Matthew Menza

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.

Parkinson's disease and anxiety: Comorbidity with depression

Parkinsons disease (PD) is frequently accompanied by symptoms of depression and anxiety. However, the relationship between anxiety and depression has not been rigorously defined in these patients. In this study, 42 patients with PD and 21 matched medical controls were evaluated using DSM-III-R criteria and a variety of psychiatric rating scales. Twelve (29%) PD patients but only one medical control had a formal anxiety disorder diagnosis. Of the 12 patients with PD who had an anxiety disorder diagnosis, 11 (92%) had a comorbid depressive disorder diagnosis. Of the 18 patients with a depressive disorder, 12 (67%) also had an anxiety disorder diagnosis. Furthermore, a stepwise regression analysis found that the depression measure explained 44% of the variance in anxiety measures whereas neither the severity of illness variables nor the levodopa dose contributed significantly to the variance. This study suggests that the excess anxiety found in PD patients is unlikely to be primarily a psychologic reaction to the illness or a side effect of levodopa treatment. Rather, we suggest that anxiety and depression are related manifestations of the underlying neurochemical changes of PD itself.

Dopamine‐related personality traits in Parkinson's disease

Studies suggest that Parkinsons disease (PD) is associated with a particular group of personality characteristics. With relative uniformity, PD patients are described as industrious, rigidly moral, stoic, serious, and nonimpulsive. In this controlled study, we used a recently developed personality questionnaire, Cloningerss Tridimensional Personality Questionnaire, to test the hypothesis that these personality traits are behavioral manifestations of damaged dopaminergic pleasure and reward systems. We found significantly less (p < 0.01) of a group of traits called ‘novelty seeking’ in PD patients compared with matched medical controls. Patients with low novelty seeking are described as being reflective, rigid, stoic, slow-tempered, frugal, orderly, and persistent, characteristics similar to those in the clinical description of PD patients. We review evidence supporting the claim that novelty seeking is dopamine-dependent, and suggest that damage to the mesolimbic dopaminergic system causes the described personality profile of PD patients.

Cognitive-behavioral therapy for depression in Parkinson's disease: a randomized, controlled trial.

OBJECTIVE Despite the negative effects of depression in Parkinsons disease, there is currently no evidence-based standard of care. The purpose of this study was to examine the efficacy of individually administered cognitive-behavioral therapy (CBT), relative to clinical monitoring (with no new treatment), for depression in this medical population. METHOD Eighty depressed (based on DSM-IV criteria) patients with Parkinsons disease participated in a randomized, controlled trial of CBT relative to clinical monitoring (1:1 ratio) in an academic medical center from April 2007 to July 2010. All patients continued to maintain stable medication regimens under the care of their personal physicians. The 17-item Hamilton Depression Rating Scale (HAM-D) total score was the primary outcome. CBT was modified to meet the unique needs of the Parkinsons disease population and provided for 10 weeks. Assessments were completed by blind raters at baseline and 5 (midpoint), 10 (end of treatment), and 14 weeks (follow-up evaluation) postrandomization. RESULTS The CBT group reported greater reductions in depression (change in HAM-D score) than the clinical monitoring group. At week 10, the mean HAM-D score change was 7.35 for CBT relative to 0.05 for clinical monitoring. CBT was also superior to clinical monitoring on several secondary outcomes (i.e., Beck Depression Inventory scores, anxiety, quality of life, coping, Parkinsons disease symptom ratings). There were more treatment responders in the CBT group than the clinical monitoring group (56% versus 8%, respectively). CONCLUSIONS CBT may be a viable approach for the treatment of depression in Parkinsons disease. Further research is needed to replicate and extend these findings.

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.

Quality of life, mood, and sexual function: a path analytic model of treatment effects in men with erectile dysfunction and depressive symptoms.

Erectile dysfunction (ED) is commonly associated with depressed mood and diminished quality of life (QoL), but few studies have investigated the causal associations involved. Therefore, we evaluated the correlation between several measures of mood, QoL, and sexual function in a retrospective analysis of a sample of depressed men (n=152), with ED enrolled in a clinical trial of sildenafil citrate (VIAGRA®). Strong correlations were observed at baseline among measures of erectile function (EF), mood, and overall QoL. Significant treatment effects were observed on all three domains, with significant interactions between changes in mood and QoL. Based on multiple regression and path analysis, a model was developed in which EF changes were associated with improved mood and quality of sexual life, which resulted in improved partner satisfaction, family life, and overall life satisfaction. These data suggest that QoL changes associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships.

Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population

A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinsons disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging. Psychiatr Genet 8:41–44 c 1998 Lippincott-Raven Publishers.

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.

Telephone-Based Cognitive–Behavioral Therapy for Depression in Parkinson Disease

Background: Although face-to-face cognitive–behavioral therapy (CBT) was found to be beneficial for the treatment of depression in Parkinson disease (dPD) in a recent randomized-controlled trial, access to care was identified as a critical issue that needs to be addressed in order to improve the management of this nonmotor complication in PD. The purpose of this study was to examine the feasibility and effect of telephone-based CBT for dPD. Methods: Twenty-one depressed people with PD participated in a National Institutes of Health–sponsored uncontrolled pilot trial of telephone-based CBT in an academic medical center from October 2009 to February 2011. The Hamilton Depression Rating Scale was the primary outcome. Treatment was provided to people with PD for 10 weeks, modified for delivery over the phone, and supplemented with 4 separate phone-based caregiver educational sessions. Assessments were completed at baseline and 5 (midpoint), 10 (end-of-treatment), and 14 weeks (follow-up) post-enrollment. Results: Twenty (95%) people with PD completed the study treatment. Phone-based CBT was associated with significant improvements in depression, anxiety, negative thoughts, and coping. Mean Hamilton Depression Rating Scale change from baseline to week 10 was 7.91 points (P < .001, Cohen d = 1.21). Conclusions: Telephone-based CBT may be a feasible and helpful approach for treating dPD and warrants further exploration in randomized-controlled trials. Results were comparable to those observed in the few in-person cognitive–behavioral treatment studies for dPD conducted to date.