Working memory training in patients with chronic schizophrenia: a pilot study.

Background. There is evidence that patients with schizophrenia suffer from decline in working memory performance with consequences for psychosocial outcome. Objective. To evaluate the efficacy of a computerized working memory training program (BrainStim) in patients with chronic schizophrenia. Methods. Twenty-nine inpatients with chronic schizophrenia were assigned to either the intervention group receiving working memory training (N = 15) or the control group without intervention (N = 14). Training was performed four times a week for 45 minutes during four weeks under neuropsychological supervision. At baseline and followup all participants underwent neuropsychological testing. Results. Pre-post comparisons of neuropsychological measures showed improvements in visual and verbal working memories and visual short-term memory with small and large effect sizes in the intervention group. In contrast, the control group showed decreased performance in verbal working memory and only slight changes in visual working memory and visual and verbal short-term memories after 4 weeks. Analyses of training profiles during application of BrainStim revealed increased performance over the 4-week training period. Conclusions. The applied training tool BrainStim improved working memory and short-term memory in patients with chronic schizophrenia. The present study implies that chronic schizophrenic patients can benefit from computerized cognitive remediation training of working memory in a clinical setting.

Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans.

AIMS: The aim of this study was to identify the mechanisms of hypocarnitinemia in patients treated with valproate. METHODS: Plasma concentrations and urinary excretion of carnitine, acetylcarnitine, propionylcarnitine, valproylcarnitine, and butyrobetaine were determined in a patient starting valproate treatment and in 10 patients on long-term valproate treatment. Transport of carnitine and valproylcarnitine by the proximal tubular carnitine transporter OCTN2 was assessed in vitro. RESULTS: In the patient starting valproate, the plasma carnitine and acetylcarnitine levels dropped for 1-3 weeks and had recovered after 3-5 weeks, whereas the plasma levels of propionyl and valproylcarnitine increased steadily over 5 weeks. The renal excretion and excretion fractions (EFs) of carnitine, acetylcarnitine, propionylcarnitine, and butyrobetaine decreased substantially after starting valproate. Compared with controls, patients on long-term valproate treatment had similar plasma levels of carnitine, acetylcarnitine, and propionylcarnitine, whereas valproylcarnitine was found only in patients. Urinary excretion and renal clearance of carnitine, acetylcarnitine, propionylcarnitine, and butyrobetaine were decreased in valproate-treated compared with that in control patients, reaching statistical significance for carnitine. The EFs of carnitine, acetylcarnitine, and propionylcarnitine were <5% of the filtered load in controls and were lower in valproate-treated patients. In contrast, the EF for valproylcarnitine approached 100%, resulting from a low affinity of valproylcarnitine for the carnitine transporter OCTN2 and competition with concomitantly filtered carnitine. CONCLUSIONS: The initial drop in plasma carnitine levels of valproate-treated patients is most likely due to impaired carnitine biosynthesis, whereas the recovery of the plasma carnitine levels is explainable by an increased renal expression of OCTN2. Renally excreted valproylcarnitine does not affect renal handling of carnitine in vivo.

Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group 'Drugs in Psychiatry' (AGATE).

OBJECTIVES: (1) To investigate the risk of extrapyramidal motor side effects (EPS) associated with the prescription of different antipsychotics under naturalistic treatment conditions; (2) to test the rationale of the terms 'typical' and 'atypical' based on EPS rates. DESIGN: Cross-sectional study in the federal state of Bavaria. SETTING: 20 psychiatric hospitals in Bavaria. PARTICIPANTS: 6,061 inpatients, aged 18-65 years, with psychotic disorders. MAIN OUTCOME MEASURES: Co-medication with the anticholinergic biperiden was used as an index of EPS. Odds ratios for EPS and numbers needed to harm [number of patients who would need to be treated to obtain one more case with an adverse outcome (i.e. EPS) as compared with the control treatment (clozapine)] were calculated to obtain risk estimates for 15 different antipsychotics. RESULTS: Groups of 'typical' and 'atypical' antipsychotics were not homogeneous in their EPS rates, and showed wide variation within each group. Nor did the frequency of EPS allow a clear distinction between the groups. There were 2 reasons for this: first, EPS rates rose continuously over the whole spectrum of drugs under study, and therefore precluded the definition of a cut-off score; second, there was considerable overlap between the 2 groups as EPS rates of various 'atypicals' (e.g. amisulpride, risperidone and zotepine) did not differ from some 'typical' substances (e.g. fluphenazine), while one 'typical' antipsychotic (perazine) even had a lower EPS risk than most 'atypicals'. CONCLUSIONS: The odds of inducing EPS are not distinguishable between 'typical' and 'atypical' antipsychotics as EPS rates rise on a continuous scale throughout both classes. We propose dropping the categorization of antipsychotics as 'typical' and 'atypical' and instead using risk estimates like number needed to harm for EPS to help in benefit/risk considerations for antipsychotic treatment.

Memantine: a therapeutic approach in treating Alzheimer's and vascular dementia.

Memantine has been clinically used in the treatment of organic disorders in Germany for over ten years and has now been approved in Europe and also in the US for moderate to severe Alzheimer's disease. The rationale for this indication is strongly related to the physiological and pathological role of glutamate in neurotransmission. Glutamate is an agonist of NMDA, kainate and AMPA (ionotropic) receptors, where its influence on NMDA receptors plays an important role with regard to neuronal plasticity effecting memory and learning. Excessive levels of glutamate result in neurotoxicity, in part by overactivation of NMDA receptors. Memantine acts as an uncompetitive antagonist of NMDA receptors and therefore compensates for this overactivation. Furthermore, memantine is a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes, as it ameliorates cognitive and memory deficits. Memantine was effective and safe in several clinical studies, particularly in Alzheimer's disease. The compound is completely absorbed after oral intake and undergoes little metabolism. Having a low probability for drug-drug interactions, memantine, in principle, is suited for elderly patients exposed to multiple therapeutic therapies.

[Diurnal variation of pain perception and heart rate in the human tourniquet pain model in healthy volunteers]. / Tagesschwankungen der Schmerzintensität und Herzfrequenz im Tourniquet-Schmerz-Modell bei gesunden Probanden.

The diurnal variation of pain threshold was studied in 13 healthy volunteers (age: 21 - 27 ys) using the tourniquet pain model. A tourniquet was inflated above systolic blood pressure for 1 minute and pain scores and heart rate were recorded at 0.5, 1.0, 1.5 and 2.0 minutes. The test was repeated during a study day at 6.00 h, 12.00 h, 18.00 h and 24.00 h. Significant differences of pain scores between clocktimes were found 1 minutes after inflation and after 1.5 minutes with regard to heart rate. Generally, the highest pain scores were found at 24.00 h.

[Determination of Reliability of Psychometric Tests in Psychiatry Using Canonical Correlation] / Bestimmung der Reliabilität psychometrischer Testverfahren in der Psychiatrie mittels der kanonischen Korrelation.

Test results (raw scores) are composed of an unknown true score and an error term. The error term can be estimated by means of test reliability which is defined by the ratio of true variance and obtained variance. Different estimates of reliability either based on single measurements (e. g. Cronbach's coefficient, split half reliability, Kuder Richardson method) or two measurements (test/retest, inter- or intrarater reliability) are available. Parallel test reliability depends on the correlation of two different tests obtained in one session. Canonical correlation methods allow an extension of the parallel test situation and split half technique. Two or more tests are performed in a sample of subjects. Randomized subsets are correlated using canonical correlation technique. The objective of this study is to estimate the homogeneity of test batteries. 94 patients (64 f, 30 m; age: 54 - 89 ys.) supposed to have dementia were tested using the clocktest (CT, scores: 1 - 5), MMSE (mini mental state examination) and SKT (Syndrom Kurztest). Four (i, j: 1 - 4) subsets of 20 patients each were determined by random and the following characteristics were calculated: Empiric correlation coefficient for n = 94 (R), canonical correlation coefficient (Rcan), eigenvalues (EV) and redundancy (Rnd) of corresponding variable sets. The results of canonical analysis showed canonical correlation coefficients in order of 0.8 to 0.9 (p-values < 0,001). This high internal consistency can be interpreted as a measure of reliability of the test batteries. In conclusion, canonical correlation based on parallel tests splitted in subsets gives information on consistency, i. e. reliability, of test batteries in addition to conventional correlation methods.

[Circannual Periodicity of Prescriptions in a Psychiatric Hospital] / Zirkannuale Rhythmen im Arzneimittelverbrauch einer psychiatrischen Klinik.

The total number per month of prescribed antibiotics or psychiatric drugs during one year (1998) was assessed by means of sine wave models [Y(t) = M + A x sin(2 x pi x t/tau + Phi)]. M (no. of prescriptions per month) denotes mean frequency over one period, A (no. per month) denotes amplitude, tau (month) corresponds to the period and Phi (month) to the phase of the fitted curve. Data were evaluated descriptively and chronograms including 95 %-confidence limits were given. Significant nonlinear regression models could be calculated for amoxicillin, paroxetine, citalopram, amitriptyline and buspirone prescription behaviour. Both circannual and ultra-annual (period shorter than one year) rhythms of prescription were found. Peak values for antibiotic drug prescription during fall and winter is probably associated with higher incidence of infectious diseases. Antidepressant drug prescription has maxima in spring and fall, which is in keeping with the epidemiology of depressive disorders. The seasonality of buspirone prescription may reflect a basic periodicity of anxiety disorders. In conclusion, the chronopharmaco-epidemiological data of antibiotic and antidepressant drug prescription with circannual and ultra-annual rhythms may reflect the periodicity of infectious and psychiatric diseases.

[Determination of reliability of psychometric tests in psychiatry using canonical correlation]. / Bestimmung der Reliabilität psychometrischer Testverfahren in der Psychiatrie mittels der kanonischen Korrelation.

Test results (raw scores) are composed of an unknown true score and an error term. The error term can be estimated by means of test reliability which is defined by the ratio of true variance and obtained variance. Different estimates of reliability either based on single measurements (e.g. Cronbach's coefficient, split half reliability, Kuder Richardson method) or two measurements (test/retest, inter- or intrarater reliability) are available. Parallel test reliability depends on the correlation of two different tests obtained in one session. Canonical correlation methods allow an extension of the parallel test situation and split half technique. Two or more tests are performed in a sample of subjects. Randomized subsets are correlated using canonical correlation technique. The objective of this study is to estimate the homogeneity of test batteries. 94 patients (64 f, 30 m; age: 54-89 ys.) supposed to have dementia were tested using the clocktest (CT, scores: 1-5), MMSE (mini mental state examination) and SKT (Syndrom Kurztest). Four (i, j: 1-4) subsets of 20 patients each were determined by random and the following characteristics were calculated: Empiric correlation coefficient for n = 94 (R), canonical correlation coefficient (Rcan), eigenvalues (EV) and redundancy (Rnd) of corresponding variable sets. The results of canonical analysis showed canonical correlation coefficients in order of 0.8 to 0.9 (p-values < 0.001). This high internal consistency can be interpreted as a measure of reliability of the test batteries. In conclusion, canonical correlation based on parallel tests splitted in subsets gives information on consistency, i.e. reliability, of test batteries in addition to conventional correlation methods.

[Circannual rhythm of drug use by a psychiatric clinic]. / Zirkannuale Rhythmen im Arzneimittelverbrauch einer psychiatrischen Klinik.

The total number per month of prescribed antibiotics or psychiatric drugs during one year (1998) was assessed by means of sine wave models [Y(t) = M + A x sin(2 x pi x t/tau + phi)]. M (no. of prescriptions per month) denotes mean frequency over one period, A (no. per month) denotes amplitude, tau (month) corresponds to the period and phi (month) to the phase of the fitted curve. Data were evaluated descriptively and chronograms including 95%-confidence limits were given. Significant nonlinear regression models could be calculated for amoxicillin, paroxetine, citalopram, amitriptyline and buspirone prescription behaviour. Both circannual and ultra-annual (period shorter than one year) rhythms of prescription were found. Peak values for antibiotic drug prescription during fall and winter is probably associated with higher incidence of infectious diseases. Antidepressant drug prescription has maxima in spring and fall, which is in keeping with the epidemiology of depressive disorders. The seasonality of buspirone prescription may reflect a basic periodicity of anxiety disorders. In conclusion, the chronopharmaco-epidemiological data of antibiotic and antidepressant drug prescription with circannual and ultra-annual rhythms may reflect the periodicity of infectious and psychiatric diseases.