Pattern of regional cerebral blood-flow changes induced by acute heroin administration--a perfusion MRI study.

PURPOSE: Although both the subjective and physiological effects of abused psychotropic substances have been characterized, less is known about their effects on brain function. We examined the actions of intravenous diacetylmorphine (heroin), the most widely abused opioid, on regional cerebral blood flow (rCBF), as assessed by perfusion-weighted MR imaging (PWI) in a double-blind and placebo-controlled setting. MATERIAL AND METHODS: Eight male subjects dependent of diacetylmorphine (mean age 36 years, range: 26 to 44 years), who had participated in a clinical diacetylmorphine maintenance program, underwent PWI with gadolinium injection. At two sessions separated by 2-7 days, the participants were examined 80 s after intravenous administration of either diacetylmorphine or saline. rCBF in four regions of interest (amygdala, vermis of the cerebellum, anterior cingulated cortex and thalamus) was compared with heroin versus placebo. RESULTS: In the cerebellum, thalamus and cingulated cortex, there were no significant differences in perfusion values between diacetylmorphine and placebo. In the amygdala, perfusion values were 0.8+/-0.4 and 0.5+/-0.2 on the left, and 0.9+/-0.4 and 0.6+/-0.3 on the right, with diacetylmorphine and with placebo, respectively (t-test results were P=0.044 and P=0.033 on the left and right sides, respectively). Other differences in perfusion values between the drug and placebo did not reach statistical significance. CONCLUSION: Perfusion MRI demonstrated differences in brain hemodynamics induced by drug intake.

[Psychiatric and psychosocial emergency situations]. / Psychiatrische und psychosoziale Notfallsituationen.

Psychiatric emergencies and crises are unforseeable by nature and can have devastating consequences. They can arise both in the course of chronic mental illness and in people who had not shown any previous signs of mental illness. Conditions that are so similar that they might be confused with one another can be caused by a wide range of internal illnesses, adverse side-effects of medications or intoxication. This is the reason why establishing a psychiatric diagnosis in emergency situations must be primarily driven by the question as to whether the differential diagnosis is an internal illness or rather intoxication. The most prevalent psychiatric emergencies in clinical practice are nervous breakdowns, psychomotor agitation and violence, suicidal tendencies, delirium, psychoses as well as addictions.

[Diagnosis and therapy of depression in the heart disease patient]. / Diagnose und Therapie der Depression beim herzkranken Patienten.

Even though depressions and depressive symptoms are frequently observed in patients with medical diseases, their psychological problems are often neither diagnosed nor treated. Diagnosis of mood state might be easy in isolated cases yet it often is not since the precise nature of normal mood cannot be expressed in quantitative terms. Furthermore, depression can only be diagnosed based on the doctor's clinical appraisal and the patient's own description of his/her complaints. There is no gold standard on which depressive symptoms can be based on--and further on, depression is not a diagnosis. Instead, it is a syndrome that calls for differential diagnoses before treatment can be offered. Diagnosing depressive comorbidity in patients with medical complaints is even more difficult because of the overlap between symptoms of depression and accompanying symptoms of the somatic illness e.g. lack of energy. Although depressive states have been known to be a risk factor for the prognosis of patients with coronary heart disease for a long time, there is a paucity of research about the therapy these patients undergo due to the fact that tricyclic anti-depressants can have cardiotoxic effects on patients with heart disease. The treatment of depression in these patients has become a much lower risk since the introduction of serotonin reuptake inhibitors. There is widespread evidence that depressive comorbidity has a negative impact on the prognosis of medical disorders. Despite the complex nature of diagnosing depression, proper diagnosis and treatment is increasingly important in internal medicine and especially cardiology.

High frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral cortex: EEG topography during waking and subsequent sleep.

Repetitive transcranial magnetic stimulation (rTMS) is a novel research tool in neurology and psychiatry. It is currently being evaluated as a conceivable alternative to electroconvulsive therapy for the treatment of mood disorders. Eight healthy young (age range 21-25 years) right-handed men without sleep complaints participated in the study. Two sessions at a 1-week interval, each consisting of an adaptation night (sham stimulation) and an experimental night (rTMS in the left dorsolateral prefrontal cortex or sham stimulation; crossover design), were scheduled. In each subject, 40 trains of 2-s duration of rTMS (inter-train interval 28 s) were applied at a frequency of 20 Hz (i.e. 1600 pulses per session) and at an intensity of 90% of the motor threshold. Stimulations were scheduled 80 min before lights off. The waking EEG was recorded for 10-min intervals approximately 30 min prior to and after the 20-min stimulations, and polysomnographic recordings were obtained during the subsequent sleep episode (23.00-07.00 h). The power spectra of two referential derivations, as well as of bipolar derivations along the antero-posterior axis over the left and right hemispheres, were analyzed. rTMS induced a small reduction of sleep stage 1 (in min and percentage of total sleep time) over the whole night and a small enhancement of sleep stage 4 during the first non-REM sleep episode. Other sleep variables were not affected. rTMS of the left dorsolateral cortex did not alter the topography of EEG power spectra in waking following stimulation, in the all-night sleep EEG, or during the first non-REM sleep episode. Our results indicate that a single session of rTMS using parameters like those used in depression treatment protocols has no detectable side effects with respect to sleep in young healthy males.

[Treatment of alcoholism]. / Die Behandlung der Alkoholkrankheit.

In view of the many non-specific symptoms a diagnosis of alcoholism can only be made by means of a detailed history and a medical checkup. Simple, standardized questions may often be sufficient. After a diagnosis a consultation with a family physician and drugs, such as disulfiram, acamprosate and naltrexone have been proved to be a highly efficient therapy. Therefore, it is worthwhile to treat alcoholics in the general practice setting.

Effects of menstrual cycle and female sex steroids on ethanol pharmacokinetics.

This study investigated the influence of menstrual cycle and female sex steroid levels on ethanol pharmacokinetics. In a within-subjects design, 24 female volunteers each consumed 0.67 g x kg(-1) ethanol during the menstrual and luteal phases of their menstrual cycle. On each test day, we collected blood samples before ethanol administration to determine estradiol (E2) and progesterone (P) levels and to confirm ovulation. We took 20 or more postdrink breath ethanol concentration readings and examined pharmacokinetic differences between the two phases, using classical pharmacokinetic measures, as well as Michaelis-Menten measures. Despite highly significant differences in measured E2 as well as P levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analysis, there were no significant differences between menstrual and luteal phases for any of the pharmacokinetic variables. We found no correlation between E2 or P levels and any of the pharmacokinetic measures. In summary, we found no evidence that the tested menstrual cycle phases or varying E2 and progesterone levels significantly influence ethanol pharmacokinetics. Because previous studies about the topic have used few subjects and revealed controversial results, we consider our negative findings based on 24 subjects meaningful.

[Treatment of alcoholic liver diseases and psychiatric and psychosocial problems]. / Behandlung der alkoholischen Lebererkrankungen und ihrer psychiatrischen und psychosozialen Probleme.

Only about 15% of the subjects abusing ethanol will eventually develop cirrhosis of the liver, suggesting that other factors in addition to the consumption of large quantities of ethanol play a role in the pathogenesis of alcoholic cirrhosis. Important contributors may be infection with hepatitis viruses, in particular HCV, protein-calorie malnutrition and immunologic factors. Abstinence improves the prognosis of patients with alcoholic cirrhosis, provided that the liver disease is not too far advanced. No pharmacotherapeutic intervention has shown a convincing improvement of the prognosis of alcoholic liver disease, so that the therapeutic efforts should be mainly directed towards abstinence. The patient with alcoholic liver disease needs support and guidance by the treating physicians. Supportive treatment with Disulfiram, Acamprosate or Naltrexon can help with achieving durable abstinence.

Self-reported somatization symptoms associated with risk for extreme alcohol use.

BACKGROUND: The high rates of alcohol use in the population, the increased general health care utilization associated with untreated alcohol problems, and the often diffuse nature of somatization symptoms led us to hypothesize that somatization symptoms might be associated with alcohol use. OBJECTIVE: To determine whether a relationship exists between somatization symptoms and alcohol use. DESIGN: Multivariable logistic regression models were used to analyze existing cross-sectional and 1-year longitudinal survey data from the National Institute of Mental Health Epidemiologic Catchment Area Program. SETTING: Community households. SUBJECTS: Probability sample. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalent and incident heavy or binge drinking ("extreme alcohol use"). These measures are part of the National Institute of Mental Health Epidemiologic Catchment Area Program public core data set that was collected without regard for specific hypotheses. RESULTS: After control for sex, age, and education, 13 self-reported somatization symptoms showed independent cross-sectional associations to prevalent extreme alcohol use. The greater the number of somatization symptoms, the greater the risk, up to a maximum increased odds ratio of 138 to 1, of having comorbid extreme alcohol use when reporting all 13 somatization symptoms in the model. A smaller set of items was associated with the risk for subsequent new onset of extreme alcohol use. CONCLUSIONS: Self-reported somatization symptoms could add to the detection of extreme alcohol use. In addition, primary care and other physicians should consider somatic complaints as possible indicators of concurrent and future risk for extreme alcohol use. Potential benefits of better detection of extreme alcohol use include supporting primary and secondary prevention efforts and reduced expenditures for the diagnostic workup of somatic complaints.

Animal models and ethological strategies for early drug-testing in humans.

The preclinical evaluation of psychotropic drugs relies on the use of animal tests which are thought to generate clinically relevant information concerning the psychiatric condition for which the drug can be used. Despite their importance, views on the usefulness of animal "models" vary widely, ranging from outright negation on the grounds that human minds are unique, to the more biological view that because of a partially common phylogenetic history, animals share many behavioural features with humans, e.g. learning, attention, aggression or sociality, which are altered in psychiatric disorders. The widespread use of ethology with its emphasis upon the function and origin of behaviour, particularly social behaviour, is based upon this evolutionary view. Many ethopharmacological tests in animals use situations which bias the animal's behaviour towards flight or sociality but their validation requires clinical feedback from humans. Unfortunately, information relating to human social mechanisms is rarely obtainable from conventional clinical-assessment schemes. To help overcome this problem, we have applied ethological principles to a new Challenge Interview Situation which is designed to bias the behaviour of healthy subjects towards flight. Analysis shows that by staring, moving closer or asking the subjects to relate emotional experiences, shifts in non-verbal behaviour towards avoidance and mild social withdrawal are achieved which resemble behavioural strategies recorded ethologically in depressed patients as well as animals in an arrested flight situation. The Challenge Interview is intended for early drug studies in humans where sociality is a target and can be adapted for concomitant endocrine and biochemical studies if required.

[Diagnosis and treatment of alcoholism]. / Diagnose und Behandlung der Alkoholkrankheit.

Alcoholism is the single most important psychiatric and psychosocial disease in Switzerland. The average Swiss citizen consumes about 10 l alcohol/year, the equivalent of half a bottle of hard liquor/week. The expenses for alcoholic beverages exceed the expenses for mandatory school education. Alcoholism is a chronic disorder which in its course and approach to treatment can be compared with diabetes, hypertension, and asthma. Similar to other chronic diseases, therapy consists in counselling and medication. The relevant goal is improvement rather than cure.

Divergence of ethanol and acetaldehyde kinetics and of the disulfiram-alcohol reaction between subjects with and without alcoholic liver disease.

Despite standardization, marked interindividual variation in the severity of the disulfiram-alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with (n = 16) and without (n = 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 +/- SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 +/- 0.10% dose x kg/mmol CO2] and 13 age- and sex-matched controls (alcoholics without significant liver disease, GEC 7.1 +/- 0.7; ABT 0.81 +/- 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, Cmax and area under the concentration-time curve (AUC) being 6.27 +/- 1.82 and 368.9 +/- 72.9 mmol x min/liter in alcoholic liver disease, and 6.62 +/- 1.71 and 377.6 +/- 124.5 in controls, respectively. In contrast, there was a strong (p < 0.001) difference in Cmax and AUC of acetaldehyde, respective values being 33.46 +/- 21.52 and 1463.8 +/- 762.5 mumol x min/liter in alcoholic liver disease, and 110.87 +/- 56.00 and 4162.0 +/- 2424.6 in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamics and pharmacokinetics of khat: a controlled study.

OBJECTIVES: To show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone. BACKGROUND: The main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published. DESIGN: The design was balanced and double blind. Six drug-naïve volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid-free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R-(-)norpseudoephedrine were determined by HPLC. RESULTS: Maximal plasma concentrations of cathinone (127 +/- 53 [SD] ng/ml) were attained after 127 +/- 30 minutes. The area under the plasma concentration-time curve from 0 to 9 hours was 415 +/- 207 ng/ml.hr, and the terminal elimination half-life was 260 +/- 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential (p < 0.01), Motor Stimulation (p < 0.02), Amphetamine-Like Effect (p < 0.005), and Stimulation-Euphoria (p < 0.005), as well as in the visual analog scales Excited-Calm (p < 0.001) and Energetic-Lethargic (p < 0.001). CONCLUSIONS: Our results provide objective evidence for the amphetamine-like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.

Light therapy in seasonal affective disorder is independent of time of day or circadian phase.

OBJECTIVE: We tested the hypothesis that phase-delayed circadian rhythms underlie seasonal affective disorder (SAD) by measuring phase position of 6-sulfatoxymelatonin excretion and comparing antidepressant response to morning or evening light given as a first treatment. DESIGN: Randomized controlled trial. SETTING: Ambulatory. PATIENTS: Thirty-two women and seven men with SAD. INTERVENTION: Light therapy (2500 lux for 1 hour for 1 week) was administered either at 7 AM or 10 PM, preceded by a baseline week and followed by a withdrawal week. RESULTS: Our SAD patient sample was moderately depressed (Hamilton Depression Scale [HAM-D] score 18); a HAM-D reduction of 50% or more was found in 12 of 18 patients given morning and in 15 of 21 patients given evening light (70% response rate). Response was not dependent on age, gender, stage of the menstrual cycle, time of year, or on the timing or duration of sleep. Urinary 6-sulfatoxymelatonin was measured in 30 patients; 22 had phase-delayed circadian rhythms. However, phase position was correlated neither with depth of depression nor with a preferential response to morning or evening light. COMMENT: Both morning and evening light therapy improved depressive symptoms in patients with SAD independent of their circadian phase or sleep timing. These findings argue against a circadian phase-delay hypothesis of the pathophysiology of SAD, or the necessity of a phase-advance by morning light for clinical efficacy. They additionally suggest more practicable and flexible schedules for light therapy in SAD, since time of day is not crucial.

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat.

Increased levels of natural benzodiazepine receptor agonists, produced in the body (endogenous) or ingested with food (exogenous) have been proposed as one of the factors causing hepatic encephalopathy in both experimental animals and human subjects. However, the divergent response of hepatic encephalopathy to benzodiazepine antagonists sheds doubt on this attractive hypothesis. Acute liver failure was induced in male Sprague-Dawley rats (n = 17) with intraperitoneal thioacetamide (600 mg/kg/day for 3 days) while 14 control rats received vehicle only. Acute liver failure developed in all treated rats (AST: 1,898 +/- 1,359 IU/L vs. controls, 45 +/- 5 IU/L, p < 0.005; bilirubin: 36 +/- 27 mumol/L vs. controls, 1.5 +/- 0.5 mumol/L, p < 0.005; centrizonal necrosis) and grade 3 or 4 hepatic encephalopathy (neurologic assessment and activity monitoring). However, benzodiazepine receptor ligand activity, measured in the supernatant of whole-brain homogenates with a [3H]flumazenil binding competition assay, was clearly increased in only 1 of 17 rats with acute liver failure compared with controls (52.7 +/- 34.1 vs. 44.3 +/- 18.9 ng diazepam equivalents/gm; NS). To evaluate whether the reported increase in benzodiazepine receptor ligand activity could be due to prolonged residence of exogenous benzodiazepine-like substances, additional rats with acute liver failure and controls were treated with diazepam (five doses of 0.5 mg/kg at 12-hr intervals by gavage). Benzodiazepine receptor ligand activity was greater in animals with acute liver failure than in controls (223 +/- 65 vs. 103 +/- 23 ng diazepam equivalents/gm; p < 0.002) 1 to 3 hr after the last diazepam dose.(ABSTRACT TRUNCATED AT 250 WORDS)

[Quantitative assessment of the quality of life of patients with a kidney transplant]. / Quantitative Erfassung der Lebensqualität bei Patienten mit einer Nierenersatztherapie.

Actually three methods are offered for the treatment of patients with chronic renal failure: 1. Hemodialysis, 2. chronic peritoneal dialysis for outpatients (CAPD) and 3. Transplantation of a kidney. In order to define the optimal therapy for these patients not only economic factors but also quantitative evaluation of life quality has to be taken into account. To this end a questionnaire called "Sickness Impact Profile", that covers most of the relevant features of life and is well established in the Anglo-Saxon countries, was translated into German language and tested in 34 hemodialysis-patients, 25 CAPD-patients and 29 patients with kidney transplant, in order to investigate the applicability. Results showed that the German issue can successfully be applied to Swiss patients with renal failure and lead to the conclusion that--in accordance to results of similar studies in the USA--life quality in patients with kidney transplant is better than in patients treated with hemodialysis or CAPD.

Paradoxical effects of mild hypoxia and moderate altitude on human visual perception.

1. Prolonged (> 10 h) exposure to hypoxia and high altitude (> 5000 m) invariably have detrimental effects on cognitive performance. Paradoxically, mild improvements in cognitive function in patients with chronic obstructive pulmonary disease after cessation of oxygen therapy have been reported. 2. We studied in each of 10 healthy subjects the effect of an acute altitude challenge [rapid helicopter transport to the Jungfraujoch (3450 m), experiment 1] and of an acute exposure to mild hypoxia (fractional inspiratory oxygen concentration 14.5% experiment 2) on a simple test of cognitive performance (the time needed to read briefly displayed letters). 3. Under both hypoxic conditions the time needed to read briefly presented letters decreased, from 12.1 +/- SD 3.8 ms to 8.3 +/- 1.5 ms (P < 0.01) in experiment 1, and from 11.9 +/- 1.9 ms to 8.1 +/- 1.1 ms (P < 0.01) in experiment 2. 4. A rapid and mild hypoxic challenge seems to improve a simple measure of cognitive performance above normal values. The common notion that exposure to hypoxia and altitude invariably impairs cognitive performance may have to be re-evaluated.

[What does the alcoholic patient need from his family physician?]. / Was braucht der Alkoholiker von seinem Hausarzt?

Chronic alcoholics are all too often not recognized in general practice. Diagnosis is only possible if the doctor assumes potential alcoholism in all his patients. Because of the tendency of the patient and often his family to deny alcohol dependence, diagnosis is only possible by taking psychiatric, somatic and psychosocial aspects into consideration in addition to an independent history. Questionnaires may be helpful. The severity of the dependence on alcohol is not a predictor of success in therapy. In practice, three types of alcoholics may be distinguished: (1) patients with stable social relationships; (2) patients with stable social relationships and severe anxiety or depression with alcohol abuse as an inadequate self medication; (3) patients who are not able to maintain stable relationships. The latter are unlikely to be successfully treated by a family physician. A careful classification of patients according to these simple criteria may reduce the rate of treatment failures. Therapy by the family physician is initiated with an extensive somatic, psychiatric and psychosocial work-up, and maintained by counseling and care. An important factor is close collaboration between physician and social worker. Disulfiram may be a powerful adjunct to the therapy of the family physician if supervised by a trustee. In our departments we work with alcoholics in a joint consultation service involving an internist and a psychiatrist. Two thirds of the patients who consent to supervised disulfiram remain in the program for a year. 3 months after initiation of the treatment, gamma-glutamyltransferase, ASAT, ALAT and MCV are normalized. A follow-up 5 years after treatment indicated the efficacy of this treatment.