David E. Adson

D-Cycloserine Augmented Exposure Therapy for Obsessive-Compulsive Disorder

BACKGROUND D-cycloserine (DCS), a glutamatergic partial N-methyl-d-aspartate (NMDA) agonist, can facilitate extinction learning related to cued fear in animals and humans. We predicted that DCS would accelerate obsession-related distress reduction in patients with obsessive-compulsive disorder (OCD) undergoing extinction-based exposure therapy. METHODS We administered DCS (125 mg) or placebo in a double-blind fashion to individuals with OCD approximately 2 hours before each exposure session. RESULTS D-cycloserine decreased both the number of exposure sessions required to achieve clinical milestones and the rate of therapy dropout. After four exposure sessions, patients in the DCS group reported significantly greater decreases in obsession-related distress compared with the placebo group; however, after additional sessions, the placebo group tended to catch up. CONCLUSIONS D-cycloserine augmentation has the potential to increase the efficiency, palatability, and overall effectiveness of standard exposure therapy for OCD.

Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants

INTRODUCTION Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials. METHODS Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14). RESULTS Clinically significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%). CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy (ClinicalTrials.gov study NCT00105196).

Inhibition of CYP2D6 activity by bupropion

Abstract: The purpose of this study was to assess the effect of bupropion on cytochrome P450 2D6 (CYP2D6) activity. Twenty-one subjects completed this repeated-measures study in which dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration. To assess CYP2D6 activity, urinary dextromethorphan/dextrorphan metabolic ratios were calculated after an 8-hour urine collection. Thirteen subjects received bupropion, and 8 received placebo. In those receiving active medication, the dextromethorphan/dextrorphan ratio increased significantly at the second assessment relative to the first (0.012 ± 0.012 vs. 0.418 ± 0.302; P < 0.0004). No such change was observed in those randomized to placebo (0.009 ± 0.010 vs. 0.017 ± 0.015; P = NS). At baseline, all subjects were phenotypically extensive CYP2D6 metabolizers (metabolic ratio <0.3); after treatment, 6 of 13 subjects receiving bupropion, but none of those receiving placebo, had metabolic ratios consistent with poor CYP2D6 metabolizers. Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6.

The superior mesenteric artery syndrome and acute gastric dilatation in eating disorders: a report of two cases and a review of the literature.

OBJECTIVE The pathophysiology and symptomatology of the superior mesenteric artery syndrome (SMA syndrome) is discussed. METHOD A review of much of the available literature concerning the SMA syndrome and the associated condition acute gastric dilatation is offered. RESULTS Two new cases of acute gastric dilatation in patients with eating disorders, one of whom was diagnosed with SMA syndrome, are presented, along with a discussion of these conditions in reference to the eating disorders. CONCLUSION The SMA syndrome and gastric dilatation are rare but potentially a very serious complication of eating disorders, and clinicians who work with these patients should be aware of such problems.

Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: A placebo-controlled, randomized study☆

BACKGROUND Evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) once-daily monotherapy for patients with major depressive disorder (MDD). METHODS In this 10-week, (8-week active treatment phase and 2-week drug-discontinuation/tapering phase), multicenter, parallel-group, placebo-controlled, double-blind, randomized, Phase III study (D1448C00003: Opal), patients initially received quetiapine XR 150 mg/day or placebo. At Week 2, inadequate responders (<20% reduction in MADRS total score) were up-titrated to 300 mg/day quetiapine XR or matching placebo for the final 6 weeks. Primary endpoint: change from randomization to Week 8 in MADRS total score. Secondary endpoints included: MADRS response (≥50% reduction in total score from randomization) and changes from randomization to Week 8 in HAM-D and CGI-S. RESULTS 310 patients were randomized. At Week 8, quetiapine XR significantly reduced mean MADRS total score versus placebo (-16.49 vs -13.10, respectively; p<0.01). Mean MADRS score was significantly reduced by quetiapine XR versus placebo at Week 1 (p<0.05). MADRS response rates were significantly greater at Week 8 for quetiapine XR versus placebo (61.9% vs 48.0%, respectively; p<0.05). Significant changes in HAM-D total score and CGI-S were seen at Week 8 for quetiapine XR versus placebo. Withdrawal rates due to AEs were 9.9% and 2.6% for quetiapine XR and placebo, respectively. Common AEs (>10% any group during the randomized phase) for quetiapine XR and placebo, respectively were dry mouth (32.9% and 6.5%), sedation (21.7% and 1.9%), somnolence (20.4% and 5.2%), and headache (10.5% and 10.3%). LIMITATIONS The study was not designed to compare quetiapine XR 150 mg/day and 300 mg/day; it was intended to reflect dose titration that might occur in clinical practice. CONCLUSIONS Quetiapine XR monotherapy is effective in patients with MDD, with symptom improvement seen as early as Week 1, and tolerability results consistent with the known profile of quetiapine.

The selectivity of inclusion and exclusion criteria in bulimia nervosa treatment studies

OBJECTIVE To examine the rates of exclusion and inclusion in various research studies for a series of 51 treatment-seeking patients. METHOD The inclusion and exclusion criteria employed in a sample of 41 studies were applied to a series of 51 treatment-seeking bulimia nervosa patients. RESULTS Of the sample of 51, 11, (21.6%) would have been excluded from 16 (39%) of the studies because of an age greater than 30; 13 (32%) of the studies would have excluded 8 (16%) of our patients because of weight > 110% ideal body weight. Thirteen (26%) would have been excluded from 22 (54%) of the studies because of active psychotropic drug use, despite the lack of response. DISCUSSION Some of the patients who may be most difficult to work with may be excluded from treatment studies.

Effect of selective serotonin reuptake inhibitors on cardiovascular morbidity and mortality

Depression in patients with coronary artery disease is associated with increased cardiovascular morbidity and mortality. It is not clear, however, if treatment with selective serotonin reuptake inhibitors (SSRIs) decreases the rate of future cardiovascular events. This paper reviews the available literature regarding the effect of SSRI use on cardiovascular outcomes. Thirteen studies addressing this issue were identified. Of these, 5 concluded that SSRI use is associated with decreased cardiovascular morbidity or mortality, 2 concluded that SSRI use was associated with worsened prognosis, and 6 studies found no statistically significant association. Almost all of the published literature examining the effect of SSRIs on cardiovascular outcomes is based on observational studies, thereby precluding definitive conclusions. Randomized controlled studies are clearly needed to definitively address this issue.

Effect of quetiapine vs. placebo on response to two virtual public speaking exposures in individuals with social phobia

OBJECTIVE Clinical practice and open-label studies suggest that quetiapine (an atypical anti-psychotic) might improve symptoms for individuals with social anxiety disorder (SAD). The purpose of this study was to provide a rigorous test of the acute impact of a single dose of quetiapine (25mg) on SAD symptoms. METHOD Individuals with SAD (N=20) were exposed to a 4-min virtual reality (VR) public speaking challenge after having received quetiapine or placebo (double-blind) 1h earlier. A parallel VR challenge occurred 1 week later using a counter-balanced cross-over (within subject) design for the medication-placebo order between the two sessions. RESULT There was no significant drug effect for quetiapine on the primary outcome measures. However, quetiapine was associated with significantly elevated heart rate and sleepiness compared with placebo. CONCLUSION Study findings suggest that a single dose of 25mg quetiapine is not effective in alleviating SAD symptoms in individuals with fears of public speaking.

An Unusual Presentation of Sertraline and Trazodone Overdose

OBJECTIVE: To report an unusual and life-threatening presentation of an overdose of sertraline and trazodone. CASE SUMMARY: A patient with a history of depression ingested sertraline 6000 mg and trazodone 1300 mg in a suicide attempt. Twenty-four hours after antidepressant administration, the patient presented with symptoms of selective serotonin-reuptake inhibitor (SSRI) overdose and serotonin syndrome, and later developed an enlarged tongue consistent with angioedema. A compromised airway resulted and endotracheal intubation was necessary. After intubation, the symptoms subsided and the patient recovered. DISCUSSION: Although SSRIs and trazodone are generally considered to be relatively safe in single-agent overdose, serious delayed reactions can occur, especially if several agents are involved. In this case the patient initially presented with symptoms typical of an SSRI overdose that did not appear to be exceptionally dangerous. Over time, symptoms consistent with angioedema appeared that necessitated intubation. Although previous reports of angioedema have been reported with SSRIs, this is the first report, to our knowledge, of a presentation this severe. CONCLUSIONS: This case demonstrates that overdose with the newer antidepressants can result in unusual and delayed presentations and must be treated with caution.

Effect of Stress and Bupropion on Craving, Withdrawal Symptoms, and Mood in Smokers

INTRODUCTION Studies suggest that in smokers attempting to quit smoking, the occurrence of stressful events is associated with smoking relapse. The purpose of this study was to determine the effect of bupropion (an agent known to increase smoking cessation rates) on the craving, withdrawal, and mood response to stressful tasks administered in a laboratory setting. METHODS Response to three tasks (a speech, math, and cold pressor task) was measured in 65 smokers during ad libitum smoking. Smokers were then randomized to either bupropion or placebo. Fourteen days after starting medication, 43 subjects (28 receiving bupropion and 15 receiving placebo) quit smoking and laboratory procedures were repeated on the third day of abstinence. RESULTS Prior to cessation, stressors presented in a laboratory setting increased craving, nicotine withdrawal symptoms, and subjective distress but decreased positive affect. Thirty minutes of relaxation after the stressors did not result in these measures returning to prestress levels. During the nicotine withdrawal period, stress-induced responses were generally smaller than during the precessation period. Bupropion (relative to placebo) reduced overall levels of craving and withdrawal symptoms but did not have significant effects on response to stress during the nicotine withdrawal period. CONCLUSIONS This study demonstrates that stress results in sustained increases in craving and withdrawal symptoms and changes in mood symptoms and that bupropion affects overall levels of these symptoms. Further research is needed to determine if modifying response to stress is predictive of an effective treatment for facilitating smoking cessation.