remission is established, the subsequent goal is to maintain remission and prevent a relapse of the episode with a minimum of 4 to 9 months of continuation treatment. Common belief suggests that all antidepressants have equivalent efficacy when measured by remission, but this may be a misconception based on limitations in current clinical trial methods. Furthermore, major depressive disorder (MDD) is a complex illness with a variety of co-occurring somatic and often painful symptoms. In addition, increasing evidence suggests that, in some depressed patients, serotonin-norepinephrine reuptake inhibitors (SNRIs) may provide benefits of treating a broader range of target symptoms than single-acting agents, such as selective serotonin reuptake inhibitors (SSRIs). Given the available evidence and the importance of remission, the pendulum has swung to consider using agents with dual reuptake inhibition (e.g., SNRIs) as standard and initial treatment for depression.

Background: Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder., Method: This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study., Results: A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88)., Conclusion: Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.

Over the last several years, the recommended end point in the treatment of depression has become remission. Patients who achieve remission not only enjoy the benefits of decreased disability and improved functioning in work, family, and social situations, they also have a lower risk of disease progression and relapse. Despite the benefits associated with remission, many patients are left with residual symptoms that prevent them from achieving these benefits. Potential obstacles to reaching remission include diagnostic issues, inadequate treatment, lack of adherence to the treatment regimen, satisfaction with partial improvement, and failure to recognize residual symptoms. Strategies for treating to remission include ensuring appropriate diagnosis, setting treatment goals, selecting antidepressants that are more likely to result in remission, providing patient education and adequate treatment, assessing for residual symptoms, and heeding partial response or lack of response by switching or augmenting treatment.

Background: This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder., Method: This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs., Results: 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis)., Conclusion: No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine.

Background: There is a clear need for effective, well-tolerated intramuscular (i.m.) agents for the acute control of agitated psychotic patients. Currently used agents, including conventional antipsychotics and/or benzodiazepines, may be associated with distressing side effects such as extrapyramidal side effects and excessive sedation., Objective: The objective of this study was to evaluate the efficacy and tolerability of the rapid-acting i.m. formulation of the novel antipsychotic ziprasidone in the treatment of inpatients with psychosis and acute agitation (DSM-IV diagnoses)., Method: In a 24-hour, double-blind, fixed-dose clinical trial, patients were randomly assigned to receive up to 4 injections (every 2 hours p.r.n.) of 2 mg (N = 54) or 10 mg (N = 63) of ziprasidone i.m. The Behavioral Activity Rating Scale measured behavioral symptoms at baseline and the response to treatment up to 4 hours after the first i.m. injection., Results: Ziprasidone i.m., 10 mg, rapidly reduced symptoms of acute agitation and was significantly more effective (p < .01) than the 2-mg dose up to 4 hours after the first injection. Patients were calmed but not excessively sedated, and over half were classed as responders 2 hours after the 10-mg dose. No acute dystonia or behavioral disinhibition was reported. One patient who received the 10-mg dose experienced the extrapyramidal side effect akathisia., Conclusion: Ziprasidone i.m., 10 mg, is rapidly effective and well tolerated in the short-term management of the agitated psychotic patient. Comparison with a study of identical design comparing 2-mg with 20-mg doses in patients with similar levels of psychopathology suggests that efficacy with 10 mg or 20 mg of ziprasidone i.m. is significant and dose related.

Historically, the emphasis in treating depression has been focused on the acute phase of treatment, with few published data on the continuation and maintenance phases of treatment. Yet the risk of depression increases with each episode, with a 50% to 90% chance of developing another episode after 1 or 2 prior episodes of depression. Moreover, subsequent episodes of depression are often of longer duration, more severe, and less responsive to treatment. Most patients with major depression require some form of long-term antidepressant treatment, and many need lifelong treatment. Optimizing efficacy and minimizing side effects are essential during both the acute and long-term phases of antidepressant treatment. Antidepressant side effects, including insomnia or somnolence, weight gain, asthenia, and sexual dysfunction, can significantly decrease patient compliance with long-term treatment for depression. Identification and management of side effects, combined with early and ongoing educational messages to the patient about treatment issues and the importance of sustaining illness remission, help improve compliance and reduce the potential for premature discontinuation of an otherwise optimal antidepressant.

The coexistence of depression and anxiety is a common occurrence that frequently poses diagnostic and treatment challenges in the clinical setting. As epidemiological studies continue to confirm the enormous prevalence of this comorbid condition, the separation in diagnosis and treatment between depression and anxiety has become increasingly less pronounced. Additionally, the discovery that pharmacotherapeutic modalities have a broader range of efficacy, often overlapping both depression and anxiety, has led to an evolving reclassification of treatment, away from 'antidepressants' and 'anxiolytics' toward one based on mechanism of action. A rational approach to the systematized management of the various comorbidities of depressive and anxiety disorders is discussed.

Retrospective analysis of two randomized, placebo-controlled trials evaluated the effectiveness of nefazodone in relieving depression-associated anxiety symptoms of patients with major depression in two practice settings. One study involved depressed patients (N = 138) treated in a family practice setting, the other, psychiatric clinic outpatients (N = 180). Nefazodone treatment was broadly effective across several measures of anxiety symptoms (HAM-D, HAM-A and SCL rating scales) in relieving depression-associated anxiety. The comparison drug, imipramine, was also found to be more effective than placebo treatment, although the treatment effect on depression-associated anxiety, as measured by several factors, was less than that seen with nefazodone. A subgroup of psychiatric clinic outpatients with comorbid major depression and panic disorder (N = 55) was identified by blinded record review. During nefazodone treatment, patients with panic disorder experienced marked global improvement compared with placebo-treated patients, including relief of panic and phobic anxiety symptoms. Imipramine treatment was not significantly better than placebo for improvement in depression and anxiety ratings in this patient group. These results extend previous findings indicating that the new antidepressant nefazodone effectively relieves anxiety and depressive symptoms of patients with major depression.

Background: Treatment-resistant depression is a common clinical challenge that often requires the use of innovative pharmacologic treatments. Recent reports suggest the efficacy of the combination of a serotonin selective reuptake inhibitor and a heterocyclic antidepressant (HCA) in depressed patients who fail monotherapy with either agent alone. We present our clinical experience with the use of fluoxetine combined with an HCA in a group of 25 treatment-resistant depressed subjects., Method: Twenty-five depressed subjects who failed to adequately respond to at least 4 weeks of open-label fluoxetine treatment (mean dose = 73 mg/day) had an HCA added to their fluoxetine. The dose of the HCA was increased to maximize efficacy and minimize side effects. Efficacy was measured using the 21-item Hamilton Rating Scale for Depression (HAM-D-21) score and the Clinical Global Impressions-Global Improvement (CGI) scale., Results: Response to treatment was defined as a 50% or greater drop in the HAM-D-21 score and a CGI of either very much improved or moderately improved from the start of the HCA. Seven (35%) of 20 subjects who demonstrated a poor or partial response to fluoxetine responded when an HCA was added to the fluoxetine. Five (71%) of the responders had previously failed to respond to monotherapy with the HCA that they responded to when used with fluoxetine. Additionally, 5 subjects who demonstrated significant improvement with fluoxetine but who had mild, residual depressive symptoms experienced at least partial further improvement with the addition of an HCA., Conclusion: The results suggest that the addition of an HCA to fluoxetine may be an effective treatment in treatment-resistant depressed patients who have failed to adequately respond to monotherapy with fluoxetine. Additional controlled trials are warranted to further explore the efficacy of this treatment combination in patients who demonstrate a poor or partial response to monotherapy. When using this drug combination, the clinician is cautioned to prescribe low doses of the HCA and monitor serum levels closely since fluoxetine can raise serum HCA levels.

We administered the Multiscale Depression Inventory (MDI) and the Beck Depression Inventory (BDI) to 84 multiple sclerosis (MS) patients, 101 patients diagnosed with major depression and 87 nonmedical, nonpsychiatric controls. The MDI consists of three separate depression scales measuring mood, vegetative, and evaluative symptoms. We found that: (a) MS patients did not significantly differ from the controls in mood symptoms, (b) the depression prevalence rate in MS patients was significantly lower when measured by the mood scale (17.7%) than by the BDI (30.5%) or MDI total score (26.6%), and (c) MS patients showed significantly less mood disturbance than a non-MS comparison group matched on BDI measured depression severity. We suggest that the inclusion of nonmood symptoms in self-report depression scales may artificially raise both prevalence rates and severity ratings of MS related depression and that the most valid measure of depression in MS is mood disturbance.

The coexistence of anxiety and depression is common and frequently poses diagnostic and treatment challenges in the clinical setting. Although precise diagnosis is important for treatment selection, it is often complicated by the shortcomings of the current classification system. Whereas some patients present with symptoms that meet the diagnostic criteria for both an anxiety disorder and major depression, others may present with "subsyndromal" symptoms of depression and/or anxiety. Epidemiologic data and a rational treatment approach to the patient with mixed anxiety and depression, depressive symptoms coexistent with "syndromal" and "subsyndromal" symptoms of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social phobia are discussed, as well as areas of future research to examine coexisting anxiety and depression.

Background: Anticonvulsants have been shown to be effective in many patients with psychiatric disorders, especially those with bipolar affective disorder. We present our clinical experience with divalproex sodium in the treatment of 63 patients with a variety of affective disorders that had proved refractory to conventional pharmacotherapy., Method: We reviewed the charts of 63 patients diagnosed as bipolar I (35 patients), bipolar II (23 patients), or schizoaffective, bipolar type (5 patients). Twelve patients who appeared to have recurrent unipolar depression had a retrospectively recognized history of "covert cycling," with brief periods of socially acceptable hypomania occurring between depressive episodes. Prior to treatment with divalproex, 45 patients had been classified as treatment failures with lithium, 29 patients had been classified as treatment failures with carbamazepine, and 35 patients had also failed on a combination of lithium and carbamazepine. Divalproex was given to these patients and titrated to achieve blood levels in the range of 50 to 100 mg/L., Results: Forty-seven (75%) of the 63 patients responded positively to the addition of divalproex to their regimens. Of 45 patients who had failed to respond to lithium, 38 (84%) responded when divalproex was added. Of 29 patients who had failed to respond to carbamazepine, 20 (69%) responded when divalproex was added. Of 26 rapid-cycling patients, 21 (81%) responded to the addition of divalproex. Side effects required drug withdrawal in 9 patients (14%)., Conclusion: The results confirm previous findings that both mania and rapid mood cycling may respond to a pharmacologic regimen that includes divalproex. Many patients who appear to have recurrent, major unipolar depression may actually be convert cyclers who will respond to divalproex, sometimes in combination with an antidepressant medication.

We report on our clinical experience with a combination of a CNS stimulant (either pemoline or dextroamphetamine) and a monoamine oxidase inhibitor (MAOI) for treating 32 depressed patients (mainly outpatients) refractory to standard antidepressant pharmacotherapy. This combination, though not approved by the FDA, appears to be safe and effective. Twenty-five (78%) of these patients experienced at least 6 months of symptom remission with a stimulant + MAOI combination. Many patients required adjunctive antidepressant treatment, including tricyclics and lithium. Side effects were not excessive, though 6 patients (3 unipolar and 3 bipolar) cycled to mania (N = 1) or hypomania (N = 5). None developed hypertensive crises. With properly motivated and complaint patients and careful clinical monitoring by the prescribing psychiatrist, stimulant potentiation of MAOIs may be a viable option for treatment-resistant depressed patients.

This chapter will briefly review the current theories on the biochemical etiology of depression that are contributing toward the development of innovative somatic treatments. A description of clinically approved pharmacological treatments will be described in detail. Investigational pharmacological treatments that have demonstrated a high probability for general clinical use will also be discussed. Finally, a description of sleep deprivation will be included.

This chapter will describe the clinical indications and safety/efficacy factors of antidepressant potentiation. Examples include TCA/MAOI combinations, MAOI/stimulant combination, antidepressant potentiation with thyroid, lithium or l-tryptophan.