A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder.

We examined the antidepressant efficacy and dose-response pattern of the n-3 docosahexaenoic acid (DHA). Thirty-five depressed adult outpatients (46% women; mean age 42+/-14 years) with a 17-item Hamilton-Depression Scale (HAM-D-17) score of >or=18 were randomized into one of three double-blind dosing arms for 12 weeks. Group A (n=14): 1 g/day of oral DHA; Group B (n=11): 2 g/day; and Group C (n=10): 4 g/day. We measured HAM-D-17 scores, plasma DHA, eicosapentaenoic acid (EPA), and n-6/n-3 ratio. Completer response rates (>or=50% decrease in HAM-D-17 score) were 83% for Group A, 40% for Group B, and 0% for Group C; Groups A and B had significant decreases in HAM-D-17 scores (p<0.05). For completers and intent-to-treat subjects, plasma DHA increased significantly (p<0.05), EPA had little change (p>0.05), and n-6/n-3 decreased significantly (p<0.05). DHA may be effective for depression at lower doses.

Early drop-outs, late drop-outs and completers: differences in the continuation phase of a clinical trial.

OBJECTIVE: The purpose of this study was to assess the differences between early and late drop-outs and completers in the continuation phase of a clinical trial. METHODS: The authors studied 119 outpatients who were treatment responders in an 8-week open trial with fluoxetine 20 mg/day, and who were then enrolled in a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). Patients were assessed using the Structured Clinical Interview for DSM-III-R--Axis I (SCID-Patient Edition), Hamilton Depression Rating Scale (HAMD-17) and the following self-rated scales: Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), Anxiety Sensitivity Index (ASI) and the Symptom Questionnaire (SQ) prior to starting the 26-week continuation phase. We defined "early drop-outs" (EDs) as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6-month continuation phase); those dropping out at Visit 3 or later were defined as "late drop-outs" (LDs) (ED < or = 2 months; LD >2 months). The Kruskal-Wallis and the Mann-Whitney U tests were used for data analysis. RESULTS: Of the 119 patients, 83 were completers (mean age: 42.1+/-9.0 years; 46 [55%] women; age of onset of major depressive disorder [MDD] = 24.3+/-12.5 years), II were EDs (mean age: 38.1 + 13.0 years: 4 [36%] women; age of onset of MDD = 22.0+/-11.1 years) and 25 were LDs (mean age: 35.2+/-10.4 years; 12 [48%] women; age of onset of MDD = 24.6+/-11.6 years). LDs were significantly younger than completers (P<.01). There was no significant difference in age between EDs and LDs, nor between EDs and completers. EDs were more likely to have been depressed for a longer period of time compared to LDs (P< .05). EDs completers were depressed for a longer period of time compared to LDs (P< .05). CONCLUSIONS: Our data suggest that late drop-outs are significantly younger than completers, although age is not a predictor between early drop-outs and late drop-outs. Further, early drop-outs are depressed for a longer duration compared to late drop-outs completers are depressed for a longer duration than late dropouts, and Early drop-outs have significantly more social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial.

Early drop-outs, late drop-outs and completers: differences in the continuation phase of a clinical trial.

OBJECTIVE: The purpose of this study was to assess the differences between early (EDs), late drop-outs (LDs) and completers in the continuation phase of a clinical trial. METHODS: The authors studied 119 outpatients who were treatment responders in an 8-week open trial with fluoxetine 20 mg/day, and who were then enrolled in a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). Patients were assessed using the Structured Clinical Interview for DSM-III-R-Axis I (SCID-Patient Edition), Hamilton Depression Rating Scale (HAMD-17) and the following self-rated scales: Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), Anxiety Sensitivity Index (ASI) and the Symptom Questionnaire (SQ) prior to starting the 26-week continuation phase. We defined 'EDs' as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6-month continuation phase); those dropping out at Visit 3 or later were defined as 'LDs' (ED < or = 2 months and LD > 2 months). The Kruskal-Wallis and the Mann-Whitney U tests were used for data analysis. RESULTS: Of the 119 outpatients, 83 were completers (mean age: 42.1 +/- 9.0 years, 46 [55%] women, age of onset of major depressive disorder [MDD] = 24.3 +/- 12.5 years), 11 were EDs (mean age: 38.1 +/- 13.0 years, 4 [36%] women, age of onset of MDD = 22.0 +/- 11.1 years) and 25 were LDs (mean age: 35.2 +/- 10.4 years, 12 [48%] women, age of onset of MDD = 24.6 +/- 11.6 years). LDs were significantly younger than completers (P<.01). There was no significant difference in age between EDs and LDs, nor between EDs and completers. EDs and completers were depressed for a longer period of time compared to LDs (P<.05). EDs also had significantly greater overall impairment in social adjustment compared to completers (P<.05). CONCLUSIONS: Our data suggest that LDs are significantly younger than completers, although age is not a predictor between EDs and LDs. Further, EDs and completers are depressed for a longer duration than LDs, and EDs have significantly greater social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial.

Fluoxetine treatment of depressed patients with comorbid anxiety disorders.

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared to major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in severity of both depressive and anxiety symptoms in outpatients with major depression with comorbid anxiety disorder following fluoxetine treatment. We enrolled 123 outpatients (mean age 38.9 +/- 10.8 years; 49% women) with major depressive disorder accompanied by one or more current comorbid anxiety disorders in our study. Patients were treated openly with fluoxetine 20 mg/day for 8 weeks. Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D) and the patient-rated Symptom Questionnaire (SQ) Scales for Depression and Anxiety. The mood and anxiety disorder modules of the Structured Clinical Interview for DSM-III-R were administered at screen and endpoint. We used 'intent-to-treat' analysis in examining all patients assigned to treatment and completing the baseline visit. The mean number of comorbid anxiety disorders per patient was 1.5 +/- 0.68. The mean HAM-D-17 score and mean Clinical Global Impressions-Severity scores decreased significantly from baseline to endpoint (week 8) following fluoxetine treatment (p < 0.0001). There were significant decreases in all four SQ scale scores, from baseline to endpoint: depression, anxiety, somatic symptoms and anger-hostility (p < 0.0001). Fifty-three percent of patients (n = 65) were depression responders (i.e. > or = 50% decrease in HAM-D-17 score at endpoint) and 46% (n = 57) were remitters (HAM-D-17 < or = 7 at endpoint). Patients with panic disorder had significantly higher baseline HAM-D-17 scores compared to those without panic disorder (p < 0.01). Patients with comorbid obsessive-compulsive disorder (OCD) were significantly less likely to be responders to fluoxetine at endpoint (> or = 50% decrease in HAM-D-17) and to be remitters (HAM-D-17 score of s 7 at endpoint) compared to patients without comorbid OCD (p < 0.01). Of the 41 patients on whom endpoint Structured Clinical Interview for DSM-III-R modules for anxiety disorders were available, 49% (n = 20) no longer met criteria for one or more of their anxiety disorder diagnoses at endpoint. Our preliminary findings suggest that fluoxetine is effective in treating outpatients with major depression with comorbid anxiety disorders, with a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are required in larger samples to confirm our findings.

Somatic symptoms in treatment-resistant depression.

The purpose of this work was to study the prevalence of somatic symptoms in patients with treatment-resistant depression (TRD) and their impact on the response to antidepressant treatment. Somatic symptoms were assessed during the screen visit with the Symptom Questionnaire (SQ) somatic symptom (SQ-SS) and somatic well-being sub-scales (SQ-SWB) in 40 patients with TRD enrolled in a 6-week open trial of nortriptyline. A logistic regression was used to test whether SQ-SS or SQ-SWB scores predicted clinical response to nortriptyline. Ninety-five percent of patients reported at least one somatic symptom. Higher SQ-SS scores during the screen visit predicted poorer response to nortriptyline. There was a trend for lower SQ-SWB scores to predict poor response to nortriptyline. None of the patients with SQ-SS scores above the mean for the sample responded to nortriptyline. The overwhelming majority of patients with TRD presented with somatic symptoms. In addition, a greater number of somatic symptoms during the screen visit placed patients at risk for further treatment resistance.

An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding.

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [18F]-setoperone for 5-HT2 binding potential (BP) and [11C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [18F]-setoperone and with [11C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as >or=50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.

Placebo response in depression.

With its naturally fluctuating course, depression is a highly placebo-responsive condition: mean placebo response rates in antidepressant clinical trials are 30% to 40%. We review the history and terminology of placebo and the proposed mechanisms underlying the placebo response, including the physician-patient relationship and biological, sociocultural, and treatment situation factors. We identify the predictors and patterns of placebo response in depressed patients, both within and outside of the clinical trial context, and differentiate between true drug response and placebo pattern response. We discuss the strategies now being advanced to minimize the placebo response given the increased placebo drift reported in recent trials, and the ethical guidelines governing placebo administration. Potential areas for future research include the identification of biological markers of placebo response, such as functional neuroimaging and quantitative electroencephalography, the development and testing of more sophisticated, alternative research designs, and the design of valid biological tools to assess antidepressant efficacy.

A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder.

OBJECTIVE: To examine the efficacy and tolerability of ethyl-eicosapentaenoate (EPA-E) monotherapy for major depressive disorder (MDD). METHOD: Fifty-seven adults with DSM-IV MDD were randomly assigned from January 2003 until June 2006 to receive 1 g/d of eicosapentaenoic acid (EPA) or placebo for 8 weeks in a double-blind, randomized, controlled pilot study. Response criteria were on the basis of the 17-item Hamilton Depression Rating Scale (HDRS-17). Subjects' plasma lipid profiles were examined by gas chromatography. RESULTS: Thirty-five subjects (63% female; mean +/- SD age = 45 +/- 13 years) were eligible for the intent-to-treat (ITT) analysis. In the ITT sample, mean +/- SD HDRS-17 scores decreased from 21.6 +/- 2.7 to 13.9 +/- 8.9 for the EPA group (n = 16) and from 20.5 +/- 3.6 to 17.5 +/- 7.5 for the placebo group (n = 19) (P = .123); the effect size for EPA was 0.55. ITT response rates were 38% (6/16) for EPA, and 21% (4/19) for placebo (P = .45). Among the 24 study completers, mean +/- SD HDRS-17 scores decreased from 21.3 +/- 3.0 to 11.1 +/- 8.1 for the EPA group and from 20.5 +/- 3.8 to 16.3 +/- 6.9 for the placebo group (P = .087); the effect size for EPA was 0.73. Completer response rates were 45% (5/11) for EPA, and 23% (3/13) for placebo (P = .39). Among EPA subjects, baseline n-6/n-3 ratio was associated with decrease in HDRS-17 score (r = -0.686, P = .030) and with treatment response (P = .032); change in n-6/n-3 ratio was associated with change in HDRS-17 score (r = .784, P = .032). Side effects, reported in 2 EPA subjects and 5 placebo subjects, were exclusively gastrointestinal, mild, and not associated with discontinuation. CONCLUSIONS: EPA demonstrated an advantage over placebo that did not reach statistical significance, possibly due to the small sample and low completer rates, which were the major study limitations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00096798.

Differences in cognitive factors between "true drug" versus "placebo pattern" response to fluoxetine as defined by pattern analysis.

OBJECTIVE: Pattern analysis has identified two types of response patterns to antidepressants: "true drug" response (TDR) and "placebo pattern" response (PPR). This study examines the relationship between cognitive factors and TDR and PPR to fluoxetine. METHODS: We assessed 310 outpatients meeting DSM-III-R criteria for major depressive disorder (MDD) who were enrolled in an 8-week open trial of fluoxetine 20 mg/day. Response patterns were determined using the clinical global impressions-improvement (CGI-I). We administered the following self-rated scales to all patients at the baseline visit and at endpoint: perceived stress scale (PSS), cognitions questionnaire (CQ), Beck hopelessness scale (BHS) and dysfunctional attitudes scale (DAS). RESULTS: One hundred and thirty-four patients had TDR, 66 patients had PPR, and 110 patients were non-responders (NR). Demographic variables and severity of depression at baseline (HAMD-17) were not significantly different between the two response pattern groups. We compared cognitive factors before and after treatment across patients with TDR and PPR, and there were no significant differences at baseline in CQ, PSS, BHS, and DAS scores. At endpoint, outpatients with PPR had significantly lower scores on the PSS (p < 0.001) compared to the patients with TDR, even after adjusting for multiple comparisons and severity of depression at endpoint. CONCLUSIONS: Significant differences in cognitive/psychological factors, specifically lower post-treatment perceived stress, accompany "placebo" pattern of response to antidepressant treatment and differentiate it from "true drug" response pattern, as defined by pattern analysis.

Serum cholesterol in treatment-resistant depression.

OBJECTIVE: Patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared with healthy controls. A previous study by our group reported that depressed patients with elevated cholesterol levels (>or=200 mg/dl) were significantly more likely to be nonresponders to fluoxetine treatment than depressed patients with nonelevated cholesterol levels. However, very little is known regarding cholesterol in patients with treatment-resistant depression (TRD). The purpose of this study was to compare cholesterol levels at baseline between depressed patients with and without TRD and to test whether cholesterol levels at baseline can predict clinical response in patients with TRD treated with open-label nortriptyline (NT). METHODS: Ninety-two patients with TRD entered a 6-week open trial of NT. Baseline cholesterol levels were randomly collected for 59 of these patients. Controlling for age and gender, we compared baseline cholesterol and triglyceride levels for 35 patients with TRD who did not respond to NT with 205 non-TRD patients who responded to an 8-week open trial of fluoxetine. Furthermore, with the use of logistic regression, we tested whether baseline cholesterol levels predicted clinical response to NT in the patients with TRD. RESULTS: Patients with TRD had higher triglyceride levels at baseline compared with depressed patients without TRD. Cholesterol defined as a dichotomous variable being elevated if equal to or greater than 200 mg/dl, predicted poor response to a 6-week open trial of NT in patients with TRD. CONCLUSIONS: The results of this study confirm the relationship between hypercholesterolemia and poor outcome in the treatment of MDD for patients with TRD.

Elevated cholesterol levels associated with nonresponse to fluoxetine treatment in major depressive disorder.

Previous studies have suggested that patients with major depressive disorder may have lower cholesterol levels compared to healthy controls. The purpose of this study was to examine the relationship between pretreatment serum cholesterol levels and clinical response to treatment with fluoxetine among outpatients with major depression. Three hundred and twenty-two depressed outpatients meeting DSM-III-R criteria for major depressive disorder were enrolled in an 8-week, fixed-dose, open trial of fluoxetine 20 mg/day. Nonfasting serum cholesterol levels were obtained for all patients before starting fluoxetine. All patients were drug free for a minimum of 2 weeks prior to the onset of the study. Clinical response was defined as a 50% or greater decrease in the 17-item Hamilton Rating Scale for Depression (HAM-D-17) score at endpoint compared to baseline. Cholesterol levels were classified as either elevated (defined as a level equal to or greater than 200 mg/dL) or nonelevated (defined as a level less than 200 mg/dL). Among the 322 outpatients, 51.6% were classified as having elevated and 48.4% as having nonelevated cholesterol levels at baseline (mean cholesterol level 238.6 +/- 33.4 mg/dL vs. 170.4 +/- 22.2 mg/dL, respectively). Depressed patients with elevated cholesterol levels did not significantly differ in gender ratio but were significantly older than depressed patients with nonelevated cholesterol levels (P <.0001). After adjusting for age, gender, and Body Mass Index (BMI), depressed patients with elevated cholesterol levels were significantly more likely to be nonresponders to fluoxetine treatment than were depressed patients with nonelevated cholesterol levels (P < 0.05). Elevated serum cholesterol levels appear to be associated with poorer response to fluoxetine treatment. Further studies are needed to confirm our findings.