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It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite's effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies. Clinical trial NCT00360399 "Predictors of Antidepressant Treatment Response: The Emory CIDAR" https://clinicaltrials.gov/ct2/show/NCT00360399. [ABSTRACT FROM AUTHOR]

Background: To compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone. Methods: Response was defined as ≥ 50% decrease from baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score at 3, 6, 9, or 12 months post-baseline. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan–Meier (KM) analysis and compared using log-rank test. Suicidality was assessed using the MADRS Item 10 score. Results: At baseline (entry into registry), the VNS + TAU group (N = 97) had more episodes of depression, psychiatric hospitalizations, lifetime suicide attempts and higher suicidality score, more severe symptoms (based on MADRS and other scales), and higher rate of prior electroconvulsive therapy than TAU group (N = 59). Lifetime use of medications was similar between the groups (a mean of 9) and was consistent with the severe treatment-resistant nature of their depression. Over 5 years, 63% (61/97) in VNS + TAU had an initial response compared with 39% (23/59) in TAU. The time-to-initial response was significantly quicker for VNS + TAU than for TAU (p < 0.03). Among responders in the first year after implant, the KM estimate of the median time-to-relapse from initial response was 15.2 vs 7.6 months for VNS + TAU compared with TAU (difference was not statistically significant). The mean reduction in suicidality score across the study visits was significantly greater in the VNS + TAU than in the TAU group (p < 0.001). Conclusions: The patients who received VNS + TAU included in this analysis had severe bipolar depression that had proved extremely difficult to treat. The TAU comparator group were similar though had slightly less severe illnesses on some measures and had less history of suicide attempts. Treatment with VNS + TAU was associated with a higher likelihood of attaining a response compared to TAU alone. VNS + TAU was also associated with a significantly greater mean reduction in suicidality. Limitations: In this registry study, participants were not randomized to the study treatment group, VNS Therapy stimulation parameters were not controlled, and there was a high attrition rate over 5 years. Trial registration ClinicalTrials.gov NCT00320372. Registered 3 May 2006, https://clinicaltrials.gov/ct2/show/NCT00320372 (retrospectively registered) [ABSTRACT FROM AUTHOR]

Side effects (SEs) are negative reactions to an appropriately delivered treatment, which must be discriminated from unwanted events (UEs) or consequences of inadequate treatment. One hundred CBT therapists were interviewed for UEs and SEs in one of their current outpatients. Therapists reported 372 UEs in 98 patients and SEs in 43 patients. Most frequent were "negative wellbeing/distress" (27% of patients), "worsening of symptoms" (9%), "strains in family relations" (6%); 21% of patients suffered from severe or very severe and 5% from persistent SEs. SEs are unavoidable and frequent also in well-delivered CBT. They include both symptoms and the impairment of social life. Knowledge about the side effect profile can improve early recognition of SEs, safeguard patients, and enhance therapy outcome. [ABSTRACT FROM AUTHOR]

Depression involves impairments in a range of cognitive and emotional capacities. It is unknown whether these functions can inform medication choice when considered as a composite predictive biomarker. We tested whether behavioral tests, grounded in the neurobiology of cognitive and emotional functions, predict outcome with common antidepressants. Medication-free outpatients with nonpsychotic major depressive disorder (N=1008; 665 completers) were assessed before treatment using 13 computerized tests of psychomotor, executive, memory-attention, processing speed, inhibitory, and emotional functions. Matched healthy controls (N=336) provided a normative reference sample for test performance. Depressed participants were then randomized to escitalopram, sertraline, or venlafaxine-extended release, and were assessed using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) and the 17-item Hamilton Rating Scale for Depression. Given the heterogeneity of depression, analyses were furthermore stratified by pretreatment performance. We then used pattern classification with cross-validation to determine individual patient-level composite predictive biomarkers of antidepressant outcome based on test performance. A subgroup of depressed participants (approximately one-quarter of patients) were found to be impaired across most cognitive tests relative to the healthy norm, from which they could be discriminated with 91% accuracy. These patients with generally impaired cognitive task performance had poorer treatment outcomes. For this impaired subgroup, task performance furthermore predicted remission on the QIDS-SR16 at 72% accuracy specifically following treatment with escitalopram but not the other medications. Therefore, tests of cognitive and emotional functions can form a clinically meaningful composite biomarker that may help drive general treatment outcome prediction for optimal treatment selection in depression, particularly for escitalopram. [ABSTRACT FROM AUTHOR]

Hippocampal atrophy is reported in major depressive disorder (MDD). However, sample sizes were generally modest, and participant characteristics, including age, differed between studies. This study used a community sample to examine relationships between current depressive symptom severity and hippocampal volume across the adult lifespan. A total of 1936 adults with magnetic resonance images of the brain and Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) scores were included. Brain volumes were quantified using the FSL program. Multiple linear regressions were performed using left, right, and total hippocampal volume as criterion variables, and predictor variables of QIDS-SR total, total brain volume, age, gender, education, psychotropic medications, alcohol use, and race/ethnicity. Post hoc analyses were conducted in participants with QIDS-SR scores 11 (moderate or greater depressive symptom severity) and <11, and older and younger adults. In the primary analysis (sample as a whole) QIDS-SR was inversely associated with total hippocampal volume (b=−0.044, p=0.032, (CI−0.019 to −0.001)) but not with left or right hippocampal volume evaluated individually. In participants with QIDS-SR scores of <11, hippocampal volumes were not associated with QIDS-SR scores. In those with QIDS-SR scores 11 total, right, and left hippocampal volumes were modestly, but significantly, associated with QIDS-SR scores. The association between QIDS-SR scores and the hippocampal volume was much stronger in older persons. Findings suggest smaller hippocampal volumes among those with greater reported depressive symptom severity-an association that is strongest in people with at least moderate depressive symptom levels. [ABSTRACT FROM AUTHOR]

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study used a series of sequenced, randomized treatment trials following a first and, if needed, subsequent treatment steps to define the tolerability and effectiveness of various options in both acute and longer term treatment. Adult outpatients (n=4041) with nonpsychotic major depressive disorder, substantial chronic and recurrent depression, and co-morbid psychiatric and general medical conditions were enrolled in 41 representative primary and specialty care settings. About one-third of participants remitted in first step treatment with citalopram, 50% of these within 6 weeks. Poorer outcomes were associated with minority status, socioeconomic disadvantage, more axis I and III co-morbid disorders, lower function and quality of life, and anxious and melancholic features. In step 2 medication switch, there were no significant differences in remission among within-class, out-of-class or dualaction agents: sertraline (27%), bupropion-sustained release (26%) and venlafaxine-extended release (25%). In step 2 medication augmentation of citalopram, there was no significant difference in remission between bupropion-sustained release (39%) and buspirone (33%), although participants using bupropion-sustained release had greater symptom reduction and better tolerability. There were no significant differences in remission in step 2 between cognitive therapy and medication treatment in either the switch (31% vs 27%) or augmentation (31% vs 33%) strategies, although participants in cognitive therapy augmentation had a longer time to remission than those in medication augmentation (55 vs 40 days). In step 3, there were no differences in remission between a switch to mirtazapine (8%) or nortriptyline (12%), or between augmentation with lithium (13%) or T3 (triiodothyronine, liothyronine) [25%], although more participants discontinued lithium due to adverse effects than discontinued T3. In the fourth step, there was no difference in remission between tranylcypromine (14%) or venlafaxine-extended release plus mirtazapine (16%), although the combination treatment had fewer adverse effects and had the advantages of not requiring a washout period or diet restrictions. Participants requiring more than two well delivered treatments may be characterized as treatment resistant given the substantially lower remission rates after that point. Treatment resistance was associated with more concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity and melancholic or anxious features. However, if participants remained in treatment for up to four steps, about 67% reached remission. Times to remission were not substantially longer for later treatment steps. The importance of reaching remission is highlighted by the lower relapse rates in naturalistic follow-up for participants entering in remission compared with those entering with response but not remission (step 1: 34% vs 59%; step 2: 47% vs 68%; step 3: 42% vs 76%; step 4: 50% vs 83%). Clinical decision making based on the itemized measurement of symptoms and adverse effects at each treatment visit was feasible in STAR*D's real world settings and resulted in adequate dosages and durations of treatment that generally exceeded those typically found in practice settings. Although switch and augmentation strategies could not be directly compared due to the equipoise stratified randomized design, the higher remission rates at step 2 with medication augmentation are intriguing and merit further study. [ABSTRACT FROM AUTHOR]

Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case–control cohort derived from the STAR*D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n=1473) for whom DNA and adverse effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted p<0.05 for each). Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes.Neuropsychopharmacology (2009) 34, 1819–1828; doi:10.1038/npp.2009.4; published online 18 March 2009 [ABSTRACT FROM AUTHOR]

Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16) score 5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.Neuropsychopharmacology (2008) 33, 2810–2819; doi:10.1038/npp.2008.6; published online 20 February 2008 [ABSTRACT FROM AUTHOR]

Number of lifetime episodes, duration of current episode, and severity of maternal depression were investigated in relation to family functioning and child adjustment. Participants were the 151 mother–child pairs in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) child multi-site study. Mothers were diagnosed with Major Depressive Disorder; children (80 males and 71 females) ranged in age from 7 to 17 years. Measures of child adjustment included psychiatric diagnoses, internalizing and externalizing symptoms, and functional impairment. Measures of family functioning included family cohesion, expressiveness, conflict, organization, and household control; parenting measures assessed maternal acceptance and psychological control. Children of mothers with longer current depressive episodes were more likely to have internalizing and externalizing symptoms, with this association being moderated by child gender. Mothers with more lifetime depressive episodes were less likely to use appropriate control in their homes. [ABSTRACT FROM AUTHOR]

Background: Whether the acute outcomes of major depressive disorder (MDD) treated in primary (PC) or specialty care (SC) settings are different is unknown.Objective: To compare the treatment and outcomes for depressed outpatients treated in primary versus specialty settings with citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org), a broadly inclusive effectiveness trial.Design: Open clinical trial with citalopram for up to 14 weeks at 18 primary and 23 specialty sites. Participants received measurement-based care with 5 recommended treatment visits, manualized pharmacotherapy, ongoing support and guidance by a clinical research coordinator, the use of structured evaluation of depressive symptoms and side effects at each visit, and a centralized treatment monitoring and feedback system.Participants: A total of 2,876 previously established outpatients in primary (n = 1091) or specialty (n = 1785) with nonpsychotic depression who had at least 1 post-baseline measure.Measurements and Main Results: Remission (Hamilton Depression Rating Scale for Depression [Hamilton] or 16-item Quick Inventory of Depressive Symptomatology-Self-Rated [QIDS-SR(16)]); response (QIDS-SR(16)); time to first remission (QIDS-SR(16)). Remission rates by Hamilton (26.6% PC vs 28.0% SC, p = .40) and by QIDS-SR(16) (32.5% PC vs 33.1% SC, p = .78) and response rates by QIDS-SR(16) (45.7% PC vs 47.6% SC, p = .33) were not different. For those who reached remission or response at exit, the time to remission (6.2 weeks PC vs 6.9 weeks SC, p = .12) and to response (5.5 weeks PC vs 5.4 weeks SC, p = .97) did not differ by setting.Conclusions: Identical remission and response rates can be achieved in primary and specialty settings when identical care is provided. [ABSTRACT FROM AUTHOR]

The success of well-developed protocols has been limited in real-world practice, where even effective strategies have not been sufficient to meet patient needs in routine clinical care owing to Axis I and III comorbidities. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial required that antidepressant medication treatment be optimal regarding dose and duration, yet accommodate flexibility to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The objective of this study was to develop a measurement-based care (MBC) approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice. Ratings of depressive symptom severity and side-effect frequency, intensity, and burden were obtained at each treatment visit using the MBC system that (1) guided medication dose adjustments and treatment duration, (2) documented clinician adherence to treatment recommendations, and (3) provided prompt feedback to clinicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side-effect burden, and dose and duration of antidepressant at each critical decision point during the acute phase treatment of major depression. Feedback was provided at the point of care by the clinical coordinators, assisted by Web-based reports following each treatment visit. On the basis of the first treatment step with citalopram, over 85% of treatment encounters had appropriate fidelity to recommendations. Most deviations from treatment recommendations occurred late in treatment and were often justifiable. MBC proved to be feasible and effective in busy primary and psychiatric settings. This approach signals a paradigm shift toward the use of measurement-based clinical decisions, both at the point of care and following each visit, to deliver optimal pharmacotherapy for depression.Neuropsychopharmacology (2007) 32, 2479–2489; doi:10.1038/sj.npp.1301390; published online 4 April 2007 [ABSTRACT FROM AUTHOR]

The Sequenced Treatment Alternatives to Relieve Depression trial enrolled outpatients with nonpsychotic major depressive disorder treated prospectively in a series of randomized controlled trials. These were conducted in representative primary and psychiatric practices. Remission rates for treatment steps 1 to 4 based on the 16-item Quick Inventory of Depressive Symptomatology-Self-report were 37%, 31%, 14%, and 13%, respectively. There were no differences in remission rates or times to remission among medication switch or among medication augmentation strategies at any treatment level. Participants who required increasing numbers of treatment steps showed greater depressive illness burden and increasingly greater relapse rates in the naturalistic follow-up period (40%-71%). Prognosis was better at all levels for participants who entered follow-up in remission as opposed to those who entered with response without remission. These results highlight the prevalence of treatment-resistant depression and suggest potential benefit for using more vigorous treatments in the earlier steps. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are often chronic conditions that require sequential decision making to achieve the best clinical outcomes. Sequential decisions are necessary to accommodate treatment response heterogeneity, a variable course of illness, and the often heavy burden associated with intensive or longer-term treatment. Yet, only a few studies in this field have been designed to address sequential decisions. Most of the experimental designs and data analytic methods that are best suited for improving sequential clinical decision making are often found in nonmedical fields such as engineering, computer science, and statistics. Promising designs and methods are surveyed with a focus on those areas most immediately useful for informing clinical decision making.Neuropsychopharmacology (2007) 32, 257–262. doi:10.1038/sj.npp.1301241; published online 8 November 2006 [ABSTRACT FROM AUTHOR]

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.Neuropsychopharmacology (2006) 31, 1841–1853. doi:10.1038/sj.npp.1301131; published online 21 June 2006 [ABSTRACT FROM AUTHOR]

This study examined the influences of proposed specific and common psychotherapeutic factors in a sample of chronically depressed adult outpatients. Participants (N = 324) were drawn from a multi-site clinical trial that compared the efficacies of the cognitive behavioral analysis system of psychotherapy (CBASP), nefazodone, and their combination. This report is limited to patients receiving CBASP alone or combination treatment. A series of regression analyses were performed to test whether: (1) the ability to utilize the skills taught in CBASP mediated the relationship between the early therapeutic alliance and endpoint depression, and (2) the therapeutic alliance moderated the relationship between skill utilization and endpoint depression. Neither model was supported. Instead, each of these factors contributed independently and additively to alleviation of depressive symptoms. [ABSTRACT FROM AUTHOR]

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-1) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-1, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 14, 6, 8, 10, and 12. Response was defined a priori as a ≥50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-1 score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-1), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-1), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-1), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30 = 32%, QIDS-SR16 = 28%, PGI1 = 22%, HDRS17 = 30%), for CBASP (IDS-SR30 = 32%, QIDS-SR16 = 30%, PGI-1 = 21%, HDRS17 = 32%), and for the combination (IDSSR30=52%, QIDS-SR16=50%, PGI-1=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-1, as opposed to specific item-based ratings, provide less valid findings. [ABSTRACT FROM AUTHOR]

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project will provide symptomatic and functional outcome data to evaluate the theoretical principles and clinical beliefs that currently guide the treatment of nonpsychotic major depression. Cognitive Therapy (CT) for depression has been chosen as a switch or augmentation treatment for patients who have failed an adequate trial of the antidepressant citalopram. We describe the rationale, organization, and role of CT in STAR*D. We discuss the issues involved in developing and implementing CT in a large, multisite, effectiveness study: therapist selection, training, certification, quality assurance, and post-training supervision. We conclude with a discussion of the implications of our implementation procedures on interpreting the results of the STAR*D study. [ABSTRACT FROM AUTHOR]

Examines the relationship between patient characteristics and the working alliance in a multisite trial for chronic depression. Increase in the number of studies about therapeutic alliance; Factors affecting therapeutic alliance; Background of the participants in the study.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on “improving the technology of clinical trials.” The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on “whole” disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) and Food and Drug Administration (FDA) participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants. [Copyright &y& Elsevier]

Abstract The symptomatology of post-traumatic stress disorder (PTSD) involves sympathetic hyperarousal. Several of these sympathetic symptoms are mediated through end-organ beta[sub 2]-adrenergic receptors ([beta[sub 2]AR). Increased sympathetic activity in PTSD could therefore be due to increased beta AR function. This study investigated beta AR function in 30 healthy controls and 20 drug-free PTSD patients, beta AR binding studies were conducted using antagonist-saturation and agonist-displacement experiments. Measures of beta AR coupling to G[sub s] protein were derived from agonist-displacement experiments. PTSD patients had significantly higher beta[sub 2]AR density - particularly in the high-conformational state - and higher beta[sub 2]AR coupling than controls, as reflected in a higher percentage of receptors in the high conformational state and a higher ratio of the agonist dissociaton constant from the receptor in the low/high-conformational state. Increased beta AR function in PTSD is consistent with the symptomatology of this disorder. Increased IlAR density and coupling may be consistent with downregulation of beta AR density and uncoupling by antidepressants and may underlie their partial efficacy in PTSD. Dysregulation in G[sub s] protein function is postulated and, agonist-mediated regulation of IlAR expression and/or beta AR kinase activity in PTSD should be investigated in future studies. [ABSTRACT FROM AUTHOR]

Abstract Low platelet membrane alpha[sub 2]-adrenergic receptor (alpha[sub 2]AR) density and low basal and forskolin-stimulated cyclic adenosine monophosphate responses, which have been reported in post-traumatic stress disorder (PTSD), suggest either abnormal alpha[sub 2]AR coupling to G[sub I] protein or dysregulation in post-receptor signal transduction mechanisms alpha[sub 2]AR density in the high-and low-conformational states, agonist affinity in both states and coupling to G[sub I] protein were investigated in 23 drug-free combat PTSD patients and 25 normal controls alpha[sub 2]AR coupling measures were not different between PTSD patients and controls. Total alpha[sub 2]AR density was higher in PTSD patients than controls, due to a higher density of the receptor in the high-conformational state. There were no differences in agonist affinity to the receptor in either conformational state. Results rule out dysregulation in alpha[sub 2]AR coupling to G[sub I] protein. Studies of post-receptor signal transduction mechanisms are warranted. [ABSTRACT FROM AUTHOR]