Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients.

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.

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.

Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate.

OBJECTIVE: Depressed men commonly have erectile dysfunction, and men with erectile dysfunction are frequently depressed. Since the etiologic and modulatory relationships between depression and erectile dysfunction have been poorly characterized, a 12-week, randomized, double-blind, placebo-controlled trial was conducted at 20 urologic clinics to evaluate the effects of sildenafil treatment in men with erectile dysfunction and mild-to-moderate comorbid depressive illness. METHOD: Men (N=152, mean age=56 years) with erectile dysfunction for > or =6 months (mean=5.7 years), a DSM-IV diagnosis of depressive disorder not otherwise specified, and a Hamilton Depression Rating Scale score > or =12 (mean at baseline=16.9) were randomly assigned to flexible-dose treatment with sildenafil citrate or matching placebo. Interviewer-rated and self-report instruments were used to assess changes in sexual function, depressive symptoms, and quality of life. Conservative criteria were used to classify erectile dysfunction treatment response and nonresponse. RESULTS: Sildenafil was strongly associated with erectile dysfunction treatment response. Fifty-eight men met the conservative criteria for response (48 given sildenafil, 10 given placebo), and 78 men did not respond (18 given sildenafil, 60 given placebo). Mean decreases of 10.6 and 2.3 in Hamilton depression scale scores were seen in treatment responders and nonresponders, respectively; 76% of treatment responders showed a > or =50% decline in Hamilton depression scale score versus 14% of nonresponders. Quality of life was similarly improved in treatment responders. CONCLUSIONS: Sildenafil is efficacious for erectile dysfunction in men with mild-to-moderate depressive illness. Improvement of erectile dysfunction is associated with marked improvement in depressive symptoms and quality of life.

Treatment of somatization disorder with nefazodone: a prospective, open-label study.

Somatization disorder (SD) is commonly seen in medical clinics and is associated with significant impairment in functioning as well as excessive utilization of health care. While antidepressants have been studied in some functional somatic syndromes such as fibromyalgia and chronic fatigue, there are no pharmacologic treatment studies of SD itself. In this prospective, 8-week, open-label study, 15 patients diagnosed with either full SD or abridged somatization, by Escobar's criteria (four unexplained physical symptoms for men or six for women), were given nefazodone, titrated to 150 mg bid. The primary outcomes included measures of physical symptom severity (visual analogue scale), functioning (SF-36), and overall improvement (CGI). Fourteen of the 15 patients achieved the target dose of 300 mg/day and completed the trial. 73% of the patients were rated as improved on the CGI, 79% improved on the self-rated visual analogue scale and 73% of the patients improved on the SF-36. There was significant improvement for the whole group (prepost) on the SF-36, as well as on the HAM-D and the HAM-A. Of the nine patients with a categorical depression diagnosis, 55% of them were rated as improved on the CGI, and 67% improved on both the VAS and the SF-36. Of the six nondepressed patients, 67% were rated as improved on the CGI, 83% improved on the SF-36, and 50% improved on the VAS. Adverse events were generally mild and resulted in only one discontinuation. Although these data need to be confirmed in a larger, double-blind, placebo-controlled trial, they suggest that patients with SD will accept and tolerate therapy with nefazodone and that nefazodone may be a useful treatment for these patients.

The personality associated with Parkinson's disease.

Since at least 1913 reports have suggested there are personality traits and behaviors that are found premorbidly in those who go on to develop Parkinson's disease (PD). This premorbid personality consists of traits such as industriousness, punctuality, inflexibility, cautiousness, and lack of novelty seeking and persists after the onset of the motor illness. The existence of this personality remains controversial but is supported by case-based anecdotes, twin studies, and comparison of patients with PD with medical control patients on standardized instruments. In addition a large number of epidemiologic studies show that people who develop PD have low lifetime risks for cigarette smoking, coffee drinking, and alcohol consumption, again suggesting that there is a behavior pattern that predates PD. Despite the retrospective nature of much of these data, the use of nonstandardized instruments, and diffuse concepts of personality, the great majority of studies show striking similarity in identifying these traits. An integrating hypothesis, involving damage to dopaminergic systems, known to predate the onset of the motor illness, is discussed.

Modafinil augmentation of antidepressant treatment in depression.

BACKGROUND: Despite a relative lack of controlled data, stimulants are often used to augment antidepressant treatment in patients who have had only a partial response to first-line therapy. Modafinil is a novel psychostimulant that has shown efficacy in, and was recently marketed for, treating excessive daytime sleepiness associated with narcolepsy. The mechanism of action of modafinil is unknown, but, unlike other stimulants, the drug is highly selective for the central nervous system, has little effect on dopaminergic activity in the striatum, and appears to have a lower abuse potential. METHOD: In this retrospective case series, we describe 7 patients with DSM-IV depression (4 with major depression and 3 with bipolar depression) for whom we used modafinil to augment a partial or nonresponse to an antidepressant. The Hamilton Rating Scale for Depression was administered as part of routine clinical practice prior to treatment and at each subsequent visit. RESULTS: At doses of 100 to 200 mg/day, all 7 patients achieved full or partial remission, generally within 1 to 2 weeks. All patients had some residual tiredness or fatigue prior to starting modafinil, and this symptom was particularly responsive to augmentation. Side effects were minimal and did not lead to discontinuation of the drug in any of the patients. CONCLUSION: Modafinil appears to be a drug with promise as an augmenter of antidepressants, especially in patients with residual tiredness or fatigue. It is a particularly attractive alternative to other stimulants because of its low abuse potential and Schedule IV status.

Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease.

There are many difficulties associated with the late stages of Parkinson's disease (PD), but psychosis and agitation may be the most disturbing for both patients and care givers, and often precipitate the pivotal decision for long-term nursing home placement. While the addition of antipsychotic drugs or the withdrawal of antiparkinsonian drugs may improve the behavioral problem, these strategies usually worsen the motor difficulties. Clozapine has been studied in PD for over a decade, and while it appears to be effective, there are safety and tolerability concerns associated with it. In addition, in New Jersey, Medicaid no longer pays for the home blood draws that are required for home-bound patients. This led to a situation in which we had patients who needed to stop clozapine and begin an alternative therapy. Because quetiapine seems particularly well suited to patients with PD based on in vitro and in vivo studies we have begun to try this medication in PD patients who need to stop clozapine. This article reports three case histories of patients with PD, confusion and dopamimetic psychosis who had been previously managed with clozapine and who were successfully switched to quetiapine. At doses from 12.5 to 150 mg/day quetiapine was well tolerated, resulting in behavioral improvement and no real increase in parkinsonism. These case histories raise the possibility that quetiapine may represent a viable alternative to clozapine in PD patients with dopamimetic psychosis and behavioral disturbances.

Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter.

Recently, a functional polymorphism in the promoter region of the serotonin transporter gene has been linked to anxiety. In cell culture, the short allele of this polymorphism synthesizes less serotonin transporter, resulting in a reduction of the removal of serotonin from the synaptic cleft. This pilot study examines depression and anxiety in Parkinson's disease patients as a function of the variation in this polymorphism. Thirty-two patients were genotyped and then blindly administered the Hamilton Depression and Anxiety Scales. Clinical data on the neurologic features of the disease were also gathered. Patients with the short allele of the serotonin transporter promotor scored significantly higher on both the depression and anxiety measures. There were no differences between groups for any neurologic variable. Patients with the short allele were more likely to have scores for anxiety and depression that indicated "caseness." This study suggests that the short allele of the serotonin transporter gene may represent a significant risk factor for the development of anxiety and depression in Parkinson's disease patients.

Effects of SSRIs on sexual function: a critical review.

Sexual problems are highly prevalent in both men and women and are affected by, among other factors, mood state, interpersonal functioning, and psychotropic medications. The incidence of antidepressant-induced sexual dysfunction is difficult to estimate because of the potentially confounding effects of the illness itself, social and interpersonal comorbidities, medication effects, and design and assessment problems in most studies. Estimates of sexual dysfunction vary from a small percentage to more than 80%. This article reviews current evidence regarding sexual side effects of selective serotonin reuptake inhibitors (SSRIs). Among the sexual side effects most commonly associated with SSRIs are delayed ejaculation and absent or delayed orgasm. Sexual desire (libido) and arousal difficulties are also frequently reported, although the specific association of these disorders to SSRI use has not been consistently shown. The effects of SSRIs on sexual functioning seem strongly dose-related and may vary among the group according to serotonin and dopamine reuptake mechanisms, induction of prolactin release, anticholinergic effects, inhibition of nitric oxide synthetase, and propensity for accumulation over time. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including waiting for tolerance to develop, dosage reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies with 5-hydroxytryptamine-2 (5-HT2), 5-HT3, and alpha2 adrenergic receptor antagonists, 5-HT1A and dopamine receptor agonists, and phosphodiesterase (PDE5) enzyme inhibitors. Sexual side effects of SSRIs should not be viewed as entirely negative; some studies have shown improved control of premature ejaculation in men. The impacts of sexual side effects of SSRIs on treatment compliance and on patients' quality of life are important clinical considerations.

Association of long variants of the dopamine D4 receptor exon 3 repeat polymorphism with Parkinson's disease.

The dopamine D4 receptor (D4DR) has a highly polymorphic region in the third exon which has been associated with novelty seeking (NS) behavior. Due to the central position of dopamine and the documented low NS in Parkinson's disease (PD), the frequency of the exon 3 variants of D4DR in 95 PD patients and 47 controls was investigated. A significantly higher frequency of exon 3 alleles with six or more repeat units was found in the PD group (p = 0.039). This provides evidence that some forms of the highly polymorphic D4DR may represent a genetic susceptibility factor for PD.

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 Parkinson's 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.

Psychiatry in the geriatric neurology practice.

This article provides a brief overview of the psychiatric syndromes most common in the elderly patient, as well as those most frequently accompanying neurologic disease. Diagnosis, work up, and treatment of depressive, psychotic, and anxiety disorders are also reviewed. This article is directed toward the practicing neurologist, with an emphasis on detection and treatment. Special attention is paid to psychiatric syndromes that accompany Parkinson's disease, stroke, and dementia. A brief review of the most common psychopharmacological agents is included as well.

Clozapine for the treatment of psychosis in Parkinson's disease: chart review of 49 patients.

The records of 49 patients with Parkinson's disease and psychosis who were treated with clozapine for up to 18 months were reviewed. Average starting dose of clozapine was 16 mg. Average maximum dose was 39 mg. The psychotic symptoms improved in 76% of the patients at 3 months, and response to clozapine within the first year ranged from 71% to 80%. This response allowed a maximization of levodopa dose. Improvements in scores on the Unified Parkinson's Disease Rating Scale and tremor subscale were seen in some patients but were not statistically significant. This study, the largest of its kind to date, suggests that clozapine is well tolerated and effective in treating psychosis in patients with Parkinson's disease.

Psychiatric symptoms in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is an unusual neurodegenerative disorder that superficially resembles Parkinson's disease (PD). It is characterized by gaze palsy, bulbar signs, parkinsonian signs, and mental changes. While mental changes are a frequent finding, they have, with the exception of dementia, been poorly defined. In this study, 19 patients with PSP were evaluated psychiatrically and compared with 42 patients with PD. Fifty-two percent of the patients had some degree of dementia, as measured by the Mini-Mental State Exam. Eight (42%) of the PSP patients had other psychiatric diagnoses, mostly relatively mild depression or anxiety, though two patients had more severe depression. Six (32%) patients had pathologic laughing or crying, and four of these had a psychiatric diagnosis other than dementia. The PSP patients did not differ from the PD patients on measures of depression or anxiety and did not have a greater rate of formal psychiatric diagnoses. This study confirms previous reports of dementia as a common feature of PSP. It further suggests that psychiatric disturbances, while common, are generally relatively mild, though more serious psychiatric illness may be seen.

Sleep in Parkinson's disease. The role of depression and anxiety.

Sleep disorders are frequent and well documented in patients with Parkinson's disease (PD). The effect of depression and anxiety on sleep in PD patients has not been carefully studied however, despite the fact that both depression and anxiety are common in PD and well known to affect sleep in patients without PD. In this questionnaire study, sleep, anxiety, and depression were evaluated in 99 patients with PD and 47 control subjects. PD patients had significantly higher scores on a variety of sleep variables as well as on measures of anxiety and depression. While anxiety and depression were correlated with some sleep measures, neither contributed significantly to overall variance in sleep quality. The effect on sleep variables was dominated by on-off symptom phenomena, levodopa dose, and age.

Personality correlates of [18F]dopa striatal uptake: results of positron-emission tomography in Parkinson's disease.

Clinicians have long associated Parkinson's disease (PD) with personality traits such as seriousness and industriousness. In previous studies, patients with PD scored lower than matched orthopedic control subjects on novelty seeking, which is thought to be dopamine dependent. In this pilot study, 6-[18F]fluorodopa ([18F]dopa) uptake in the caudate and putamen was measured by PET in 9 patients with PD. Patients were also rated on three personality traits thought to be related to central monoamine function. Uptake of [18F]dopa in the left caudate, but not in other areas measured, was significantly correlated with novelty seeking. Results suggest that the personality traits long observed in PD patients may be partially mediated by striatal deficits in dopamine.

Parkinson's disease and depression: the relationship to disability and personality.

In a study of 104 patients with Parkinson's disease (PD) and 61 control subjects with equal disability scores, PD patients had higher depression scores (P < 0.001) than control subjects. Functional disability was correlated with depression in PD and, in a regression analysis, explained 9% of the variance in depression (P < 0.001). Depression was not correlated with novelty seeking, a personality trait related to dopaminergic pleasure and reward systems. Harm avoidance, a trait related to central serotonergic systems, was, however, correlated with depression (P < 0.001) and explained 31% of the variance in depression scores. Results support the hypotheses that both physiologic and psychologic factors contribute to depression seen in these patients and that serotonergic function plays a more critical role than dopaminergic function.

Parkinson's disease and anxiety: comorbidity with depression.

Parkinson's 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.