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Several studies have reported low brain serotonin transporter (SERT) binding in individuals with major depression. We hypothesized that the SERT standardized uptake ratio (SUR) values using [(123) I]-ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [(123) I]-ADAM scans were acquired before and after 12 weeks of CBT from 20 depressed subjects and on two occasions 12 weeks apart from 10 nondepressed, healthy volunteers. The primary outcome measure was change over time in SUR values in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated low pretreatment mean SUR values that significantly increased over time in the midbrain (P = .011), right medial temporal lobe (P = .008), and left medial temporal lobe (P = .000) regions. Treatment responders showed a significant increase over time in SUR values in left medial temporal lobe (P = .029) and right medial temporal lobe (P = .007) regions. Partial and nonresponder subjects also showed a significant increase over time in SUR values in the left medial temporal region (P = .040) (vs. healthy volunteers), but to a lesser degree. The findings suggest that low pretreatment SERT binding may increase over time in some depressed individuals who experience symptom improvement., (Copyright © 2013 by the American Society of Neuroimaging.)

Background: We examined striatal dopamine transporter (DAT) distribution volume ratio (DVR) values in subjects with unipolar or bipolar major depressive episode (versus non-depressed healthy volunteers) using the selective DAT radioligand [(99m)Tc]TRODAT-1 and single photon emission computed tomography (SPECT). We hypothesized that striatal DVR values would be greater in depressed versus non-depressed subjects, and that greater DVR values may represent a possible clinical biomarker of depression., Methods: [(99m)Tc]TRODAT-1 spect images were acquired from 39 depressed and 103 non-depressed drug-free subjects. The primary outcome measure was the DVR value of [(99m)Tc]TRODAT-1 binding for the putamen region and the combined putamen plus caudate region., Results: DVR values were significantly correlated across all striatal regions within both subject groups (p<0.005). Depressed subjects had significantly greater DVR values (versus non-depressed subjects) in the putamen (p<0.0005) and the combined putamen plus caudate (p<0.0005) regions. There was no difference in DVR values between unipolar (n=24) and bipolar (n=15) depressed subjects, and no difference in DVR values for depressed subjects with or without prior antidepressant exposure. The predictive probability of the putamen or combined putamen plus caudate DVR value to distinguish depressed from non-depressed subjects was significant (p<0.0005)., Limitations: DAT values could potentially be influenced by age, gender, diagnosis, prior psychotropic dug exposure, illness length, or symptom severity., Conclusion: Results confirm prior observations of greater striatal DAT density in depressed versus non-depressed subjects, and suggest that greater DVR values may possibly represent a potential diagnostic biomarker for distinguish depressed from non-depressed individuals., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We examined midbrain, medial temporal lobe, and basal ganglia serotonin transporter (SERT) distribution volume ratio (DVR) values in subjects with major depressive disorder versus healthy volunteers using a selective SERT radioligand and single photon emission computed tomography (SPECT). We hypothesized that the DVR value for SERT binding would be lower in depressed versus non-depressed subjects. [(123)I]-ADAM SPECT scans were acquired from 20 drug free, depressed subjects and 20 drug-free depressed subjects and 10 drug-free healthy volunteers. The primary outcome measure was the DVR value for [(123)I]-ADAM uptake in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated significantly lower DVR values in the midbrain, right and left medial temporal lobe, and right and left basal ganglia. There was significant probability that lower DVR values could distinguish between depressed and non-depressed subjects in the midbrain, medial temporal lobe, and the right and left basal ganglia. These findings confirm prior observations of lower SERT binding in depression, and suggest that low SERT binding may represent a putative biomarker of depression. Future studies are needed to confirm these observations., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: As part of a long-term, relapse-prevention study of antidepressant versus mood stabilizer monotherapy of bipolar II major depressive episode, we prospectively examined the efficacy and mood conversion rate of initial fluoxetine monotherapy. We hypothesized that there would be a statistically significant reduction in depressive symptoms without a clinically meaningful increase in mood conversion symptoms., Methods: Patients received open-label fluoxetine monotherapy 10 to 80 mg daily for up to 14 weeks. Primary outcome was change over time in Hamilton Depression Rating score, with secondary outcomes including the proportion of treatment responders and remitters, change over time in Young Mania Rating Scale (YMRS) score, and frequency of mood conversion episodes., Results: One hundred forty-eight patients had at least 1 post-baseline measurement. Mean Hamilton Depression Rating score decreased by 9.0 points (P < 0.0005). There were 88 responder patients (59.5%; 95% confidence interval [CI], 51.1%-67.4%) (P < 0.0005) and 86 remitter patients (58.1%; 95% CI, 49.7%-66.2%) (P < 0.0005). Mean time to remission was 64.4 days (95% CI, 59.1-69.7 days). Six patients (4.1%; 95% CI, 1.5%-8.6%) (P < 0.0005) had hypomania, and 29 patients (19.6%; 95% CI, 13.5%-26.9%) (P < 0.0005) had subsyndromal hypomania, which did not result in treatment discontinuation. Six patients (4.1%; 95% CI, 1.5%-8.6%) had a YMRS score of 8 or greater (P < 0.0005), and 4 patients (2.7%; 95% CI, 0.7%-6.8%) (P < 0.0005) had a YMRS score of 12 or greater at any study visit., Conclusions: Although design limitations constrain the interpretation of the current findings, fluoxetine monotherapy may be an effective short-term treatment of bipolar II major depressive episode with a relatively low rate of syndromal hypomanic episodes.

Objective: We examine the safety and efficacy of venlafaxine monotherapy in bipolar type II (BP II) patients with major depressive episode (MDE) who were unresponsive to prior lithium monotherapy. We hypothesized that venlafaxine would be superior to lithium with a low hypomanic conversion rate., Method: Seventeen patients who were unresponsive to prior lithium monotherapy were crossed to venlafaxine monotherapy for 12 weeks. The primary outcome was within-subject change in total Hamilton Depression Rating (HAM-D) score over time. Secondary outcomes included the change in Young Mania Rating (YMRS) and clinical global impressions severity (CGI/S) and change (CGI/C) scores., Results: Venlafaxine produced significantly greater reductions in HAM-D (P < 0.0005), CGI/S (P < 0.0005), and CGI/C (P < 0.0005) scores vs. prior lithium. There was no difference in mean YMRS scores between treatment conditions (P = 0.179)., Conclusion: Venlafaxine monotherapy may be a safe and effective monotherapy of BP II MDE with a low hypomanic conversion rate in lithium non-responders.

Objective: Tachyphylaxis often refers to the loss of antidepressant efficacy during long-term treatment. However, it may also refer to the gradual loss of efficacy after repeated antidepressant exposures over time. The aim of this study was to examine the phenomenon of tachyphylaxis in patients with Bipolar II major depression treated with either venlafaxine or lithium. We hypothesized that a greater number of prior antidepressant exposures would result in a reduced response to venlafaxine, but not lithium, therapy., Methods: 83 patients were randomized to treatment with either venlafaxine (n=43) or lithium (n=40). The primary outcome was a >or= 50% reduction in baseline Hamilton Depression Rating score. A detailed history of prior drug therapy was obtained. Logistic regression was used to test the hypothesis that prior antidepressant exposure was associated with reduced response to venlafaxine therapy., Results: The mean number of prior antidepressant and mood stabilizer exposures was significantly higher in venlafaxine non-responders versus responders (p=0.02). There was no significant association between response to lithium and the number of prior antidepressant and mood stabilizer exposures (p=0.38). The odds of responding to venlafaxine or lithium therapy decreased with an increasing number of prior antidepressant exposures (p=0.04). Response was not significantly affected by the number of prior mood stabilizer exposures (p=0.30). Adjustment for clinical and demographic covariates sharpened the estimated impact of prior antidepressant exposure on treatment outcome., Limitations: This study was a post hoc exploratory analysis. The study was not specifically powered to test the hypothesis of an association between number of prior antidepressant drug exposures and response to venlafaxine or lithium therapy., Conclusion: These observations support earlier findings suggesting the presence of tachyphylaxis occurring after repeated antidepressant drug exposures. Possible mechanisms of tachyphylaxis may include genetic predisposition for non-response, physiological adaptation after repeated antidepressant exposures, and inherent illness and pharmacokinetic heterogeneity.

Background: There is a paucity of controlled clinical data on the best initial therapy for treating patients with bipolar type II (BP II) major depressive episode (MDE). In this analysis, we examined the safety and antidepressant efficacy of short-term venlafaxine versus lithium monotherapy in rapid and non-rapid cycling patients with BP II MDE. We hypothesized that lithium would have superior efficacy to venlafaxine, with fewer syndromal and sub-syndromal hypomanic and mixed mood conversions in the rapid cycling BP II MDE patients., Methods: Patients were randomized to monotherapy with either venlafaxine 37.5-375 mg daily or lithium 300-2100 mg daily for 12 weeks. The primary outcome measure was the 28-item Hamilton Depression Rating (HAM-D 28), with embedded 'typical' HAM-D 17 and 'atypical' HAM-D 17-R symptom scores. Secondary outcomes included the Young Mania Rating Scale (YMRS), clinical global impressions severity (CGI/S) and change (CGI/C) ratings, the proportion of responders (with > or =50% reduction in baseline HAM-D score) and remitters (with a final HAM-D score or =4 affective episodes per year). We did not employ a patient-recorded daily chrono-record to identify ultra-short mood conversions. The study used a randomized, parallel group, open-label design., Conclusion: These observations from this exploratory analysis suggest that venlafaxine monotherapy may be more effective than lithium monotherapy, with a similar mood conversion rate, in rapid and non-rapid cycling patients with BP II MDE. These data support prior observations that venlafaxine monotherapy may be effective initial treatment for BP II MDE.

Objective: Chronic fatigue syndrome (CFS) is a debilitating disorder with prominent symptoms of malaise, fatigue, myalgia, arthralgia, and impaired concentration. The symptoms of CFS may often overlap those of Major Depressive Disorder (MDD). Treatment of CFS has generally been disappointing. We hypothesized that s-citalopram therapy may improve the symptoms of both disorders in CFS patients with co-morbid depression., Methods: 16 patients received s-citalopram 10 mg to 20 mg daily for up to 12 weeks. Outcome measures of CFS included the Chalder Fatigue Questionnaire (CFQ), the multi-dimensional Fatigue Impact Scale (FIS), the CFS symptom rating (CFS-SR) 100 mm visual analogue scale, and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. Secondary outcomes of MDD included the Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and the CGI/S and CGI/C ratings of MDD., Results: We observed reductions in the mean CFQ score (p<0.0005), FIS score (p<0.0005), and CGI/S (p<0.0005) and CGI/C (p<0.0005) ratings over time. There was a significant improvement in 5 of the 8 CFS-SR symptoms: post-exertion malaise (p=0.001), headaches (p<0.0005), un-refreshing sleep (p<0.0005), and impaired memory and concentration (p<0.0005). There was also a reduction in mean HAM-D (p<0.0005), BDI (p<0.0005), CGI/S (p=0.001) and CGI/C (p<0.0005) ratings of MDD., Limitations: The sample size was limited and the study design was not double-blind or placebo controlled., Conclusion: We observed a significant reduction in both CFS and co-morbid MDD symptom severity ratings, and improvement in 5 of 8 core somatic symptoms of CFS during s-citalopram therapy.

Objectives: Increased levels of dopamine transporter (DAT) binding have been reported in patients with major depression. We used the selective DAT radiopharmaceutical Tc-TRODAT-1 and SPECT brain imaging, to examine differences in DAT levels in healthy subjects with and without depressive affect., Methods: We compared striatal DAT binding affinity in 73 healthy subjects to their scores on the depressive symptoms subscale of the Profile of Mood States (POMS). Regions of interest in the basal ganglia of the brain were examined. Distribution volume ratios (DVRs) of Tc-TRODAT-1 binding affinity were calculated from the SPECT scan data, and comparisons among subjects with low and high depressive symptom ratings were calculated using unpaired t-tests and the Pearson correlation., Results: We observed a greater Tc-TRODAT-1 DVR in the right caudate of subjects with high POMS mood scores compared to subjects with low scores on depressive items on the POMS (2.99+/-0.35 and 2.79+/-0.35, respectively; P=0.009). There was also a weak, but significant correlation between higher Tc-TRODAT-1 DVRs in the right caudate and depressive symptoms scores (r=0.23, P=0.05)., Conclusions: These data suggest that Tc-TRODAT-1 binding affinity to DAT sites may be associated with depressive affect in healthy subjects. The finding also supports prior observations of greater Tc-TRODAT-1 DVRs in patients with major depressive episode.

Objective: The presence of co-morbid depressive symptoms may have a negative impact on the management of diabetes mellitus. Moreover, some antidepressants may adversely affect glycemic control. Selective serotonin reuptake inhibitors (SSRIs) may improve glycemic control and may be beneficial for patients with co-morbid depression and diabetes. We examined the safety and efficacy of s-citalopram therapy in patients with co-morbid depression and diabetes, and its ability to improve glycemic control., Research Design and Methods: 17 patients were enrolled into the trial and 14 patients received open-label s-citalopram therapy for up to 16 weeks. Clinical outcome measures included the 17-item Hamilton depression rating (HAM-D 17) and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. In addition, fasting glucose, fructosamine, and glycosylated hemoglobin-A(1C) measures were obtained before and during s-citalopram therapy., Results: We observed a significant reduction in mean HAM-D 17 (p<0.001), CGI/S (p=0.001) and CGI/C (p=0.001) ratings during s-citalopram therapy. We also observed a modest, non-significant reduction in fasting glucose, fructosamine, and glycosylated hemoglobin-A(1C) levels during s-citalopram therapy., Limitation: Limitations of this study include a modest patient sample size and a 16-week treatment duration which may have been insufficient to demonstrate the full effect of SSRI therapy on glycemic control., Conclusion: We observed a significant reduction in depressive symptoms and modest, non-significant reductions in fasting glucose, fructosamine, and glycosylated hemoglobin-A(1C) levels during SSRI therapy of co-morbid depression and diabetes., ((c) 2006 S. Karger AG, Basel.)

Objective: Evidence-based data suggest that MAOI therapy may be effective in up to 50% of patients with treatment-resistant depression (TRD). We hypothesized that MAOI therapy is similarly effective in patients with advanced stage TRD who are unresponsive to > or = 4 prior antidepressant drug (AD) trials compared to patients with early stage TRD who are unresponsive to < or = 3 prior AD trials., Methods: To test this hypothesis, data were harvested from 400 patient charts. Of these, 59 patients received a total of 75 MAOI treatment trials. 50 patients had 1 MAOI trial and 9 patients had 2 or more MAOI trials. Response was assessed using the Clinical Global Impressions Change (CGI/C) scale., Results: 56% of MAOI trials resulted in a CGI/C score of 1 ("very much better") or 2 ("much better"). Only 25% resulted in a CGI/C score of 4 or more ("no change" or "worse"). 32.5% of MAOI trials resulted in a CGI/C score of 1 in patients with early stage TRD, while only 12.1% of MAOI trials resulted in a CGI/C score of 1 in patients with advanced stage TRD (p=0.04). There was a significant negative correlation between the number of prior, failed AD trials and the final CGI/C score (p=0.03). The odds associated with attaining a CGI/C score of 1 diminished by a factor of 30% with each prior failed AD trial. We observed only 1 case of acute hypertension which responded to sublingual nifedipine therapy., Limitations: The sample size was limited, and MAOI outcome was not compared with other AD therapy. The adequacy of prior AD trials could not always be verified., Conclusion: These data suggest that MAOI therapy may be beneficial in patients with early stage TRD who are unresponsive to < or = 3 prior treatments. However, the relative efficacy of MAOI therapy in advanced stage TRD remains uncertain.

Unlabelled: The serotonergic system may play an important role in the pathophysiology of major depressive disorder (MDD). Few imaging studies have examined serotonin transporter (SERT) binding in patients with MDD. We hypothesized that SERT binding activity may be altered in patients with MDD. This study compared SERT binding in patients with MDD with that in healthy controls., Methods: We studied SERT activity in 7 patients (22-50 y old) with moderate to severe MDD and 6 healthy controls (24-56 y old) using (123)I-labeled 2-((2-((dimethylamino)methyl) phenyl)thio)-5-iodophenylamine (ADAM) and SPECT brain imaging. Subjects underwent SPECT 4 h after intravenous administration of 185 MBq (5 mCi) of (123)I-ADAM. Images were reconstructed in the axial plane, and region-of-interest demarcations were placed on the midbrain, medial temporal region, and basal ganglia region., Results: (123)I-ADAM binding to SERT in the midbrain was significantly lower (P = 0.01) in MDD patients (1.81 +/- 0.07) than in controls (1.95 +/- 0.13). Age-adjusted (123)I-ADAM binding in the midbrain correlated significantly with scores on the Hamilton Depression Rating Scale (r = 0.82; P = 0.02). A significant negative correlation was observed between (123)I-ADAM SERT binding in the midbrain and age in the healthy control group (r = 0.98; P = 0.0002). SERT binding in the basal ganglia or medial temporal regions of interest did not significantly differ between groups., Conclusion: The findings from this preliminary study suggest the possibility of decreased SERT binding in the midbrain region of patients with MDD, with the degree of decrease correlating with the severity of depressive symptoms. There also appears to be an age-related decline in midbrain (123)I-ADAM SERT binding in healthy subjects.