Multi-trial, aggregated, individual participant data mega-analysis of short-term antidepressant versus mood stabilizer monotherapy of bipolar type II major depressive episode.

BACKGROUND: Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega-analyses of prospective trials of individual participant-level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy. METHODS: Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega-analysis). Hierarchical log-linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores. RESULTS: Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = -2.33, t = -6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = -0.414, t = -6.32, p < 0.001), and a significant improvement in CGI/C across time (b = -0.47, t = -7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62). CONCLUSION: Findings from this IPD mega-analysis of bipolar II depression trials suggest a divergence from current evidence-based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega-analysis suggests that antidepressant monotherapy may provide superior short-term effectiveness without clinically meaningful increase in treatment-emergent hypomanic symptoms compared to lithium monotherapy.

Effectiveness and safety of monoamine oxidase inhibitor treatment for bipolar depression versus unipolar depression: An exploratory case cohort study.

OBJECTIVE: Patients with bipolar disorder spend most of their clinical lifetime in the depressive phase of their illness. However, antidepressants are discouraged in the treatment of bipolar depression due to concerns over manic induction and drug ineffectiveness. Some reports suggest that monoamine oxidase inhibitors (MAOIs) may be safe and effective compared to other antidepressants in treating bipolar depression. The present study compared the safety and effectiveness of MAOI therapy in patients with bipolar versus unipolar depression. METHODS: Data were collected from approximately 2500 clinical research charts of patients treated with MAOI therapy at a university mood disorder clinic between 1983 and 2015. A mixed-effects model was created with patient entered as the random effect. The model included the primary diagnosis (i.e., either unipolar or bipolar depression) and other clinical covariates as fixed-effect predictors. RESULTS: Patients with bipolar depression demonstrated lower post-treatment clinical global impressions/severity scores versus patients with unipolar depression (p = 0.04). Neither group demonstrated a full syndromal manic or hypomanic episode. A higher proportion of patients with bipolar depression reported myoclonic tics and tremors, which may have resulted from concomitant lithium use. Amongst the covariates, only the number of prior antidepressant trials predicted poorer outcomes from MAOI therapy. CONCLUSION: MAOIs may be more effective-and as safe-for patients with bipolar depression versus unipolar depression. Future studies should explore this possible advantage using a larger sample size.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Putative Antidepressant Effect of Chamomile (Matricaria chamomilla L.) Oral Extract in Subjects with Comorbid Generalized Anxiety Disorder and Depression.

Objectives: This exploratory analysis examined the putative antidepressant effect of Matricaria chamomilla L. (chamomile) extract in subjects with generalized anxiety disorder (GAD) with or without comorbid depression. It was hypothesized that chamomile extract would demonstrate similar anxiolytic activity in both subgroups, but superior antidepressant activity in GAD subjects with comorbid depression. Design: As part of a randomized double-blind placebo-controlled trial of chamomile extract for relapse prevention of GAD, 179 subjects received initial therapy with open-label chamomile extract 1500 mg daily for 8 weeks. Linear mixed-effect models were used to identify clinically meaningful changes in anxiety and depression symptoms between diagnostic subgroups. Settings/Location: The study took place at the University of Pennsylvania in Philadelphia, PA. Subjects: Subjects were ≥18 years old with a primary DSM IV-TR diagnosis of GAD. They were subcategorized into two diagnostic groups: GAD without comorbid depression (n = 100) and GAD with comorbid depression (n = 79). Interventions: Open-label chamomile extract 1500 mg was given daily for 8 weeks. Outcome measures: Generalized anxiety disorder (GAD-7), Hamilton rating scale for anxiety, Beck anxiety inventory, Hamilton rating scale for depression (HRSD), the six-item core HRSD (items 1, 2, 3, 7, 8, and 13), and the Beck depression inventory (BDI). Results: The authors observed similar anxiolytic effects over time in both diagnostic subgroups. However, there was a greater reduction in HRSD core symptom scores (p < 0.023), and a trend level reduction in HRSD total scores (p = 0.14) and in BPI total scores (p = 0.060) in subjects with comorbid depression. Conclusions: M. chamomilla L. may produce clinically meaningful antidepressant effects in addition to its anxiolytic activity in subjects with GAD and comorbid depression. Future controlled trials in subjects with primary major depressive disorder are needed to validate this preliminary observation.

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial.

Importance: Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear. Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD. Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018. Interventions: Maintenance of or withdrawal from treatment with ADM. Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases. Results: A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88). Conclusions and Relevance: Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear. Trial Registration: ClinicalTrial.gov identifier: NCT00057577.

Relative Effectiveness of Monoamine Oxidase Inhibitor and Tricyclic Antidepressant Combination Therapy for Treatment-Resistant Depression.

PURPOSE/BACKGROUND: We examined the relative safety and effectiveness of adding a monoamine oxidase inhibitor (MAOI) to a failed tricyclic antidepressant (TCA) trial versus adding a TCA to a failed MAOI trial or adding a TCA to a failed TCA trial in treatment-resistant depression. METHODS/PROCEDURES: Data were retrospectively harvested from approximately 2500 treatment charts of subjects with treatment-resistant depression who attended a university mood disorders clinic between 1983 and 2015. Hierarchical linear modeling was used to examine the effectiveness of treatment condition on outcome. Relative adverse event profiles were also examined. FINDINGS/RESULTS: Eighty-four treatment outcome observations were made from 54 subjects who received combination therapy: TCA plus TCA (n = 22), TCA plus MAOI (n = 44), and MAOI plus TCA (n = 18). Treatment condition predicted a poorer (albeit not statistically significant) outcome for TCA plus TCA compared with TCA plus MAOI, or MAOI plus TCA therapy (P = 0.098). Specific adverse events occurred with significantly greater frequency between treatment groups; that is, impotence was more frequent with TCA plus MAOI therapy; headaches and insomnia were more frequent with MAOI plus TCA therapy; and constipation was more frequent with TCA plus TCA therapy. There were no reported or observed hypertensive or serotonergic events. IMPLICATIONS/CONCLUSIONS: In contrast to conventional wisdom that combined TCA and MAOI therapy should be avoided, the judicious use of this combination may be relatively safe and effective compared with combined TCA plus TCA therapy. However, sample sizes were limited, and the analysis was nonrandomized and retrospective.

Prior Antidepressant Treatment Trials May Predict a Greater Risk of Depressive Relapse During Antidepressant Maintenance Therapy.

BACKGROUND: We examined the influence of prior antidepressant treatment trials on the likelihood of depressive relapse, and time to depressive relapse, during maintenance therapy of bipolar II disorder in treatment-responsive subjects who had recovered from a major depressive episode. METHODS: Data were derived from a prospective, randomized, double-blind trial of 148 adult subjects with bipolar II major depressive episode who were initially administered open-label fluoxetine monotherapy for 12 weeks. Remitters with a final Hamilton Rating Scale for Depression score of 8 or lower were then randomized to continuation therapy with either fluoxetine (n = 28), lithium (n = 26), or placebo (n = 27) for 50 additional weeks. RESULTS: An increase in the number of prior antidepressant treatment trials was significantly associated with a greater likelihood of depressive relapse for all treatment conditions taken together [odds ratio (OR) = 1.42, z = 2.49, P = 0.01] and for the 2 active treatment conditions together (OR = 1.51, z = 2.28, P = 0.02). An increase in the number of prior antidepressant trials was also associated with a trend-level shortening in the time to relapse for all treatment conditions taken together (hazard ratio = 1.15; confidence interval, 0.99-1.35; P = 0.07) and a significantly shorter time to relapse for subjects in the 2 active treatment conditions (hazard ratio = 1.30; confidence interval, 1.05-1.62; P = 0.02). CONCLUSIONS: These findings support prior evidence of a negative influence of the number of prior antidepressant treatment trials on the likelihood of response and suggest that the number of prior antidepressant trials may also be associated with a greater odds of depressive relapse, and a shorter time to relapse, during antidepressant maintenance therapy in recovered depressed subjects with bipolar II disorder.

Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression.

OBJECTIVES: Antidepressants may be less effective in treatment-resistant depression (TRD). In this exploratory study, we examined the widely held hypothesis that monoamine oxidase inhibitor (MAOI) therapy may be superior to tricyclic antidepressant (TCA) therapy for TRD. We also examined the influence of the number of prior treatment trials on TCA versus MAOI effectiveness in TRD. METHODS: Data were retrospectively extracted from approximately 2,500 treatment charts of patients with TRD who were attending a university mood disorder clinic between 1983 and 2015. Hierarchical linear modeling was used to examine the efficacy of drug class on outcome as well as the interaction between drug class and the number of prior antidepressant trials. RESULTS: 147 treatment outcome observations were made from 94 unipolar, depressed patients who either received TCA (N = 47) or MAOI (N = 100) monotherapy for TRD. For patients unresponsive to at least one prior trial, drug class significantly predicted end-of-treatment CGI/S scores, with TCAs showing worse (i.e., higher) end-of-treatment CGI/S scores relative to MAOI therapy (b = 1.04, t = 4.98, p < 0.0001). When examining the interaction between drug class and the number of prior antidepressant trials, the interaction effect was significant (b = -0.50, t = -2.43, p = 0.02); however, the advantage for MAOI versus TCA therapy decreases with more prior, failed, antidepressant trials. CONCLUSION: Results suggest that MAOIs may be more effective than TCAs for early stage TRD. This difference in effectiveness between MAOIs and TCAs diminished as the number of prior treatment trials increased. However, the TCA sample size was limited and the analysis was retrospective with non-randomized conditions.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

Increase in pharmacodynamic tolerance after repeated antidepressant trials in treatment-responsive bipolar I depressed subjects: An exploratory study. / Wzrost tolerancji farmakodynamicznej po wielokrotnym leczeniu lekami antydepresyjnymi pacjentów z choroba afektywna dwubiegunowa typu II podatna na leczenie. Badanie eksploracyjne.

OBJECTIVES: This study examined the presence of increased pharmacodynamic tolerance with reduced effectiveness following repeated antidepressant trials over the course of the affective illness in subjects with treatment-responsive bipolar II depression. METHODS: Data were derived from the open-label phase of a prospective, randomized, placebo-controlled trial of long-term fluoxetine versus lithium monotherapy in 148 subjects >=18 years old with treatment-responsive bipolar II depression, who were initially administered open-label fluoxetine monotherapy for 12 weeks. Response was defined as >=50% reduction in baseline Hamilton Rating Scale for Depression (HRSD) score, and remission was defined as a final HRSD score =<8. RESULTS: Subjects reported a mean (SD) total of 1.61 (1.85) (range: 0-9) prior adequate, antidepressant trials over the course of their affective illness, before study enrollment. There was a 25% reduction in the likelihood of fluoxetine response (p < 0.01) and a 22% lower likelihood of remission (p = 0.02), respectively, with each increase in the number of prior antidepressant treatment trials over the illness course. There was no clinically meaningful correlation between fluoxetine response or remission and any other baseline clinical or demographic variable. Thus, only the number of prior antidepressant trials meaningfully impacted the likelihood of fluoxetine response or remission. CONCLUSIONS: Limitations. This was an exploratory study of post hoc, analyses, and the trial was not specifically powered to test the development of increased pharmacodynamic tolerance. Disease heterogeneity or inter-individual differences in antidepressant responsiveness may have influenced fluoxetine effectiveness. Conclusion. These results confirm prior observations of an increased pharmacodynamic tolerance after repeated antidepressant administration, resulting in a step-wise loss of antidepressant effectiveness over the course of the illness.

An exploratory study of salivary cortisol changes during chamomile extract therapy of moderate to severe generalized anxiety disorder.

OBJECTIVES: Dysfunctions in stress biology are hypothesized to contribute to anxiety disorders, and to be ameliorated during successful treatment, but limited clinical data exist to support this hypothesis. We evaluated whether increases in morning cortisol and the diurnal cortisol slope, markers of stress biology, are associated with clinical response to chamomile therapy among subjects with generalized anxiety disorder (GAD). METHODS: Among 45 subjects with DSM-IV diagnosed GAD in an open-label clinical trial of chamomile, salivary cortisol was assessed for three days each pre- and post-treatment, at 8am, 12pm, 4pm, and 8pm. Mixed model analyses assessed whether GAD symptom change predicted the degree to which cortisol levels changed during treatment. RESULTS: Symptom improvement during treatment was significantly associated with pre-to-post treatment changes in cortisol. Subjects who experienced more symptomatic improvement experienced significant increases in their morning salivary cortisol (ß = 0.48, p < 0.001), and a greater decrease in cortisol from morning to the rest of the day (ß = 0.55, p < 0.001). In addition, at baseline a lower cortisol level (ß = -0.24, p = 0.023) and a lesser decrease in cortisol after morning (ß = 0.30, p = 0.003) were associated with greater symptomatic improvement. CONCLUSION: Increases in morning salivary cortisol and the diurnal cortisol slope are associated with symptom improvement in chamomile treatment of GAD. Response to treatment for GAD could partially stem from normalization of stress biology dysfunction, but further work involving establishing abnormalities within-sample, ruling out of confounds (e.g., sleep), and a placebo control is necessary to conclude an amelioration effect. REGISTRATION CODE: NCT01072344. URL: https://clinicaltrials.gov/ct2/show/NCT01072344.

Effects of venlafaxine versus lithium monotherapy on quality of life in bipolar II major depressive disorder: Findings from a double-blind randomized controlled trial.

Bipolar disorder is associated with decreased quality of life, especially during depressive episodes. There are few studies that have examined whether quality of life improves following pharmacological treatments of bipolar depression. In this exploratory study, we examined the effects of antidepressant versus mood stabilizer monotherapy on quality of life ratings in bipolar II subjects during acute (12 week) treatment. Data were derived from a randomized double-blind comparison of venlafaxine (n = 65) versus lithium (n = 64) monotherapy. The Quality of Life Index (QLI) was administered at baseline (n = 126; 98%) and again at the end of treatment. We explored treatment differences in continuous changes on the QLI using last-observation carried forward. Additionally, we explored the likelihood of experiencing clinically-significant improvements as well as baseline correlates of QLI and changes in QLIe. Venlafaxine was superior to lithium in reducing symptoms of depression during acute treatment. However, there were no significant differences between treatments in QLI ratings. Changes in symptoms of depression were correlated to, but not redundant, with improvements in QLI ratings. These findings suggest that quality of life may be an important secondary outcome to target and measure as a part of comparative clinical trials of pharmacotherapy for bipolar II depression.

Residual anxiety may be associated with depressive relapse during continuation therapy of bipolar II depression.

BACKGROUND: Anxiety symptoms are common in bipolar disorder. We explored the effect of anxiety on the outcome of acute and continuation pharmacotherapy of bipolar II depression. METHODS: Data were derived from a randomized double-blind 12-week acute (N = 129) and 6-month continuation (N = 55) comparison of venlafaxine versus lithium monotherapy in bipolar II depression in adults. We distinguished between the items of the Hamilton Rating Scale for Depression (HRSD) that capture depression vs. anxiety (i.e., psychomotor agitation, psychic anxiety, somatic anxiety, hypochondriasis, and obsessive-compulsive concerns) and examined the effect of treatment on depression and anxiety. Additionally, we explored whether baseline anxiety or depression predicted changes over time in depression and anxiety ratings or moderated treatment outcomes. We also explored whether residual depressive and anxious symptoms predicted relapse during continuation therapy. RESULTS: Venlafaxine was superior to lithium in reducing both depression and anxiety, though its effects on anxiety were more modest than those on depression. Baseline anxiety predicted change over time in anxiety, but not depression. By contrast, baseline depression did not predict change over time in depression or anxiety. Residual anxiety, specifically uncontrollable worry, was a stronger predictor of relapse than residual depression. CONCLUSION: Successful treatment of symptoms of anxiety in bipolar depression may protect against depressive relapse.

Comparison of treatment outcome using two definitions of rapid cycling in subjects with bipolar II disorder.

OBJECTIVES: We examined differences in treatment outcome between Diagnostic and Statistical Manual Fourth Edition (DSM-IV)-defined rapid cycling and average lifetime-defined rapid cycling in subjects with bipolar II disorder. We hypothesized that, compared with the DSM-IV definition, the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment. METHODS: Subjects ≥18 years old with a bipolar II major depressive episode (n=129) were categorized into DSM-IV- and average lifetime-defined rapid cycling and prospectively treated with either venlafaxine or lithium monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. RESULTS: These exploratory analyses found moderate agreement between the two rapid-cycling definitions (κ=0.56). The lifetime definition captured subjects with more chronic courses of bipolar II depression, whereas the DSM-IV definition captured subjects with more acute symptoms of hypomania. There was no difference between rapid-cycling definitions with respect to the response to acute venlafaxine or lithium monotherapy. However, the lifetime definition was slightly superior to the DSM-IV definition in identifying subjects who went on to experience hypomanic symptoms during continuation therapy. CONCLUSIONS: Although sample sizes were limited, the findings suggest that the lifetime definition of rapid cycling may identify individuals with a chronic rapid-cycling course and may also be slightly superior to the DSM-IV definition in identifying individuals with hypomania during relapse-prevention therapy. These findings are preliminary in nature and need replication in larger, prospective, bipolar II studies.

Industry-corrupted psychiatric trials. / Zjawisko korupcji w badaniach psychiatrycznych.

The goal of this paper is to expose the research misconduct of pharmaceutical industry sponsored clinical trials via three short case studies of corrupted psychiatric trials that were conducted in the United States. We discuss the common elements that enable the misrepresentation of clinical trial results including ghostwriting for medical journals, the role of key opinion leaders as co-conspirators with the pharmaceutical industry and the complicity of top medical journals in failing to uphold standards of science and peer review. We conclude that the corruption of industry-sponsored clinical trials is one of the major obstacles facing evidence-based medicine.

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 (ß=-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 (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.

Step-wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression.

OBJECTIVE: This study examined the relationship between the number of prior antidepressant treatment trials and step-wise increase in pharmacodynamic tolerance (or progressive loss of effectiveness) in subjects with bipolar II depression. METHODS: Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. RESULTS: After controlling for baseline covariates of prior medications, there was a 25% reduction in the likelihood of response to treatment with each increase in the number of prior antidepressant trials (odds ratio [OR]=0.75, unstandardized coefficient [B]=-0.29, standard error (SE)=0.12; χ2 =5.70, P<.02], as well as a 32% reduction in the likelihood of remission with each prior antidepressant trial (OR=0.68, B=-0.39, SE=0.13; χ2 =9.71, P=.002). This step-wise increase in pharmacodynamic tolerance occurred in both treatment conditions. Prior selective serotonin reuptake inhibitor (SSRI) therapy was specifically associated with a step-wise increase in tolerance, whereas other prior antidepressants or mood stabilizers were not associated with pharmacodynamic tolerance. Neither the number of prior antidepressants, nor the number of prior SSRIs, or mood stabilizers, were associated with an increase in relapse during continuation therapy. CONCLUSIONS: The odds of responding or remitting during venlafaxine or lithium monotherapy were reduced by 25% and 32%, respectively, with each increase in the number of prior antidepressant treatment trials. There was no relationship between prior antidepressant exposure and depressive relapse during continuation therapy of bipolar II disorder.

Specific Pharmacological Effects of Paroxetine Comprise Psychological but Not Somatic Symptoms of Depression.

BACKGROUND: Meta-analyses of placebo-controlled trials of SSRIs suggest that only a small portion of the observable change in depression may be attributed to "true" pharmacological effects. But depression is a multidimensional construct, so treatment effects may differ by symptom cluster. We tested the hypothesis that SSRIs uniquely alter psychological rather than somatic symptoms of depression and anxiety. METHOD: Outpatients with moderate to severe MDD were randomly assigned to receive paroxetine (n = 120) or placebo (n = 60). RESULTS: Paroxetine significantly outperformed placebo on all psychological subscales of the syndrome measures, but not on any of the somatic subscales. The difference in score reduction between paroxetine and placebo was more than twice as great for the psychological symptoms compared to the somatic symptoms. CONCLUSIONS: Paroxetine appears to have a "true" pharmacological effect on the psychological but not on the somatic symptoms of depression and anxiety. Paroxetine's influence on somatic symptoms appears to be mostly duplicated by placebo.

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance.

OBJECTIVE: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States. METHODS: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-(NMG) were deconstructed. RESULTS: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic researchers solicited as 'authors'. CONCLUSION: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.