Antidepressant Efficacy Trials Research Articles

CORONARY ARTERY DISEASE AND DEPRESSION: A MISSING PILLAR IN MANAGEMENT

Patients with coronary artery disease have multiple co-morbids that include dyslipidemia, hypertension, diabetes mellitus, smoking and physical inactivity. It has been seen that depression is another issue in these patients that need close attention. Studies have shown that it affects between 20% and 40% in patients with coronary artery disease (CAD) and have a higher prevalence than in general population.1 One of the study done by SS Bokhari et al.2 has shown a point prevalence of depression in CAD as 37% (31.3% males and 53.8% females).
 Numerous studies have shown that patients with CAD and depression have poor health outcomes.3 Depression in different aspects in Pakistani population after myocardial infarction,4 after PCI5 and in in-hospital patients with CAD6 were evaluated and found to have significant mental illness which co-relates with the results of other international studies.
 Keeping all the research studies American Heart Association wrote a scientific statement and endorsed depression as a risk factor for cardiac morbidity and mortality.7 Importance of depression screening as a part of myocardial infarction protocol for caring patients with Ischemic Heart Disease was seen in TRIUMPH trial (Translational Research Investigating Underlying Disparities in Acute Myocordial Infarction Patients Health Status)8 ENRICHD Trial (Enhancing Recovery in Coronary Heart Disease)9 use of citalopram or serlatine plus as clinical management was used for depressive symptoms with CAD in CREATE Trial (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy).10
 In Pakistan where prevalent of CAD is high i.e. one in 4 middle age adults,11 managing such patients are numerous that includes revascularization (Surgical and Interventional), drugs and treatment of modifiable and nonmodifiable risk factors. Despite all these efforts it’s a need of time to focus on diagnosing depression in CAD to improve outcomes. Depression screening should be conducted to identify these important risk factors and treated with drugs in reducing morbidity and mortality.
 References
 
 Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, Robins C, et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med. 2004;66:305-15.
 Bokhari SS, Samad AH, Hanif S, Hadique S, Cheema MQ, Fazal MAS, et al. Prevalence of depression in patients with coronary artery disease in a tertiary care hospital in Pakistan. J Pak Med Assoc. 2002;52(9):436-9.
 Jackson CA, Sudlow CLM, Mishra GD. Psychological Distress and Risk of Myocardial Infarction and Stroke in the 45 and Up Study. Circ Cardiovasc Qual Outcomes. 2018;11:e004500.
 Saeed H, Khan F, Mohsin SF, Qizilbash FH, Fraz TR, Jawed Q, et al. Pattern of Depression Among Patients of Myocardial Infarction in Karachi, Pakistan: A Cross-sectional Study. Cureus. 2018;10(8):e3199
 Mujtaba SF, Sial JA, Karim M. Depression and Anxiety in patients undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome. Pak J Med Sci. 2020;36(5):1100-5.
 Khan SA, Azhar S, Asad SM, Iqbal A, Kousar R, Ahmad M, et al. Assessment of anxiety and depression in hospitalized cardiac patients of Faisalabad Institute of Cardiology, Pakistan. Trop J Pharm Res. 2016;15(11):2483-7
 Lichtman JH, Froelicher ES, Blumenthal JA, Carney RM, Doering LV, Frasure-Smith N, et al. Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: systematic review and recommendations: a scientific statement from the American Heart Association. Circulation 2014;129:1350-69.
 Smolderen KG, Buchanan DM, Gosch K, Whooley M, Chan PS, Vaccarino V, et al. Depression Treatment and 1-Year Mortality Following Acute Myocardial Infarction: Insights from the TRIUMPH Registry. Circulation 2017;135:1681-9.
 Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003;289:3106-16.
 Lespérance F, Frasure-Smith N, Koszycki D, Laliberté MA, van Zyl LT, Baker B, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007;297:367-79.
 Jafar TH, Jafary FH, Jessani S, Chaturvedi N. Heart disease epidemic in Pakistan: women and men at equal risk. Am Heart J. 2005;150(2):221-6.

Applying the inclusion/exclusion criteria in placebo-controlled studies to a clinical sample: A comparison of medications

BackgroundWe previously compared the inclusion/exclusion criteria in the studies of vortioxetine to other antidepressants and found that they were significantly more restrictive in the vortioxetine studies. In the present study, we tested the hypothesis that the differences in psychiatric inclusion/exclusion criteria used in the studies of some antidepressants resulted in differences in generalizability to clinical samples. MethodsWe applied the inclusion and exclusion criteria used in 161 antidepressant efficacy trials to 1,271 patients presenting to an outpatient practice who received a principal diagnosis of major depressive disorder. The patients underwent a thorough diagnostic evaluation. We compared the percentage of patients that would be excluded in studies of different medications. ResultsThe percentage of patients that would have been excluded was significantly higher in the vortioxetine studies than other medications. For the 15 medications that were included in at least 5 trials, we computed the mean percentage of patients that would be excluded. The values ranged from 76.0% (for fluoxetine) to 99.1% (for quetiapine). LimitationsWhile our calculations were based on the exclusion criteria stated in the published articles, we have no way of knowing how these criteria were actually applied. ConclusionStudies of different medications vary in how representative the samples are of patients in clinical practice. The variability in the inclusion/exclusion criteria used to select samples for antidepressant efficacy trials, and the evidence that studies of different medications vary in their generalizability, makes it more difficult to interpret network analyses comparing the relative efficacy of medications.

Have Treatment Studies of Depression Become Even Less Generalizable? Applying the Inclusion and Exclusion Criteria in Placebo-Controlled Antidepressant Efficacy Trials Published over 20 Years to a Clinical Sample

Background: Antidepressants are amongst the most frequently prescribed medications. More than a decade ago, our clinical research group applied a prototypic set of inclusion/exclusion criteria used in an antidepressant efficacy trial (AET) to patients presenting for treatment in our outpatient practice and found that most patients would not qualify for the trial. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we apply the psychiatric inclusion/exclusion criteria used in 158 placebo-controlled studies to a large sample of depressed patients who presented for outpatient treatment to determine the range and extent of the representativeness of samples treated in AETs and whether this has changed over time. Method: We applied the inclusion and exclusion criteria used in 158 AETs to 1,271 patients presenting to an outpatient practice who received a principal diagnosis of major depressive disorder. The patients underwent a thorough diagnostic evaluation. Results: Across all 158 studies, the percentage of patients that would have been excluded ranged from 44.4 to 99.8% (mean = 86.1%). The percentage of patients that would have been excluded was significantly higher in the studies published in 2010 through 2014 compared to the studies published from 1995 to 2009 (91.4 vs. 83.8%, t(156) = 3.74, p < 0.001). Conclusions: Only a minority of depressed patients seen in clinical practice are likely to be eligible for most AETs. The generalizability of AETs has decreased over time. It is unclear how generalizable the results of AETs are to patients treated in real-world clinical practice.

Has the symptom severity inclusion requirement narrowed the definition of major depressive disorder in antidepressant efficacy trials?

BackgroundThe inclusion criteria of all placebo-controlled studies of antidepressants have required a minimum level of severity on standardized measures of symptoms of depression. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project we examined the association between scores on the Hamilton Depression Rating Scale (HAMD) and the number of criteria met for MDD, as well as the impact of different HAMD cutoff scores on the distribution of the number of DSM-IV criteria met. We speculated that the use of a minimum symptom severity score (MSSS) for inclusion in an antidepressant efficacy trial (AETs) disproportionately excludes patients who are at or just above the diagnostic threshold for MDD, whereas patients who are well above the diagnostic threshold are not excluded. MethodsSeven hundred forty outpatients with current MDD were evaluated with a semi-structured diagnostic interview. We compared the distribution of DSM-IV MDD criteria scores in patients who scored at or above or below the 3 cutoff scores on the HAMD most commonly used for inclusion in an AET. ResultsThe distribution of the number of DSM-IV MDD symptom criteria met was significantly associated with HAMD scores. Compared to patients scoring below 18 on the HAMD the patients scoring 18 and above were less likely to report 5 MDD criteria (13.9% vs. 43.7%, χ2=82.2, p<0.001; RR 0.32 [95% C.I. 0.24–0.41]) and more likely to report 9 criteria (9.3% vs. 0.3%, χ2=27.6, p<0.001; RR 28.7 [95% C.I. 4.0–207.5]). The pattern was similar when comparing patients scoring above and below the cutoffs of 20 and 22. At a cutoff of 22 on the HAMD more than 85% of the patients meeting 5 or 6 MDD criteria would be excluded from a trial. In contrast, less than 10% of the patients meeting 8 or 9 criteria would be excluded based on a HAMD cutoff of 18. LimitationsThe present study was conducted in a single outpatient practice in which the majority of patients were white, female, and had health insurance. Although the study was limited to a single site, a strength of the recruitment procedure was that the sample was not selected for participation in a treatment study, and exclusion and inclusion criteria did not reduce the representativeness of the patient groups. ConclusionsWhile there is not a perfect relationship between the HAMD score and the number of DSM MDD criteria present, the results of the current study suggest that HAMD scores can be thought of as a proxy for the number of DSM diagnostic criteria. Thus, the recruitment strategy for AETs has increasingly redefined the MDD diagnostic category by requiring a greater number of criteria than that required in the DSM.

Inclusion/exclusion criteria in late life depression antidepressant efficacy trials.

The generalizability of antidepressant efficacy trials (AETs) has been questioned. No studies have examined the inclusion/exclusion criteria used in placebo-controlled studies of late life depression and compared them to the criteria used in non-late life AETs. We conducted a comprehensive literature review of placebo-controlled AETs published from January, 1995 through December, 2014. We compared the inclusion/exclusion criteria used in the 18 studies of late life depression to those used in non-late life depression. There were nine inclusion/exclusion criteria that were used in more than half of the late life depression AETs: minimum severity on a symptom severity scale (100.0%), significant suicidal ideation (77.8%), psychotic features during the current episode of depression or history of a psychotic disorder (94.4%), history of bipolar disorder (77.8%), diagnosis of alcohol or drug abuse or dependence (83.3%), presence of a comorbid nondepressive, nonsubstance use Axis I disorder (55.6%), episode duration too short (66.7%), and an insufficient score on a cognitive screen (88.3%) or the presence of a cognitive disorder (55.6%). There were some differences between the late life and non-late life depression studies-use of a screening measure of cognitive functioning, presence of a cognitive disorder such as dementia, and the minimum depression severity cutoff score required at baseline. The inclusion/exclusion criteria in AETs of late life depression were generally similar to the criteria used in non-late life depression AETs. Copyright © 2016 John Wiley & Sons, Ltd.

The Psychiatric Inclusion and Exclusion Criteria in Placebo-Controlled Monotherapy Trials of Bipolar Depression: An Analysis of Studies of the Past 20Years.

Concerns about the generalizability of pharmacotherapy efficacy trials to "real-world" patients have been raised for more than 40years. Almost all of this literature has focused on treatment studies of major depressive disorder (MDD). The aim of the study was to review the psychiatric inclusion and exclusion criteria used in placebo-controlled trials that assessed the efficacy of medications for bipolar depression (bipolar disorder efficacy trials [BDETs]) and compare the criteria used in BDETs with those used in efficacy trials of antidepressants to treat MDD (antidepressant efficacy trials [AETs]). We searched the MEDLINE, Embase, and PsycINFO databases for articles published from January 1995 through December 2014. We identified 170 placebo-controlled AETs and 22 BDETs published during these 20years. Two of the authors independently reviewed each article and completed a pre-specified information extraction form listing the psychiatric inclusion and exclusion criteria used in the study. Six inclusion/exclusion criteria were used in at least half of the BDETs: minimum severity on a depression symptom severity scale, significant suicidal ideation, diagnosis of alcohol or drug use disorder, presence of a comorbid nondepressive, nonsubstance use Axis I disorder, current episode of depression being too long, and absence of current manic symptoms. BDETs were significantly less likely than AETs to exclude patients with a history of psychotic features/disorders, borderline personality disorder, and post-traumatic stress disorder and more likely to exclude individuals who scored too low on the first item of the Hamilton Depression Rating Scale. Nearly two-thirds of the BDETs placed an upper limit on the duration of the current depressive episode, three times higher than the rate in the AETs. There was no difference on other variables between the AETs and BDETs. Similar to treatment studies of nonbipolar MDD, the treatment studies of bipolar depression frequently excluded patients with comorbid psychiatric and substance use disorders and insufficient severity of depressive symptoms as rated on standardized scales. These findings indicate that concerns about the generalizability of data from trials of recently approved medications for the treatment of bipolar depression are as relevant as the concerns that have been raised about studies of antidepressants for nonbipolar depression.

Symptom Severity and the Generalizability of Antidepressant Efficacy Trials: Changes During the Past 20 Years.

The most commonly used inclusion/exclusion criterion in antidepressant efficacy trials (AETs) is a minimum score on a symptom severity scale. In the present study, we reviewed placebo-controlled AETs published during the past 20 years to determine whether there has been a change in the symptom severity inclusion criterion threshold subsequent to publications that highlighted the unrepresentativeness of the depressed patients studied in AETs. We identified 170 AETs published during the past 20 years and compared the studies published during the past 5 years (2010-2104, n = 56) with the studies published during the previous 15 years (n = 114). The symptom severity threshold for inclusion has increased in the more recent cohort of studies. On the 17-item Hamilton Depression Rating Scale, almost half of the studies of the past 5 years used a cutoff of 22 or greater to select patients versus less than one-fifth of the studies during the previous 15 years (44.0% vs 17.5%; χ(2) = 7.4; P < 0.01). Similarly, the cutoff on the Montgomery-Asberg Depression Rating Scale required for study inclusion has been higher in studies of the past 5 years with approximately three-quarters of the recent studies using a cutoff of at least 25, in contrast to one-quarter of the older studies (76.2% vs 25.0%; χ(2) = 8.2; P < 0.01). A significantly higher percentage of patients in our clinical practice would be excluded on the basis of the severity thresholds of the past 5 years (59.3 ± 13.5 vs 49.0 ± 15.1; t121 = 3.1; P < 0.005). These findings suggest that the results of AETs may not be applicable to less severely depressed patients who make up at least half of the patients treated in routine clinical practice. Questions are raised about the Food and Drug Administration labeling of antidepressants.

Variability in the substance use disorder exclusion criterion in antidepressant efficacy trials

BackgroundSubstance use disorders are the most commonly excluded psychiatric disorder in antidepressant efficacy trials (AETs). In a recent review of AETs we noticed variability in the definition of the substance use disorder exclusion criterion. In the present report we examined in greater detail the variability in defining the substance use disorder exclusion criterion, the potential impact of this variability on excluding patients from an AET, and whether the definition of the criterion has changed in the past 20 years. MethodsWe identified 170 AETs published during the past 20 years and compared the studies published during the past 5 years (n=56) to the studies published during the 15 prior years (n=114). ResultsSubstance abuse was more frequently used as an exclusion criterion than substance dependence. Six time frames have been used as the basis of exclusion, the most frequent being the past 12 months. The time frame had a greater impact on the number of patients who would be excluded than the abuse/dependence distinction. The definition of the substance use exclusion criterion was no different in the studies of the past 5 years compared to the prior 15 years. LimitationsA limitation of the present analysis is that it was based on published placebo-controlled studies of antidepressants. ConclusionStudies varied in whether abuse or dependence was the basis of exclusion, whether alcohol or illicit drugs or both were the basis of exclusion, and the time frame of the disorders' presence. We raise the question of whether the routine exclusion of patients with a substance use disorder should be reflected in a product's label.

Problems in the Descriptions of the Psychiatric Inclusion and Exclusion Criteria in Publications of Antidepressant Efficacy Trials: A Qualitative Review and Recommendations for Improved Clarity.

We recently conducted a comprehensive review of the psychiatric inclusion and exclusion criteria used in 170 placebo-controlled antidepressant efficacy trials (AETs) that were published between 1995 and 2014. In conducting this literature review, we identified a number of instances in which the descriptions of the inclusion/exclusion criteria were vague, redundant, or difficult to interpret. In the present article, we describe nine problems we encountered in our literature review. We recommend that future publications follow the examples found in a few studies in which the inclusion/exclusion criteria are clearly defined and listed in a table.

Inclusion/exclusion criteria in placebo-controlled studies of vortioxetine: Comparison to other antidepressants and implications for product labeling

BackgroundWe recently conducted a comprehensive review of the psychiatric inclusion/exclusion criteria used in 170 placebo-controlled antidepressant efficacy trials (AETs) published during the past 20 years and found that the criteria of more recent studies were significantly more restrictive than prior studies. Vortioxetine is the most recently approved medication for the treatment of major depressive disorder (MDD). We compared the inclusion/exclusion criteria of the vortioxetine studies to the criteria used in other AETs, and discuss the broader issue of the generalizability of AETs and the implications this might have for the labeling of antidepressants receiving FDA approval. MethodsWe conducted a comprehensive literature review of placebo-controlled AETs published from January, 1995 through December, 2014. We identified 170 AETs published during this 20 year period and compared the inclusion/exclusion criteria used in the 12 studies of vortioxetine to those used in the nonvortioxetine studies. A second analysis compared vortioxetine to the 3 antidepressants most recently approved prior to vortioxetine (desvenlafaxine, levomilnacipran extended release, vilazodone). ResultsCompared to the nonvortioxetine AETs, the vortioxetine studies significantly more often excluded patients with any comorbid Axis I disorder (p<.001) and more often required the current depressive episode to be longer than the DSM minimum symptom duration requirement of 2 weeks (p<.01). The cutoff on the Montgomery Asberg Depression Rating Scale required for inclusion in the vortioxetine studies was higher than the cutoff used in the other AETs (p<.01). LimitationsA limitation of the present analysis is that it was based on published placebo-controlled studies of antidepressants. ConclusionThe inclusion/exclusion criteria in the studies of vortioxetine were more restrictive than the criteria used in other AETs. Inconsistent with FDA guidelines on the labeling of medications, the label of vortioxetine does not include a description of the limits to the group of patients with MDD for whom the medication has been shown to be effective.

Have Treatment Studies of Depression Become Even Less Generalizable? A Review of the Inclusion and Exclusion Criteria Used in Placebo-Controlled Antidepressant Efficacy Trials Published During the Past 20 Years

ObjectiveTo compare the inclusion and exclusion criteria used in antidepressant efficacy trials (AETs) published during the past 5 years with those used in studies published during the previous 15 years. Patients and MethodsWe conducted a comprehensive literature review of placebo-controlled AETs published from January 1995 through December 2014. We included trials whether or not the medication has received regulatory approval for the treatment of depression. We compared the inclusion and exclusion criteria of studies published during the past 5 years (2010-2014) with those of studies published during the previous 15 years (1995-2009). ResultsWe identified 170 placebo-controlled AETs published during the past 20 years, 56 of which were published during the past 5 years. The more recent studies were significantly more likely to exclude patients with comorbid Axis I disorders and personality disorders, patients with the episode duration either too long or too short, and patients who had made a suicide attempt in the past. The severity threshold on depression rating scales required for inclusion was higher in the more recent studies. ConclusionThe inclusion and exclusion criteria of AETs have become more stringent over the past 5 years, thereby suggesting that AETs may be even less generalizable than they were previously (when concerns about their generalizability had already been raised).

Influence of sociodemographic and socioeconomic features on treatment outcome in RCTs versus daily psychiatric practice

Sociodemographic and socioeconomic characteristics of participants in antidepressant and psychotherapy efficacy trials (AETs and PETs) for major depressive disorder (MDD) may limit the generalizability of the results. We compared trial participants with daily practice patients. We subsequently assessed the influence of socio-demographic and socioeconomic status on treatment outcome in daily practice. Data on daily practice patients were derived through routine outcome monitoring (ROM). We included 626 patients with MDD according to the MINIplus. Distributions of age, gender, race, marital status and employment status were compared with participants in 63 selected AETs and PETs. Influence of these features on treatment outcome was explored through multivariate regression analysis. Trial participants were older, more often male (diff. 4%, p=0.05), white (diff. 4%, p<0.001) and not married (diff. 7%, p=0.003). Although significant, most differences were relatively small. However, the difference in employment status was striking: 34% of the ROM patients were currently working versus 68% of the trial participants (diff. 34%, p<0.001). Being employed contributed to a positive treatment outcome: OR 1.8 for response [50% reduction of Montgomery Asberg Rating Scale for Depression (MADRS)], OR 1.9 for remission (MADRS ≤10). Employment status should be taken into account while interpreting results from randomized controlled trials and as predictor of treatment success in daily practice.

Symptom differences between depressed outpatients who are in remission according to the Hamilton Depression Rating Scale who do and do not consider themselves to be in remission

Remission is usually defined as a score below a predetermined cutoff on a symptom severity scale. Depressed patients' global perception of their remission status only partially overlaps with scale-based definitions of remission. Patients' self-perceived remission status is likely to impact on their desire for modification in their treatment. The identification of specific symptoms that distinguish patients who do and do not consider themselves to be in remission could represent the most salient targets of add-on treatment strategies desired by patients. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we compared the symptom profiles of patients who were in remission on the Hamilton Rating Scale for Depression (HAMD) who did and did not consider themselves to be in remission. We interviewed 274 psychiatric outpatients diagnosed with DSM-IV major depressive disorder who were in ongoing treatment. The patients completed the Clinically Useful Depression Outcome Scale (CUDOS). Approximately half of the patients scoring 7 and below on the HAMD did not consider themselves to be in remission. The mean number of symptoms on the CUDOS was significantly higher in the self-described non-remitters. Almost all symptoms were less frequent in the self-rated remitters, though the absolute frequency of the individual symptoms was related to the threshold used to define symptom presence. Consistent with the findings of other studies we found high rates of residual symptoms in patients who were considered to be in remission, and patients with residual symptoms typically had more than 1 such symptom. These results raise questions about the strategy of add-on treatments targeting specific individual symptoms. Remission was defined according to the 17-item version of the HAMD. We focused on the 17-item HAMD because it is the most commonly used measure in antidepressant efficacy trials, and the cutoff used to define remission has been generally accepted. We would anticipate that our findings would be similar in studies of longer versions of the HAMD as well as other depression severity scales such as the Montgomery-Asberg Depression Rating Scale. Self-perceived remission status was based on the patients' response to a single question. The sample was drawn from a single, large, general adult outpatient private practice setting in which the majority of the patients were white, female, and in their 30s and 40s. Generalizability to samples with different demographic characteristics needs to be demonstrated.

The drugs don't work? antidepressants and the current and future pharmacological management of depression.

Depression is a potentially life-threatening disorder affecting millions of people across the globe. It is a huge burden to both the individual and society, costing over £9 billion in 2000 alone: the World Health Organisation (WHO) cited it as the third leading cause of global disability in 2004 (first in the developed world), and project it will be the leading cause by 2030. The serendipitous discovery of antidepressants has revolutionized both our understanding and management of depression: however, their efficacy in the treatment of depression has long been debated and recently been brought very much into the public limelight by a controversial publication by Kirsch, in which the role of placebo response in antidepressant efficacy trials is highlighted. Whilst antidepressants offer benefits in both the short and long term, important problems persist such as intolerability, delayed therapeutic onset, limited efficacy in milder depression and the existence of treatment-resistant depression.

Socio-demographic features of participants in randomized con-trolled trials for major depression: generalizability and individu-alization.

Rationale, Aims and Objectives: It is important for clinicians to know to what extent the results of randomized controlled trials (RCTs) are generalizable to their psychiatric practice, since RCTs are considered to be the most reliable source of evidence for treatment guideline development. Furthermore, it is important to know whether results from individual randomised controlled trials (RCTs) can be directly compared to each other. Socio-demographic and socio-economic (SES) features influence treatment-outcome in major depressive disorder (MDD). Differences in (reporting of) SES features of participants in RCTs will hamper comparison and jeopardise the external validity (generalizability) of their results. We explored the reporting of SES features in RCTs for depression. Methods: We selected 45 antidepressant efficacy trials (AETs) and 19 psychotherapy efficacy trials (PETs). We listed the reported socio-demographic and -economic features. Results: Reporting on SES-features was very diverse and often limited. Especially important SES features like educational level, socio-economic status and income were reported insufficiently. The mean age of RCT participants in MDD trials was 41 years. Participants are predominantly female (62%) and white (89%). Of the participants 61% were employed and 45% of the participants were married/cohabitating. Conclusions: Standardisation of reporting on socio-demographic and socio-economic status is needed to adequately judge the generalizability of RCTs to daily practice and to facilitate comparisons within the body of RCTs in order to move increasingly towards more individualized and person-centered models of clinical practice.

No medication without representation? Generalizing from antidepressant clinical efficacy trials to clinical practice

No medication without representation? Generalizing from antidepressant clinical efficacy trials to clinical practice

The generalizability of antidepressant efficacy trials to routine psychiatric out-patient practice

Generalizability of antidepressant efficacy trials (AETs) to daily practice is questioned because of their very stringent patient selection. This study aims to determine eligibility for AETs of out-patients suffering from major depression in a routine out-patient setting and investigates influence of eligibility on treatment outcome. Data collection (n = 1653) was performed through routine outcome monitoring by independent trained research nurses. The Mini-International Neuropsychiatric Interview Plus and the Dimensional Assessment of Personality Pathology, short Dutch version were used for diagnostic assessment and personality pathology screening. The Montgomery-Asberg Depression Rating Scale (MADRS) was used for assessment of baseline severity and treatment outcome. Eligibility was assessed by stepwise application of commonly used exclusion criteria. Influence of eligibility on treatment outcome was investigated in a subsample of the 1653 patients who had at least one follow-up assessment (n = 626). Eligible and non-eligible patients were compared on proportion of response (50% reduction) and remission on MADRS (MADRS ≤ 10). Altogether, 17-25% of the patients were eligible for AETs. The most common reasons for exclusion would be 'not meeting minimum baseline severity' and 'presence of co-morbid Axis I disorder'. Eligible and non-eligible patients did not differ in treatment outcome. Only 'meeting the minimum baseline severity' is associated with remission. The majority of 'real life' out-patients are not eligible for AETs. However, the influence of eligibility on treatment outcome seems to be small. This suggests that stringent patient selection by eligibility criteria is not the major reason for lack of generalizability of AETs. Exclusion of less severely depressed patients from the analyses resulted in better treatment outcome. Milder depression is highly prevalent in daily practice and more research into treatment effectiveness in milder depression is warranted.

Do Efficacy and Effectiveness Samples Differ in Antidepressant Treatment Outcome?

Because of strict inclusion and exclusion criteria, results drawn from placebo-controlled randomized antidepressant efficacy trials may not be transferable to real-world patients. This study was performed from March 2000 to September 2005 as a prospective, multicenter follow-up. Patients were recruited from February 2000 to June 2005. All patients were hospitalized (N = 1,014) and met DSM-IV criteria for major depressive episode. Assessments with the 21-item Hamilton Depression Rating Scale were conducted biweekly until discharge. According to the most commonly applied exclusion criteria in randomized controlled antidepressant efficacy trials, patients were retrospectively divided into 2 groups: (1) patients not fulfilling exclusion criteria and therefore eligible for a randomized placebo-controlled trial, referred to as "efficacy sample," and (2) patients fulfilling at least 1 exclusion criterion, not being eligible for inclusion in an efficacy trial ("nonefficacy sample"). The efficacy sample was compared with the nonefficacy sample in terms of sociodemographic and clinical baseline variables and outcome measures, such as remission and response rates, 17-item Hamilton Depression Rating Scale mean scores, time to remission, and time to response. Significant differences were found, with the efficacy sample being older (P = .03) and being more often treated at a university hospital (P = .02). The efficacy sample demonstrated superior outcome only in significantly higher mean Global Assessment of Functioning scores at discharge (P = .03). There were no differences regarding remission (P = .68) and response (P = .06) rates, length of hospital stay (P = .49), 17-item Hamilton Depression Rating Scale total score at discharge (P = .13), or time to response (P = .39) or remission (P = .16). Both groups differed significantly in several baseline measures and final Global Assessment of Functioning scores but not in any other outcome measure. Challenging current beliefs, our findings show that results from efficacy antidepressant trials might be more generalizable than previously thought.

Last‐Observation‐Carried‐Forward Imputation Method in Clinical Efficacy Trials: Review of 352 Antidepressant Studies

To determine the prevalence, over 40 years, of using the last-observation-carried-forward (LOCF) imputation method in clinical trials, the association between use of LOCF and how the trials were conducted, and the extent of information about attrition and LOCF use in published reports. Retrospective analysis of the reports of randomized antidepressant efficacy trials published over a 40-year period (1965-2004). MEDLINE database, Cochrane reviews, reference- and bibliography-based manual search, and publication list services. A total of 352 trials met the following criteria for analysis: antidepressant comparative efficacy trial, randomized design, patients with major depressive disorder, English-language article, published during 1965-2004, and first report of a trial. Design, attrition, and data analysis characteristics were recorded by investigators and trained assistants. Analyses included descriptive statistics of the trial size, duration, and number of patients who dropped out in LOCF versus non-LOCF studies, as well as the extent to which dropouts and the potential bias associated with attrition was discussed in the published report. The frequency of published antidepressant clinical trials increased from less than 1 trial/year (1965-1974) to 19 trials/year (1990-1994). Trials using the LOCF method were significantly larger than non-LOCF trials (p<0.01), and the proportion of subjects dropping out was significantly greater (p<0.05) in LOCF versus non-LOCF trials. The proportion of subjects dropping out remained relatively constant over time (approximately 30%) but was significantly greater among LOCF (30.9%) than non-LOCF (28.8%) trials (p<0.01). The LOCF study articles were more likely to report dropouts, but only 7% of these articles reported outcomes recorded for subjects before they dropped out. Less than 16% of articles discussed bias associated with dropouts, 6.8% discussed the direction of bias, and only about 2% suggested the magnitude of the bias. The percentage of clinical antidepressant trials using the LOCF method and the percentage of study subjects' data imputed by using LOCF increased many-fold during 1965-2004. Published reports of trials provided little information to allow readers to assess possible bias introduced by use of the LOCF method.

The antidepressant debate and the balanced placebo trial design: An ethical analysis

There is ongoing debate about whether randomized, placebo-controlled trials under a double-blind have reliably established the pharmacological efficacy of antidepressants. Numerous meta-analyses of antidepressant efficacy trials, e.g., Kirsch et al. [Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. (2002). The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. food and drug administration. Prevention and Treatment, 5, Article 23. (Retrieved July 19, 2007 from http://journals.apa.org/prevention/volume5)], have shown a modest drug-placebo difference but methodological problems with standard trial design preclude a definitive conclusion that this difference results from specific biological effects of antidepressants or the nonspecific factors that have not been adequately excluded. Standard trial design assumes the additivity thesis of pharmacological efficacy, being the assumption that the specific or “true” magnitude of the pharmacological effect is limited to the difference between the drug and placebo responses in a standard trial. If the drug effects are as small as these meta-analyses suggest, then their clinical effectiveness is questionable. If the drug effects are actually larger but masked by placebo effects, then the additivity thesis is not valid and we risk false negative results with standard trial design. Kirsch et al. propose an alternative, four arm balanced placebo trial design (BPTD) that can accurately test the additivity thesis. The BPTD uses antidepressants, active placebos and the intentional deception of research subjects. My focal question is whether the BPTD is ethically defensible. I will explore two objections that can be raised against it: 1) lying to BPTD research subjects violates their autonomy and exploits their illness and 2) the BPTD may not enable us to test the additivity thesis with accuracy, i.e., it may contribute to the masking of drug effects that it aims to avoid. I argue that these objections support the conclusion that the BPTD is ethically indefensible.