Treatment of the “on-off” phenomenon in parkisnonism with lithium carbonate

Six patients with severe parkinsonism complicated by the “on-off” phenomenon were treated with lithium carbonate in addition to regular antiparkinsonian medications. A randomized double-blind crossover trial of lithium versus placebo was conducted, followed by an open trial of lithium therapy. Five patients had marked reductions in akinesia (mean, 70%) and improved by one grade in parkinson staging. This result was more striking in male than in female patients, and in all responders benefit has been maintained during the open phase of lthium treatment (mean follow-up of 36 weeks). In no patient was reduction in akinesia observed during placebo treatment. Lithium carbonate appears to offer a new and potentially effective approach to treatment of the on-off phenomenon.     

Treatment of motor fluctuations in Parkinson's disease with an oral sustained-release preparation of L-dopa: clinical and pharmacokinetic observations

Ten patients with idiopathic Parkinson's disease and severe motor-fluctuations participated in an open inpatient trial comparing the efficacy of standard L-Dopa/benserazide (Madopar) treatment with that of an oral sustained-release preparation (Madopar HBS) combined with the standard drug. Clinical assessments of the patients' parkinsonian disabilities were performed daily by one of the investigators and subjects kept self-scoring "on-off" diaries throughout the trial. Plasma concentrations of L-Dopa were followed during both types of therapy in five cases using standard high performance liquid chromatography technique. Sustained-release L-Dopa treatment led to a reduction in end-of-dose deterioration and on-off swings in six patients and doses needed averaged 1.6-fold of previous standard L-Dopa. Drug-induced dyskinesias decreased in one case with sustained-release therapy, remained unchanged in three, and increased in six cases when compared with conventional L-Dopa. Plasma levels of L-Dopa were more stable with the sustained-release preparation in four of five patients. During subsequent outpatient follow-ups of up to 4 months, three of the six responders in this study continued to obtain benefit from the trial drug. It is concluded that oral sustained-release L-Dopa treatment can reduce response-fluctuations in patients with Parkinson's disease.     

Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults

Summary Responses of seizures to therapy is one of the most important prognostic factors in epilepsy. Absences are among the seizure types with a good response to antiepileptic drug treatment and, usually, remission before adult age. Absence patients attending an epilepsy clinic for adults can be expected to represent a group with negative bias because they have not yet remitted. Furthermore, the majority have additional generalized tonic-clonic seizures, which is a recognized negative factor in prognosis. We studied 229 adolescents and adults who were under our care for at least 2 years, and divided them into three groups according to their becoming absence free for at least 1 year: (1) responders to simple therapy (one anti-absence drug in doses not exceeding 2 g/day); (2) responders to complex therapy (one anti-absence drug in higher dose or combination of anti-absence drugs); (3) non-responders. Groups 1 and 2 can be considered jointly as responders as opposed to the non-responder group. Similarly, groups 2 and 3 can be considered jointly as a group with poor as opposed to good therapeutic response. It was found that significant differences exist between good and poor responders, and 15 factors which had a negative effect on therapeutic response could be identified. No single factor or combination was responsible for non-response, but non-responders had the highest score of negative factors. Patients with complete absence control had a 93% chance of total seizure control, and, with constant medication, relapses after 1 year of control were very infrequent. The conclusion of this study is that complete absence control is of great prognostic importance for patients having this seizure type. With active treatment using, if necessary, high doses of succinimides or valproic acid alone or in combination, excellent results can be achieved even in a patient group biased towards a poor prognosis.Dr. Inoue, from the National Epilepsy Centre, Shizuoka, Japan, is a scholar of the Deutscher Akademischer Austauschdienst (DAAD)     

The influence of sleep position and obesity on sleep apnea

The influence of sleep position and the degree of obesity were examined in 257 subjects with sleep apnea. Subjects were divided into three groups according to obesity: normal weight (body mass index (BMI) under 24.0 kg/m2), mild obese (BMI 24.0-26.4 kg/m2) and obese group (BMI 26.4 kg/m2 and heavier). The apnea + hypopnea index (AHI), the intraesophageal pressure and the lowest oxygen saturation became significantly worse according to the degree of obesity. The subjects were also divided into two groups according to the reduction in the AHI by lateral position: good responders showed 50% or more reduction of AHI in lateral position and poor responders indicated less than 50% reduction. The percentage of good responders to sleep position change was 90.9% in normal weight group, 74.0% in mild obese group and 57.4% in the obese group. The ratio of the subjects who had indicated two or more obstructive sites in normal weight group was 36.0% in good responders and 40.0% in poor responders. The ratio in the mild obese group was 51.8% in good responders and 66.7% in poor responders. In the obese group, the ratio was 59.4% in good responders and 78.9% in poor responders.     

The L-dopa on-off effect in parkinson disease: Treatment by transient drug withdrawal and dopamine receptor resensitization

It has been suggested that patients with Parkinson disease partially compensate for neuron loss by developing denervation supersensitivity, and, if so, that prolonged levodopa (L -dopa) therapy might lead to desensitization. As a preliminary test of this hypothesis, and in order to study whether it was possible to “resensitize” a patient who had already presumbly been desensitized by previous L -dopa therapy, a patient who had become unpredictably responsive to L -dopa was investigated. The patient had been taking L -dopa for eight years and had exhibited severe dyskinesia-akinesia oscillation (“on-off” phenomenon) before the study. There was no consistent response to his hourly doses of Prolopa (L -dopa and benserazide in a 4:1 ratio). He was first lowered, over 33 days, to 20% of his original Prolopa dose. The dosage was then increased until a consistent response were observed. The three main results achieved were, first, overall reduction by 64% of the daily requirement for L -dopa; second, conversion from a previously unpredictable to a predictable response to each dose of L -dopa; and, third, change in his movement fluctuations to a pattern more typical of “end-of-dose” akinesia than the “on-off” phenomenon. The results support the idea of dopamine receptor resensitization upon reduction of the L -dopa dosage.     

EEG differences between good and poor responders to methylphenidate in boys with the inattentive type of attention-deficit/hyperactivity disorder.

OBJECTIVES: This study investigated electroencephalographic (EEG) differences between good and poor responders to methylphenidate in boys with the Inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD).METHODS: Twenty good and 15 poor responders to methylphenidate, based on the results of a continuous performance task, and 35 age- and sex-matched control subjects, participated in this study. EEG was recorded from 21 sites during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and absolute and relative power in the delta, theta, alpha and beta bands, and for the theta/alpha and theta/beta ratios.RESULTS: EEG differences were found between the ADHD children and controls which were compatible with previous literature on the Inattentive type. Differences were also found between the good and poor responders to methylphenidate.CONCLUSIONS: Good responders had EEG profiles that suggested that they were more cortically hypoaroused than poor responders.     

EEG differences between good and poor responders to methylphenidate and dexamphetamine in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: This series of studies investigated (1) electroencephalographic (EEG) differences between good and poor responders to methylphenidate, (2) EEG differences between good and poor responders to dexamphetamine, and (3) differences in the EEGs of good responders to methylphenidate versus dexamphetamine, within samples of children with the combined type of attention-deficit/hyperactivity disorder (ADHD). METHODS: Twenty good and 20 poor responders to each of methylphenidate and dexamphetamine, based on the results of a continuous performance task, and 20 age-matched control subjects, participated in this study. EEG was recorded from 21 sites during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and absolute and relative power in the delta, theta, alpha and beta bands, and for the theta/alpha and theta/beta ratios. RESULTS: EEG differences were found between the good and poor responders to each medication. Good responders to methylphenidate had EEG profiles that suggested that they were more cortically hypoaroused than poor responders. In contrast, the good responders to dexamphetamine appeared to be more maturationally lagged than the poor responders. The two good-responder groups had EEG profiles which suggested that there were two different underlying central nervous system (CNS) dysfunctions. CONCLUSIONS: Children with the combined type of ADHD do not constitute a homogeneous clinical group, as different types of CNS dysfunction are present within this population. These results also indicate the need for medication testing to be undertaken before a child is prescribed stimulant medication for ADHD.     

Compulsive use of dopaminergic drug therapy in Parkinson's disease: Reward and anti‐reward

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use (“dopamine dysregulation syndrome”—DDS). DDS patients commonly identify aversive dysphoric “OFF” mood‐states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non‐motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the “OFF”‐state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full “ON”‐state was achieved. In the “OFF”‐state, DDS patients reported lower positive affect, and more motor and non‐motor disability. In the “ON”‐state, DDS patients had higher expressions of drug “wanting,” reward responsivity, and dyskinesias. Positive and negative affect, non‐motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication. © 2010 Movement Disorder Society     

Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: as a biological predictor of response to group cognitive behavioral therapy

Little is known about biological predictors of treatment response in panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common etiologies of depression and anxiety, the authors examined serum BDNF levels of the patients with panic disorder, and its correlation with therapeutic response to group cognitive behavioral therapy (CBT). Group CBT (10 consecutive 1 h weekly sessions) was administered to the patients with panic disorder after consulting the panic outpatient special service. Before treatment, serum concentrations of BDNF and total cholesterol were measured. After treatment, we defined response to therapy as a 40% reduction from baseline on Panic Disorder Severity Scale (PDSS) score as described by [Barlow, D.H., Gorman, J.M., Shear, M.K., Woods, S.W., 2000. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA. 283, 2529-2536]. There were 26 good responders and 16 poor responders. 31 age- and sex-matched healthy normal control subjects were also recruited in this study. The serum BDNF levels of the patients with poor response (25.9 ng/ml [S.D. 8.7]) were significantly lower than those of the patients with good response (33.7 ng/ml [S.D. 7.5]). However, there were no significant differences in both groups of the patients, compared to the normal controls (29.1 ng/ml [S.D. 7.1]). No significant differences of other variables including total cholesterol levels before treatment were detected between good responders and poor responders. These results suggested that BDNF might contribute to therapeutic response of panic disorder. A potential link between an increased risk of secondary depression and BDNF remains to be investigated in the future.     

Clinical characteristics and treatment response in poor and good insight obsessive-compulsive disorder.

The DSM-IV criteria recognize the existence of obsessive-compulsive disorder (OCD) with poor insight. However, there is paucity of literature on the clinical correlates and treatment response in poor and good insight OCD. In this study, insight is measured by using the Brown Assessment of Beliefs Scale (BABS) developed specifically to assess insight. One hundred subjects with DSM-IV OCD were ascertained from the OCD clinic of a large psychiatric hospital in India. All subjects were evaluated extensively by using structured instruments and established measures of psychopathology. The subjects were treated with adequate doses of drugs for adequate period. The results showed that 25% of the subjects had poor insight. Poor insight was associated with earlier age-at-onset, longer duration of illness, more number of obsessive-compulsive symptoms, more severe illness and higher comorbidity rate, particularly major depression. Of the subjects who were treated adequately (N = 73), 44 (60%) were treatment responders. Poor insight was associated with poor response to drug treatment. In the step-wise logistic regression analysis, baseline BABS score was highly predictive of poor treatment response. Poor insight appears to be associated with specific clinical correlates and poor response to drug treatment. Further studies are needed in larger samples to replicate our findings.     

EEG sleep changes as predictors in depression.

The authors conducted a study of 18 depressed patients to see whether EEG sleep measurements might provide a predictive tool for response to antidepressant medication. They found that although the sedative characteristics of amitriptyline did not differentiate good responders from poor responders until the third week of drug treatment, the good responders showed significant increases in REM latency, decreases in REM sleep time, decreases in REM sleep percent, and decreases in REM activity after only 2 nights of drug treatment.     

The neurobiological mechanisms of physical exercise in methamphetamine addiction

Methamphetamine (METH) is the primary drug within amphetamine‐type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long‐term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: (“physical exercise” OR “exercise”) AND “methamphetamine.” Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood‐brain barrier as disclosed by preclinical data. Exercise‐based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction.     

Effect of a ketogenic diet on EEG: Analysis of sample entropy.

Although ketogenic diet (KD) is an effective alternative therapy for controlling intractable seizures, the anticonvulsant mechanism still remains unclear. Sample entropy (SampEn) provides a generalized measure of regularity in time-series data. To investigate the potential anticonvulsive mechanism of a KD, we analyzed the SampEn of electroencephalography (EEG) data in patients with intractable pediatric epilepsy before and after treatment with a KD. Seventeen pediatric patients with epilepsy who were treated with KD were enrolled in present study. Patients were classified as good responder and poor responder according to therapeutic responsiveness on KD. Thirty segments of 30-s epochs were selected before and after KD from each patient which were subject to SampEn. The KD increased the SampEn in the whole patient population; the SampEn increased significantly in all electrodes in the good responders, but the change in SampEn varied according to the electrode in the poor responders. Before the KD, the good responders had significantly lower SampEn values than the poor responders, but after the KD, SampEn values were higher in the good responders than in the poor responders. KD may have an anticonvulsive effect by decreasing the regularity of the EEG dynamics.     

Characteristics of the tree‐drawing test in chronic schizophrenia

Aims: A tree‐drawing test acts as both a projective psychological examination as well as a supplementary psychodiagnostic tool. There is little information relating the characteristics of schizophrenia and the tree‐drawing test. The present study compared the structural and morphological differences in the results of the tree‐drawing test between schizophrenic patients and healthy individuals, as well as between schizophrenic patients who responded well to treatment and those who responded poorly. Methods: The subjects included 202 chronic schizophrenic patients and 113 healthy individuals. The schizophrenic patients were categorized as ‘good responders’ or ‘poor responders’ based on their response to medical treatments. The tree‐drawing test was performed on all subjects. The tree drawn by each subject was analyzed structurally and morphologically. Results: There were significant differences between the trunk and branches drawn by schizophrenic patients and those drawn by healthy controls. There were no significant differences between the good responders and the poor responders in any aspect of the tree drawings. Multiple regression models showed that the ratio of the tree area to the total area of the drawing paper, the width of the trunk, the trunk base opening, and the size of the branch ends were significantly associated with schizophrenia. Conclusion: The present study suggests that the trees drawn by schizophrenic patients are significantly different from those drawn by healthy individuals, but among schizophrenic patients, it is difficult to distinguish between good responders and poor responders using the tree‐drawing test.     

帕金森病丘脑底核脑深部电刺激术后的长期随访研究

目的 研究丘脑底核脑深部电刺激(STN-DBS)术治疗帕金森病(PD)的长期临床效果.方法 对采用STN-DBS术治疗的75例PD患者进行术后长期随访.对患者手术前抗PD药物“关”与“开”状态进行统一帕金森病评定量表(UPDRS)评估;术后第1、3、5和10年,在STN-DBS持续治疗下对患者药物“关”与“开”状态进行...     

Mental state attribution in schizophrenia: What distinguishes patients with “poor” from patients with “fair” mentalising skills?

PurposeAlthough many patients with schizophrenia are impaired in mental states attribution abilities, a significant number perform within normal or near-normal ranges in mental state attribution tasks. No studies have analysed cognitive or behavioural differences between patients with – to some extent – preserved mental state attribution skills and those with poor mentalising abilities.Material and methodsTo examine characteristics of “poor” and “fair” mentalisers, 58 patients with schizophrenia performed a mental state attribution task, a test of general intelligence, and two executive functioning tests. “Poor” and “fair” mentalising skills were defined according to a median-split procedure; the median score in the patient group was also within two standard deviations of the control group. In addition, patients’ social behavioural skills and psychopathological profiles were rated.ResultsPatients performing within normal or near normal ranges on the mental state attribution task had fewer social behavioural abnormalities than patients with poor mentalising abilities (even when controlled for intelligence), but did not differ in executive functioning. Fair mental state performers showed less disorganisation and excitement symptoms than poor performers. The degree of disorganisation mediated the influence of mental state attribution on social behavioural skills.ConclusionsSchizophrenia patients with (partially) preserved mentalising skills have fewer behavioural problems in the social domain than patients with poor mentalising abilities. Conceptual disorganisation mediates the prediction of social behavioural skills through mentalising skills, suggesting that disorganised patients may require special attention regarding social-cognitive skills training.     

Non response at week 4 as clinically useful indicator for antidepressant combination in major depressive disorder. A sequential RCT

We aimed to compare the efficacy and tolerability of mirtazapine versus SSRIs and to assess whether “non-response at week 4” may be a clinical indicator for combining mirtazapine and SSRIs for subsequent treatment. One-hundred fifty-four outpatients with MDD were randomized to receive mirtazapine or SSRIs in step I (4 weeks). Non-responders in step I were randomly assigned to either mirtazapine or SSRIs monotherapy or their combination in step IIa while responders in step I continued the same monotherapy in step IIb for 4 weeks. In step I, mirtazapine showed significantly faster improvement as shown by higher remission rate at week 2 with NNT = 8 compared to SSRIs. Somnolence rate was higher in mirtazapine and nausea rate was higher in SSRIs. In step IIa, combination therapy showed a more favorable time course than SSRIs monotherapy. For subjects taking SSRIs in step I, combination therapy showed significant better improvement in the Hamilton Depression Rating (HAM-D) score both at week 6 (p = 0.006) and 8 (p = 0.013) than SSRIs monotherapy. About 80% of responders at week 4 could reach remission at week 8 and 64% of non-responders could not reach remission at week 8 for patients who continued monotherapy. When mirtazapine was added on for SSRIs non-responders at week 4, the remission rate increased by 5% and HAM-D score improved by 4 points. While for mirtazapine non-responders, SSRIs add-on was not equally effective.Mirtazapine may provide a faster improvement and “non-response at week 4” may be indicator to mirtazapine add-on for patients receiving SSRIs.     

Increased basal platelet activity, plasma adiponectin levels, and diabetes mellitus are associated with poor platelet responsiveness to in vitro effect of aspirin

INTRODUCTION: Aspirin is one of the most effective antiplatelet agents and is now commonly used to prevent vascular events. In some patients, however, recurrent vascular events have been demonstrated despite aspirin therapy. Our objective was to characterize individuals showing poor response to in vitro effect of aspirin, using PFA-100. METHODS: One hundred sixty-eight healthy male subjects were analyzed. We assessed platelet function tests, including PFA-100, whole blood aggregation, and optical platelet aggregation. Also measured were hemostatic and other parameters including von Willebrand factor (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), soluble vascular adhesion molecule-1 (sVCAM-1), high sensitive C-reactive protein (hs-CRP), and adiponectin. Poor responders were defined as having a collagen/epinephrine-induced closure time (CEPI-CT) under 250 s with PFA-100 when incubated with 10 microM aspirin, whereas good responders were defined as having a CEPI-CT of more than 250 s. RESULTS AND CONCLUSIONS: PFA-100 tests revealed that 40 subjects (24%) were poor responders (PR) and 128 (76%) were good responders (GR). Poor responsiveness was significantly associated with (1) higher basal platelet activities in PFA-100, as well as in whole blood aggregation and aggregometer;(2) increased level of adiponectin (8.8+/-4.1 micro g/mL [PR] vs 7.3+/-2.9 micro g/mL [GR], p=0.010);and (3) the presence of diabetes mellitus (17.5% [PR] vs 4.7% [GR], p=0.009). Importantly, whereas 24% of the subjects showed insufficient inhibition in PFA-100 when incubated with 10 microM aspirin, almost all subjects showed maximum inhibition with 30 microM aspirin. These observations suggest that higher doses of aspirin might overcome aspirin resistance.     

Ocular dyskinesias in patients with Parkinson's disease treated with levodopa

Abnormal involuntary eye movements were found in 8 of 27 patients with Parkinson's disease who were receiving levodopa and dopa decarboxylase inhibitors. The dyskinetic eye movements were smooth, slow, “to-and-fro” ocular deviations of large amplitude. They were suppressed by visual fixation and were prominent only in darkness or behind closed lids when patients were alert. They generally appeared in conjunction with involuntary body and limb movements but could occur alone. Many of the patients with ocular dyskinesias had prominent “on-off” responses to levodopa. Ocular dyskinesias were present in 8 of 10 patients with bodily dyskinesias. This suggests that if recording conditions are appropriate, these eye movements will commonly be found in patients with Parkinson's disease who develop abnormal involuntary bodily movements while they are receiving levodopa therapy.     

Treatment of "on-off effect" with a dopa decarboxylase inhibitor.

Irregularities in motor response after continuing levodopa therapy of Parkinson disease (the "on-off effect") were assessed with the addition of L-alpha-methyldopa hydrazine (carbidopa) in a double-blind study. Thirteen of 20 patients improved while receiving carbidopa and levodopa while only four of 17 patients improved while receiving placebo and levodopa. Twenty-three of 37 patients improved in a subsequent non-blind trial of carbidopa plus levodopa. Improvement was not dependent on an increase in dose or frequency of levodopa administration. Adverse effects included dyskinesia, imbalance, and confusion; nausea was eliminated. On patient died of glomerulonephritis that predated the drug trial, but worsened progressively during and after it. Carbidopa's suppression of the "on-off effect" suggests that extracerbral factors may be important in this phenomenon.