Charles DeBattista

An open label trial of C-1073 (mifepristone) for psychotic major depression*

BACKGROUND The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained. METHODS Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days. RESULTS All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group. CONCLUSIONS These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.

Sildenafil Treatment of Women With Antidepressant-Associated Sexual Dysfunction: A Randomized Controlled Trial

CONTEXT Antidepressant-associated sexual dysfunction is a common adverse effect that frequently results in premature medication treatment discontinuation and for which no treatment has demonstrated efficacy in women. OBJECTIVE To evaluate the efficacy of sildenafil for sexual dysfunction associated with selective and nonselective serotonin reuptake inhibitors (SRIs) in women. DESIGN, SETTING, AND PARTICIPANTS An 8-week prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 1, 2003, and January 1, 2007, at 7 US research centers that included 98 previously sexually functioning, premenopausal women (mean [SD] age 37.1 [6] years) whose major depression was remitted by SRIs but who were also experiencing sexual dysfunction. INTERVENTION Forty-nine patients were randomly assigned to take sildenafil or placebo at a flexible dose starting at 50 mg adjustable to 100 mg before sexual activity. MAIN OUTCOME MEASURES The primary outcome measure was the mean difference in change from baseline to study end (ie, lower ordinal score) on the Clinical Global Impression sexual function scale. Secondary measures included the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale-female version, the University of New Mexico Sexual Function Inventory-female version, a sexual activity event log, and the Hamilton Depression Rating scale. Hormone levels were also assessed. RESULTS In an intention-to-treat analysis, women treated with sildenafil had a mean Clinical Global Impression-sexual function score of 1.9 (95% confidence interval [CI], 1.6-2.3) compared with those taking placebo (1.1; 95% CI, 0.8-1.5), with a mean end point difference of 0.8 (95% CI, 0.6-1.0; P = .001). Assigning baseline values carried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6-1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3-0.8; P = .03). Baseline endocrine levels were within normal limits and did not differ between groups. The mean (SD) Hamilton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treatment, but no patients withdrew because of serious adverse effects. CONCLUSION In this study population, sildenafil treatment of sexual dysfunction in women taking SRIs was associated with a reduction in adverse sexual effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00375297.

Mifepristone versus Placebo in the Treatment of Psychosis in Patients with Psychotic Major Depression

BACKGROUND Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD. METHODS 221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment. RESULTS Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression. CONCLUSION A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.

A Prospective Trial of Modafinil as an Adjunctive Treatment of Major Depression

Abstract: Modafinil is a wake-promoting agent approved by the Federal Drug Administration for the treatment of narcolepsy. Preliminary evidence indicates that modafinil may improve fatigue and excessive sleepiness associated with a variety of conditions. The purpose of this study was to investigate the utility of modafinil as an adjunctive treatment of depressed patients. Subjects with a history of major depression with partial response on a stable therapeutic dose of an antidepressant were eligible to participate. All subjects endorsed complaints of significant fatigue and/or excessive sleepiness on clinical assessment. Modafinil was added to their existing regimen at a dose of 100 to 400 mg/d for 4 weeks. Subjects were assessed at 2-week intervals for improvement using the standard depression scales (HDRS, BDI, CGI), fatigue scales (VASF, FSI), and a neuropsychologic battery. Thirty-five subjects were entered and 31 subjects completed the 4-week trial. Significant improvements were seen across all 3 measures of depression (HDRS, BDI, CGIS) and both measures of fatigue (VASF, FSI). On the neurocognitive battery, significant gains in the Stroop Interference Test were seen at 4 weeks, whereas the other cognitive tests showed no change. Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression.

The use of mifepristone in the treatment of neuropsychiatric disorders.

Mifepristone is a potent glucocorticoid and progesterone receptor antagonist. The pathophysiology of a number of neuropsychiatric disorders implicates abnormalities in glucocorticoid function. These include mood disorders such as psychotic major depression and bipolar depression. In addition, cognitive disorders such as Alzheimers disease might also be partially mediated by abnormalities in the hypothalamic-pituitary-adrenal axis. Preliminary studies suggest that mifepristone might have a role in the treatment of a number of neuropsychiatric disorders.

HPA axis activation in major depression and response to fluoxetine: a pilot study

Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine. Premenopausal women (n = 20) who met criteria for major depression with no other confounding Axis I disorders, medications, or medical illnesses and were not taking hormonal contraceptives were evaluated with an evening metyrapone challenge before the onset of treatment. Twenty-one normal women were also studied with the evening metyrapone challenge. The depressed patients then entered an open label treatment with fluoxetine for 6 weeks. Subjects were classified as responders if they demonstrated a 50% or greater decrease in Hamilton Depression Rating Scale rating. As a group, the depressed women demonstrated significantly increased ACTH secretion compared to control women before the onset of treatment, during the metyrapone challenge. Before treatment, women who were non-responders to fluoxetine showed increased HPA axis activation compared to controls, while the fluoxetine responders did not differ significantly from normal subjects in their ACTH levels during metyrapone challenge. These results suggest that overactivity of the HPA axis may be one factor associated with slower response to fluoxetine. This may reflect the greater severity of subjects with HPA axis dysregulation or the need to normalize the HPA axis with medications for optimal response.

A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants.

Many patients fail to achieve an adequate response to a given antidepressant trial. The best-studied augmentation agents, lithium and thyroid supplementation are less commonly used. Augmenting antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Several case reports and 2 open label studies suggest efficacy of this strategy. The purpose of this study is to further examine the utility of bupropion sustained release (SR) augmentation in patients with inadequate response to selective serotonin reuptake inhibitors. Patients who met DSM-IV criteria for major depression and had failed to achieve adequate response to an SSRI were considered for this study. Eligible patients were required to have a score of 16 on the 24-item Hamilton Depression Rating Scale (HDRS). Patients were treated openly for 6 weeks with bupropion SR added to their existing antidepressant. The dose range of bupropion was 150 to 300 mg per day. At each visit, patients were assessed using the Beck Depression Inventory (BDI), the Hamilton Depression Ratings Scale (HDRS), and the Clinical Global Impression (CGI). Twenty-eight patients (12 men, 16 women) entered the study. Twenty-five patients completed the six-week trial. With respect to the clinical benefit of bupropion SR augmentation, 15 out of 28, or 54% of patients, were classified as responders, showing a decrease in their HDRS or BDI scores of 50% or more between baseline and Week 6. This prospective, open-label trial supports the use of bupropion SR in the augmentation of SSRIs and venlafaxine. Placebo controlled trials should be completed to further evaluate the efficacy of this strategy.

Modafinil Augmentation of Selective Serotonin Reuptake Inhibitor Therapy in MDD Partial Responders with Persistent Fatigue and Sleepiness

BACKGROUND Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue. METHODS This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4). RESULTS Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI. CONCLUSIONS Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.

Sertraline versus imipramine to prevent relapse in chronic depression

BACKGROUND Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone.

High circulating levels of glucocorticoid hormones adversely affect cognition. Previous studies exploring the hypothalamic-pituitary-adrenal (HPA) axis and basal cortisol levels in the elderly reported that subjects with mid-range cortisol levels outperformed subjects with high cortisol levels on assessments of memory and attention. This study examines the efficacy of mifepristone, a glucocorticoid-antagonist, in decelerating the rate of cortisol-related cognitive decline in subjects with mile-to-moderate Alzheimer’s disease (AD). Rate of cognitve decline is compared in AD subjects randomized to receive 200 mg of mifepristone daily for 6 mo or placebo. The Alzheimer’s Disease Assessment Scale (ADAS) and the Folstein Mini Mental Status Exam (MMSE) will be the primary measures used to assess change in cognitve function over the 6 mo period, supplemented by a neuropsychological battery testing memory and language and reasoning skills. During each visit, subjects will have samples collected for determination of plasma adrenocorticotropin (ACTH), serum cortisol and salivary cortisol levels to assess HPA axis activity. The placebo arm of this study also investigate whether subjects with high baseline cortisol levels experience greater declines in cognitive impairment over time relative to subjects with Ad who have low baseline cortisol levels. Additionally, this study test the hypothesis that AD subjects with elevated cortisol at baseline will perform more poorly on neuropsychological exams that do subjects with low cortisol.