Lori L. Davis

The role and interpretation of pilot studies in clinical research.

Pilot studies represent a fundamental phase of the research process. The purpose of conducting a pilot study is to examine the feasibility of an approach that is intended to be used in a larger scale study. The roles and limitations of pilot studies are described here using a clinical trial as an example. A pilot study can be used to evaluate the feasibility of recruitment, randomization, retention, assessment procedures, new methods, and implementation of the novel intervention. A pilot study is not a hypothesis testing study. Safety, efficacy and effectiveness are not evaluated in a pilot. Contrary to tradition, a pilot study does not provide a meaningful effect size estimate for planning subsequent studies due to the imprecision inherent in data from small samples. Feasibility results do not necessarily generalize beyond the inclusion and exclusion criteria of the pilot design. A pilot study is a requisite initial step in exploring a novel intervention or an innovative application of an intervention. Pilot results can inform feasibility and identify modifications needed in the design of a larger, ensuing hypothesis testing study. Investigators should be forthright in stating these objectives of a pilot study. Grant reviewers and other stakeholders should expect no more.

Major depression and comorbid substance use disorders

Purpose of review The presentation of major depressive disorder is often complicated by the co-occurrence of substance use disorders, such as alcohol and illicit drug abuse or dependence. The article reviews the recent systematic research on the distinguishing baseline characteristics including demographic characteristics and the influence of family history, and clinical features such as depressive symptomatology and suicidal ideation, and the outcome of treatment for depression in patients with comorbid major depressive disorder and substance use disorders. The review also addresses the possible explanations cited in the literature as to why these two disorders tend to co-occur and the implications of the comorbidity of these illnesses on treatment. Recent findings Nearly one-third of patients with major depressive disorder also have substance use disorders, and the comorbidity yields higher risk of suicide and greater social and personal impairment as well as other psychiatric conditions. Although the treatment of comorbid major depressive disorder and substance use disorders with medication is likely effective, the differential treatment effects based on substance use disorder comorbidity have been understudied. Summary Emerging results of recent studies comparing the outcome of major depressive disorder patients with comorbid major depressive disorder and substance use disorders suggest that there are fewer differential effects based on comorbidity than previously anticipated by older assumptions from smaller, less methodologically rigorous studies.

Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care

Background: People with known risk factors for chronic obstructive pulmonary disease (COPD) are important targets for screening and early intervention. We sought to measure the prevalence of COPD among such individuals visiting a primary care practitioner for any reason. We also evaluated the accuracy of prior diagnosis or nondiagnosis of COPD and identified associated clinical characteristics. Methods: We recruited patients from three primary care sites who were 40 years or older and had a smoking history of at least 20 pack-years. Participants were asked about respiratory symptoms and underwent postbronchodilator spirometry. COPD was defined as a ratio of forced expiratory volume in the first second of expiration to forced vital capacity (FEV1/FVC) of less than 0.7 and an FEV1 of less than 80% predicted. Results: Of the 1459 patients who met the study criteria, 1003 (68.7%) completed spirometry testing. Of these, 208 were found to have COPD, for a prevalence of 20.7% (95% confidence interval 18.3%–23.4%). Of the 205 participants with COPD who completed the interview about respiratory symptoms before spirometry, only 67 (32.7%) were aware of their diagnosis before the study. Compared with patients in whom COPD had been correctly diagnosed before the study, those in whom COPD had been over-diagnosed or undiagnosed were similar in terms of age, sex, current smoking status and number of visits to a primary care practitioner because of a respiratory problem. Interpretation: Among adult patients visiting a primary care practitioner, as many as one in five with known risk factors met spirometric criteria for COPD. Underdiagnosis of COPD was frequent, which suggests a need for greater screening of at-risk individuals. Knowledge of the prevalence of COPD will help plan strategies for disease management.

Selecting Among Second-Step Antidepressant Medication Monotherapies: Predictive Value of Clinical, Demographic, or First-Step Treatment Features

CONTEXT Little is known about selecting among second-step medications for major depressive disorder after intolerance or lack of remission with an initial selective serotonin reuptake inhibitor. OBJECTIVE To determine whether sociodemographic, clinical, or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide. DESIGN An equipoise stratified randomized study. Participants were recruited from July 17, 2001, through April 20, 2004. SETTING Public or private sector primary care (n = 18) and psychiatric care (n = 23) settings across the United States. PARTICIPANTS Representative outpatients aged 18 to 75 years with nonpsychotic major depressive disorder (N = 727). INTERVENTIONS Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d. Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d. Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d. MAIN OUTCOME MEASURES The 16-item Quick Inventory of Depressive Symptomatology, Self-Rated and the Frequency, Intensity, and Burden of Side Effects Rating. RESULTS Remission was more likely among participants who were white, employed, cohabiting or married, or privately insured or who had prior intolerance to citalopram or at least a response to citalopram, and no prior suicide attempts. Remission was less likely among participants with concurrent generalized anxiety, obsessive-compulsive, panic, or posttraumatic stress disorders; social phobia; anxious or melancholic features; or more severe depression. Intolerance was less likely for Hispanic participants, but more likely for participants with previous suicide attempts or intolerance to citalopram. Participants with concurrent substance use were less likely to remit (odds ratio, 0.37) and more likely not to tolerate extended-release venlafaxine. Intolerance to citalopram was associated with intolerance to sertraline (P = .04). CONCLUSIONS Clinical, demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and at least a response to citalopram in the first step. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00021528.

Comprehensive review of the psychiatric uses of valproate

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Concurrent anxiety and substance use disorders among outpatients with major depression: Clinical features and effect on treatment outcome

BACKGROUND Depressed patients often present with comorbid anxiety and/or substance use disorder. This report compares the four groups defined by the disorders (anxiety disorder, substance use disorder, both, and neither) in terms of baseline clinical and sociodemographic features, and in terms of outcomes following treatment with citalopram (a selective serotonin reuptake inhibitor). METHODS The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial enrolled 2838 outpatients with non-psychotic major depressive disorder (MDD) from 18 primary and 23 psychiatric care clinics. Clinical and sociodemographic features were assessed at baseline. These baseline features and the treatment outcomes following treatment with citalopram were compared among the four groups. RESULTS Participants with non-psychotic MDD and comorbid anxiety and/or substance use disorder showed several distinctive baseline sociodemographic and clinical features. They also showed greater depression severity; length of illness; likelihood of anxious, atypical or melancholic features; more intolerance/attrition; and worse remission/response outcomes with treatment. Participants with either anxiety or substance use disorder showed outcomes generally intermediate between those with both and those with neither. CONCLUSIONS Comorbid anxiety and/or substance use disorder are clinically identifiable, and their presence may define distinct MDD subgroups that have more problems and worse pharmacological treatment outcomes. They may benefit from more aggressive, multi-faceted treatment and psychosocial rehabilitation targeted at reducing their psychological comorbidity and functional impairment.

Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

BACKGROUND Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. METHODS The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3beta. RESULTS The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. CONCLUSIONS Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.

Substance use disorder comorbidity in major depressive disorder: a confirmatory analysis of the STAR*D cohort

The demographics and clinical features were compared between those with (29.4%) and without concurrent substance use disorder (SUD) in 2541 outpatients with major depression (MDD) enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Compared to those without SUD, MDD patients with concurrent SUD were more likely to be younger, male, divorced or never married, and at greater current suicide risk, and have an earlier age of onset of depression, greater depressive symptomatology, more previous suicide attempts, more frequent concurrent anxiety disorders, and greater functional impairment (p = 0.048 to <0.0001). They were also less likely to be Hispanic and endorse general medical comorbidities (p = 0.006 and 0.002, respectively).

Baclofen Treatment for Chronic Posttraumatic Stress Disorder

OBJECTIVE: Previous studies have shown the efficacy of γ-aminobutyric acid B (GABAB) receptor agonists in treating anxiety in patients with panic disorder and in treating depression and anxiety in alcoholic patients. We hypothesized that baclofen, a GABAB agonist, would be an effective treatment in the symptomatic management of veterans with chronic posttraumatic stress disorder (PTSD). METHODS: Fourteen male veterans with chronic, combat-related PTSD were enrolled in an open-label, 8-week, monotherapy trial of baclofen titrated to a maximum of 80 mg/d in 3 divided doses. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS), and secondary outcome measures included the Hamilton Rating Scale for Anxiety, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning Scale, and the Clinical Global Impressions. RESULTS: In the 11 patients who completed the 8-week trial, the mean total CAPS score decreased significantly from baseline (from 82.9 ± 16.1 to 63.5 ± 21.2). The avoidance and hyperarousal subscales showed significant decreases (from 36.2 ± 6.2 to 26.5 ± 9.6 and from 31.9 ± 6.5 to 22.1 ± 7.1, respectively), whereas the re-experiencing subscale remained unchanged. Significant improvements were also noted on all secondary outcome measures. Treatment response was noted within the first 4 weeks of treatment and was maintained throughout the trial. Baclofen therapy was well tolerated, as only 1 patient dropped out due to adverse effects. CONCLUSIONS: Baclofen therapy was effective in treating both the PTSD symptoms and accompanying depression and anxiety in patients with chronic PTSD due to combat. Larger, double-blind, placebo-controlled studies are needed to confirm the efficacy of baclofen in the treatment of PTSD.

Clonazepam for Treatment of Sleep Disturbances Associated with Combat-Related Posttraumatic Stress Disorder

BACKGROUND: Clonazepam is widely used for the treatment of posttraumatic stress disorder (PTSD)—related sleep disturbances despite very limited published data supporting its use for this indication. OBJECTIVE: We conducted a pilot-controlled trial to provide more data on this clinical practice and lay the foundation for more definitive studies. METHODS: The study was designed as a randomized, single-blind (ie, patient only), placebo-controlled, crossover clinical trial involving administration of clonazepam 1 mg at bedtime for one week followed by 2 mg at bedtime for one week. The following week served as a washout period before the alternate treatment was begun. Patients completed sleep diaries each morning upon awakening throughout the study. Parameters included quantity of sleep, quality of sleep, frequency and intensity of difficulty falling or staying asleep, and frequency and intensity of recurrent distressing dreams. RESULTS: Six patients with combat-related PTSD participated in the study. There were no statistically significant differences between clonazepam and placebo for any measure, although clonazepam therapy resulted in mild to moderate numeric improvements in difficulty falling or staying asleep. Adverse effects of clonazepam were generally mild and essentially indiscernible from those attributed to placebo. Only one patient elected to receive further treatment with clonazepam at the conclusion of the trial. CONCLUSIONS: Clonazepam therapy was largely ineffective in improving sleep disturbances, particularly nightmares, associated with combat-related PTSD. The small sample size was a significant limitation of this study, but the prospective design and single-blind, placebo-control parameters were strengths. Further studies are needed to further define the role of this widespread clinical practice.