Zolpidem, Complex Sleep-Related Behaviour and Volition.

A commonly prescribed hypnotic, Zolpidem, has been linked to accidental death, driving offences and a very uncommon legal defence ­ automatism. The deaths and prima facie criminal behaviour that have triggered legal concern and considerable publicity have occurred while the person was in a sleep-like state and apparently acting involuntarily after ingesting the drug. Australian courts have had a mixed response to these claims, and have closely examined the expert evidence that is essential to establishing the link between the conduct and the medication. Accepting that a connection has been established, in 2014 a Victorian Coroner suggested that guidelines issued in Australia should reduce recommended dosages of Zolpidem and increase warnings about adverse effects. However, forensic issues associated with unpredictable, complex sleep-related behaviour triggered by Zolpidem will not be resolved entirely by these changes. Exploration of the legal implications of this conduct is essential as the issue is likely to be of continuing and particular significance in Australia, where reports of adverse effects associated with this hypnotic have been more frequent than in other countries.

[Neuroscientific basic in addiction]. / Neurowissenschaftliche Basis der Sucht.

The growing evidence of Neuroscience leads to a better understanding of cerebral processes in cases of acute or chronic intake of psychotropic substances (ps). Predominantly, structures of the "reward system" contributed to the development of addiction. Chronic consumption of ps provides changing in brain equilibrium and leads to adaptations in the brain architecture. In this article, the complex responses of neurons and neuronal networks are presented in cases of chronic intake of ps. The alterations affect the cognitive, emotional and behavioral processings and influence learning and stress regulation. In summary, all cerebral adaptations are integrated in a complex model of biological, psychological and social factors and therefore, addiction arises as a consequence of combination of individual protecting and risk factors.

Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series.

STUDY OBJECTIVES: To describe zolpidem-associated complex behaviors, including both daytime automatisms and sleep-related parasomnias. METHODS: A case series of eight clinical patients and six legal defendants is presented. Patients presented to the author after an episode of confusion, amnesia, or somnambulism. Legal defendants were being prosecuted for driving under the influence, and the author reviewed the cases as expert witness for the defense. Potential predisposing factors including comorbidities, social situation, physician instruction, concomitant medications, and patterns of medication management were considered. RESULTS: Patients and defendants exhibited abnormal behavior characterized by poor motor control and confusion. Although remaining apparently interactive with the environment, all reported amnesia for 3 to 5 hours. In some cases, the episodes began during daytime wakefulness because of accidental or purposeful ingestion of the zolpidem and are considered automatisms. Other cases began after ingestion of zolpidem at the time of going to bed and are considered parasomnias. Risk factors for both wake and sleep-related automatic complex behaviors include the concomitant ingestion of other sedating drugs, a higher dose of zolpidem, a history of parasomnia, ingestion at times other than bedtime or when sleep is unlikely, poor management of pill bottles, and living alone. In addition, similar size and shape of two medications contributed to accidental ingestion in at least one case. CONCLUSIONS: Sleep driving and other complex behaviors can occur after zolpidem ingestion. Physicians should assess patients for potential risk factors and inquire about parasomnias. Serious legal and medical complications can occur as a result of these forms of automatic complex behaviors.

Fluoxetine toxicity in a preterm infant.

We describe a preterm infant with marked motor automatism and skin manifestations after being exposed to fluoxetine in utero. The fluoxetine level drawn at 96 hours of age was 92 ng/ml, which was in adult therapeutic range. The neurologic symptoms resolved by 7 days and follow-up at 4 months revealed normal neurodevelopmental examination.

[The effect of fluctuating currents on the time course of apomorphine-induced stereotypy in rats]. / Vliianie fliuktuiruiushchikh tokov na vremenennúiu dinamiku apomorfinovoi stereotipii u krys.

The external rhythmogenic influence (repeated fluctuation low intensity) disorganized the time-course and attenuated the apomorphine-induced stereotyped behavior in rats. A decrease in the number of 4-9-minute waves on chronograms in comparison with control an animals indicated reduction of stability of the pharmacological response and the rapid formation of tolerance to the drug.

[Automatic actions with amnesia induced by taking hypnotic drugs. Association with personal and familial history of somnambulism and epilepsy]. / Activités automatiques avec amnésie induites par la prise de médicaments hypnotiques. Association à un passé personnel et familial de somnambulisme et d'épilepsie.

A family which combined sleep-walking drug-induced sleep-walking and epilepsy is reported. This co-morbidity suggest various mechanisms which could explain drug induced sleep-walking. We stated the hypothesis that these behaviors were epileptic states due to a mini-withdrawal syndrome. This mini-withdrawal including of course a rebound of anxiety and insomnia during the day, but also a pro-convulsivant effect.

Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats.

The influence of phenobarbital (PHB, 10, 20, 40 or 80 mg/kg i.p.) and primidone (PRI, 40 or 80 mg/kg i.p.) on metrazol-induced motor seizures was studied in rats 7, 12, 15, 18, 25 and 90 days old. PHB blocked both types of seizures induced by metrazol-minimal (mMS) as well as generalized tonic-clonic (MMS)--in all age groups where they appeared under control conditions. The effect against major seizures was always better expressed than against mMS. Pretreatment with PHB led to the appearance of mMS in 7- and 12-day-old rat pups, where control animals did not exhibit this type of seizure. Combined administration of the 2 high doses of PHB and metrazol resulted in the appearance of behavioral automatisms in young rats. PRI abolished MMS in adult rats only, no changes were seen in 25-day-old animals and specific suppression of the tonic phase of MMS was observed in younger rats. mMS were influenced only in 7- and 12-day-old rats, where an increase in their incidence was recorded. Pretreatment with PRI never induced automatisms. The different actions of PHB and PRI speak in favor of an anticonvulsant action of PRI itself.

[The characteristics of the temporal dynamics of stereotypic behavior in rats during chronic fenamine administration]. / Osobennosti vremennói dinamiki stereotipnogo povedeniia krys pri khronicheskom vvedenii fenamina.

Amphetamine-induced stereotyped behavior is a nonsteady oscillatory process. In its structure waves with 2-3, 4-5 and 10-15 minute periods may be distinguished. In some animals (30%) after chronic amphetamine administration the stereotyped behavior was attenuated with reorganization of its rhythmical pattern but in other cases (35%) stereotype on the contrary increased. Tolerance developed in the animals which had initially the more pronounced stereotype with the predomination of short-period (2-3 min) waves on the chronogram. These animals demonstrated low locomotor activity in the opened field, greater immobility in the forced swimming test and better relearning in Y-maze.

[Memory gaps and hypercomplex automatisms after a single oral dose of benzodiazepines: clinical and medico-legal aspects]. / Lacunes mnésiques et automatismes hypercomplexes après prise orale de benzodiazépines: aspects cliniques et médico-légaux.

From 8 original observations and from an overview of published cases, the authors make out two kinds of mental disorders connected with benzodiazepines use: 1) transient global anterograde amnesia; 2) amnesic complex automatism. Consequences for forensic medicine are finally investigated.

Intrahippocampal bethanechol in rats: behavioural, electroencephalographic and neuropathological correlates.

Unilateral microinjections of bethanechol chloride into the CA3 subfield of the dorsal hippocampus in unrestrained rats produced a seizure-related type behavioural and disseminated brain damage syndrome. Injection of bethanechol in the dose of 50 micrograms resulted in locomotor activation, mouth movements, teeth chattering, chewing, wet dog shakes and mild limbic seizures. Shortly after intrahippocampal injection the electroencephalogram (EEG) showed an increase in the frequency of the theta rhythm in both hippocampi. Then EEG showed spiking activity of high frequency in the injected hippocampus, with rapid propagation to the lateral septum, amygdala, neocortex and contralateral hippocampus. The periods of spiking activity of high frequency were followed by depression in the background EEG rhythm with some interspersed spike and wave complexes of very low frequency. Histological examination of frontal forebrain sections revealed disseminated, apparently seizure-mediated pattern of brain damage. The patterning of distant damage after intrahippocampal injections of bethanechol involved the piriform cortex, entorhinal cortex, olfactory tubercle, anterior olfactory nucleus, subiculum, amygdaloid complex, temporoparietal cortex and hypothalamic nuclei. Neuropathological alterations were occasionally observed in the lateral septum and thalamus. These results seem to establish a causative relationship between excessive stimulation of cholinergic muscarinic receptors in the hippocampal formation and epileptic brain damage.

The concept of drug automatism.

The drug-automatism hypothesis implies a medication-induced absence of intentionality for self-poisoning and a relative amnesia for serial or single overdosage. Controversy stems from problems encountered in the formulation and verfication of the hypothesis. The author reviews the literature, presents a case associated with a proprietary sleeping preparation, and discusses psychopharmacological and psychophysiological elements in the mechanism of drug automatism and its differential diagnosis.

Electroencephalographic findings in phencyclidine intoxication.

The first report of electroencephalographic findings in clinically encountered phencyclidine intoxication is presented. When first seen, the patient was in a coma, initially distinguished only by nystagmus, waxy rigidity of the extremities, and an EEG with a widespread, sinusoidal theta rhythm interrupted every few seconds by periodic slow-wave complexes. The similarity of the EEG to that of deep ketamine anesthesia suggested intoxication with a ketamine-related (phenylcyclohexylamine) drug. Phencyclidine, the prototype of the phenylcyclohexylamine compounds and a widely abused hallucinogen, was subsequently identified in the urine and blood.