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Does unilateral dopamine deficit contribute to depression?
Abstract
A system of emotional control of behavior is believed to be lateralized to the right hemisphere. Given that dopaminergic pathways are involved in affective behavior, depression, which is recognized as an integral part of Parkinson's disease, may be associated with a dopamine imbalance. The present study examined this hypothesis in patients with unilateral symptomatology indicating either left hemisphere parkinsonism (LHP) or right hemisphere parkinsonism (RHP). Sixteen patients were tested on a battery of neuropsychological tests and several scales for evaluating mood. The two groups did not differ significantly on either cognitive or emotional measures. However, RHP patients rated themselves higher on the Present Scale of Cantril, and showed some neglect of the left visual field, as compared to LHP patients.
... Others found widespread cognitive deficits in participants with worse left-sided dysfunction while participants with worse rightsided dysfunction were relatively cognitively spared (Direnfeld et al., 1984; Tomer, Levin, & Weiner, 1993). Still others found no cognitive differences in regard to motor asymmetry (Barber, Tomer, Sroka, & Myslobodsky, 1985; Huber, Freidenberg, Shuttleworth, Paulson, & Clapp, 1989; St. Clair, Borod, Sliwinski, Cote, & Stern, 1998) or suggest that type, rather than side, of predominant or initial motor manifestation is the most important factor (Riklan, Stellar, & Reynolds, 1990; Zetusky & Jankovic, 1985). Some of this work was limited by use of non-specific or poorly validated tasks, small sample sizes or participants in varied stages of disease progression. ...
... Additionally, researchers used different scales for measuring motor deficits and based group inclusion criteria on different aspects of asymmetry, which may contribute to the controversy. For example, some investigators chose to categorize participants according to initial side of symptom onset (Amick et al., 2006; Katzen, Levin, & Weiner, 2006; Tomer et al., 1993) while others used current ratings of absolute motor asymmetry (Barber et al., 1985; Blonder et al., 1989; Riklan et al., 1990); relatively little attention has been paid to the degree of motor asymmetry at the time of cognitive testing (Huber et al., 1992; Tomer et al., 1993). The purpose of this study was to determine whether PD asymmetry affects short term spatial memory performance. ...
Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD (n=35) and control (n=28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory.
... This association is also found for anxiety [90]. Moreover, there is no definitive association between depression and the side of greatest motor impairment [59,91,92], similar to anxiety [90], although (mild) depression may be more severe in patients with bilateral symptoms [84]. ...
Depression is one of the most frequent and burdensome non-motor symptoms in Parkinson’s disease (PD), across all stages. Even when its severity is mild, PD depression has a great impact on quality of life for these patients and their caregivers. Accordingly, accurate diagnosis, supported by validated scales, identification of risk factors, and recognition of motor and non-motor symptoms comorbid to depression are critical to understanding the neurobiology of depression, which in turn determines the effectiveness of dopaminergic drugs, antidepressants and non-pharmacological interventions. Recent advances using in vivo functional and structural imaging demonstrate that PD depression is underpinned by dysfunction of limbic networks and monoaminergic systems, depending on the stage of PD and its associated symptoms, including apathy, anxiety, rapid eye movement sleep behavior disorder (RBD), cognitive impairment and dementia. In particular, the evolution of serotonergic, noradrenergic, and dopaminergic dysfunction and abnormalities of limbic circuits across time, involving the anterior cingulate and orbitofrontal cortices, amygdala, thalamus and ventral striatum, help to delineate the variable expression of depression in patients with prodromal, early and advanced PD. Evidence is accumulating to support the use of dual serotonin and noradrenaline reuptake inhibitors (desipramine, nortriptyline, venlafaxine) in patients with PD and moderate to severe depression, while selective serotonin reuptake inhibitors, repetitive transcranial magnetic stimulation and cognitive behavioral therapy may also be considered. In all patients, recent findings advocate that optimization of dopamine replacement therapy and evaluation of deep brain stimulation of the subthalamic nucleus to improve motor symptoms represents an important first step, in addition to physical activity. Overall, this review indicates that increasing understanding of neurobiological changes help to implement a roadmap of tailored interventions for patients with PD and depression, depending on the stage and comorbid symptoms underlying PD subtypes and their prognosis.
... Individuals with Parkinson's disease (PD) without dementia exhibit deficits in multiple domains of visuospatial functioning (reviewed in Cronin-Golomb, 2010), including line bisection (Barber, Tomer, Sroka, & Myslobodsky, 1985;Davidsdottir, Wagenaar, Young, & Cronin-Golomb, 2008;Lee, Harris, Atkinson, & Fowler, 2001a;Lee, Harris, Atkinson, Nithi, & Fowler 2002;Starkstein, Leiguarda, Gershanik, & Berthier, 1987). It has been found that PD patients with initial motor symptoms on the right side of the body (RPD; predominant left basal ganglia dysfunction) perform similarly to healthy control adults, whereas those whose initial symptoms originate on the left side of the body (LPD; predominant right basal ganglia dysfunction) tend to deviate to the right of center on horizontal line bisection tasks (Lee et al., 2001a;Davidsdottir et al., 2008) and downward on vertical line bisection tasks (Lee et al., 2002). ...
Parkinson's disease (PD) is characterized by disorders of visuospatial function that can impact everyday functioning. Visuospatial difficulties are more prominent in those whose motor symptoms begin on the left body side (LPD) than the right body side (RPD) and have mainly been attributed to parietal dysfunction. The source of visuospatial dysfunction is unclear, as in addition to subcortical-cortical changes, there are irregularities of visual scanning and potentially of retinal-level vision in PD. To assess these potential contributors, performance on a visuospatial task-line bisection-was examined together with retinal structure (nerve fiber layer thickness, measured by optical coherence tomography [OCT]), retinal function (contrast sensitivity, measured by frequency-doubling technology [FDT]), and visual scanning patterns. Participants included 20 nondemented patients (10 LPD, 10 RPD) and 11 normal control (NC) adults. Relative to the other groups, LPD were expected to show rightward bias on horizontal line bisection, especially within the left visual hemispace, and downward bias on vertical bisection. LPD relative rightward bias was confirmed, though not mainly within the left hemispace and not correlated with retinal structure or function. Retinal thinning was seen in LPD relative to RPD. Qualitative visualization of eye movements suggested greater LPD exploration of the right than left side of the line during horizontal bisection, and some overall compression of scanning range in RPD (both orientations) and LPD (primarily vertical). Results indicated that rightward visuospatial bias in our LPD sample arose not from abnormalities at the retinal level but potentially from attentional biases, reflected in eye movement patterns. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
... On the one hand, some studies found no difference in cognitive performance between patients with right-vs. left-side motor onset [12,13]; on the other hand, it has been reported that patients with right-sided symptoms (left hemisphere dysfunction) perform more poorly on verbally mediated tasks, whereas patients with left-sided symptoms perform worse on visuospatial tasks [14]. These conflicting findings may partly be due to methodological limitations, since many studies did not analyze subgroups of patients according to motor phenotype (tremor dominant vs. rigid-bradykinetic phenotype). ...
... A limitation of several of these studies is that they prevalently investigated global lateralized brain functions in patients with variable disease severity. Few studies have correlated PD motor asymmetry with behavioral and personality traits, such as mood disorders or impulsive-compulsive behaviors [16][17][18][19], which are influenced by dopamine replacement treatments. Risk factors for impulse control disorders in PD are still poorly defined, and we hypothesized that side dominance of dopaminergic depletion may influence the generation of behavioral abnormalities. ...
Dopamine neurotransmission plays a key role in several brain activities, including motor, cognitive, and behavioral functions. Parkinson's disease (PD) typically begins with asymmetrical motor features related to asymmetrical dopamine denervation. This study was designed to examine whether distinct cognitive, behavioral, and personality features are related to this asymmetry.
Fifty-six patients with mild PD and lateralized motor features were grouped according to dominant side of motor features and evaluated using a neuropsychological assessment focused on attention and executive functions, impulse control disorders, and personality inventory.
There were no differences in neuropsychological functions between patients with right and left lateralized PD, but differences occurred in personality features. Patients with motor impairment predominant on the left-hand side had prevalence of hypomania and conversion profile.
This study suggests that side dominance of dopaminergic denervation may be related to personality features in patients with PD that could influence behavioral aspects.
... A positive correlation between depression and unilateral motor changes would support the hypothesis of a laterality of structures mediating mood states. [19] Some studies have found an association between depression and right-sided hemiparkinsonism. The determination of this relationship appears to depend largely on the screening tool used to assess depression; patients with right-sided hemiparkinsonism had significantly more depressive symptoms when assessed using the Hamilton Depression Rating Scale (HDRS), but not when using the Geriatric Depression Scale. ...
Parkinson’s disease (PD) is a common neurological illness and various degrees of depression frequently complicate its course. Risk factors for developing depression with PD include right-sided hemiparkinsonism, akinesia, increased severity of disability, anxiety and psychosis. Onset of parkinsonism at a younger age, female gender and the use of levodopa are arguable risk factors. Depression may be difficult to diagnose in patients with PD because the signs of the 2 disorders overlap. In addition, patients with atypical PD more commonly have depression than patients with classical PD presentations.
Antidepressant response to antiparkinsonian treatment has been limited. Enhancement of catecholamine levels in the CNS by selegiline (deprenyl), a monoamine oxidase (MAO) type B inhibitor, has shown potential antidepressant as well as neuroprotective effects. Other MAO inhibitors have shown antidepressant efficacy in animal models but have not been well tolerated by patients with PD. A catechol-O-methyltransferase (COMT) inhibitor combined with an MAO inhibitor might synergistically maximise the levels of catecholamines in the CNS.
Antidepressant medications used in patients without PD include tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), but only TCAs have been carefully studied for their antidepressant effects in PD. Electroconvulsive therapy has proven efficacy as antidepressant therapy in patients with PD, and transcranial magnetic stimulation has provided temporary relief of depression under experimental conditions.
Adverse effects of polypharmacy in the attempted treatment of depression in patients with PD are common in the elderly. A ‘serotonin syndrome’ has occurred frequently enough to preclude the coadministration of selegiline with SSRIs or TCAs, and multiple interactions between antiparkinsonian and antidepressant medications further complicate treatment strategies in patients with PD.
An algorithmic approach to the pharmacological treatment of depression is described in this article.
Verhaltensstörungen, Depressionen, isolierte kognitive Störungen, pharmakotoxische Psychosen und schließlich dementive Veränderungen werden in zunehmendem Maße bei Parkinson-Patienten beobachtet und mÜssen bei der Behandlung berÜcksichtigt werden. Zur Zeit James Parkinsons stand die Beurteilung der motorischen StÖrung vÖllig im Vordergrund. HÖhere psychische Funktionen — mit Ausnahme von Depressionen, seltenen sensorischen Mißempfindungen und im Finalstadium auftretende delirante Zustandsbilder — wurden im wesentlichen bis zur EinfÜhrung der modernen Anti-Parkinson-Therapie selten und nur am Rande beschrieben. In den letzten hundert Jahren hat sich die durchschnittliche Lebenserwartung in den Industriestaaten nahezu verdoppelt, und es kam zu einer explosionsartigen Zuwachsrate der Hochbetagten von mehreren 100 bis über 1000% (Rückert 1984).
Until recently, the “conventional wisdom” within the field of neuropsychology was that depression had little or no impact upon neuropsychological test performance. In many of the currently influential neuropsychology textbooks, depression is either not dealt with (e.g., Golden, 1981) or is dismissed as an insignificant variable. For example, Reitan and Wolfson (1985) state that “a severe and clinically significant degree of depression... usually seem[s] to be irrelevant to interpretation of neuropsychological test findings.” There has been a growing body of research in recent years, however, that clearly challenges this long-held belief. Studies with ability tests and neuropsychological measures with psychiatric populations have been accumulating and growing interest in this area has recently spawned a flurry of research showing that depression can have a significant impact upon neuropsychological test performance.
Aims:
Though impaired cognition in Parkinson's disease (PD) is well known, data in early PD is sparse. This study was designed to assess the cognitive profile in patients with early PD (motor symptoms <5 years and Hoehn and Yahr stage <2), and to compare the cognitive profile between these patients with right versus left side onset of motor symptoms.
Materials and methods:
National Institute of National Health and Neurosciences (NIMHANS) neuropsychological battery was used to assess the cognitive profile in 50 patients with early PD and compared with 50 age-, education-, and gender-matched healthy controls. Within the PD group, the cognitive profile was also compared between patients with right side onset motor symptoms (RPD) versus those with left side onset (LPD). The neuropsychological tests assessed the executive functions, memory, attention, visuospatial functions, and psychomotor speed.
Results:
Among the 50 patients, 25 each were RPD and LPD. The two subgroups were matched for age, gender, education, age at disease onset, disease duration, and degree of motor disability. There was no significant difference between the groups on Hoehn and Yahr staging or Unified Parkinson Disease Rating Scale (UPDRS) motor score. Patients with early PD performed significantly worse in the tasks involving memory, executive functions, and attention compared to controls. However, there was no difference in the cognitive profile between RPD and LPD subgroups.
Conclusions:
Patients with early PD have cognitive dysfunction with predominant involvement of frontal and temporal lobes. Side of onset of motor symptoms probably does not have significant role in future development or profile of cognitive dysfunction in PD.
Objectives: The goal of this study was to investigate the antidepressive effect of Bupleuri Radix (BR). Methods : The forced swimming test (FST) was performed. Also the expression of corticotropin releasing factor (CRF), c-Fos and tyrosine hydroxylase (TH) was measured immunohistochemically at paraventricular nucleus (PVN) and locus coeruleus (LC). Concentration of adrenocorticotrophic hormone (ACTH) was measured in plasma by ELISA method. Results : The immobility in BR400 Group was significantly decreased in comparison with the control group (p
Although Parkinson's disease (PD) is diagnosed on the basis of motor symptoms, including slowness of movement, tremor, rigidity and difficulties with balance and walking, now we are aware that non-motor symptoms are highly prevalent, since they can anticipate motor symptoms and can cause severe consequences. Several studies have shown that non-motor symptoms, such as depression, anxiety and apathy, psychosis (e.g., hallucinations, delusions), sleep disturbance, and pain may have a greater adverse impact on quality of life and health economics compared with motor symptoms. Non-motor symptoms can be divided into four domains: neuropsychiatric (e.g., depression, anxiety, apathy, hallucinations, dementia), autonomic (e.g., constipation, orthostatic hypotension, urinary changes, sweating abnormalities), sleep (e.g., insomnia, sleep fragmentation, excessive daytime sleepiness, rapid eye movement, sleep behavioural disorder, restless leg syndrome), and sensory dysfunction (e.g., pain, olfactory dysfunction). This review addresses diagnosis and treatment of these disorders. The causative mechanisms remain complex, since they reflect the widespread brainstem and cortical pathology of PD, with involvement of several neurotransmitters, including dopamine (DA), serotonin, norepinephrine, and acetylcholine. The diagnosis is often challenging, especially for psychiatric disorders, and in particular affective disorders, because somatic features of psychopathology may overlap with the movement disorder itself. Treatments used are limited and psychiatric drugs may not be as effective as in general population. Evidence based medicine is quite poor and it still requires well-designed clinical studies.
Parkinson's disease is heterogeneous, both in terms of motor symptoms and mood. Identifying associations between phenotypic variants of motor and mood subtypes may provide clues to understand mechanisms underlying mood disorder and symptoms in Parkinson's disease. A total of 513 patients were assessed using the Hospital Anxiety and Depression Scale, and separately classified into anxious, depressed, and anxious-depressed mood classes based on latent class analysis of a semistructured interview. Motor subtypes assessed related to age-of-onset, rate of progression, presence of motor fluctuations, lateralization of motor symptoms, tremor dominance, and the presence of postural instability and gait symptoms and falls. The directions of observed associations tended to support previous findings with the exception of lateralization of symptoms, for which there were no consistent or significant results. Regression models examining a range of motor subtypes together indicated increased risk of anxiety in patients with younger age-of-onset and motor fluctuations. In contrast, depression was most strongly related to axial motor symptoms. Different risk factors were observed for depressed patients with and without anxiety, suggesting heterogeneity within Parkinson's disease depression. Such association data may suggest possible underlying common risk factors for motor subtype and mood. Combined with convergent evidence from other sources, possible mechanisms may include cholinergic system damage and white matter changes contributing to non-anxious depression in Parkinson's disease, while situational factors related to threat and unpredictability may contribute to the exacerbation and maintenance of anxiety in susceptible individuals.
At disease onset, patients with Parkinson's disease (PD) typically report one side of the body to be more affected than the other. Previous studies have reported that this motor symptom asymmetry is associated with asymmetric dopaminergic degeneration in the brain. Research on the cognitive repercussions of this asymmetric degeneration has yielded inconsistent results. Here, we review studies that reported on the cognitive performance of patients with left-sided (LPD) or right-sided (RPD) motor symptom predominance. We present evidence that patients with RPD typically experience problems with language-related tasks and verbal memory, whereas patients with LPD more often perform worse on tasks of spatial attention, visuospatial orienting and memory and mental imagery. In general, no differences were found between both groups on tasks measuring attention and executive function. The association between motor asymmetry and cognitive performance indicates that PD does not lead to one typical cognitive profile. The effect of symptom laterality on the cognitive complaints should be considered in the assessment and treatment of each individual patient.
Orientadora : Maria A.B.F. Vital Co-orientador : Roberto Andreatini Dissertaçăo (mestrado) - Universidade Federal do Paraná, Setor de Cięncias Biológicas, Programa de Pós-Graduaçăo em Farmacologia. Defesa: Curitiba, 2005 Inclui bibliografia
SYNOPSIS
Seventeen patients with Parkinson's disease which was markedly asymmetric and worse on the right side of the body (RHP) were compared with 13 patients whose signs were worse on the left (LHP). The two groups of patients were well matched for age, duration of symptoms, disability, overall severity of signs, and medication.
The mean scores on ratings of depression, using both a self-rating scale and semi-structured interview rating, were almost twice as great in the LHP group. The LHP group also had significantly more symptoms of anxiety. The prevalence of clinically significant psychopathology was increased about five fold in the LHP group compared with the RHP group.
There was a close correlation between anxiety and depressive symptoms. The depression experienced by the patients was ‘atypical’, with relatively little anhedonia and evidence of a negative view of self, and prominent symptoms of anxiety. The best predictor of symptoms of depression and anxiety was a measure of social support and stress. They also correlated with the overall severity of Parkinson's disease.
Monkeys made hemiparkinsonian by infusion of a solution of MPTP into one carotid artery appeared to ignore food presented from the contralateral side. Initial observations suggested neglect of visual stimuli presented as fruit treats by automated delivery system in the half-field contralateral to MPTP treatment. Further studies in which fruit treats were left in the 'neglected' visual field indicated that this apparent neglect, unlike neglect attending cortical lesions, was rather a marked delay in initiating movements (unilateral hypokinesia). These observations may explain apparent subcortical neglect and are consistent with the known role of nigrostriatal dopaminergic neurones in movement regulation. This is a useful animal model in which difficulties in initiation of movement (hypokinesia). a cardinal symptom of Parkinson's disease, can be studied separately from other deficits in motor performance.
A consecutive series of 105 outpatients with Parkinson's disease (PD) were examined for the presence of depression. Twenty-one percent met diagnostic criteria for major depression, 20% had minor depression, and the remainder were not depressed. The frequency of depression showed a bimodal distribution over time, with highest frequencies occurring in the early and late stages of the disease. Although other factors such as a positive family history of psychiatric disorders, quality of social functioning, and severity of tremor, rigidity, and akinesia did not show a significant association with depression, depressed patients had significantly higher impairment scores in activities of daily living and cognitive function than nondepressed PD patients. There was also a significant correlation between impairment and depression scores. In addition, among patients with mainly unilateral symptoms, depression was significantly associated with greater left hemisphere involvement. These findings suggest that depression in the early stages of the disease may be related to left hemisphere dysfunction, while later in the disease, depression and impairment in activities of daily living are interrelated. This may indicate more than one etiology of depression or that depression may have an adverse impact on the course of the disease.
A yin-yang hypothesis is presented linking noradrenergic activity, thromboxane, melatonin, left hemisphere functioning, and cyclic AMP on the one hand, and dopamine, beta-endorphin, calcium, right hemisphere functioning, and cyclic GMP on the other. It is further suggested that there is a yoking of NA, TXA2, serotonin and melatonin in the left hemisphere, and a similar yoking of DA, BE, calcium and cGMP in the right. Evidence is presented to support the hypothesis that each element (NA, TXA2, etc.) on one side can modulate or balance a corresponding element (DA, BE, etc.) on the other. It is suggested that thromboxane is the key element in noradrenergic overactivity and that not taking this into consideration has confounded much prior research. This theory takes into account information processing models as well as pharmacological data and neurochemical theory on coupling of adenylate cyclase to its hormone receptors. Inhibiting noradrenergic overactivity can be obtained by inhibiting thromboxane and concomitantly activating opiate receptors. This protocol may have clinical utility in treating a wide range of disorders such as: anxiety, depression, schizophrenia, sleeplessness, withdrawal states, enuresis, Gilles de la Tourette syndrome, Parkinsonism, Alzheimers, dementia, anorexia, infant ruminations, essential tremor, spasticity of spinal cord injury, diarrhoea, ulcerative colitis, extrapyramidal symptoms, akathisia, neuroleptic malignant syndrome, attention deficit disorder, hyperhidrosis, and possibly AIDS.
Studies attempting to relate cognitive impairment to asymmetry of motor symptoms in Parkinson's disease (PD) have found contradictory results. We examined 88 patients with unilateral onset of idiopathic PD who underwent a comprehensive neuropsychological assessment, including language, visuospatial abilities, abstraction and reasoning, attention and mental tracking, set shifting, and memory. Patients whose motor signs began on the left side of the body consistently performed more poorly on the battery of cognitive measures than did patients with right-side onset. Significant differences were found on immediate and delayed verbal recall, word retrieval, semantic verbal fluency, visuospatial analysis, abstract reasoning, attention span, and mental tracking. These differences could not be attributed to differences in the overall severity of motor symptoms at the time of cognitive assessment, or the current pattern of motor asymmetry. This finding suggests that damage to right-hemisphere dopamine systems plays a disproportionately greater role in PD-related cognitive decline than a presumably comparable left-hemisphere dopamine depletion.
Parkinsonians with predominantly unilateral signs provide an interesting experimental means to evaluate if asymmetric nigro-striatal degeneration may affect neuropsychological functions. The aim of our study was to establish if the side of onset of idiopathic Parkinson's disease, right (PDR) or left (PDL), determines a selective pattern of cognitive performances. Furthermore, we verified if PDR and PDL groups show a different frequency of dementia. PDR and PDL patients with at least seven years of disease duration, matched for age, schooling, severity of extrapyramidal symptomatology and index of lateralization, were evaluated by using an extensive neuropsychological battery aimed at assessing hemispheric cognitive asymmetries. Current side of greater motor impairment was the same as the one affected at the onset of the disease.
Only subtle differences in the profile of neuropsychological dysfunction emerged from the comparison of PDR and PDL subjects. Moreover, the number of parkinsonians showing dementia syndrome was the same in both groups. Our results suggest that the side of onset of motor impairment does not significantly influence the cognitive performances in PD. Subcortical anatomic and/or functional asymmetries seem to play a less important role in the intellectual functions than in motor activities.
Using the National Center of Health Statistics' mortality statistics databases for 1991 through 1996 (12,430,473 deaths), we isolated 144,364 individuals 40 years of age or older with a primary diagnosis of Parkinson's disease (PD). Of these, 122 died by suicide. The rate of suicide in the general population was about 10 times higher than in patients with PD (0.8% compared with only 0.08%, respectively). These different rates of suicide cannot be attributed to differences in age, gender, race, education, or marital status. Compared with patients with suicidal PD, patients with PD who died from other causes manifested significantly lower rates of affective disorders. The referent population exhibited a higher rate of malignancy and a lower rate of depression. The findings suggest that marital status, mood disorder, and somatic comorbidity provide only a limited understanding of completed suicide.
Depression has been shown to be more common in Parkinson's disease (PD) than in other chronic and disabling disorders. Neurochemical and functional disturbances are important etiopathogenic factors. The prevalence and clinical features associated with depression in PD remain controversial. The purpose of this study is to estimate the prevalence of depressive symptoms in our patients, as related to other clinical data, and to assess clinical outcomes of these symptoms. A series of PD patients were evaluated over a 9-year period, using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage (HY), Schwab and England Scale (SE), Mini-Mental State Examination (MMSE), and Yesavage Geriatric Depression Scale (GDS). Presence of depressive symptoms was considered if GDS score was higher than 10: mild-moderate (MD) for GDS scores between 11 and 20 and moderate-severe (SD) for GDS scores greater than 20. Three hundred and fifty-three patients were included in this study and additional follow up information was obtained for 184 patients. MD and SD were found in 40.2 and 16.7% of PD patients, respectively. Female gender, high HY, high UPDRS total and subtotal, and low MMSE and SE scores were significantly associated with depressive symptoms. According to changes in GDS score, 34% of patients remained stable, 35% showed an improvement, and 30.9% worsened in the follow up study. Gender, age, age of onset, HY, UPDRS, and PD duration are not related to depression outcome.
It is well known that many patients with Parkinson's disease experience neuropsychological decline. However, the nature and extent of mental status change varies widely, with some patients showing mild or no cognitive impairments and others exhibiting frank dementia. Research has shown that several clinical disease parameters may differentially correlate with patterns of neuropsychological dysfunction. The present study examined side and type of motor symptom at disease onset and their relationship to cognition in idiopathic Parkinson's disease (PD). We identified 58 patients who initially presented with one of the following symptom profiles: right-side tremor onset (RSO-T; n = 15), right-side bradykinesia/rigidity onset (n = 12), left-side tremor onset (n = 19), and left-side bradykinesia/rigidity onset (n = 12). There were no differences between groups in disease duration, overall mental status, education, or depression severity. We administered a battery of neuropsychological measures to the four PD subgroups and a group of matched control subjects (n = 40). MANCOVAs controlling for age revealed patients with RSO-T performed significantly better than the other three PD subgroups across the entire neuropsychological battery. Further, the RSO-T subgroup performed comparably to controls. In contrast, the other three PD subgroups showed widespread cognitive deficits. These findings suggest an intricate relationship between motor symptom and side of disease onset and it is the combination of these factors that may influence the disease course and extent of cognitive deterioration. Furthermore, patients who develop tremor on the right side of their body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function.
Regional brain glucose utilization following unilateral lesion of the substantia nigra in rat was studied by [14C]-2-deoxyglucose autoradiography. Substantia nigra lesions were performed by perinigral injections of 6-hydroxydopamine (6-OHDA) . HBr, 6 microgram, in rats pretreated 30 min earlier with desmethylimipramine (DMI), 25 mg/kg, subcutaneously. The lesion produced extensive destruction of the ipsilateral substantia nigra pars compacta and a greater than 99% reduction in dopamine concentration in the ipsilateral striatum. Pretreatment with DMI prevented any reduction in the concentration of norepinephrine in ipsilateral forebrain structures. Glucose utilization was increased in the ipsilateral globus pallidus at 11, 21, 53, and 104 days after substantia nigra lesion with the largest increase (about 140% of control) occurring at 21 days post-lesion. In addition, glucose utilization in ipsilateral lateral habenular nucleus was increased at each of the above time points. No changes in glucose utilization were noted in frontal cortex, striatum, subthalamic nucleus, entopeduncularis, or ventral tier nuclei of the thalamus. These results suggest that lesion of the substantia nigra with depletion of striatal dopamine content results in disinhibition of some striatal, and perhaps olfactory cortical, efferents producing increased metabolism and glucose utilization in terminal fields within the globus pallidus and lateral habenular nucleus.
Synopsis: Levodopa2 is the laevo optical stereoisomer of the L-configurational form of dopa [L-(−)-dopa] and is advocated for the symptomatic treatment of Parkinson’s syndrome. It is probably of no practical value in drug-induced Parkinsonism.
Unlike dopamine, levodopa crosses the blood-brain barrier and is converted to dopamine by the enzyme dopa decarboxylase. As the activity of this enzyme is greater in the periphery (eg. liver, kidneys, heart) than in the brain, much of the administered levodopa is converted to dopamine outside the central nervous system. Owing to the rapid extracerebral metabolism of levodopa high dosages are needed to replenish brain dopamine stores. Results of prolonged therapeutic trials have demonstrated the efficacy of such ‘replacement’ therapy with levodopa in the treatment of Parkinsonism. Overall, about two-thirds of patients have experienced amelioration of symptoms greater than would have been expected with previously used combinations of anticholinergic drugs. There seems to be no doubt that levodopa is the most effective agent available for the drug treatment of Parkinsonism. Response to treatment has been variable and individual improvement in symptoms has ranged from slight to spectacular. Hypokinesia and rigidity have improved sooner and more consistently than tremor. The improvement in neurological symptoms has been accompanied by a similar improvement of functional ability. Although it is not possible to predict accurately which patients will benefit most, younger patients with less severe Parkinsonism usually tolerate higher dosages and derive greater benefit from treatment than frail elderly patients with severe pre-treatment disability. However, some elderly and severely disabled patients derive considerable benefit from levodopa therapy. At present it is not known if the beneficial effect of levodopa can be maintained indefinitely, or if the progression of the disease is altered by its use. Also, there is no certainty that continued use for many years will not result in the emergence of new and serious side-effects.
The usual initial daily dosage is 0.25 to 1 g in three or more divided doses. It is mandatory that the dosage of levodopa be carefully titrated for each individual patient, until either maximum therapeutic response is observed, side-effects preclude further increments, or until a daily dosage of 8 g is reached over a period of about 3 or 4 months. The maximum tolerated daily dosage varies considerably from one individual to another and may range from 0.5 to 8 g although the average daily dosage usually ranges from 2 to 6 g in three or more divided doses.
Side-effects are common and the majority of patients experience nausea and/or anorexia with or without vomiting. Abnormal involuntary movements of a choreoathetoid nature, which constitute the most common dose-limiting side-effect of the drug, frequently coincide with optimum symptomatic improvement and tend to appear in an increasing proportion of patients as treatment progresses. Initially these movements are usually faciolingual, and later may involve the limbs and trunk. Postural hypotension and psychiatric disturbances (which often occur in patients with a history of mental illness) may also necessitate a reduction in dosage or withdrawal of treatment. Cardiac dysrhythmias have been reported infrequently. Apart from the rare cardiovascular complications all side-effects have been dose-dependent and reversible. Levodopa should be given with extreme caution to patients with cardiovascular, endocrine, renal, hepatic or pulmonary disease.
Visual evoked potentials (VEPs) were recorded bilaterally from the parietal areas in patients with hemiparkinsonism. VEPs recorded over the hemisphere contralateral to the side of parkinsonian symptomatology showed diminished maximal amplitude of secondary components and increased peak latency of an early positive component (P100). After a period of levodopa treatment symmetry of latencies and reversal of VEPmax asymmetry were observed.RésuméOn a enregistré bilatéralement des potentiels évoqués visuels (PEV) dans les aires pariétales de patients atteints de Parkinson unilatéral, Les PEV recueillis sur l'hémisphère contralatéral au côté de la symptomatologie parkinsonienne montraient une diminution de l'amplitude maximale de leurs composantes secondaires et un allongement de la latence du pic d'une composante précoce (P100). Après une période de traitement à la L-DOPA, on a noté un retour à des latences symétriques et un renversement de l'asymétrie du PEVmax.
It is possible that some "postpsychotic depressions" may be a toxic effect of antipsychotic drugs. Out of a total of 94 schizophrenic patients, 28 developed a mild akinesia and 32 never developed extrapyramidal symptoms. Those who developed akinesia became less psychotic, but they also experienced a significant, although modest, increase in depression ratings. Successful treatment of the akinesia resulted in significant improvements in depression, somatic concern, anxiety, emotional withdrawal, blunted affect, and motor retardation on both physicians' and nurses' ratings. A high association between akinesia and both objectively rated and subjectively experienced sedative effect indicates that an 'akinetic depression' is not likely if the patient does not look or feel drowsy. The 32 nonakinetic patients also became less psychotic, but not more depressed.
Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.
Sensory neglect was studied in cats after unilateral lesions of: lateral hypothalamus (LH); internal capsule (IC) adjacent to the LH; substantia nigra (SN) or the ventromedial hypothalamus (VMH). Special behavioral tests were employed to yield quantifiable data and also to exclude any confounding due to simple movement deficits. Lesions of SN or IC produced severe and enduring contralateral visual and somesthetic deficits and a facilitation of ipsilateral visual responsiveness. In contrast, LH lesions sparing the adjacent IC produced only weak and transient deficits and VMH lesions had no effects on sensory function. This suggests that lesions of the SN or its forebrain connections are important for producing sensory neglect and that sensory deficits after LH lesions are due to infringement on fibers of passage to or from the SN. Lesions which produced neglect often suppressed the amplitude of flash evoked responses in the ipsilateral caudate nucleus and visual and association cortex. However, these evoked potential effects were transient. There was no effect on the spontaneous EEG and this fails to support the hypothesis of a lack of hemispheric arousal in sensory neglect. The results are discussed in relation to nigrotectal projections and the process of attention. This lesion-behavior model is suggested for studies of recovery of function.
The regional distribution and properties of the sodium-independent "specific" binding of [3H]GABA to membranes prepared from human brains (control and Parkinsonian patients) have been investigated. The affinity of [3H]GABA for the binding site was similar for human cerebellar cortex (Kd = 3.4 x 10(-7) M) and whole rat brain brain (Kd = 5.1 x 10(-7) M) and was inhibited by bicuculline (ID50 = 2.2 X 10(-5) M). In the normal human brain the cerebellar cortex demonstrated the highest number of binding sites, in accordance with the large number of GABA interneurons in this structure. The hippocampus also displayed a high capacity to bind [3H]GABA, whereas cerebral cortical areas showed a lesser capacity. [3H]GABA binding was similar in many regions of the basal ganglia (amygdala, putamen, caudate or accumbens) but was lower than that for the cortical regions. The binding of [3H]GABA to membranes from the substantia nigra, thalamus and internal or external pallidum was lower than for the above regions. Subcortical white matter did not exhibit specific binding for [3H]GABA. In membranes prepared from Parkinsonian patients [3H]GABA binding was greatly decreased in the substantia nigra, but not in other brain areas examined. From this observation it was concluded that there are [3H]-brain areas examined. From this observation it was concluded that there are [3H]-GABA binding sites on the cell bodies (or dendrites) of the nigral dopamine neurons.
Synopsis: Levodopa2 is the laevo optical stereoisomer of the L-configurational form of dopa [L-(−)-dopa] and is advocated for the symptomatic treatment of Parkinson’s syndrome. It is probably of no practical value in drug-induced Parkinsonism.
Unlike dopamine, levodopa crosses the blood-brain barrier and is converted to dopamine by the enzyme dopa decarboxylase. As the activity of this enzyme is greater in the periphery (eg. liver, kidneys, heart) than in the brain, much of the administered levodopa is converted to dopamine outside the central nervous system. Owing to the rapid extracerebral metabolism of levodopa high dosages are needed to replenish brain dopamine stores. Results of prolonged therapeutic trials have demonstrated the efficacy of such ‘replacement’ therapy with levodopa in the treatment of Parkinsonism. Overall, about two-thirds of patients have experienced amelioration of symptoms greater than would have been expected with previously used combinations of anticholinergic drugs. There seems to be no doubt that levodopa is the most effective agent available for the drug treatment of Parkinsonism. Response to treatment has been variable and individual improvement in symptoms has ranged from slight to spectacular. Hypokinesia and rigidity have improved sooner and more consistently than tremor. The improvement in neurological symptoms has been accompanied by a similar improvement of functional ability. Although it is not possible to predict accurately which patients will benefit most, younger patients with less severe Parkinsonism usually tolerate higher dosages and derive greater benefit from treatment than frail elderly patients with severe pre-treatment disability. However, some elderly and severely disabled patients derive considerable benefit from levodopa therapy. At present it is not known if the beneficial effect of levodopa can be maintained indefinitely, or if the progression of the disease is altered by its use. Also, there is no certainty that continued use for many years will not result in the emergence of new and serious side-effects.
The usual initial daily dosage is 0.25 to 1 g in three or more divided doses. It is mandatory that the dosage of levodopa be carefully titrated for each individual patient, until either maximum therapeutic response is observed, side-effects preclude further increments, or until a daily dosage of 8 g is reached over a period of about 3 or 4 months. The maximum tolerated daily dosage varies considerably from one individual to another and may range from 0.5 to 8 g although the average daily dosage usually ranges from 2 to 6 g in three or more divided doses.
Side-effects are common and the majority of patients experience nausea and/or anorexia with or without vomiting. Abnormal involuntary movements of a choreoathetoid nature, which constitute the most common dose-limiting side-effect of the drug, frequently coincide with optimum symptomatic improvement and tend to appear in an increasing proportion of patients as treatment progresses. Initially these movements are usually faciolingual, and later may involve the limbs and trunk. Postural hypotension and psychiatric disturbances (which often occur in patients with a history of mental illness) may also necessitate a reduction in dosage or withdrawal of treatment. Cardiac dysrhythmias have been reported infrequently. Apart from the rare cardiovascular complications all side-effects have been dose-dependent and reversible. Levodopa should be given with extreme caution to patients with cardiovascular, endocrine, renal, hepatic or pulmonary disease.
L-dopa was administered to 15 institutionalized parkinsonian patients with significant impairment or instability of higher cortical functions. All of these patients save 2 with post-encephalitic disease showed substantial reduction of parkinsonian symptoms and disabilities; however, within one to fifteen weeks, they developed crippling adverse reactions with the continued administration of L-dopa. In 11 of 15 patients these reactions took the form of confusionai or hallucinatory states of abrupt onset and great severity, associated with chorea and akathisia and followed by the development of stupor or coma; 4 patients moved at once into stuporous or comatose states without preceding periods of excitement. All patients who had experienced severe delirious disorganization showed exacerbated intellectual deficits many months after the withdrawal of L-dopa. It is concluded that parkinsonian patients with dementia may suffer prolonged and perhaps permanent disorganization of higher functions from the administration of L-dopa and should be given this drug only with the utmost caution.
An acute confusional hallucinatory syndrome, followed by stupor and permanent dementia occurred in a patient with mild idiopathic parkinsonism receiving trihexyphenidyl, amantadine, and levodopa. During the stuporous period, his eyes were divergent, with absent oculocephalic reflexes. There were no abnormalities of other cranial nerve functions or long tract signs. Intravenous doses of pyridoxine were of no benefit. The electroencephalogram was diffusely slow. Results of laboratory studies were unremarkable, except for mild hydrocephalus ex vacuo. Seventeen days after onset, he began to recover from stupor, and became alert but profoundly demented until his death four months later. Neuropathological changes included depigmentation, neuronal loss, gliosis and Lewy bodies in the substantia nigra, mild hydrocephalus, mild atherosclerotic changes in basilar and carotid arteries, and a few tiny cerebellar infarcts Pathological changes did not explain the acute illness.
Two groups of left (N = 80) and right (N = 80) brain-damaged patients were given a battery of neuropsychological tests, with the aim of carrying out a detailed analysis of their emotional reactions in front of failures. Behaviors denoting a catastrophic reaction , or indicating an anxious-depressive orientation of mood (anxiety reactions, bursts of tears, vocative utterances, depressed renouncements or sharp refusals to go on with the examination) were found to be statistically more frequent among left brain-damaged patients. On the contrary, symptoms denoting an opposite emotional reaction (anosognosia, minimization, indifference reactions and tendency to joke) and expressions of hate toward the paralyzed limbs were found to be significantly more frequent among patients suffering from a lesion of the minor hemisphere. The depressivecatastrophic reactions of the left brain-damaged patients were found chiefly in subjects with severe aphasia, and appeared generally after repeated failures in verbal communication. They seemed due, as Goldstein argued, to the desperate reaction of the organism, confronted with a task that it cannot face.
The topographical distributions of dopamine, norepinephrine, and serotonin were mapped in the human neostriatum in 6 normal brains and in 2 brains from patients with Parkinson's disease. The neostriatum was divided into putamen and four sections of the caudate nucleus: inferior and superior heads and rostral and caudal tails.In normal man, the monoamine occurring in highest concentration is dopamine, which is fairly evenly distributed throughout the entire neostriatum (at a concentration around 3500 ng/g) except for the caudal tail. This region has a concentration of dopamine only 20% of that in the remainder of the neostriatum. Norepinephrine is virtually non-existent in the neostriatum except in the inferior head of the caudate nucleus where a concentration of 262 ng/g is found. Serotonin is evenly distributed throughout the entire neostriatum at a concentration around 800 ng/g.The difference in the distribution of these three monoamines implies a difference in function among the regions of the neostriatum. There is evidence in the literature to support the concept of somatotopic localization in the neostriatum.In Parkinson's disease there is a reduction of all three monoamines, with the greatest loss of dopamine in the putamen. All regions of the caudate also show a reduction of dopamine, although this is less severe than in the putamen. Norepinephrine in the inferior head of the caudate nucleus is significantly reduced. Serotonin is unevenly reduced throughout the entire neostriatum.The uneven reduction of dopamine and serotonin appears to preclude the possibility of a defect in the transport of precursor amino-acids into brain and in the synthesis, storage, and degradation of the monoamines in Parkinson's disease. Rather, it seems that the most likely explanation of these results is a defect of the neuronal cell bodies that contain monoamines and neuromelanin pigment. The etiology of such an unevenness of involvement of this system degeneration is not known, but could involve an infectious, nutritional, toxic, or other unknown factor. An analysis of the results in these patients and of the data in the literature also suggests that: (1) akinesia results from reduction of neostriatal dopamine; (2) rigidity is secondary to reduction of neostriatal dopamine plus some additional unknown factor; (3) chorea may be related to an increased dopamine/receptor ratio in the neostriatum and that serotonin and norepinephrine may also play a role; and (4) tremor at rest may result from reduced neostriatal content of dopamine and serotonin plus some additional factor, perhaps involvement of the rubro-olivo-cerebello-rubral loop or of rubrotegmentospinal fibers.
The concentrations of somatostatin in the cortex, hippocampus and caudate nucleus of subjects with Parkinson's disease were determined by radioimmunoassay. Somatostatin levels in the frontal cortex were significantly reduced in Parkinsonian subjects who were slightly or severely demented compared to controls and to non-demented Parkinsonians. Significant reductions were also observed in the hippocampus and entorhinal cortex of severely demented subjects.
The hypothesis was tested that unilateral dopamine deficiency leading to the contralateral extrapyramidal syndrome (hemi-parkinsonism) would cause distinctly asymmetric EEG sleep patterns. In 7 hemi-Parkinson's patients 2 nights of sleep were monitored along with pre-sleep waking periods. No medication was given prior to the first night. The second night followed at least 2 months of L-DOPA medication. Although in all patients sleep architecture was disturbed, no statistically significant asymmetries of sleep patterns were obtained. L-DOPA medication improved the quality of sleep. Delta sleep was most visibly improved. Also, post-treatment enhancement of the mean delta power over the parkinsonian hemisphere was supported statistically. The role of dopamine in slow wave sleep control and mechanisms of contralateral hemisphere involvement are discussed.
Repeated electroconvulsive shock, applied to rats, induces a subsensitivity of dopamine autoreceptors located in the substantia
nigra as indexed by single-unit electrophysiological techniques. This reduced sensitivity is time-dependent, since effects
similar to those seen with repeated treatment were also observed when single electroconvulsive shock was followed by an appropriate
treatment-free interval. These data, coupled with identical results after the repeated administration of tricyclic antidepressants,
raise the possibility that a reduction of dopamine autoreceptor sensitivity could underlie both electroconvulsive shock and
pharmacological treatment of depression.
Abnormalities of cerebral oxidative metabolism were investigated in "animal models" of Parkinson disease by in situ optical measurements of local cerebral blood volume and cytochrome oxidase redox shifts in rats two weeks after unilateral 6-hydroxydopamine lesions of the substantia nigra with or without interruption of ascending noradrenergic pathways. The data demonstrate oxidative metabolic dysfunction of ipsilateral cerebral hemispheres caused by lesions that involve both dopaminergic and noradrenergic systems but not when dopaminergic neurons only are affected. We speculate that the dementia of Parkinson disease may be more prevalent when degeneration of catecholaminergic systems is widespread and not restricted to the dopaminergic system.
An extensive set of neuropsychological measures was administered to 60 Parkinson's disease patients and age-, sex-, and education-matched controls in order to investigate the nature and prevalence of the cognitive deficit in the disease. Parkinsonian patients performed significantly poorer on all measures with the exception of tests for apraxia and object recognition, and on a test of vocabulary knowledge. Discriminant analysis of the test data revealed that over 93% of patients are impaired relative to matched controls, but that assigning a prevalence rate for dementia in the disease may be difficult due to the continuous distribution of cognitive deficits.
Nineteen patients with L-DOPA treated parkinsonism involving depressive symptoms, the therapeutic effect of nortriptyline was compared to placebo in a controlled trial. The depressive and neurological symptoms were evaluated by rating scales. Nortriptyline had a clinical significant effect with regard to the depressive symptoms, whereas the neurological parameters were unchanged. The authors suggest the depression in Parkinson's disease to be of both reactive and endogenous origins.
20, not yet severely disabled, drug-free patients with Parkinson's disease were investigated with regard to their motor deficit and mood disturbances. Global scores of depression indicated a high depressive morbidity which did not correlate with the severity of parkinsonism and which could not be adequately explained by physical disability. The apathic syndrome had a close relationship to the severity of parkinsonism. In contrast, the somatic-depressive syndrome did not show such a relationship. Patients predominantly affected by tremor felt subjectively better than the others. These facts demonstrate that it is necessary to break down the complex syndromes of parkinsonism and depression into more elementary dysfunctions in order to evaluate their mutual interdependence.
The antiparkinsonian effect of electroconvulsive therapy (ECT) was investigated in nine parkinsonian patients with “on-off” phenomena. The patients were maintained on previously adjusted doses of antiparkinsonian drugs during and after ECT. Parkinsonian as well as mental symptoms were rated before and after treatment.
Basal serum levels of prolactin (PRL) and growth hormone (GH) as well as apomorphine induced changes (0.24 mg i.v.) in these levels were investigated three days before start of treatment.
Marked improvement of parkinsonian symptoms was seen in five patients. Two further patients showed slight improvement. The improvement persisted for 2–41 weeks. Improvement after ECT was found to correlate with age at the time of treatment and with duration of L-dopa therapy as well as the estimated life-dose of L-dopa. No correlation was found between improvement of parkinsonian symptoms and either scores of mental depression before treatment, basal serum levels of GH and PRL or apomorphine induced changes in these hormone levels. The investigation indicates that ECT is a valuable adjuvant in the treatment of a selected group of parkinsonian patients with “on-off” phenomena. Furthermore, the results support our earlier proposal that ECT increases the responsiveness in postsynaptic dopamine sensitive structures.
Dopamine (DA) has largely been ignored in considering possible mechanisms underlying the therapeutic effects of tricyclic anti-depressants (TCA). Most previous work done has focused on the ability of some TCAs to block the in vitro re-uptake of DA--an effect which unfortunately requires very high doses. Recently, however, Serra et al. proposed that TCAs may exert their therapeutic effects by inducing a subsensitivity of presynaptic receptors located on the dendrites and soma of DA neurones (DA autoreceptors). This hypothesis was directly tested by examining the influence of TCAs on the demonstrated ability of the DA agonist, apomorphine, to depress selectively the spontaneous activity of single DA cells. We now report that repeated administration of both typical and atypical TCAs induces a progressive subsensitivity of DA autoreceptors, and that this gradual augmentation of DA autoreceptor subsensitivity depends on the passage of time rather than daily TCA administration. The latter finding suggests that daily drug administration may not be therapeutically necessary.
The fact that there is a need for assessing depression, whether as an affect, a symptom, or a disorder is obvious by the numerous scales and inventories available and in use today.
- C L Mallows
Mallows. C.L. Some comments on CP. Technomerrics,
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Hemisyndromes of temporal lobe epilepsy: Review of evidence relating psychopathological manifestations in epilepsy to right- and left-sided epilepsy
- Flor-Henry
Cerebral lateralization in the rat and tentative extrapolations to man
- Glick
Parkinsonism: Onset, progression, and mortality
- Hoehn
Is there hemi-aging?
- Lapidot
Experimental analysis of cerebral dominance in man
- Rossi
Hemisphere laterality vs. hemisphere interdependence: An answer from analysis of dopamine hemi-deficiency syndrome
- Myslobodsky
Pharmacopsychotherapy and aberrant brain laterality
- Myslobodsky