Fast versus slow onset of depressive episodes: a clinical criterion for subtyping patients with major depression.

PURPOSE: The speed of onset of depressive episodes is a clinical aspect of affective disorders that has not been sufficiently investigated. Thus, we aimed to explore whether patients with fast onset of the full-blown depressive symptomatology (≤7 days) differ from those with slow onset (>7 days) with regard to demographic and clinical aspects. SUBJECTS AND METHODS: Data were obtained within an observational study conducted in outpatients with major depression who were treated with duloxetine (30-120 mg/day). Onset of depression (without any preceding critical life event) was fast in 416 (less than one week) and slower in 2220 patients. RESULTS: Compared to patients with slow onset, those with fast onset of depression had more suicide attempts in the previous 12 months (2.7% versus 1.3%, P=0.046) and less somatic comorbidity (61.7% versus 74.1%, P<0.0001). In addition, they were slightly younger at onset of depression (mean±SD 40.2±14.6 versus 42.8±14.2 years, P<0.001) and used analgesics at baseline significantly less frequently (22.8% versus 33.4%, P<0.0001). DISCUSSION AND CONCLUSION: The speed of onset of depression has to be regarded as a relevant clinical characteristic in patients with unipolar depression.

Does pain improve earlier than mood in depressed patients with painful physical symptoms treated with duloxetine?

INTRODUCTION: In depressed patients tricyclic antidepressants and selective serotonin and noradrenaline reuptake inhibitors can reduce not only depressive, but also painful physical symptoms. We investigated whether under treatment with duloxetine pain improves earlier than mood. METHODS: Data were obtained within a prospective 6-month multi-centre naturalistic study in adult out-patients with depressive episodes treated with duloxetine (fl exible doses: 30-120 mg/day). Pain and mood were assessed daily by visual analogue scales. For responders (n = 622) "time to 50 % pain response" and "time to 50 % mood response" were determined by counting the earliest day between day 0 and 27, at which the patient achieved 50 % improvement. RESULTS: Mean time to 50 % pain response (mean 6.3 days, SD 5.3) was significantly shorter than time to 50 % mood response (mean 7.6 days, SD 6.0, mean difference 1.3 days, SD 6.4; p < 0.0001). DISCUSSION: In duloxetine-responders to both pain and mood, self-rated pain improved slightly earlier than self-rated mood. The short temporal dissociation between pain and mood improvement might be explained by an earlier conscious perception of pain than mood changes.

Treatment of severe agitation with olanzapine in 166 patients with schizophrenia, schizoaffective, or bipolar I disorder.

INTRODUCTION: Agitation is a common phenomenon in schizophrenia or acute mania. Because of the inability of patients to give informed consent in such situations, data from consenting studies are limited. METHODS: This observational prospective 5-day study evaluated the effectiveness of olanzapine in a sample of highly agitated patients with aggression. Primary endpoint was mean change of the PANSS-Excited Component (PANSS-EC) score. RESULTS: Mean PANSS-EC score at baseline was 25.5 points, 60.2% were severely agitated and 41.6% severely aggressive. A significant decrease in PANSS-EC total score (-13.3 points) was observed with rapid dose escalation and an average daily dose of 21.2 mg/day of olanzapine. 40 patients (24.1%) required treatment with another antipsychotic and 21 patients (12.7%) were not treated with olanzapine at day 5. At endpoint, 64.2% of patients were in remission of agitation. PANSS-EC reduction was not significantly different in patients with or without concurrent benzodiazepine use. DISCUSSION: Severe agitation with aggression may be well controlled with olanzapine in many cases, possibly by higher initial and overall doses of olanzapine. Controlled studies are needed to confirm these findings.

Rates and predictors of remission and recovery during 3 years in 392 never-treated patients with schizophrenia.

OBJECTIVE: Few studies have prospectively examined remission and recovery as well as their predictors in schizophrenia simultaneously. Aims of the study were to identify remission and recovery rates as well as their predictors in schizophrenia. METHOD: 392 never-treated patients with schizophrenia were assessed over 3 years. Combined remission and recovery required concurrent achievement of symptomatic and functional remission as well as adequate quality of life for at least 6 and 24 months respectively. Predictors were analysed using stepwise logistic regression models. RESULTS: At 3 years, remission rates for symptoms, functioning and subjective wellbeing were 60.3%, 45.4% and 57.0%; recovery rates were 51.7%, 35.0% and 44.3%. Of those, 28.1% were in combined remission and 17.1% in combined recovery. Predictors mainly included the baseline functional status and early remission within the first 3 months. CONCLUSION: The proportion of patients who met combined remission or recovery criteria is low. Early treatment adaptations in case of early non-remission are mandatory.

Corticostriatal covariance patterns of 6-[18F]fluoro-L-dopa and [18F]fluorodeoxyglucose PET in Parkinson's disease.

6-[18F]fluoro-L-dopa (FDOPA) is a common presynaptic dopaminergic tracer used in examinations by positron emission tomography (PET) for patients with Parkinson's disease (PD). The distinct metabolic covariance pattern in the uptake of [18F]fluorodeoxyglucose (FDG) can also be used to investigate PD pathology. Although the two tracers are widely used in PD research and clinical assessment, no thorough comparative studies of the tracers have been made. In this study, 25 PD patients were examined with FDOPA and FDG to investigate relationships and clinical correlates of metabolic and monoaminergic function in the Parkinsonian brain. A VOI (volume-of-interest) analysis was achieved by 3D spatial normalisation and fixed VOI-sets. The hemisphere ipsi- and contralateral to the predominant symptoms of PD was identified in each data set, and data across subjects were related using that laterality, rather than body side. Regional covariance patterns for FDOPA and FDG were derived from principal component analysis (PCA). The results demonstrated hemispheric asymmetries and sex-differences in the striatal FDOPA uptake, which were not seen with FDG. In addition, the PCA analysis identified a positive relationship between a major component in FDOPA uptake (associated with the striatal uptake) and an FDG component, which had positive loadings in the thalamus and the cerebellum. The subject scores for these components correlated positively, and both had a negative association with the clinical severity of the disease. The specific extrastriatal FDG covariance pattern contained the thalamus and the cerebellum, components of the previously reported PD related pattern, but not the striatum. The network correlated with both the severity of clinical symptoms of PD and the severity of nigrostriatal dopaminergic hypofunction. The results indicate that FDG PET, when combined with multivariate network analysis at group-level, can be used as an indicator of PD severity.

Efficacy of pergolide in treatment of restless legs syndrome: the PEARLS Study.

OBJECTIVE: To evaluate the short- and long-term safety and efficacy of pergolide therapy for restless legs syndrome (RLS) in a double-blind, placebo-controlled, randomized trial (Pergolide European Australian RLS [PEARLS] study). METHODS: We randomized 100 patients with idiopathic RLS were randomized to pergolide, 0.25 to 0.75 mg, in the evening or placebo for 6 weeks (phase 1); thereafter, patients with response on the Patient Global Impression (PGI) scale continued on double-blind pergolide or placebo, and nonresponders received open-label pergolide up to 1.5 mg/d for 12 months of treatment (phase 2). Sleep efficiency (SE) and periodic limb movements during sleep (PLMS) arousal index were monitored by centrally evaluated polysomnography (PSG). The severity of RLS was assessed using the validated International RLS Scale (IRLS). RESULTS: In phase 1 (change from baseline to week 6), pergolide reduced PLMS arousal index vs placebo (mean +/- SD, -12.6 +/- 10.0 vs -3.6 +/- 15.9; p = 0.004), and SE did not improve (mean +/- SD, +11.3 +/- 11.9% vs +6.1 +/- 18.6%; p = 0.196). Pergolide improved RLS severity score (-12.2 +/- 9.9 vs -1.8 +/- 7.5 placebo; p < 0.001) and was associated with a higher PGI response (68.1% vs 15.1%; p < 0.001) and improvements in periodic limb movements (PLM) index, PGI improvement scale, Clinical Global Impression improvement, and IRLS (all p < 0.001), patient-reported SE (p = 0.019), and quality of sleep (p < 0.001). After 12 months (phase 2), double-blind pergolide maintained improvements in PLMS arousal index and PLM index. Placebo patients switched to open-label pergolide in phase 2 exhibited marked improvements in these measures that were maintained at 12 months. Pooled results from the blinded and open-label pergolide groups demonstrated improvements at 12 months in the PLMS arousal index (p = 0.028) and PLM index (p < 0.0001) compared with placebo. Nausea and headache were more frequent with pergolide than with placebo treatment. CONCLUSIONS: Pergolide substantially improves periodic limb movement measures and subjective sleep disturbance associated with restless legs syndrome. Low-dose pergolide was well tolerated and maintained its efficacy in the long term.

Pergolide protects dopaminergic neurons in primary culture under stress conditions.

Dopamine agonists are an important therapeutic strategy in the treatment of Parkinson's disease. They postpone the necessity for and reduce the required dose of L-3,4-dihydroxyphenylalanine (L-DOPA) medication thus protecting against the development of motor complications and potential oxidative stress due to L-DOPA metabolism. In primary cultures from mouse mesencephalon we show that pergolide, a preferential D(2) agonist enhanced the survival of healthy dopaminergic neurons at low concentrations of 0.001 microM. About 100 fold higher concentrations (0.1 microM) were necessary to partially reverse the toxic effects of 10 microM 1-methyl-4-phenylpyridinium (MPP(+)). Pergolide was equally effective in preventing the reduction of dopamine uptake induced by 200 microM L-DOPA. Furthermore, between 0.001-0.1 microM it also reduced lactate production thus promoting aerobic metabolism. The present findings suggest that pergolide protects dopaminergic neurons under conditions of elevated oxidative stress.

A new design of a polysomnography-based multi-center treatment study for the restless legs syndrome.

Periodic limb movements (PLM) cause sleep disorders and daytime symptoms and are frequently associated with restless legs syndrome (RLS). Treatment of RLS with increased PLM during sleep (PLMS) has been evaluated in studies limited in size, methodology and study length. This long-term, placebo-controlled, multi-center, study with polysomnography (PSG) recordings has been designed in order to assess efficacy and safety parameters of pergolide treatment in RLS. This novel approach for a study was created to assure consistently high quality of sleep recording and analysis. Using defined criteria, 21 sleep centers were approved for the study after a pilot phase. Seventeen centers with 16 different PSG systems randomized 100 patients. Digital sleep recordings from 4 visits (baseline, 6 weeks, 6 months, 1 year) were submitted to one central evaluation center following previously defined standardized operating procedures. Visual scoring of all recordings was performed by one independent scorer. Reliability of scoring was evaluated for 20 randomly selected baseline recordings. The mean epoch by epoch agreement for sleep stages was 88% (range 81-96%), mean arousal re-scoring differed by 0.5 (range: -16 to 20), and mean PLM index re-scoring differed by 0.1 (range: -1.5 to 2.1). Using one scorer with a demonstrated high reliability in PSG scoring for all sleep recordings was very effective in terms of study cost, study duration, and data quality.

Adaptive frequency decomposition of EEG with subsequent expert system analysis.

We present a hybrid system for automatic analysis of clinical routine EEG, comprising a spectral analysis and an expert system. EEG raw data are transformed into the time-frequency domain by the so-called adaptive frequency decomposition. The resulting frequency components are converted into pseudo-linguistic facts via fuzzification. Finally, an expert system applies symbolic rules formulated by the neurologist to evaluate the extracted EEG features. The system detects artefacts, describes alpha rhythm by frequency, amplitude, and stability and after artefact rejection detects pathologic slow activity. All results are displayed as linguistic terms, numerical values and maps of temporal extent, giving an overview about the clinical routine EEG.

Long-term effects of pergolide in the treatment of restless legs syndrome.

An open follow-up of a controlled study in patients with restless legs syndrome (RLS) shows that the beneficial effect of pergolide on RLS symptoms persists throughout at least 1 year. Twenty-two patients of 28 (78.6%) continued to take pergolide. Polysomnographic measurements showed a persistent improvement of PLM index, PLMS arousal index, total sleep time, and sleep efficiency (p = 0.0001). Side effects, in particular nausea, were common but were well controlled by domperidone in most patients.

Efficacy and safety findings from naturalistic fluoxetine drug treatment in adolescent and young adult patients.

This article reports on the efficacy and safety of the selective serotonin reuptake inhibitor, fluoxetine, in 213 patients (ages 11-23 years) treated by psychiatrists/neurologists (PN) or general practitioners/internists (GPI). Data were derived from naturalistic drug utilization observation (DUO) studies with fluoxetine (n = 18,759 patients). Data collection--at the start and the end of the observation period (< or =6 weeks)--included patient characteristics, diagnoses, medication, co-medication, efficacy, and adverse events (AEs). Nonparametric statistics and descriptive p values (two-tailed) were used. Analyses revealed various differences between PN (n = 56) and GPI (n = 157) samples as to patient and treatment characteristics (p < 0.001-0.08). Based on both Clinical Global Impression (CGI; all p < 0.001) and self-assessment (total n = 47; Zung SDS, all p < or = 0.003), both PN and GPI patients showed improvements in their symptomatology over time, including suicidality (all p < 0.001; there were no group differences). Overall AE rates were higher in PN patients (p < 0.01; 17.9% vs. 4.5%); the frequency and type of AEs in both subgroups were typical for fluoxetine and the total DUO samples. In fact, AE rates were lower compared to controlled trials. Findings suggest that PN patients were more severely ill at observation start and suffered a more complicated treatment course. However, clinical efficacy showed highly significant improvements in both subgroups; AE rates were low in both--although higher in PN patients. Thus, results support a positive benefit/risk ratio of fluoxetine use for this young patient population.

The course of cortico-hypoglossal projections in the human brainstem. Functional testing using transcranial magnetic stimulation.

Cortico-hypoglossal projections were investigated in 11 patients with unifocal ischaemic lesions of different brainstem levels using transcranial magnetic stimulation. Lesion topography was documented by MRI studies. In seven patients the projections to the ipsi- and contralateral hypoglossal nuclei were separately affected. Pontine lesions at the ventral paramedian base close to the midline affect the contralateral projections while lateral lesions at the pontine base affect the ipsilateral projections. Lesions of the paramedian dorsal pontine base do not involve the cortico-hypoglossal projections. Our findings indicate that the cortico-hypoglossal fibres branch off the main ventral pyramidal tract. Lesions of the dorso- and mediolateral medulla impair only the ipsilateral projections. We conclude that ipsilateral projections enter the hypoglossal nucleus from its lateral aspect and that the contralateral projections cross the midline at the pontomedullary junction.