Quantitative electroencephalogram in smoking and smoking deprivation.

After being deprived of cigarettes for 24 hours, eight young males who were heavy smokers showed significant changes in the electroencephalogram analyzed electronically and by digital computer. Compared to their records before smoking deprivation, there was a significant increase in slow frequencies. Resumed smoking reversed these trends.

The discovery of antidepressant drugs by computer-analyzed human cerebral bio-electrical potentials (CEEG).

Antidepressant properties of six compounds were predicted based on their computer-analyzed human electroencephalographical (CEEG) profiles. The clinical investigations with mianserin (GB-94) confirmed the CEEG prediction. This compound has now been marketed as the first antidepressant of which the clinical effects were discovered solely by the quantitative pharmaco-EEG method. As predicted by the CEEG, clinical antidepressant properties of GC-46, mesterolone, and estradiol valerate were observed in preliminary investigations. No extensive studies with definite statistical results were yet carried out with these compounds. No systematic large studies could be conducted with cyclozocine and cyproterone acetate because of the intolerable side effects with these compounds. The optical isomers of mianserin, GF-59 and GF-60, both predicted as antidepressant by the computer EEG data base, have not yet been tested in depressive patients. None of these compounds possess the "typical" pharmacological and/or biochemical profiles of marketed antidepressants. Thus, the discovery of the established antidepressant properties of mianserin (GB-94) by computer analyzed EEG method challenges the well-known biochemical hypotheses of depression and the "classical" development of antidepressant drugs.

Comparative symptomatological and evoked potential studies with d-amphetamine, thioridazine, and placebo in hyperkinetic children.

In a double-blind study, 62 hyperkinetic children were randomly assigned to 8 weeks of treatment with either placebo, thioridazine, or d-amphetamine. The overall clinical symptomatology improved with all three substances, although d-amphetamine was significantly superior to placebo and thioridazine. Out of eight symptom clusters rated by the parents, two improved significantly with placebo, one with thioridazine, and six with d-amphetamine. The d-amphetamine was superior to placebo in reducing muscular tension and superior to thioridazine in decreasing hyperactive-impulsive behavior, psychosomatic problems, and muscular tension. Out of four teachers' symptom clusters, inattentive-passive behavior was significantly improved by thioridazine (which was also superior to placebo), while hyperactivity was reduced by d-amphetamine. Quantitative evaluation of visual evoked potentials (VEPs) revealed an increase in latencies and decrease in amplitudes during thioridazine treatment. Paradoxically, d-amphetamine also increased latencies, while tending to augment amplitudes. Regression and correlation analysis of clinical symptomatology with VEP variables showed that the shorter the pretreatment latencies and the higher the amplitudes, the more disturbed was the child. Short latencies and small amplitudes in the pretreatment period were predictors of good therapeutic outcome with subsequent thioridazine treatment, while short latencies and high amplitudes were indicative of such with d-amphetamine treatment. During therapy, the greater the drug-induced augmentation of latencies, the greater the clinical improvement. Finally, VEP differences between therapy-responsive and -resistant patients were explored and discussed.

The significance of pharmacodynamic measurements in the assessment of bioavailability and bioequivalence of psychotropic drugs using CEEG and dynamic brain mapping.

There are a variety of problems in evaluating the bioavailability of psychotropic drugs. Psychotropics have many metabolites; there are discrepancies between peripheral plasma levels and therapeutic effects, and psychotropics must penetrate the blood-brain barrier to have an effect on their target organ. Therefore, "classical" pharmacokinetic evaluation may not be sufficient to determine the bioavailability and bioequivalence of these drugs. Additional and more precise information may be obtained by adding pharmacodynamic procedures to these evaluations. Quantitative pharmaco-EEG (QPEEG), which uses the computer-analyzed electroencephalogram (CEEG), may be the method of choice for determining the pharmacodynamic profiles of psychotropic drugs at the central nervous system (CNS) level. The difficulties in evaluating the bioavailability of psychotropics, as well as the results of several studies that confirm the significance of CEEG as a pharmacodynamic measure, are discussed.

Comparative efficacy and safety of nortriptyline and fluoxetine in the treatment of major depression: a clinical study.

The safety and efficacy of nortriptyline and fluoxetine were compared in a double-blind, randomized, multicenter 5-week trial involving 205 outpatients with acute major depression of moderate severity. Seventy-two nortriptyline and 84 fluoxetine patients completed at least 2 weeks of medication and were included in the efficacy analysis; all patients were evaluated for side effects. Average total scores on the Hamilton Rating Scale for Depression (HAM-D) for both treatment groups declined from 22-23 at baseline to 11.5 at the conclusion of the 5-week period. At Week, 5, 71% of nortriptyline patients and 65% of fluoxetine patients were much or very much improved. Fluoxetine was associated more frequently with nausea (p less than .05), while nortriptyline was associated more frequently with dry mouth (p less than .05). These results are discussed in the context of selecting between nortriptyline and fluoxetine for a particular depressed patient.

Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression.

A double-blind, placebo- and amitriptyline-controlled comparison study was performed to evaluate the antidepressant efficacy of sertraline, a specific serotonin uptake inhibitor. Patients with DSM-III-defined major depression randomly received either sertraline (N = 149), amitriptyline (N = 149), or placebo (N = 150) once daily for the 8-week study period. The mean final daily medication dose for the all-patients group was 145 mg and 104 mg for the sertraline- and amitriptyline-treatment groups, respectively. As measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions Scale, both the sertraline and amitriptyline treatment groups showed a significantly greater improvement from baseline (p less than or equal to .001) than the placebo group. The sertraline group had a higher proportion of gastrointestinal complaints and male sexual dysfunction than either the amitriptyline or the placebo group. The amitriptyline group showed a higher proportion of anticholinergic and sedative side effects and dizziness compared with patients who received either sertraline or placebo.

Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients.

Two hundred forty-one elderly depressed patients entered the 8-week, double-blind phase of this parallel-group, multicenter study; 161 patients were randomized to receive sertraline (50-200 mg/day) and 80 were randomized to receive amitriptyline (50-150 mg/day). Among evaluable patients, there were no statistically significant differences between treatments in any of the primary efficacy variables: change in total Hamilton Rating Scale for Depression (HAM-D) score (17 items), percentage change in HAM-D score, change in HAM-D Item 1, change in Clinical Global Impressions (CGI) Severity score, change in the Depression Factor of the 56-item Hopkins Symptom Checklist, and the CGI Improvement score at the last visit. Similar results were obtained using data from all patients (intention-to-treat analysis), except that amitriptyline was superior in HAM-D Total score (p = .044). The two drugs produced a similar degree of response: on the basis of the HAM-D criterion, 69.4% of sertraline patients and 62.5% of amitriptyline patients responded, and, on the basis of CGI criterion, 79.5% of sertraline and 73.4% of amitriptyline patients responded. Twenty-eight percent of the sertraline patients withdrew from the study because of a treatment-related side effect and 2.5% (4) because of a laboratory abnormality. In comparison, 35% of the amitriptyline patients withdrew because of treatment-related side effects. Sertraline was associated with a statistically lower frequency of somnolence, dry mouth, constipation, ataxia, and pain and a higher frequency of nausea, anorexia, diarrhea/loose stools, and insomnia; thus, anticholinergic effects were less common and gastrointestinal effects were more common with sertraline than with amitriptyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Central mechanisms of clonidine and propranolol in man. Quantitative Pharmaco-EEG with antihypertensive compounds.

Direct CNS effects of clonidine (0.2 mg) and propranolol (40 mg and 80 mg) were established in healthy young male subjects within three hours after oral administration. They were demonstrated in two studies using procedures of the Quantitative Pharmaco-EEG (QPEEG) method. Quantitatively, the greatest CNS effects were attained with 0.2 mg clonidine followed by 80 mg, and finally by 40 mg propranolol. Based on the computer-analyzed EEG (CEEG) profiles obtained and using the HZI Research Center CEEG data base, the psychotropic properties of these compounds were predicted. Propranolol, in the 40-mg dose, showed a similarity to vigilance-enhancing compounds, whereas the 80-mg dose and the 0.2-mg dose of clonidine were established as primarily similar to mood-elevating (sedative antidepressant) drugs. However, despite some overall similarities in the mode of action between the high dose of propranolol and the clonidine, some differences in their CNS effects were detected based on their secondary effects (anxiolytic and sedative effects, respectively).

Analgesic-antiinflammatory drugs inhibit orbicularis oculi reflexes in humans via a central mode of action.

1. A cross-over single blind study examined the possible central effects of non-opioid analgesic drugs on the trigeminal reflexes. 2. The corneal reflex and blink reflex (R1, R2) were recorded electromyographically and response areas measured in healthy volunteers before and after intramuscular injection of piroxicam (40 mg); and after intravenous injection of lysine acetylsalicylate (500 mg). After the last drug recording the subjects received intravenous naloxone (2 mg) followed 5 minutes later by further reflex testing. Saline was used as a placebo in control experiments. 3. Both analgesics reduced the corneal reflex: piroxicam induced a 27% and lysine acetylsalicylate a 21% a reduction that naloxone did not reverse. Neither drug reduced the early or the late component of the blink reflex. 4. The marked inhibitory changes that the two non-narcotic analgesics produced on the corneal reflex--a nociceptive response--indicate a centrally-mediated action. 5. Naloxone's failure to reverse the induced analgesia argues against opiate receptor mediation.

CNS effects of citalopram, a new serotonin inhibitor antidepressant (a quantitative pharmaco-electroencephalography study).

Citalopram, a new phthalane derivative and a specific serotonin re-uptake inhibitor in animal pharmacological tests, was evaluated in a double-blind, crossover, quantitative pharmaco-EEG (QPEEGTM) study in healthy human volunteers. The CNS effects of citalopram are linear, dose- and time-related, can statistically be differentiated from placebo, and indicate a rapid onset of effects with short duration. According to the Computer Data Bank, citalopram has a mode of action similar to mood elevators (antidepressants) with fewer sedative properties. Thus the therapeutic action of citalopram is predicted to be similar to desipramine and protriptyline from the tricyclics, and fluvoxamine from non-tricyclics. According to data bank assessment, it is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t.i.d. in clinical trials.

CNS pharmacology and clinical therapeutic effects of oxiracetam.

Oxiracetam, a new substance found to be a nootropic in experimental pharmacological studies, was tested in three clinical trials: a single rising dose tolerance and dose-finding study with quantitative pharmaco-electroencephalogram (pharmaco-EEG) and quantitative pharmacopsychology in healthy volunteers; a dose-finding study, at three dose levels for 3 months, with quantitative pharmaco-EEG in mild to moderate dementia patients; and a safety and efficacy study with increasing dosages for 12 weeks with subjective and objective tests in elderly patients with dementia. In single and repeated oral dosages up to 2,400 mg, oxiracetam is a safe compound. According to HZI Data Bank Classification Systems, oxiracetam is a vigilance-enhancing compound with some effects on spontaneous memory. The therapeutic effect of oxiracetam can be discriminated from placebo, and in comparison with piracetam, oxiracetam exhibits greater improvement in memory factor.

Dynamic brain mapping methodology and application.

Brain mapping has opened important perspectives for the neurophysiological evaluation of patients, for the discrimination of drug effects on the brain and for the study of the relationship between the brain and behavior. Our Dynamic Brain Mapping System is the result of many years of EEG quantification. It was designed as a software-oriented system to favor the largest clinical application and simultaneously stimulate new research objectives. Data collection and analysis procedures are critically important in brain mapping for a good understanding of the results. For clinical use, the maps should answer relevant EEG questions and be interpretable with the consolidated knowledge. Therefore, we have developed a new type of brain mapping technology which is called "Field blending interpolation" mapping offered together with the conventional technology with user-selectable interpolation algorithms. In addition to diagnosis, the use of computer-analyzed EEG and brain mapping can be instrumental in drug monitoring, drug selection and drug discriminations. Prospective studies are, however, required to validate the use of brain mapping in each of these new areas. Spatial analysis is the original goal of brain mapping. The development of a new data collection procedure and analysis will be instrumental in the determination of an adequate time and space resolution.

Computer-analyzed EEG (CEEG) and dynamic brain mapping in AIDS and HIV related syndrome: a pilot study.

In a group of HIV positive young male patients without any significant neuropsychiatric signs, computer-analyzed EEG (CEEG) and Dynamic Brain Mapping evaluations were conducted. These patients, who only had micro-neuropsychiatric symptoms, demonstrated CEEG profiles that more closely resemble those of patients diagnosed as suffering from mild dementia than age-related normals from our CEEG data base. The CEEGs of patients diagnosed as having Acquired Immune Deficiency Syndrome (AIDS), compared to patients with HIV positive, showed greater similarity in CEEG patterns to severely demented patients than to normal control groups. The findings of this pilot study suggest that CEEG may be useful for early determination of the Central Nervous System's (CNS) involvement with the AIDS virus and monitoring the progress of the illness.

The effects of mesterolone, a male sex hormone in depressed patients (a double blind controlled study).

Based on computer EEG (CEEG) profiles, in high doses, antidepressant properties of mesterolone, a synthetic androgen, were predicted. In a double-blind placebo controlled study, the clinical effects of 300-450 mg daily mesterolone were investigated in 52 relatively young (age range 26-53 years, mean 42.7 years) male depressed outpatients. During 6 weeks of mesterolone treatment, there was a significant improvement of depressive symptomatology. However, since an improvement was also established during the placebo treatment, no statistically appreciable difference in the therapeutic effects of mesterolone was established compared to placebo. Mesterolone treatment significantly decreased both plasma testosterone and protein bound testosterone levels. Patients with high testosterone levels prior to treatment seem to have had more benefit from mesterolone treatment than patients with low testosterone levels. The degree of improvement weakly correlated to the decrease of testosterone levels during mesterolone treatment.