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 RESEARCH ARTICLE

Excluding the typical patient: Thirty years of pharmacotherapy efficacy trials for obsessive-compulsive disorder

Brian L. Odlaug, MPH

Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Eric Weinhandl, MS

Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota, USA

Maria C. Mancebo, PhD

Butler Hospital, Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA

Erik L. Mortensen, MSc

Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Jane L. Eisen, MD

Butler Hospital, Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA

Steven A. Rasmussen, MD

Butler Hospital, Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA

Liana R. N. Schreiber, BA

School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA

Jon E. Grant, JD, MD, MPH

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, USA

BACKGROUND: Over the past 30 years, clinical trials have resulted in several successful pharmacotherapies for obsessive-compulsive disorder (OCD), yet patients in clinical settings often report inadequate response. This study compares clinical characteristics of treatment-seeking OCD patients to the inclusion/exclusion criteria used in pharmacotherapy trials.

METHODS: The sample consisted of 325 community members with a DSM-IV diagnosis of OCD who underwent systematic interviews with clinicians knowledgeable in the diagnosis and treatment of OCD. We compiled pharmacotherapy studies for OCD published between 1980 and 2010 using Medline, PubMed, and library resources, and estimated the proportion of patients in each decade satisfying the most common inclusion/exclusion criteria.

RESULTS: We included 39 clinical trials and found 72% of the 325 patients would have been excluded from trials conducted between 1980 and 2010. Exclusion was projected as dramatically lower for trials conducted between 1980 and 1989 (19.7%) compared with 74.8% for trials conducted between 1990 and 1999 and 76.9% for trials between 2000 and 2010.

CONCLUSIONS: The majority of treatment-seeking individuals with OCD would not qualify for OCD treatment studies due to comorbid psychiatric disorders, and failure to meet OCD severity threshold criteria. This illustrates the need to include a more community-representative sample of OCD patients in clinical trials examining pharmacotherapy efficacy.

Keywords: obsessive-compulsive disorder, drug therapy, clinical trials, anxiety disorders

ANNALS OF CLINICAL PSYCHIATRY 2014;26(1):39-46

  INTRODUCTION

Obsessive-compulsive disorder (OCD) is a disabling mental illness characterized by recurrent thoughts and repetitive behaviors that are time consuming and cause significant impairment and disability. Prevalence studies have found that more than 2.2 million people in the United States have OCD, and previous research has indicated a prevalence of 1.2% to 3%, although clinical recognition and community awareness of the disorder is quite low.1-6 OCD comprises one of the top causes of global disability according to the World Health Organization.7

Efficacious treatments are available for OCD, including FDA-approved medication. Reviews have demonstrated the efficacy and superiority of the serotonin reuptake inhibitors (SRIs) (clomipramine, paroxetine, fluoxetine, sertraline, and fluvoxamine) to placebo in OCD. A review of 13 pharmacotherapy studies (N=2,697 patients) suggests that patients receiving SRIs were nearly twice as likely as those receiving placebo to achieve clinical response (defined as a ≥25% reduction in symptoms).8 Approximately 40% to 60% of OCD patients respond initially to an SRI.9-11 Factors such as early OCD onset, OCD severity, chronicity of illness, low social functioning, poor insight, comorbid disorders,12-15 and marital status16 all have been associated with a decreased treatment response.17

Questions remain, however, about whether individuals with OCD in the community respond as well to treatment as individuals who enroll in clinical trials. In fact, few studies have assessed the naturalistic course of individuals with OCD in a clinical setting. In 1965, Grimshaw18 reported follow-up information on 100 cases (all treatment-seeking individuals) of “obsessional disorder” and observed that the group receiving no specialized treatment (eg, pharmaco- or psychotherapeutic intervention) improved the most, with 70% reporting satisfactory results at follow-up, which ranged from 6 months to 14 years (mean=5.1±3.4 years).18 More recent studies following patients for 2 to 40 years found full recovery rates ranging from 6% to 42% and partial recovery rates ranging from 28% to 47%, even with medication or psychotherapy.14,16,19,20

The apparent inconsistency in treatment response between controlled studies and naturalistic designs suggests that patients enrolled in controlled studies represent a highly selected subset of treatment-seeking individuals with OCD. Similar research in depression21,22 and cannabis dependence23 has found that clinical trial exclusionary criteria resulted in a patient sample that did not adequately reflect “typical” patients. Because standards of care often are based on the results of research trials, assessment of whether treatment-seeking OCD patients have similar rates of non-representation in clinical pharmacotherapy efficacy trials for OCD is timely and prudent. Understanding the representativeness of clinical efficacy trials for the “typical” patient with OCD comprises a public and clinical health initiative as medicine moves towards better understanding multimodality in treatment settings.24

Aims of the study

This study sought to examine whether the inclusion and exclusion criteria of pharmacotherapy studies conducted from 1980 to 2010 represented the characteristics of the “typical” OCD patient. To accomplish this goal, we compared the clinical characteristics of a large sample of treatment-seeking individuals with OCD to the inclusion/exclusion criteria of a sample of double-blind pharmacotherapy clinical research trials a) conducted over 3 decades 1980 to 2010 and b) between 3 separate time periods (1980 to 1989, 1990 to 1999, 2000 to 2010).

  METHODS

We obtained de-identified data for 325 patients with a diagnosis of DSM-IV OCD from the Brown Longitudinal Obsessive Compulsive Study (BLOCS),11 which is an observational study of a large clinical sample of OCD sponsored by the National Institute of Mental Health. We chose BLOCS for a number of reasons. First, patients had in-person, comprehensive interviews with clinicians knowledgeable in diagnosing and treating OCD. Second, they were followed over a number of years and the sample size (N=325) is relatively large for the OCD population. Further, all patients had a primary diagnosis of OCD and were recruited systematically from multiple treatment settings, aiding in the generalizability of the BLOCS sample to the general population of patients with OCD.25 Finally, the BLOCS study was quite unrestrictive, requiring only that patients 1) be age ≥19; 2) have DSM-IV OCD as their primary diagnosis; 3) be seeking treatment; and 4) have no organic mental disorders or developmental disabilities.25 Patient data for this analysis were obtained from intake interviews conducted from 2001 to 2004 where clinical severity of OCD symptoms was quantified using the Yale-Brown Obsessive Compulsive Scale (YBOCS). Patient referrals for this sample were obtained from a variety of psychiatric settings, including an outpatient OCD clinic, community health clinics, and individual clincians.26 In order to ensure confidentiality of the patients and in the spirit of the hypotheses for this analysis, the age and sex of the patient were the only demographic variables available to the research team conducting this analysis. Study procedures were approved by the institutional review board of Butler Hospital.

Literature review

We obtained articles assessing the efficacy of pharmacotherapy for the treatment of OCD published from 1980 to 2010 through a comprehensive literature search using Medline, PubMed, and the assistance of master’s level library science personnel. Search keywords included, “obsessive-compulsive disorder,” “efficacy,” “pharmacotherapy,” “medication,” “double-blind,” “placebo-controlled,” “clomipramine,” “fluoxetine,” “paroxetine,” “sertraline,” and “fluvoxamine.” We only included the 5 FDA-approved medications indicated for OCD in the literature search. As such, we excluded studies using escitalopram or citalopram exclusively from the literature review. Inclusion/exclusion criteria for these studies were compiled systematically. Two members of our research team reviewed a total of 39 articles reporting results of double-blind efficacy trials for pharmacotherapeutic interventions for patients with OCD to ensure accuracy in the documentation of inclusion and exclusion criterion.

Assessments

Our research team evaluated several initial intake variables of patients:

OCD diagnosis and psychiatric comorbidity were assessed using the Structured Clinical Interview for DSM-IV (SCID).27

Yale-Brown Obsessive Compulsive Scale (YBOCS).28 This is a reliable and valid, 10-item, clinician-administered scale that rates symptom severity over the past 7 days. The YBOCS contains 2 subscales: the first 5 items of the YBOCS comprise the obsessions (urge/thought) subscale (time occupied with urges/thoughts; interference and distress due to urges/thoughts; resistance against and control over urges/thoughts), and items 6 through 10 consist of the compulsion, or “behavior,” subscale. This assesses the time spent engaging in the compulsions, interference and distress due to engaging in the behavior, and the patients’ ability to resist engaging in and controlling their compulsions.

Hamilton Depression Rating Scale (HAM-D).29 This is a valid and reliable, 17-item, clinician-administered rating scale assessing severity of current depressive symptoms.

Butler Hospital OCD database30 is a semi-structured, clinician-rated questionnaire designed to capture patient demographics and the symptoms of OCD. The questionnaire obtains information on course of illness, age of symptom onset, and severity of symptoms over time.

Data analysis

To examine whether efficacy trials for OCD had become more representative over a 30-year period, we separated articles by the decade in which they were published: Group A: 1980 to 1989; Group B: 1990 to 1999; Group C: 2000 to 2010. To determine if each treatment-seeking individual with OCD would have qualified for the treatment efficacy trials, we operationalized the most common inclusion/exclusion criteria as those criteria that were present in ≥65% of the clinical trials assessed.

The most common exclusion criteria for the 9 trials conducted during the period 1980 to 1989 were: 1) duration of OCD illness ≤1 year; 2) presence of a psychotic disorder; and 3) major depressive disorder (MDD).

The most common exclusion criteria for the 30 studies conducted between 1990 and 2010 included the following: 1) lifetime bipolar disorder; 2) lifetime psychotic disorders or schizophrenia; 3) diagnosis of alcohol or drug abuse or dependence within the last 6 months; 4) current MDD; 5) current anxiety disorder (other than OCD); 6) duration of illness <1 year; 7) significant risk of suicide; 8) presence of significant depressive symptoms as determined by a threshold on the HAM-D; and 9) inadequate OCD symptom severity as determined by a threshold score on the YBOCS. HAM-D and YBOCS score exclusion thresholds differed and are explained later in the results. The diagnostic criteria for psychiatric comorbidity were based on DSM-III or DSM-IV criteria.

We estimated the proportion of patients in the BLOCS cohort who satisfied each of these criteria, as well as the proportion of patients who satisfied any criteria. We constructed 95% confidence intervals around proportions with the usual normal approximation method. We also estimated Pearson correlation estimates among the criteria. All analyses were conducted using SAS, version 9.2 (Cary, North Carolina).

  RESULTS

Brown Longitudinal Obsessive Compulsive (BLOCS) study sample

The BLOCS study sample utilized in this study included 325 individuals (mean age 40.1±12.8 years; 54.5% female) with a primary diagnosis of OCD. The chronicity of OCD was found to be substantial across the study sample, with patients reporting a mean duration of illness of 21.6±13.3 years.

Clinical trial exclusion results

Overall Clinical Trial study sample. The mean YBOCS score required for participation across the 39 clinical trials conducted over the past 30 years was 18.1±2 (ie, to be included in the study, patients needed to have a YBOCS score at or above this threshold). The mean HAM-D score allowed for patients was 17.5±1.91 (ie, to be included in the study, patients needed to have a HAM-D score below this threshold). To provide the most conservative estimate of patients that would have been excluded from these studies, we chose an YBOCS cut-off of at least 16 and a HAM-D score of no more than 16 (these fall outside one standard deviation from the mean). In other words, patients reporting YBOCS scores ≤16 or HAM-D scores ≥16 were deemed as excluded.

Our overall results indicate that 72% (95% CI 66.8% to 76.8%) of patients derived from this treatment-seeking OCD sample would have been excluded from the clinical trials included in this assessment (TABLE 1). We found that almost all studies excluded psychotic disorders, including schizophrenia. The presence of a current comorbid anxiety disorder (other than OCD) was the most common criterion by which the sample would be excluded (42.5%). Additionally, 28.9% of the sample had YBOCS scores of ≤16, while 9.8% of the sample had HAM-D scores of ≥16, results that would have excluded them from trial participation.


TABLE 1

Cumulative projected exclusion of 325 patients with OCD for pharmacotherapy safety and efficacy trials conducted between 1980 and 2010

Exclusion criterion % 95% CI
    Lower Upper
Bipolar disordera  3.1% 1.5 5.6
Alcohol or drug abuse 5.2% 3.1 8.2
Psychotic disordera  2.8% 1.3 5.2
Major depressive disorder 16.3% 12.5 20.8
Other anxiety disorder 42.5% 37.0 48.0
Any comorbid conditionb  54.2% 48.6 59.7
OCD duration <1 year 1.8% 0.7 4.0
YBOCS score ≤16 28.9% 24.1 34.2
HAM-D score ≥16 9.8% 6.8 13.6
Any criterion 72.0% 66.8 76.8
aLifetime prevalence.
bAny comorbid condition is an amalgam of the preceding 5 psychiatric conditions.
HAM-D: Hamilton Depression Rating Scale; OCD: obsessive-compulsive disorder; YBOCS: Yale-Brown Obsessive Compulsive Scale.

Correlations between criteria can be found in TABLE 2. Not surprising, HAM-D scores and a diagnosis of MDD shared the highest correlation (r=0.525) with current anxiety disorders, and HAM-D scores also shared a high correlation with MDD (r=0.218). Alcohol or drug abuse and MDD also had a fairly substantial correlation (r=0.158) as did the presence of a psychotic disorder and YBOCS scores of ≤ 16 (r=-0.108)


TABLE 2

Correlation matrix: Exclusionary criteria for pharmacotherapy OCD trials

  Bipolar disorder Alcohol or drug abuse Psychotic disorder Major depressive disorder Other anxiety disorder OCD duration <1 year YBOCS score ≤16 HAM-D score ≥16
Bipolar disorder   0.038 –0.030 –0.079 0.063 –0.024 –0.074 0.061
Alcohol or drug abuse     –0.040 0.158 0.022 –0.032 –0.058 0.108
Psychotic disorder       0.027 –0.069 –0.023 –0.108 –0.056
Major depressive disorder         0.143 0.063 –0.190 0.525
Other anxiety disorder           0.021 –0.109 0.218
OCD duration <1 year             –0.037 –0.045
YBOCS score ≤16               –0.120
HAM-D score ≥16                
HAM-D: Hamilton Depression Rating Scale; OCD: obsessive-compulsive disorder; YBOCS: Yale-Brown Obsessive Compulsive Scale.

Exclusion criteria in study samples, stratified by decade of publication, are described below:

Group A: 1980 to 1989 (TABLE 3)


TABLE 3

Group A: Projected exclusion of 325 OCD patients: Criteria for efficacy trials conducted between 1980 and 1989

Exclusion criterion % 95% CI
    Lower Upper
Psychotic disordera  2.8% 1.3 5.2
Major depressive disorder 16.3% 12.5 20.8
OCD duration <1 year 1.8% 0.7 4.0
Any criterion 19.7% 15.5 24.4
aLifetime prevalence.
OCD: obsessive-compulsive disorder.

We found that studies conducted during this period were fairly representative of symptoms in the naturalistic study sample. Only 19.7% (95% CI 15.5% to 24.4%) of the study sample would have been excluded from these trials. The most common exclusion criterion that would have prohibited study participation was the presence of current MDD (16.3%), followed by the presence of a psychotic disorder (2.8%), and duration of illness of <1 year (1.8%).

Group B: 1990 to 1999 (TABLE 4)


TABLE 4

Group B: Projected exclusion of 325 OCD patients: Criteria for efficacy trials conducted between 1990 and 1999

Exclusion criterion % 95% CI
    Lower Upper
Bipolar disordera  3.1% 1.5 5.6
Alcohol or drug abuse 5.2% 3.1 8.2
Psychotic disordera  2.8% 1.3 5.2
Major depressive disorder 16.3% 12.5 20.8
Other anxiety disorder 42.5% 37.0 48.0
Any comorbid conditionb  54.2% 48.6 59.7
OCD duration <1 year 1.8% 0.7 4.0
YBOCS score ≤17 33.5% 28.4 39.0
HAM-D score ≥17 7.1% 4.5 10.4
Any criterion 74.8% 69.7 79.4
aLifetime prevalence.
bAny comorbid condition is an amalgam of the preceding 5 psychiatric conditions.
HAM-D: Hamilton Depression Rating Scale; OCD: obsessive-compulsive disorder; YBOCS: Yale-Brown Obsessive Compulsive Scale.

The mean YBOCS score required for participation across the 17 clinical trials during this time frame was 17.1±1.8, while the mean HAM-D score was 17.9±1.8. Based upon these means, we chose a cut off of 16 for the YBOCS and 17 for the HAM-D, respectively, as a means of assessing qualification for study participation. With these exclusion criteria, we found that 74.8% (95% CI, 69.7% to 79.4%) of the study sample would have been excluded from trials conducted during this time frame.

Group C: 2000 to 2010 (TABLE 5)


TABLE 5

Group C: Projected exclusion of 325 OCD patients: Criteria for efficacy trials conducted between 2000 and 2010

Exclusion criterion % 95% CI
    Lower Upper
Bipolar disordera 3.1% 1.5 5.6
Alcohol or drug abuse 5.2% 3.1 8.2
Psychotic disordera 2.8% 1.3 5.2
Major depressive disorder 16.3% 12.5 20.8
Other anxiety disorder 42.5% 37.0 48.0
Any comorbid conditionb 54.2% 48.6 59.7
OCD duration <1 year 1.8% 0.7 4.0
YBOCS score ≤19 37.5% 32.3 43.1
HAM-D score ≥16 9.8% 6.8 13.6
Any criterion 76.9% 72.0 81.4
aLifetime prevalence.
bAny comorbid condition is an amalgam of the preceding 5 psychiatric conditions.
HAM-D: Hamilton Depression Rating Scale; OCD: obsessive-compulsive disorder; YBOCS: Yale-Brown Obsessive Compulsive Scale.

The mean YBOCS score required for participation across the 13 clinical trials during this time frame rose slightly to a mean of 19.4±1.8, while the mean allowed HAM-D score decreased to an average of 16.4±1.7. YBOCS cut-off scores of 19 and a HAM-D score of 16 were chosen to assess participant eligibility for trials conducted during this time period. With these exclusion criteria, we found that 76.9% (95% CI 72.0% to 81.4%) of the study sample would have been excluded from trials conducted during this time frame.

  DISCUSSION

This study sought to compare the relationship between the clinical characteristics of a sample of treatment-seeking OCD patients to the inclusion/exclusion criteria of a sample of double-blind pharmacotherapy clinical research trials. The age and sex distribution of our sample, derived from a naturalistic study of OCD patients who underwent comprehensive clinical assessments, is consistent with the characteristics of other OCD patients reported in the literature.4,10 The results of the BLOCS analysis illustrate the chronic nature of illness as patients reported a mean duration of illness of over 21 years.

The first important finding from this study was that, overall, the majority of OCD patients would not qualify for an OCD treatment study for a number of reasons, including the presence of co-occurring psychiatric disorders. The BLOCS sample was particularly useful as a comparison group given the detailed clinical assessment that all patients underwent and the accuracy of diagnosis. This fact may explain why the rates of response to SRIs in clinical trials are, on average, 8 times greater than improvement seen in naturalistic longitudinal studies. This finding highlights the need for treatment trials to include patients who reflect the larger OCD population, as these trials otherwise may give patients distorted expectations for treatment.

The second important finding from this study was that the treatment-seeking patients were more likely to meet inclusion/exclusion criteria for a study 30 years ago than recently. Over the last 30 years of clinical trials, the number of criteria for inclusion/exclusion in efficacy trials for the treatment of OCD has increased. Over the past 20 years, with the adoption of formal scales to quantify OCD symptom severity, OCD symptom severity requirements for clinical trial inclusion have increased (as evidenced by the increased mean threshold of YBOCS scores required for trial inclusion) while tolerance of depressive diagnoses and symptoms have decreased (as evidenced by using high scores on the HAM-D to exclude subjects). The consequence of these scale inclusions in the past approximately 20 years is evident in our results. While studies from 1980 to 1989 were fairly inclusive (19.7% of our sample would have been excluded), trials conducted over the past 20 years have been much more restrictive, indicating that approximately 75% of OCD patients would have been excluded for clinical trials.

Similar examinations of clinical trial exclusionary criteria in depression research revealed results that were comparable to our OCD study. Studies by Zimmerman and colleagues22 and Zetin and Hoepner21 of psychiatric outpatients seeking treatment for depression have found that >91% presenting for outpatient treatment for depression would have been excluded from participation in antidepressant efficacy trials. Similarly, Okuda and colleagues23 found that >80% of a community sample of Cannabis-dependent adults would have been excluded from Cannabis treatment efficacy trials.

These findings can be interpreted in many ways. Increasing the threshold for YBOCS scores arguably yields a more clinically severe OCD patient and, if treated successfully by the clinical trial in which they are enrolled, provides a significant finding for the treatment of a more severe presentation of OCD. Discovering pharmacotherapeutic options for severe OCD presentation is of vital importance. However, research indicates that OCD co-occurs at a high rate with other psychiatric disorders and it is unlikely that those with a more clinically severe form of OCD have minimal or non-existent psychiatric comorbidity. Studies have consistently shown high rates of co-occurring depression (36.8% to 56%), bipolar disorder (6% to 21.5%), generalized anxiety disorder (14% to 31.4%), panic disorder (10.2% to 22.1%), and specific phobia (15.1% to 22%) in large samples of patients with OCD.1,6,31-35 Pallanti et al31 asserts that, based on prior research and at the time of presentation for treatment, at least one-third of patients with OCD have co-occurring MDD. With such high rates of current co-occurring psychiatric conditions in the OCD populations, clinical trials established to treat patients with OCD may wish to soften their inclusion criteria to include a more community-representative sample of patients; the disease has been shown to negatively impact the overall health and psychosocial function of patients across their entire lifespan.32-36

There also are potential implications for clomipramine, the more commonly used and longest-studied medications in the treatment of OCD.37 We found that, in general, the clinical trials from 1980 to 1989—which were largely clomipramine trials—did not require that participants meet certain severity threshold requirements for inclusion, nor did they exclude patients based upon scale scores for depression. Most of these studies only required a primary DSM-III diagnosis of OCD in the absence of psychosis. Clomipramine may be regarded as one of the most useful pharmacotherapeutic options for OCD because these clinical trials arguably included more typical OCD patients.

Because this study only examined pharmacotherapy studies published from 1980 to 2010 and did not include pharmacotherapy plus cognitive-behavioral therapy (CBT) or mono-psychotherapy studies, our results and the interpretation of these results are limited. Future research may wish to examine CBT studies or combination treatments (pharmacotherapy plus CBT) in a similar methodology because CBT is a proven and effective first-line treatment for OCD.38,39

  CONCLUSIONS

This study illustrates the ability of patients with a severe and disabling mental health condition, OCD, to qualify for clinical trials established to test the efficacy of treatments for their disorder. We found that an extremely high percentage of individuals with OCD would have been excluded from these trials. With such high rates of non-responsiveness, incomplete symptom management, and treatment discontinuation in this population, stakeholders in the clinical trial industry may wish to critically examine their inclusion/exclusion criteria in order to develop more efficacious and representative first-line treatments for OCD. In particular, the exclusion of patients with comorbid psychiatric conditions may be too extreme in the examination of potential treatment options. The adaptation of clinical trials to include more community-representative individuals with OCD, as done in “practical” clinical trials,40 may enhance the effectiveness of pharmaco- and psychotherapeutic interventions for individuals with OCD and other mental illness.

ACKNOWLEDGMENTS: This research is supported, in part, by a research grant from the Trichotillomania Learning Center to Mr. Odlaug, and by an American Recovery and Reinvestment Act (ARRA) grant from the National Institute on Drug Abuse (1RC1DA028279-01), a Center for Excellence in Gambling Research grant by the National Center for Responsible Gaming (NCRG) to Dr. Grant, and a grant from the National Institute of Mental Health to Dr. Rasmussen (1R01MH0602018).

DISCLOSURES: Mr. Odlaug has received research grants from the Trichotillomania Learning Center, is a consultant for Lundbeck Pharmaceuticals, and has received honoraria and royalties from Oxford University Press. Dr. Mancebo has received research support from the National Institute of Mental Health (K23MH091032-02). Drs. Rasmussen and Eisen have received research support from the National Institute of Mental Health (R01MH0602018). Dr. Grant has received research grants from the National Institute on Drug Abuse (1RC1DA028279-01), the National Center for Responsible Gaming, Forest Pharmaceuticals, Psyadon Pharmaceuticals, Roche Pharmaceuticals, Transcept Pharmaceuticals, and the University of South Florida. He serves as the Editor-in-Chief of the Journal of Gambling Studies. Mr. Weinhandl, Mr. Mortensen, and Ms. Schreiber report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: Brian L. Odlaug, MPH Department of Public Health, Faculty of Health and Medical Sciences University of Copenhagen Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark E-MAIL: brod@sund.ku.dk