inzmayer L

Memory Deficits in Patients with DSM-IV Obsessive-Compulsive Disorder

Neuropsychological testing provides increasing evidence that certain memory deficits might play an essential role in the emergence of doubts and, as a result, in perpetuating checkers’ rituals. Another account of doubting implicates metacognitive factors, such as confidence in memory. The present study examined mnestic functioning and self-perception of memory ability in a group of 27 nondepressed patients with obsessive-compulsive disorder (OCD) and 27 normal controls. All patients met DSM-IV and ICD-10 criteria for OCD, displayed prominent behavioral checking rituals and had to show a score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) of at least 16. Significant deficits in intermediate (Lern- und Gedächtnistest; LGT-3) and immediate (Corsi Block-Tapping Test) nonverbal memory were identified in the patients with OCD compared to normal controls. Contrary to predictions, OCD patients also showed a significant deficit in general memory and verbal memory (LGT-3). With respect to metacognition, OCD patients reported less confidence in their memories than controls. These findings suggest that obsessional doubt reflects a deficit in memory as well as a deficit in memory confidence. Depending on which dysfunction predominates, different therapeutic procedures seem to be required.

Nonorganic insomnia in generalized anxiety disorder. 1. Controlled studies on sleep, awakening and daytime vigilance utilizing polysomnography and EEG mapping.

Objective and subjective sleep and awakening quality as well as daytime vigilance of insomniac patients with generalized anxiety disorder (GAD) were investigated, as compared with normal controls. Forty-four outpatients (25 females, 19 males), aged 24-65 (mean 43) years, diagnosed with non-organic insomnia (ICD-10: F 51.0), related to mild GAD (F 41.1), with a Hamilton anxiety (HAMA) score of 22 +/- 6 and a Zung self-rating anxiety (SAS) score of 37 +/- 6 were included. After 1 adaptation night, sleep induction, maintainance and architecture were measured objectively by polysomnography, subjective sleep and awakening quality were assessed by self-rating scales and visual analog scales, objective awakening quality was measured by a psychometric test battery, and diurnal tiredness was measured by a 3-min vigilance-controlled EEG (V-EEG) and a 4-min resting EEG mapping. In polysomnography patients demonstrated-as compared with normals-significantly increased wake time during the total sleep period and more early-morning awakening, decreased total sleep and sleep efficiency. Subjective sleep quality was deteriorated as well, as were well-being, drive, mood, and wakefulness in the morning. In noopsychic performance, GAD patients did rather well in attention, concentration, attention variability, and numerical memory, while fine-motor activity and reaction time were deteriorated. In psychophysiology, critical flicker frequency was decreased in the morning, while muscle strength, blood pressure and pulse rate showed no differences. EEG mapping during the late morning hours (10.00-12.00 h) demonstrated hypervigilance in the V-EEG, while in the resting recording an increased sleep pressure was detected. The latter was correlated significantly to the SAS score, but less so to the observer-rated Hamilton anxiety score. Our findings suggest that CNS hypervigilance and hyperarousal, as actual symptoms of GAD, lead to nocturnal insomnia, which in turn may cause-as a consequence of sleep pressure not slept off-diurnal tiredness.

Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression

In a double-blind, placebo-controlled study, the antidepressant and vigilance-promoting properties of transdermal oestrogen in post-menopausal depression were investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty-nine menopausal women, aged 45–60 years without previous hormonal replacement therapy, diagnosed as major depression without psychotic or suicidal symptoms (DSM-III-R criteria), were randomly assigned to a 3-month treatment with transdermal oestradiol [Estraderm TTS (ETTS) 50 µg, applied twice weekly] or placebo. No other psychoactive medication was allowed. After removal of protocol violators, 32 patients were evaluable in each group, which did not differ in age, height or weight. As five patients discontinued prematurely in both groups and in one placebo patient a post-drug EEG could not be obtained, 27 patients remained in the ETTS and 26 in the placebo group for efficacy analysis. While in the placebo group, oestradiol (E2) and follicle stimulating hormone (FSH) remained unchanged, E2 increased and FSH decreased significantly in the ETTS group. Syndromal evaluation showed a significant improvement in the Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both groups, with no inter-group difference. However, EEG mapping demonstrated significant interdrug differences in brain function, mostly over the left temporal region. While ETTS patients showed an increase of alpha and alpha-adjacent theta activity and a decrease of beta activity, as well as an acceleration of the delta/theta centroid and a slowing of the alpha, beta and total power centroid, no changes occurred in the placebo-treated patients. These neurophysiological findings suggest improvement of vigilance by oestrogen, previously referred to as “mental tonic” effect. There were no changes, however, in the frontal alpha asymmetry index, reflecting left frontal hypo- and right frontal hyperactivation. Thus, this neurophysiological variable represents a state-independent marker for depression. The tolerability of ETTS was very good.

On Central Effects of Serotonin Re-uptake Inhibitors: Quantitative EEG and Psychometric Studies with Sertraline and Zimelidine

In a double-blind placebo-controlled cross-over study the encephalotropic and psychotropic properties of sertraline — a new potent and highly selective inhibitor of synaptosomal serotonin uptake — were studied along with blood levels of the parent drug and main metabolite in ten normal healthy volunteers. They received randomized at weekly intervals oral single doses of placebo, 100, 200 and 400 mg setraline and 100 mg zimelidine as reference drug. Blood sampling, EEG recordings, psychometric tests and evaluation of pulse, blood pressure and side-effects were carried out at the hours 0, 2, 4, 6, and 8. Blood level investigations demonstrated that sertraline is slowly absorbed with dose-dependent blood concentrations peaking in the 4th to 6th hour and remaining high thereafter, while the main metabolite, CP-53261 exhibited an even slower rise in plasma concentration up to the 8th hour. Computer-assisted spectral analysis of the EEG demonstrated slight effects of 100 mg zimelidine and 100 mg sertraline on human brain function, but moderate to marked effects after 200 and 400 mg sertraline as compared with placebo. Changes after 100 mg sertraline and the reference compound resembled the pharmaco-EEG profiles of antidepressants of the desipramine type and were indicative of some vigilance-improving properties while higher doses of sertraline induced alterations reminiscent of those after antidepressants of the imipramine type, thereby reflecting vigilance changes of the dissociative type. This neurophysiological conclusion was supported by the psychometric and psychophysiological data showing partly after 100 mg sertraline and zimelidine an improvement in psychometric performance, while 200 and 400 mg sertraline induced a deterioration of noopsyche and thymopsyche of the normal volunteers. Psychophysiological variables exhibited a dose-dependent change in CNS activation and a widening of the pupillary size. Time-efficacy calculations based on pharmacodynamic changes demonstrated maximal encephalotropic effects after 100 mg zimelidine in the 2nd to 4th hour, and after setraline in the 4th to the 6th hour, which is in agreement with the blood level data. Pulse, systolic and diastolic blood pressure showed no clinically relevant findings. Side-effects were non-existent to minimal after 100 mg zimelidine and sertraline, but marked after 200 and 400 mg sertraline characterized by nausea, vomiting, diarrhea, giddiness, restlessness, tremor and trismus.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

Combined naloxone/methadone preparations for opiate substitution therapy

Every opportunity should be used to reduce the risk of HIV-1 infection and transmission among intravenous drug users (IVDUs). Methadone maintenance is widely accepted to keep the drug user away from risk-laden practices and to stop intravenous drug use. In order to minimize the diversion and intravenous abuse of methadone in maintenance programs, the effects of a combined naloxone/methadone preparation through oral intake and the effects of an intravenous administration were tested. In opiate addicts, the intravenous administration of this mixture caused a severe withdrawal syndrome lasting for 15 to 30 minutes. The oral administration of this combination was indistinguishable from methadone alone. It is argued that this combination therapy prevents the intravenous abuse of methadone in maintenance programs.

Brain protection of nicergoline against hypoxia: EEG brain mapping and psychometry

SummaryIn a double-blind, placebo-controlled trial human brain function and mental performance as well as the antihypoxidotic properties of nicergoline were studied utilizing blood gas analysis, EEG brain mapping and psychometry. Hypoxic hypoxidosis was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 16 healthy volunteers. They received randomized after an adaptation session placebo, 10 mg, 30 mg and 60 mg nicergoline (NIC). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 hrs oral drug administration. Blood gas analysis demonstrated a drop in PO2 from 95 to 35 and 34 mm Hg in the 14 and 23 min of inhalation, respectively. PCO2 decreased too (38 to 34 and 34 mm Hg), while pH increased (7.39 to 7.44 and 7.44). Base excess increased (−0.6 to 0.6 and 0.4) while standard bicarbonate decreased (24.4 to 24.1 and 23.8 mmol/l). Thus, blood gases remained stable between the 14 and 23 min of hypoxia during which time the neurophysiological and behavioral evaluations were carried out. EEG brain mapping exhibited an increase in delta/theta activity mostly over the parietal, temporal and central regions (left more than right), while alpha activity decreased (mostly over the parietal, central, frontal, frontotemporal and temporo-occipital regions). 30 and 60 mg NIC attenuated this deterioration of vigilance. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymospsyche which was mitigated by NIC. Based on 13 psychometric variables, the hypoxia-induced performance decrement was on the overall (2nd–8th hr) 43% after placebo as compared with pretreatment normoxic values, while only 29, 24 and 31% after 10, 30 and 60 mg nicergoline, respectively. The difference between placebo and the optimal dosage of nicergoline 30 mg reached the level of statistical significance (p<0.01, multiple Wilcoxon).

Double-Blind, Placebo-Controlled, Clinical, Psychometric and Neurophysiological Investigations with Oxiracetam in the Organic Brain Syndrome of Late Life

The therapeutic efficacy and safety of oxiracetam (ISF 2522), a new nootropic cyclic GABA derivative, were investigated in a double-blind, placebo-controlled study in 40 patients with organic brain syndrome in late life. The psychopathology was characterized by memory deficits, intellectual dysfunction, lack of drive, and disturbance of affectivity. Patients were randomly assigned to a 4-week treatment with either 2 X 400 mg oxiracetam capsules t.i.d. or identical placebo capsules in the same dosing schedule. Evaluation of the psychopathology and side effects was carried out at weeks 0, 1 and 4; laboratory tests (hematology, blood chemistry and urinalysis), a battery of psychometric tests and quantitative EEG investigations were done at weeks 0 and 4. In the oxiracetam group a slight but significant improvement in global symptomatology was observed within 1 week, with further improvement after 4 weeks. In the placebo group, an improvement was seen only in the 4th week. Evaluation of the detailed psychopathology by means of the Sandoz clinical assessment geriatric scale (SCAG) showed in the oxiracetam group significant improvements in loss of appetite and vertigo after 1 week and in short-term memory, anxiety, emotional lability, fatigue, loss of appetite and vertigo after 4 weeks. In contrast, not a single item improved significantly during placebo treatment. Although the differences in SCAG scores between the two groups failed to reach statistical significance, the overall trend towards improvement was significantly better in the oxiracetam group. The tolerability of the drug was good.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry.

SummaryIn a double-blind, placebo-controlled study, the encephalotropic and psychotropic effects of tianeptine (TIA) — a new tricyclic antidepressant, enhancing serotonin reuptake — were investigated as compared with the serotonin reuptake inhibiting antidepressant, fluvoxamine (FLU), utilizing EEG mapping, psychometric and psychophysiological measures. 16 healthy volunteers (8 males, 8 females) aged 21–35 (man 27) years received randomized and at weekly intervals single oral doses of placebo, 12.5 and 25 mg TIA and 50mg FLU. EEG recordings, psychometric and psychophysiological tests and evaluation of pulse, blood pressure and side effects were carried out at 0,2,4,6 and 8 hours; blood sampling, in addition, at hour 1.TIA plasma levels rose fast to peaks at 1–2 hours and declined rapidly as well, while the MC5 metabolite peaked in the 4th hour and declined more slowly. EEG mapping demonstrated that both TIA and FLU induced significant changes in brain function between the 1st and 8th hour, which, however, differed in their time course. 12.5 mg TIA exhibited, as compared with placebo, slight activating properties in the EEG (decrease of delta and theta, increase of alpha and beta, acceleration of the centroid), parallelled by thymopsychic improvement (mood elevation). 25 mg TIA showed EEG activation up to the 4th hour, later EEG sedation, accompanied by an initial thymopsychic improvement and differential changes thereafter (improved mood, decreased vigility), with the noopsyche improving at all times (attention, Pauli test). 50mg FLU induced initially sedation and thereafter activation, accompanied by thymopsychic deterioration and subsequent improvement, the latter also being observed in the noopsyche (attention, memory). In pupillary and skin conductance measures, generally a slight activation occurred after placebo, which was attenuated by 25 mg TIA. Correlation maps between plasma levels and EEG changes demonstrated: the higher the TIA plasma levels, the more absolute and relative beta power, the less alpha power and the faster the centroid of the total power spectrum, reflecting CNS-activation. Topographically, the correlations were mostly seen over both fronto-temporal regions. In the latter, dominant frequency signalled desactivation in the right and activation in the left hemiphere after both antidepressants, which thereby induced changes in brain function opposite to those observed in depression. Both drugs were well tolerated.

Receptor Test (Pupillary Dilatation after Application of 0.01% Tropicamide Solution) and Determination of Central Nervous Activation (Fourier Analysis of Pupillary Oscillations) in Patients with Alzheimer’s Disease

Memory loss and severe cognitive deficits in Alzheimer patients are supposed to be related to a reduction of acetylcholine as well as to central nervous deactivation. For the investigation of cholinergic deficits and deactivation, we used computer-assisted pupillometry. Cholinergic deficits caused by a particularly severe loss of cholinergic neurons may be responsible for cognitive and mnemonic performance deficits. The control of the pupillary diameter represents a balance between cholinergic and adrenergic innervation and is influenced directly or indirectly by central and autonomic nervous system inputs. Either of these systems could be affected in Alzheimer patients. A reduced innervation of the target muscle through neuronal cell death, axon retraction, reduced release, increased reuptake of altered amounts or function of neurotransmitter receptors seems to affect the pupillary response to cholinergic antagonists in Alzheimer patients. There is, however, no relationship between pupillary diameter and central deactivation, but between central nervous activation and pupillary oscillations which reflect the physiological corticodiencephalic activity, a relationship has to be assumed. Frequencies and amplitudes of pupillary oscillations measured by means of Fourier analysis are modulated corticodiencephalically. Therefore, Alzheimer patients were compared to healthy controls with respect to their pupillary diameters and responses to an acetylcholine antagonist. Twenty-nine patients, aged between 55 and 85 years, suffering from mild to moderate Alzheimer’s disease (AD) and 29 normal controls of similar age (56–85 years) participated in the study. The cholinergic receptors of the pupil were blocked by the acetylcholine antagonist tropicamide. It could be assumed that the larger the pupillary dilatation, the larger the extent of cognitive deficits. Alzheimer patients show abnormal acetylcholine neurotransmission. Changes of pupillary diameter after instillation of 1 drop of 0.01% tropicamide solution were measured and Fourier analysis of pupillary oscillations was performed. Times of measurement were: 0 (baseline), 20, 40, 60, 80, and 100 min. After 4 min tropicamide was instilled. Forty min after the instillation of tropicamide into the left eye, the Alzheimer patients showed a pronounced dilatation of 41.57%. The dilatation in normal controls was 28.5%. Fourier analysis of pupillary oscillations (sum of frequency bands = power) demonstrated a marked deactivation (low amplitudes in low-frequency bands, but in contrast to our expectations no higher amplitudes in the higher frequency bands) in patients with AD which remained constant at all times of measurement. By means of discriminant analysis of pupillary diameter and pupillary oscillations (frequency band 0.00–1 Hz), 89.7% were correctly predicted to be Alzheimer patients, 89% to be normal controls.