Irene Soeller

A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder.

Objective: We conducted a randomized, double-blind, placebo-controlled efficacy and tolerability trial of Matricaria recutita (chamomile) extract therapy in patients with mild to moderate generalized anxiety disorder (GAD). We hypothesized that chamomile would be superior to placebo in reducing GAD symptoms with a comparable tolerability profile. Materials and Methods: Sixty-one outpatients with mild to moderate GAD were enrolled, and 57 were randomized to either double-blind chamomile extract (n = 28) or placebo therapy (n = 29) for 8 weeks. The study was powered to detect a statistically significant and clinically meaningful group difference in change over time in total Hamilton Anxiety Rating (HAM-A) scores. Secondary outcomes included change in the Beck Anxiety Inventory, Psychological Well Being, and Clinical Global Impression Severity scores and the proportion of patients with 50% reduction or more in baseline HAM-A score. Results: We observed a significantly greater reduction in mean total HAM-A score during chamomile versus placebo therapy (P = 0.047). Although the study was not powered to identify small to moderate differences in secondary outcomes, we observed a positive change in all secondary outcomes in the same direction as the primary outcome measure. One patient in each treatment group discontinued therapy for adverse events. The proportion of patients experiencing 0, 1, 2, or 3 adverse events or more was not significantly different between groups (P = 0.417). Conclusions: This is the first controlled clinical trial of chamomile extract for GAD. The results suggest that chamomile may have modest anxiolytic activity in patients with mild to moderate GAD. Future studies are needed to replicate these observations.

Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial

BACKGROUND We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. HYPOTHESIS We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. STUDY DESIGN Phase II randomized placebo controlled clinical trial. METHODS 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. RESULTS Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (-8.2, 95% confidence interval [CI], -12.7 to -3.6) versus R. rosea (-5.1, 95% CI: -8.8 to -1.3) and placebo (-4.6, 95% CI: -8.6 to -0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44-8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38-5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012). CONCLUSIONS Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression.

Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study

OBJECTIVE Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing depressive relapse in bipolar II disorder. METHODS Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium monotherapy for 12 weeks. Responders with a ≥50% reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy. Primary outcome was depressive relapse during continuation monotherapy. Secondary outcomes included sustained response rate from initiation of treatment to study end-point, relapse hazard, time to relapse, change in mania ratings, and frequency of treatment-emergent sub-syndromal hypomania and/or depressive episodes. RESULTS Venlafaxine produced greater sustained response rate versus lithium (p<0.0001); however, there was no difference in relapse rate for venlafaxine (7.5%) versus lithium (26.7%) (p=0.079); relapse hazard (p=0.073), or time to relapse (p=0.090) between treatment conditions during continuation monotherapy. There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes. There were more sub-syndromal depressive episodes during lithium monotherapy (p=0.03). LIMITATIONS Sample size was limited by the lower sustained response rate for lithium versus venlafaxine; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups. CONCLUSION Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium, with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring. Larger, prospective trials are needed to confirm these observations.

Greater striatal dopamine transporter density may be associated with major depressive episode.

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.

Randomized, double-blind, placebo-controlled trial of Cimicifuga racemosa (black cohosh) in women with anxiety disorder due to menopause.

Objective: We conducted a randomized, double-blind, placebo-controlled, parallel group trial of the efficacy and tolerability of Cimicifuga racemosa (black cohosh) extract for the treatment of anxiety disorder due to menopause. We hypothesized that black cohosh would be superior to placebo in reducing anxiety symptoms of menopause, with a comparable tolerability profile to placebo. Materials and Methods: Subjects were randomized to therapy with either pharmaceutical-grade black cohosh extract (n = 15) or placebo (n = 13) for up to 12 weeks. The primary outcome measure was changed over time in total Hamilton Anxiety Rating Scale (HAM-A) scores. Secondary outcomes included a change in scores on the Beck Anxiety Inventory, Green Climacteric Scale (GCS), and Psychological General Well-Being Index (PGWBI) and the proportion of patients with a change of 50% or higher in baseline HAM-A scores. Results: There was neither a significant group difference in change over time in total HAM-A scores (P = 0.294) nor a group difference in the proportion of subjects with a reduction of 50% or higher in baseline HAM-A scores at study end point (P = 0.79). There was a significantly greater reduction in the total GCS scores during placebo (vs black cohosh; P = 0.035) but no group difference in change over time in the GCS subscale scores or in the PGWBI (P = 0.140). One subject (3.6%) taking black cohosh discontinued treatment because of adverse events. Conclusions: We found no statistically significant anxiolytic effect of black cohosh (vs placebo). However, small sample size, choice of black cohosh preparation, and dosage used may have been limiting factors producing negative results.

Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive episodes: effectiveness and mood conversion rate

BACKGROUND Controversy exists over antidepressant use in bipolar II depression. AIMS To compare the safety and effectiveness of antidepressantv.mood stabiliser monotherapy for bipolar type II major depressive episodes. METHOD Randomised, double-blind, parallel-group, 12-week comparison of venlafaxine (n= 65)v.lithium (n= 64) monotherapy in adult out-patients (trial registration numberNCT00602537). RESULTS Primary outcome - venlafaxine produced a greater response rate (67.7%)v lithium (34.4%,P<0.001). Secondary outcomes - venlafaxine produced a greater remission rate (58.5%v 28.1%,P<0.001); greater decline in depression symptom scores over time (β = -5.32, s.e. = 1.16, χ(2)= 21.19,P<0.001); greater reduction in global severity scores over time (β = -1.05, s.e. = 0.22, w(2)= 22.33,P<0.001); and greater improvement in global change scores (β = -1.31, s.e. = 0.32, χ(2)= 16.95,P<0.001) relative to lithium. No statistically significant or clinically meaningful differences in hypomanic symptoms were observed between treatments. CONCLUSIONS These findings suggest that short-term venlafaxine monotherapy may provide effective antidepressant treatment for bipolar II depression without a statistically significant increase in hypomanic symptoms relative to lithium.

Change Over Time in Brain Serotonin Transporter Binding in Major Depression: Effects of Therapy Measured with [123I]-ADAM SPECT

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 [123I]‐ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [123I]‐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.

Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial.

BACKGROUND Generalized Anxiety Disorder (GAD) is one of the most common anxiety disorders treated in primary care, yet current therapies have limited efficacy and substantial side effects. PURPOSE To evaluate long-term chamomile (Matricaria chamomilla L.) use for prevention of GAD symptom relapse. METHODS Outpatients from primary care practices and local communities with a primary diagnosis of moderate-to-severe GAD were enrolled for this two-phase study at a large US academic medical center. During Phase 1, eligible participants received 12 weeks of open-label therapy with chamomile pharmaceutical grade extract 1500mg (500mg capsule 3 times daily). During Phase 2, treatment responders were randomized to either 26 weeks of continuation chamomile therapy or placebo in a double-blinded, placebo-substitution design. The primary outcome was time to relapse during continuation therapy, analyzed using Cox proportional hazards. Secondary outcomes included the proportion who relapsed, treatment-emergent adverse events, and vital sign changes. This study is registered at ClinicalTrials.gov, identifier NCT01072344. RESULTS Between March 1, 2010, and June 30, 2015, we enrolled 179 participants. Of those, 93 (51.9%) were responders and agreed to continue in the double-blind randomized controlled trial. A numerically greater number of placebo-switched (n=12/47; 25.5%) versus chamomile-continuation (n = 7/46; 15.2%) participants relapsed during follow-up. Mean time to relapse was 11.4 ± 8.4 weeks for chamomile and 6.3 ± 3.9 weeks for placebo. Hazard of relapse was non-significantly lower for chamomile (hazard ratio, 0.52; 95% CI, 0.20-1.33; P = 0.16). During follow-up, chamomile participants maintained significantly lower GAD symptoms than placebo (P = 0.0032), with significant reductions in body weight (P = 0.046) and mean arterial blood pressure (P = 0.0063). Both treatments had similar low adverse event rates. CONCLUSIONS Long-term chamomile was safe and significantly reduced moderate-to-severe GAD symptoms, but did not significantly reduce rate of relapse. Our limited sample size and lower than expected rate of placebo group relapse likely contributed to the non-significant primary outcome finding. Possible chamomile superiority over placebo requires further examination in large-scale studies.

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder

BACKGROUND Conventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD. HYPOTHESIS We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile. STUDY DESIGN We report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD. METHODS Subjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined. RESULTS Of 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=-8.4 [95% CI=-9.1 to -7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred. CONCLUSION Chamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD.

Long-Term Chamomile Therapy of Generalized Anxiety Disorder: A Study Protocol for a Randomized, Double-Blind, Placebo- Controlled Trial

BACKGROUND Anxiety symptoms are among the most common reasons for consumers to use Complementary and Alternative Medicine (CAM) therapy. Although many botanicals have been proposed as putative remedies for anxiety symptoms, there has been a paucity of controlled trials of these remedies. A preliminary study of the anxiolytic effect of Chamomile (Matricaria recutita) in humans suggests that chamomile may have anxiolytic and antidepressant activity. We now seek to conduct a 5-year randomized, double-blind, placebo-substitution study to examine the short and long-term safety and efficacy of chamomile extract in Generalized Anxiety Disorder (GAD). METHODS/DESIGN 180 subjects with moderate to severe GAD will receive initial open-label pharmaceutical-grade chamomile extract 500-1,500 mg daily for 8 weeks. Responders to treatment who remain well for an additional 4 weeks of consolidation therapy, will be randomized to double-blind continuation therapy with either chamomile extract 500-1,500 mg daily or placebo for an additional 26 weeks. The primary outcome will be the time to relapse during study continuation therapy in each treatment condition. Secondary outcomes will include the proportion of subjects in each treatment condition who relapse, as well as the proportion of subjects with treatment-emergent adverse events. Quality of life ratings will also be compared between treatment conditions during short and long-term therapy. DISCUSSION Many individuals with mental disorders decline conventional therapy and seek CAM therapies for their symptoms. Thus, the identification of effective CAM therapy is of relevance to reducing the burden of mental illness. This study builds upon our prior findings of significant superiority of chamomile versus placebo in reducing GAD symptoms. We now extend these preliminary findings by conducting a randomized long-term safety and efficacy study of chamomile in GAD.