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Earlier investigations suggested an involvement of the right hemisphere and the left prefrontal cortex (PFC) in the pathogenesis of depression. This paper presents our own electroencephalographic (EEG) topography and low-resolution brain electromagnetic tomography (LORETA) data obtained in unmedicated depressed patients, and the effects of two representative drugs of non-sedative and sedative antidepressants, i.e., citalopram (CIT) and imipramine (IMI), as compared with placebo in normal subjects. Sixty female menopausal syndrome patients with the diagnosis of a depressive episode without psychotic symptoms as well as 30 healthy controls were investigated. Concerning the effects of antidepressants, normal healthy subjects received single oral doses of 20 mg CIT, 75 mg IMI and placebo p.o. A 3-min vigilance-controlled EEG and a 4-min resting EEG was recorded pre- and post-drug administration and analyzed by means of EEG mapping and LORETA. In the EEG mapping, depressed patients demonstrated a decrease in absolute power in all frequency bands, an augmentation of relative delta/theta and beta and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an acceleration of the alpha and beta centroid, which suggests vigilance decrements. In the alpha asymmetry index, they showed right frontal hyper- and left frontal hypoactivation correlated with the Hamilton Depression Score (HAMD). LORETA predominantly revealed decreased power in the theta and alpha-1 frequency band. Negative correlations between theta power and the HAMD were observed in the ventro-medial PFC, the bilateral rostral anterior cingulate cortex (ACC) and the left insular cortex; between alpha-1 power and the HAMD in the right PFC. In the EEG mapping of antidepressants, 20 mg CIT showed mainly activating, 75 mg IMI partly sedative properties. LORETA revealed that CIT increased alpha-2, beta-1, beta-2 and beta-3 power more over the right than over the left hemisphere. However, also a left temporal and frontal delta increase was observed. In conclusion, EEG topography and tomography of depressed menopausal patients demonstrated a right frontal hyper- and left frontal hypoactivation in the alpha asymmetry index as well as a vigilance decrease, with a right-hemispheric preponderance. Within antidepressants at least 2 subtypes may be distinguished from the electrophysiological point of view, a non-sedative and a sedative. LORETA identifies cerebral generators responsible for the pathogenesis of depression as well as for the mode of action of antidepressants.

In a double-blind, placebo-controlled crossover study, the effects of S-adenosyl-l-methionine (SAMe) on brain function measures of 12 normal elderly volunteers (6 m/6 f, aged 57-73 years, mean: 61 years) were investigated by means of EEG mapping and psychometry. In random order, the subjects were orally administered a pharmaceutical dose of 1600 mg SAMe, a nutraceutical dose of 400 mg SAMe and placebo, each over a period of 15 days, with wash-out periods of 2 weeks in between. EEG recordings, psychometric tests and evaluations of tolerability and side effects were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 15. Multivariate analysis based on MANOVA/Hotelling T2 tests of quantitative EEG data demonstrated significant central effects of SAMe as compared with placebo after acute, subacute and superimposed drug administration of both the nutraceutical and the pharmaceutical dose. EEG changes induced by SAMe were characterized by an increase in total power, a decrease in absolute and relative power in the delta/theta and slow alpha frequencies, an increase in absolute and relative power in the alpha-2 and beta frequencies as well as an acceleration of the alpha centroid and the centroid of the total power spectrum. The delta/theta and the beta centroid showed variable changes over time. The dominant alpha frequency was accelerated, the absolute and relative power in the dominant alpha frequency attenuated after SAMe as compared with placebo. These acute and subacute pharmaco-EEG findings in elderly subjects are typical of activating antidepressants. Time-efficacy calculations showed that acute oral administration of SAMe in both the nutraceutical and the pharmaceutical dose induced the pharmacodynamic peak effect in the first hour with a subsequent decline. The 3rd and 6th hours still showed a significant encephalotropic effect after the 1600 mg dose. The maximum EEG effect was noted after 2 weeks of oral administration of both 1600 mg/die and 400 mg/die. The superimposed dose induced significant encephalotropic effects in the 3rd hour after 400 mg and in the 3rd and 6th hours after 1600 mg as compared with pre-treatment. Dose-efficacy calculations showed that the pharmaceutical dose of 1600 mg had a more pronounced effect on the CNS than the nutraceutical dose of 400 mg, with both doses being superior to placebo. Psychometric tests concerning noopsychic and thymopsychic measures as well as critical flicker fusion frequency generally demonstrated a lack of differences between SAMe and placebo, which reflects a good tolerability of the drug in elderly subjects. This was corroborated by the findings on side effects, pulse and blood pressure.

Clinically well-defined diagnostic subgroups of mental disorders, such as schizophrenia with predominantly plus and minus symptomatology, major depression, generalized anxiety disorder, agoraphobia, obsessive-compulsive disorder, multiinfarct dementia, senile dementia of the Alzheimer type and alcohol dependence, show electroencephalogram (EEG) maps that differ statistically both from each other and from normal controls. Representative drugs of the main psychopharmacological classes, such as sedative and nonsedative neuroleptics and antidepressants, tranquilizers, hypnotics, psychostimulants and cognition-enhancing drugs, induce significant and typical changes to normal human brain function compared with placebo, in which many variables are opposite to the above-mentioned differences between psychiatric patients and normal controls. Thus, by considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. This is supported by low-resolution brain electromagnetic tomography (LORETA), which identifies brain regions affected by psychiatric disorders and psychotropic drugs.

Nonorganic insomnia is a frequent sleep disorder that has a high comorbidity with other psychiatric illnesses. In our sleep outpatient clinic, 41% of the patients showed neurotic, stress-related and somatoform disorders, 31% affective disorders and 1.6% schizophrenia. Sleep laboratory investigations in patients for diagnostic purposes and in normal subjects for the evaluation of drug effects suggest that changes in the sleep architecture of patients with nonorganic insomnia due to psychiatric disorders, compared with normal controls, are opposite to alterations induced by psychotropic drugs intended for their treatment, compared with placebo (key-lock principle). Evidence for this principle was found regarding nonorganic insomnia related to generalized anxiety disorder or panic disorders and benzodiazepines, depressive episodes, recurrent depression or dysthymia and sedative antidepressants and finally schizophrenia and sedative neuroleptics. Polysomnography (PSG) findings of other mental disorders are rather scarce and often depend upon the subtype and stage of the disease. In conclusion, sleep laboratory studies may be helpful for choosing the right drug for an individual insomniac patient.

Utilizing computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (EEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ: the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG profiles and maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described in this paper. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects, therapeutic efficacy and pharmacokinetic and pharmacodynamic data will be discussed. In recent times, imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be demonstrated for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently.

Daytime tiredness and daytime sleepiness are frequent complaints occurring in 29% and 14% of the Austrian population. Epidemiological studies demonstrate a high comorbidity between nonorganic hypersomnia and mental disorders. Especially comorbidity with affective disorders increases steadily from the general population over primary to tertiary care settings. Diagnostic criteria of nonorganic hypersomnia have been described in the International Classification of Diseases (ICD-10). Nonorganic hypersomnia can be primary or associated with a number of psychiatric disorders such as reaction to severe stress or adjustment disorders, affective disorders, other functional disorders, tolerance to or withdrawal of CNS-stimulating substances and chronic use of CNS-sedating substances. Diagnostic procedures comprise case history and symptom evaluation, sleep-specific and supplementary investigations. Concerning the latter, this article will focus on sleep questionnaires, vigilance and psychological tests as well as CNS investigations. Therapy of nonorganic hypersomnia rests on 3 pillars: psychological, somatic and pharmacological treatment. In view of the wide variety of psychiatric causes, resulting in a number of therapeutic options, it seems desirable that apart from subjective clinical assessment also objective methods be used in diagnosis and treatment. On the neurophysiological level objective measures can be obtained by means of EEG mapping during the day and polysomnography at night. Different mental disorder patients show different brain activity patterns as compared with normal controls and different classes of psychotropic substances cause different changes in neurophysiological variables. The fact that the changes in electrophysiological brain activity caused by mental disorders are exactly opposite to those induced by the psychotropic drugs used for their treatment suggests a key-lock principle in the diagnosis and treatment of nonorganic hypersomnia.

Utilizing polysomnography (PSG) and psychometry, objective and subjective sleep and awakening quality was investigated in 11 patients (mean age 50 +/- 14) with nonorganic insomnia (F 51.0) related to dysthymia (F 34.1) as compared with 11 age- and sex-matched normal controls. Patients demonstrated decreased sleep efficiency and sleep stage S2 as well as increased sleep latency to S1, S2 and S3, wakefulness within the total sleep period, number of awakenings, S1 and REM sleep. There was no intergroup difference in REM latency. Subjective sleep quality and the total score of the Self-Assessment Scale for Sleep and Awakening Quality (SSA) were deteriorated as were evening and morning well-being, mood, affectivity and drowsiness. Noopsychic measures showed deteriorated numerical memory, fine motor activity and reaction time variability. In a placebo-controlled crossover design study, the acute effects of 100 mg trazodone, a serotonin reuptake inhibitor with a sedative action due to 5HT(2) and alpha(1) receptor blockade, were investigated in the patients. As compared with placebo, trazodone induced an increase in slow-wave sleep (S3 + 4), a lengthening of REM latency, a decrease in REM sleep and a normalization of the periodic leg movement (PLM) index. In the morning, there was a minimal increase in somatic complaints and a decrease in critical flicker frequency and systolic blood pressure. In conclusion, our study demonstrated that dysthymia induced significant changes in objective and subjective sleep and awakening quality, which were counteracted by 100 mg trazodone, thus suggesting a key-lock principle in the treatment of nonorganic insomnia related to dysthymia with this drug., (Copyright 2001 S. Karger AG, Basel)

Between 1992, the year in which the Sleep Out-Patient Clinic at the Department of Psychiatry, University of Vienna, Allgemeines Krankenhaus (General Hospital) Vienna, was established, and 1996, 817 patients (58% females, average age 52 years; 42% males, average age 48 years) were treated for sleep disorder. According to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) of the World Health Organization (WHO), 70% of the patients presented with a non-organic sleep disorder and 30% with an organic sleep disorder as main diagnosis. Non-organic insomnia was by far the most frequently diagnosed sleep disorder (48%), while within the organic sleep disorders sleep apnea was dominant (12%). In regard to the additional non-organic (mental disorder) diagnoses rounding off the clinical picture, neurotic, stress related, and somatoform disorders were the most common (41%), followed by affective disorders (31%) and mental and behavioural disorders due to intake of psychoactive substances, e.g. alcohol, drugs (15%). Additional organic diagnoses related to sleep disorders involved primarily endocrine disorders such as adipositas (23%), followed by cardiovascular disorders (19%), and primary snoring (17%). The sleep out-patient clinic has at its disposal a supportive diagnostic armamentarium such as all-night sleep polysomnography, 24-hour polysomnography, the Multiple Sleep Latency Test, EEG and EEG-mapping in the affiliated sleep laboratory, the evaluation of event-related potentials (P300) and actometry in the psychophysiological laboratory, as well as psychological and psychophysiological tests in the clinical psychodiagnostic laboratory, in order to determine the right treatment or preventive measures for the individual patients.