Humberto Marin

A controlled trial of antidepressants in patients with Parkinson disease and depression

Background: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care. Methods: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks. Results: Nortriptyline was superior to placebo for the change in HAM-D (p < 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p < 0.079). Response rates favored nortriptyline (p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated. Conclusions: Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors. ARR = absolute risk reduction; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAM-A = Hamilton Anxiety Scale; HAM-D = Hamilton Depression Rating Scale; MMSE = Mini-Mental State Examination; NNT = number needed to treat; PD = Parkinson disease; PDQ = Parkinson’s Disease Questionnaire; PSQI = Pittsburgh Sleep Quality Index; SCID = Structured Clinical Interview; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; UPDRS = Unified Parkinson’s Disease Rating Scale.

Sleep Disturbances in Parkinson's Disease

Sleep disturbances are very common in patients with PD and are associated with a variety of negative outcomes. The evaluation of sleep disturbances in these patients is complex, as sleep may be affected by a host of primary sleep disorders, other primary medical or psychiatric conditions, reactions to medications, aging or the neuropathophysiology of PD itself. In this article, we review the evaluation of the common disturbances of sleep seen in PD. This includes the primary sleep disorders, the interaction of depression and insomnia, the impact that medications for PD have on sleep, as well as the role of factors such as nocturia, pain, dystonia, akinesia, difficulty turning in bed, and vivid dreaming. The treatment of sleep disturbances in PD is largely unstudied but recommendations based on clinical experience in PD and research studies in other geriatric populations can be made. Important principles include, diagnosis, treating the specific sleep disorder or co‐occurring disorder, and control of the motor aspects of PD.

The impact of treatment of depression on quality of life, disability and relapse in patients with Parkinson's disease†

Parkinsons disease (PD) is a common neurodegenerative disease affecting up to one million individuals in the United States. Depression is found in 40 to 50% of these patients and is associated with a variety of poor outcomes for both patients and their families. Despite this, there are few evidence‐based data to guide clinical care. This was an NIH‐funded, randomized, controlled trial of paroxetine, nortriptyline, and placebo. It included an 8 week acute phase and a 16 week blind extension phase. This report details the impact of depression treatment on quality of life (QoL) and disability in the acute and extension phase of this study. Secondary outcomes included relapse, tolerability, safety, and the impact of depression treatment on PD physical functioning. Patients who had improvement in depression, compared with those who did not, had significant gains in measures of QoL and disability (PDQ‐8, P = 0.0001; SF‐36, P = 0.0001) at 8 weeks and maintained their gains in the extension phase. Patients who were on active drug were significantly less likely to relapse in the extension phase than those on placebo (P = 0.041). Though relatively modest in size, this trial provides the first controlled data on the impact of treatment of depression on QoL and disability in PD. It suggests that successfully treating depression in PD leads to important, sustained improvements in these outcomes and that patients who improve on antidepressants are less likely to relapse than are patients who initially improve on placebo.

Treatment of insomnia in Parkinson's disease: A controlled trial of eszopiclone and placebo†

Parkinsons disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Sleep disturbances, typically in sleep maintenance, are found in up to 88% of these individuals and are associated with a variety of poor outcomes. Despite being common and important, there are few data to guide clinical care. We conducted a 6‐week, randomized, controlled trial of eszopiclone and placebo in 30 patients with PD and insomnia. Patients with other primary sleep disorders (PSG defined) were excluded. The primary outcome was total sleep time (TST), and secondary measures included wake after sleep onset (WASO), number of awakenings, and quality of sleep, among others. The groups did not significantly differ on TST, but significant differences, favoring eszopiclone, did emerge in number of awakenings (P = 0.035), quality of sleep (P = 0.018), and in physician‐rated CGI improvement (P = 0.035). There was also a trend toward significance in WASO (P = 0.071). There were no significant differences between groups in measures of daytime functioning. The drug was well tolerated, with 33% of patients on eszopiclone and 27% of patients on placebo reporting adverse events. Although modest in size, this is the first controlled study of the treatment of insomnia in patients with PD. Eszopiclone did not increase TST significantly but was superior to placebo in improving quality of sleep and some measures of sleep maintenance, which is the most common sleep difficulty experienced by patients with PD. Definitive trials of the treatment of sleep disorders in this population are warranted.

Depression and Sexual Functioning in Minority Women: Current Status and Future Directions

Despite the increasing number of non-Caucasians in the United States, the overwhelming majority of research into both depression and sexuality has been conducted with European-American (Caucasian) samples. Sexual dysfunction and depression often co-occur, impacting relationship satisfaction, quality of life, and treatment adherence. These issues may be particularly salient for African-American, Hispanic, and Asian-American women, yet this area of research has been relatively unexplored. Cultural factors may shape womens response to sexual dysfunction, resulting from the depression itself as well as antidepressant medication. Further research emphasizing gender and culture is needed to elucidate the prevalence, impact, and treatment of sexual dysfunction in specific groups of depressed minority women.

Ramelteon for the treatment of insomnia in menopausal women

Objective Sleep disturbances have been reported to be one of the most troubling manifestations of menopause. While hormone replacement therapy (HRT) has historically been considered a first-line treatment for menopausal insomnia, many women are now seeking alternative treatments due to concerns about the risks and side-effects of HRT. The goal of this study was to evaluate the effect of ramelteon, a selective melatonin receptor agonist, for the treatment of menopausal insomnia. Study design A total of 20 healthy peri- and postmenopausal women with insomnia participated in this six-week, prospective, open-label trial of ramelteon (8 mg) at an academic medical centre. Participants completed sleep–wake diaries on a daily basis for six weeks. Self-report measures of sleep impairment, daytime functioning, quality of life and mood were also completed on a bi-weekly basis. Results Significant improvements in latency to sleep onset, total sleep time and sleep efficiency were observed in diary data while gains in sleep quality, sleep impairment, daytime functioning, quality of life and mood were found in self-report measures. There was no evidence of tolerance or rebound over the course of the trial. Conclusions Overall, results suggest that ramelteon is an effective non-hormonal approach for the treatment of insomnia in menopause. Randomized-controlled trials are needed to further evaluate the efficacy of this intervention.

Depression in Parkinson's Disease: Symptom Improvement and Residual Symptoms After Acute Pharmacologic Management

OBJECTIVE Parkinsons disease (PD) is frequently complicated by depression and there is a paucity of controlled research that can inform the management of this disabling nonmotor complaint. A randomized controlled trial of nortriptyline, paroxetine, and placebo for the treatment of depression in PD (dPD) was recently completed. The purpose of this article is to describe the baseline pattern of depressive symptom presentation in PD, the specific symptoms of dPD that improve with pharmacotherapy, and the residual symptoms that remain in patients who meet a priori criteria for response or remission after acute treatment (8 weeks). SETTING The Departments of Psychiatry and Neurology at Robert Wood Johnson Medical School, New Jersey. PARTICIPANTS : Fifty-two depressed patients (major depression or dysthymia based on Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria) with Parkinsons disease (by research criteria). DESIGN/INTERVENTION A randomized controlled trial of nortriptyline, paroxetine, and placebo. MEASUREMENT The four subscales (core mood, anxiety, insomnia, and somatic) and individual items from the Hamilton Rating Scale for Depression-17 were the focus of this study. These measures were assessed at baseline and Week 8. RESULTS Baseline depressive symptoms were unrelated to motor functioning. Treatment response was associated with significant improvements in the core mood, anxiety, insomnia, and somatic symptoms seen in dPD. Residual symptoms, such as sadness and loss of interest, persisted in treatment responders in a milder form than was initially present. CONCLUSIONS Antidepressants may influence all symptoms of dPD, including those that share great overlap with the physical disease process. Additional research regarding adjunctive interventions is needed to help optimize the management of dPD.

Psychopharmacological research ethics: special issues affecting US ethnic minorities

RationaleThis article is intended to explore how minority status and cultural factors affect the participation of subjects in clinical psychopharmacology research.Objectives and methodsA literature review was performed using key words “clinical psychopharmacology trials”, “psychiatric ethics” and “minority groups”. Major goals of this review were to examine current knowledge base and identify existing gaps in this fairly new area of psychiatric research.ResultsWe found extremely few papers addressing the issue directly. Most references to minority groups were made peripherally, and many of these were extrapolated to psychiatric patients from work done on medical populations. We found no empirical studies done in psychiatric populations.ConclusionsSystematic, well-designed research studies are needed to elucidate how culture, race and ethnicity impact on such issues as accrual, retention, informed consent and safeguards against the potential exploitation of minority research subjects. On the basis of the literature review and our personal experience doing clinical research with minority patients, we provide several recommendations and specific suggestions to clinical researchers who include minority patients in their clinical trials.

Bupropion improves sexual functioning in depressed minority women: an open-label switch study.

Minority women often have a unique set of beliefs and expectations about medical treatment. At this time, there is a dearth of research looking at how depressed minority women respond to pharmacological interventions for the sexual concomitants of depression. This was the first study to examine the impact of a medication switch, from a selective serotonin reuptake inhibitor to bupropion SR, on the sexual functioning of depressed minority women. Eighteen minority women (5 Hispanic, 10 African American, 2 Asian American, and 1 Native American), who were experiencing poor tolerability and/or lack of efficacy on an adequate trial of a selective serotonin reuptake inhibitor for depression, along with low sexual desire, were enrolled in this prospective open-label study. The selective serotonin reuptake inhibitor and bupropion SR were cross-tapered with a target dose of 150 to 300 mg of bupropion SR. The patients were followed for 10 weeks, and measures of sexual functioning and depression (Hamilton Rating Scale for Depression) were administered in an academic medical setting. Data were collected from July 2003 to December 2004. In the group as a whole, there were significant improvements in desire (F1,17 = 34.86, P < 0.001), arousal (F1,17 = 25.99, P < 0.001), and orgasm (F1,17 = 20.16, P < 0.001), on the Changes in Sexual Functioning Questionnaire. African-American women demonstrated the greatest improvement in depression (F1,16 = 9.55, P = 0.006), desire (F1,16 = 8.62, P = 0.01), and arousal (F1,16 = 8.83, P = 0.009) after the medication switch. Overall, this intervention appeared to be an effective treatment of low sexual desire in a diverse group of depressed minority women. The majority of women successfully completed the trial and planned to continue using bupropion SR after their participation in the study.

Clinical Psychopharmacology: A Practical Approach

of a recent article.While adjusting to the rigors of a new job, particularly a teaching role, following familiar patterns from residency can feel like a security net. However, a book like Clinical Psychopharmacology: A Practical Approach reminds us of the science behind the medications we use in psychiatry. The book is small in size, with a total of 308 pages, divided into 19 chapters. The earlier chapters cover broad topics like absorption and metabolism of medications, as well as neurotransmitters and receptors. While these chapters are necessarily simplistic, it is important to understand these topics in order to fully comprehend the latter chapters, which discuss classes of medication like antipsychotics, antidepressants, and benzodiazepines. After laying out this groundwork, the authors discuss individual medications and treatments as a whole for certain disorders (i.e., anxiety disorders, mania, bipolar depression, attention disorders, dementia, and alcohol use disorders). The final chapter focuses on drug-drug interactions, with an especially helpful but brief appendix regarding review questions limited to the final chapter. Although thorough, the chapters are further divided into subtopics that at times require jumping back and forth between pages to obtain specific information. The book has multiple tables and charts that are demonstrative and easy to follow. Marin and Escobar analyze relevant studies, including CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study), STAR-D (Sequenced Treatment Alternatives to Relieve Depression), and STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder), among others, using evidencebased recommendations for specific treatments. Less helpful are their “bottom line” recommendations that, at times, seem less feasible to follow. For example, in discussing extrapyramidal symptoms related to antipsychotics, they recommend, “whenever possible, decreasing the antipsychotic dose or switchingmedications rather thanusing adjunctivemedication to control the adverse effects (p. 41).” This would be an ideal recommendation if you are treating a medication-naive patient, or one with few medication trials. I think, however, this recommendation should have been further expanded to discuss when, as often happens, you cannot apply their initial recommendation. I would also have liked to see the authors include a cost comparison between medications. Furthermore, an exploration of the use of these medications in subpopulations would have been helpful. For example, they discuss the use of antidepressants during pregnancy but not antipsychotics, mood stabilizers, or anxiolytics. Recommendations are limited to adults and not for children or adolescents. This bookwill be useful to young trainees, particularlymedical students and residents, and seasoned psychiatrists, as well as beneficial to those in other disciplines, like family practitioners, internists, psychologists, and nurse practitioners. Despite some limitations, Clinical Psychopharmacology is a practical teaching tool that provides updated information on psychotropic medications. It is easy to assign a short reading assignment to trainees that is understandable, succinct, and readily applicable to their everyday clinical practice. As an early-career psychiatrist, I find this book a helpful evidencebased adjunct to my anecdotal experiences during residency. ABBY ORNELAS LOZANO, M.D. Dr. Lozano is affiliated with the Department of Psychiatry, Denver Health Medical Center, as well as the Department of Psychiatry at the University of Colorado School of Medicine, Denver. The author reports no financial relationships with commer-