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Abstract Background Genetically manipulated animals like mice or rabbits play an important role in the exploration of human cardiovascular diseases. It is therefore important to identify animal models that closely mimic physiological and pathological human cardiac function. Methods In-vivo phase contrast cardiovascular magnetic resonance (CMR) was used to measure regional three-directional left ventricular myocardial motion with high temporal resolution in mice (N=18), rabbits (N=8), and humans (N=20). Radial, long-axis, and rotational myocardial velocities were acquired in left ventricular basal, mid-ventricular, and apical short-axis locations. Results Regional analysis revealed different patterns of motion: 1) In humans and rabbits, the apex showed slower radial velocities compared to the base. 2) Significant differences within species were seen in the pattern of long-axis motion. Long-axis velocities during systole were fairly homogeneously distributed in mice, whereas humans showed a dominant component in the lateral wall and rabbits in the base. 3) Rotational velocities and twist showed the most distinct patterns in both temporal evolution and relative contribution of base, mid-ventricle and apex, respectively. Interestingly, a marked difference in rotational behavior during early-systole was found in mice, which exhibited clockwise rotation in all slice locations compared to counter-clockwise rotation in rabbits and humans. Conclusions Phase contrast CMR revealed subtle, but significantly different regional myocardial motion patterns in mice, rabbits and humans. This finding has to be considered when investigating myocardial motion pattern in small animal models of heart disease.

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

High rates of depression are observed in Parkinson's disease, and limited access to care complicates management. The purpose of this pilot project was to evaluate the feasibility and impact of a personalized cognitive-behavioral telemedicine program for depression in Parkinson's disease (dPD). Thirty-four individuals with dPD and their carepartners participated in this pilot study. A 10-module self-help workbook, tailored to the unique needs of the dPD population, was created to be used as either a stand-alone intervention, with minimal therapist support, or a supplement to formal telephone-administered cognitive-behavioral therapy sessions. Improvements in depression, anxiety, quality of life, sleep, negative thoughts, and caregiver burden were observed over the course of the 4-month study, independent of treatment modality (guided self-help vs formal telephone-based psychotherapy). Future research will utilize randomized controlled designs and continue to focus on delivery models that can improve access to this and other evidence-based mental health interventions for dPD.

Three quarters of patients who respond to treatment with the newer antidepressants still complain of fatigue. Fatigue is one of the most common and disturbing residual symptoms of depression. Increased serotonin activity in certain areas of the brain contributes to fatigue. It can be counteracted by dopaminergic agents which, interestingly, are enhanced by exercise. Specific steps that can be used to address residual fatigue include cognitive interventions based on those used to address somatoform disorders; graded aerobic exercise; dose reduction or discontinuation of fatigue-inducing antidepressants; and the prescription of such medications as dopaminergic antidepressants (bupropion), stimulants, thyroid preparations, and modafinil.

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.

Background: Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants., Method: Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study., Results: One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants., Conclusion: Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy.

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.

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.

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.

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.

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.

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.

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 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.

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.

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 (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.

Studies suggest that Parkinson's 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, Cloningers's Tridimensional Personality Questionnaire, to test the hypothesis that these personality traits are behavioural 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.

Somatoform disorders are a group of syndromes in which patients focus on and complain of physical symptoms when there is no demonstrable underlying organic pathology or when complaints are in excess of what is expected. Medical and psychiatric physicians must seek better treatment and diagnosis.

Previous studies have suggested that tardive dyskinesia may occur more frequently in patients who smoke. Further evidence of an interaction between smoking and movement disorders includes the low lifetime exposure to cigarettes found in Parkinson's disease patients. In this study 126 patients with chronic psychiatric illnesses were blindly evaluated for tardive dyskinesia, neuroleptic-induced parkinsonism, and akathisia. Patients who smoked received significantly higher doses of neuroleptics but did not have significantly more frequent or more severe tardive dyskinesia or parkinsonism. Female smokers did have significantly more akathisia. These results are discussed with regard to interactions between smoking, central dopaminergic tone, and the psychopathology of extrapyramidal syndromes. The effect of smoking on neuroleptic blood levels as well as clinical symptomatology is also discussed.

Clinicians have long observed an anecdotal association of Parkinson's disease with stoic, industrious, and inflexible personality traits, both premorbidly and after the onset of motor symptoms. In this study, using the Tridimensional Personality Questionnaire, we found significantly less novelty-seeking behavior (behavior thought to be dopamine-dependent) in Parkinson's disease patients than in matched controls, but no differences between groups in behaviors thought to be dependent on serotonin and norepinephrine. We discuss the literature and propose a mechanism that may explain the relationship between brain dopaminergic systems and personality in Parkinson's disease.

Ten patients with idiopathic Parkinson's disease and motor fluctuations were rated for mood changes during discrete "off," "on," and "on with dyskinesia" periods. The Profile of Mood States and visual analogue scales were used. Significant changes in mood and anxiety were found to parallel changes in motor fluctuations. One patient rated his moods as consistently improving from the "off" state to the "on" state and finally to the "on with dyskinesia" state, a finding that is consistent with concomitant central dopaminergic changes. All other patients showed moods that improved significantly from the "off" state to the "on" state but then worsened significantly in the "on with dyskinesia" state, a finding that is consistent with the fact that patients feel worse when impaired by dyskinesias. It is suggested that these results argue for multiple etiologies of depression in Parkinson's disease. The literature on dopamine and depression in Parkinson's disease is briefly reviewed and the opportunity provided by "on-off" phenomena to study the effect of dopamine on mood changes is discussed.

In a prospective study, the intensity of extrapyramidal symptoms (EPS) was rated in two groups of delirious, medically ill patients. Fourteen patients received intravenous (IV) haloperidol and benzodiazepines for control of severe agitation and four received IV haloperidol alone. Patients were rated daily by a standardized scale for EPS by raters blind to the dose of haloperidol and benzodiazepines. Patients receiving haloperidol and benzodiazepines had significantly (p less than 0.001) less EPS than patients receiving IV haloperidol alone. In the haloperidol and benzodiazepine group there were only one case of very mild parkinsonian-like EPS and no cases of akathisia or dystonia. No adverse respiratory or cardiac reactions were seen in any patients. The literature on the use of IV haloperidol alone and in combination with benzodiazepines is briefly reviewed and possible explanations of the lower intensity of EPS with IV haloperidol in combination with benzodiazepines are discussed.

Programmed electrical stimulation, also known as electrophysiologic studies (EPS), is a cardiologic technique used to help guide physicians in their management of selected patients with cardiac arrhythmias. Data are presented for 14 consecutive patients undergoing EPS seen in psychiatric consultation who had a diagnosis related to anxious mood. Successful management strategies, which evolved from work with these patients, included psychologic approaches (supportive psychotherapy and education) and psychopharmacologic agents (most commonly alprazolam). EPS and related physiologic aspects of anxiety and stress are briefly reviewed.

The case history of a patient with presumed psychogenic catatonia who responded dramatically to two mg of IM lorazepam is presented. This patient, who had been largely mute and immobile for over a week despite neuroleptic therapy, became freely conversant and mobile within 30 minutes of the administration of lorazepam. This response was repeated the next day after the patient had again become mute and immobile. Catatonia and its diverse etiologies are discussed, with an emphasis on its syndromic nature. The literature on the response of catatonia to the benzodiazepines is reviewed and it is suggested that a trial of benzodiazepines may be helpful in both the evaluation and long term management of patients with catatonia.

In a preliminary, prospective study, the intensity of extrapyramidal symptoms was rated in four patients receiving intravenous haloperidol and six patients receiving oral haloperidol. The raters were blind to the route of administration. In this pilot study, the first systematic evaluation of intravenous haloperidol and extrapyramidal symptoms, the patients receiving intravenous haloperidol experienced significantly (p less than .01) less intense extrapyramidal symptoms than did the patients receiving oral haloperidol. The literature on intravenous haloperidol is briefly reviewed, and possible explanations of the lower intensity of extrapyramidal symptoms with intravenous haloperidol in the patients studied are discussed.