A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.

Effect of paroxetine on physiological response to stress and smoking.

OBJECTIVE: Smokers often smoke during stressful events, which leads to large increases in cardiovascular measures such as blood pressure (BP) and heart rate (HR). Because exaggerated cardiovascular response to stress is associated with cardiovascular disease risk, this study examined paroxetine's effect on the physiological response to combining stress and smoking. METHODS: Sixty-two participants completed this randomized, double-blind, crossover study in which BP, HR, plasma epinephrine, norepinephrine, and cortisol concentrations were measured at rest, while smoking, and during a speech and math task. Laboratory sessions occurred after 1 month of paroxetine and after 1 month of placebo. RESULTS: Significant increases occurred for all measures (except cortisol) during smoking, with further increases occurring during the speech task (time effect, p < .001). After 1 month of paroxetine, norepinephrine and HR values were lower and cortisol values were higher (versus placebo) throughout the laboratory session (treatment effect, p < .001). Treatment × time effects were observed for BP and HR (all, p < .01). For systolic and diastolic BP, a smaller increase (from baseline to measures during speech) was observed after paroxetine compared with placebo (both, p < .006). In both measures, the increase in response to smoking was similar for both treatments; however, the further increase during the speech was smaller when taking paroxetine (versus placebo). CONCLUSIONS: This study suggests that paroxetine affects physiological response to stress in smokers. Further research is needed to determine the impact of these results on cardiovascular health. Trial Registration clinicaltrials.gov Identifier: NCT00218439.

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.

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.

Physiological response to a speech stressor presented in a virtual reality environment.

The feasibility of using virtual reality (VR) technology to induce a physiological response to stress was assessed in 12 volunteers during a laboratory session in which each participant completed a speech task within a VR environment and a math task outside the VR environment. Both tasks were effective in eliciting a physiological response with significant increases observed in response to each stress task in systolic and diastolic blood pressure and heart rate. Increases in plasma epinephrine and norepinephrine concentrations were observed during the speech task and in plasma epinephrine concentrations during the math task although these differences did not reach statistical significance. The use of VR technology may be a viable alternative to methods currently employed in presenting stressful tasks with the potential advantage of decreased variability in the audience response to the participants' performance.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism.

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

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 bupropion on physiological measures of stress in smokers during nicotine withdrawal.

Studies suggest that among cigarette smokers trying to quit, stress undermines abstinence. Little research has assessed if therapies that increase smoking cessation rates impact physiological measures of stress response. Forty-three subjects completed this repeated-measures study in which a laboratory assessment was completed at baseline and after 17 days of treatment with either placebo (n=15), bupropion sustained release (150 mg twice daily) (n=14) or bupropion with stress reduction counseling (n=14). All subjects quit smoking 3 days prior to the second laboratory assessment. At each laboratory assessment physiological measures of stress (i.e. blood pressure, heart rate, plasma epinephrine, norepinephrine and cortisol concentrations) were measured during rest periods and in response to a speech, a math and a cold pressor task. Among subjects taking placebo, physiological measures of stress were generally lower at rest and during the stressors after smoking cessation. In those taking bupropion these measures were equivalent at the two assessments. Additionally, compared to placebo, those on bupropion had a greater diastolic blood pressure response to the speech stressor and greater systolic blood pressure response to the math stressor during the second laboratory session. This study suggests that bupropion may be maintaining physiological measures of stress during the nicotine withdrawal period.

Inhibition of CYP2D6 activity by bupropion.

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.

Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors.

BACKGROUND: Depression and anxiety are common disorders and have substantially overlapping symptom complexes. Not surprisingly, treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors (SSRIs) as the initial therapy of choice. However, after first line treatments have been deployed, residual symptoms are often problematic. Augmentation strategies to address these difficulties are an area of active investigation. This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder. METHODS: Ten patients who had been receiving SSRIs for at least 6 weeks, but still had clinically significant anxiety symptoms, were enrolled in an open label, flexibly-dosed study of adjunctive aripiprazole. Clinical status was assessed with the Hamilton Anxiety Rating Scale (HAM-A), Montgomery Asberg Rating Scale (MADRS), and Sheehan Disability Scale (SDS). RESULTS: Eighty percent of the subjects had a greater than 50% reduction of symptoms on these outcome measures by week 2 of therapy, and continued with further decrements in symptoms throughout the course of the study. CONCLUSIONS: The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression. More rigorous double-blind studies are warranted to confirm and elucidate the potential role of aripiprazole in these conditions.

Update on drug-induced depression in the elderly.

BACKGROUND: Depression is a common disorder in the elderly. Use of certain medications may be a potentially preventable cause of new-onset depression or worsening of established depression. OBJECTIVE: This paper reviews recent publications evaluating medications commonly used in the elderly as potential causes of depressive symptoms. METHODS: Relevant articles examining the association between medication use and symptoms of depression were identified through searches of MEDLINE (1996-March 2005) and International Pharmaceutical Abstracts (1996-March 2005) using the MeSH heading depression and the subheading chemically induced. Included articles were limited to those that discussed medications commonly used in the elderly and that employed a rigorous study design. RESULTS: A wide variety of medications have been implicated as potential causes of depressive symptoms in numerous reports, although many of these reports relied on data obtained from observational rather than experimental studies. The most extensively studied agents include anti hypertensives, lipid-lowering drugs, and selective estrogen-receptor modulators. The data on antihypertensive agents were contradictory; however, most studies found no association between use of the newer lipid-lowering drugs (statins) or selective estrogen-receptor modulators and the emergence of depressive symptoms. Corticosteroids, although not studied recently, generally have been associated with depressive symptoms in the older literature. CONCLUSIONS: The recent data evaluating whether medications can induce or worsen symptoms of depression are largely contradictory. This reflects a relative lack of controlled studies of this association and the difficulties in determining whether depressive symptoms are caused by a particular medication or by other factors. Nonetheless, when new or worsening symptoms of depression occur, medications should be considered a potential cause and withdrawn as appropriate. Nonpharmacologic and/or pharmacologic treatment is indicated for those whose depressive symptoms do not resolve.

Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors.

Treatment of depression and anxiety disorders with selective serotonin reuptake inhibitors (SSRIs) has been shown by numerous studies to be generally effective. Less well understood is how clinically to address the residual anxiety symptoms a significant minority of such patients treated with SSRIs continue to experience. We assessed quetiapine as adjunctive therapy to SSRIs for patients with anxiety symptoms complicating a depressive or anxiety disorder. Patients receiving a stable dosage of an SSRI for at least 6 weeks who also had persistent anxiety symptoms (Hamilton Anxiety scale [HAM-A] > or =16), were enrolled in a 9-week, open-label, variable dose study. Changes in clinical status were assessed with the Hamilton Depression Rating Scale (HAM-D), HAM-A, and State Anxiety Inventory (SAI). Statistically and clinically significant reductions of > or =50% in the HAM-D and HAM-A occurred by the second week of treatment in 10 of the 11 patients. These improvements continued throughout the study along with a significant improvement on the SAI scale. The most frequent side effects reported were mild dry mouth, constipation, and transient drowsiness with dose escalation. The results provide evidence that quetiapine may be an effective adjunctive treatment for recalcitrant anxiety symptoms in individuals treated with SSRIs for either anxiety or depressive disorders. Given the open-label design of the trial, more rigorous studies are clearly indicated.

Premature ejaculation associated with citalopram withdrawal.

OBJECTIVE: To report a case of premature ejaculation occurring subsequent to citalopram discontinuation. CASE SUMMARY: A 43-year-old white man being treated for depression with citalopram wished to discontinue treatment. Four or 5 days after stopping citalopram he reported that, during sexual intercourse, his genitals seemed to be extremely sensitive and orgasm was achieved within approximately 1 minute. These symptoms continued over the next 3-4 weeks and remitted after citalopram was restarted. Several subsequent attempts to discontinue citalopram resulted in a return of these symptoms despite using a slow tapering regimen. An objective causality assessment revealed a probable relationship between drug withdrawal and the observed symptoms. DISCUSSION: The ability of selective serotonin-reuptake inhibitors (SSRIs) to delay ejaculation has been well documented; however, discontinuation of these agents generally results in a return to baseline function. Although discontinuation of SSRI therapy has been associated with a number of withdrawal symptoms, this is the first report (MEDLINE, September 2003), to our knowledge, of the emergence of sexual adverse effects in someone with no previous history of these symptoms. CONCLUSIONS: Premature ejaculation is a possible withdrawal effect after SSRI discontinuation. Since patients are usually reluctant to spontaneously report sexual adverse effects, it is important to specifically inquire about them both when starting and stopping treatment with an SSRI.

A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling.

BACKGROUND: This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of paroxetine in the treatment of pathological gambling. METHOD: Patients fulfilling DSM-IV criteria for pathological gambling and scoring > or = 5 on the South Oaks Gambling Screen were enrolled if no other Axis I disorder was present. A 1-week placebo run-in phase was followed by 8 weeks' treatment with paroxetine or placebo. The initial paroxetine dose of 20 mg/day could be increased after week 2 by 10 mg/week to a maximum of 60 mg/day. Changes in clinical status were assessed using the Gambling Symptom Assessment Scale (G-SAS) and the Clinical Global Impressions scale (CGI). Treatment-emergent symptoms were assessed weekly. RESULTS: Forty-five patients were included in an intent-to-treat analysis (N = 23 paroxetine, N = 22 placebo). Statistically significantly greater reductions in the total score of the G-SAS were observed in the paroxetine group compared with the placebo group at weeks 6 through 8 (p = .003, .003, and .042, respectively). Improvement on the CGI was also significantly greater in the paroxetine than in the placebo group at the same timepoints (p = .033, .014, and .025, respectively). A significantly greater proportion of patients in the paroxetine group were responders at weeks 7 and 8 (p = .011 and .010, respectively). CONCLUSION: The results of this trial indicate that paroxetine may be effective in the treatment of pathological gambling. There were no unexpected side effects from this treatment. However, additional studies with larger patient samples and a longer treatment phase are required to establish conclusively the efficacy and safety of paroxetine for this indication.