Observational and experimental studies on sleep duration and aggression: A systematic review and meta-analysis.

Short sleep duration has been linked to higher levels of aggression. To synthetize all available research on this association, a systematic review and meta-analysis was performed. We included observational and experimental studies, using various measures of sleep duration and aggression. Eighty eligible papers were identified, describing 82 studies comprising a total number of 76.761 participants. Meta-analysis of results was possible for 60 studies. Pooled observational results on the association between sleep duration and aggression showed a correlation estimate of -0.16 (95%CI -0.19, -0.12; I2 = 83.9%) and an odds ratio estimate of 1.83 (95%CI 1.47, 2.28; I2 = 0.0%). For experimental studies, the pooled Standardized Mean Difference after manipulation of sleep duration was -0.37 (95%CI -0.80, 0.05; I2 = 89.05%) for controlled designs and -0.34 (95%CI -0.54, -0.14; I2 = 89.05%) for pre-post designs. Effect estimates were stronger for individuals with psychological vulnerabilities and younger persons. Exclusion of studies with low methodological quality strengthened the effect estimate in experimental but not in observational studies. To conclude, short sleep duration is associated with higher levels of aggression, with observational research strongly supporting the association and experimental studies providing mixed results. More well-designed prospective and experimental studies are needed to establish causality and optimize treatment, especially for individuals with psychological vulnerabilities.

[Intoxicated women: A study into gender differences in substance abuse in forensic psychiatric patients]. / Vrouwen onder invloed: een studie naar genderverschillen in middelengebruik bij forensisch psychiatrische patiënten.

BACKGROUND: Substance abuse is an important risk factor for (violent) offending, but is mostly studied in male populations. More knowledge about women is needed.
AIM: To gain insight into possible gender differences in substance abuse and offending in forensic psychiatric patients.
METHOD: Files were analysed of 275 women and 275 men who have been admitted between 1984 and 2014 to one of four Dutch forensic psychiatric facilities and related to incidents of violence during treatment or recidivism after discharge (for 78 women).
RESULTS: Although substance abuse was common in women (57%), it was significantly more prevalent in men (68%). Men were more often diagnosed with substance dependency and more often committed the index-offense whilst intoxicated. Predictive accuracy for violent incidents during treatment was better for men. Both women and men with substance abuse had significantly more historical risk factors compared to those without substance abuse. A history of substance abuse was not a significant predictor for recidivism after discharge in women.
CONCLUSION: There are gender differences in substance abuse and the relationship with offending was stronger for men. These differences may have implications for substance use treatment in forensic mental health services.

[Sleep: the basis of a healthy lifestyle]. / Slaap: de basis voor een gezonde leefstijl.

BACKGROUND: The use of sleep as modifiable lifestyle factor is not yet self-evident in psychiatry.
AIM: To increase knowledge about sleep as health-affecting factor.
METHOD: Description of normal sleep, effects of disturbed sleep and lifestyle advice to promote healthy sleep.
RESULTS: Disturbed sleep negatively impacts physical and mental health. Targeted lifestyle advice can improve sleep and bring about positive effects in multiple areas.
CONCLUSION: From preventive and treatment perspectives, interventions optimizing sleep in psychiatric care seem promising.

Poor sleep quality at baseline is associated with increased aggression over one year in forensic psychiatric patients.

OBJECTIVE: In forensic psychiatric patients, sleep problems as well as impulsivity and aggression are highly prevalent, yet studies on their association over time are lacking. This study investigates the association between sleep quality and changes in impulsivity and aggression in forensic psychiatric patients over one year. METHODS: Data were drawn from an ongoing prospective observational study in adult forensic psychiatric patients admitted to a forensic treatment facility between October 2006 and January 2018. Validated self-reports and observational instruments were used to assess sleep quality, impulsivity and aggression upon admission to the hospital and after one year. Linear regression analyses were performed to examine the association between sleep quality, impulsivity and aggression. All models were adjusted for baseline values of outcome measures, demographic features and general psychopathology. RESULTS: Data from 83 men (age 37.7 ± 11.7 years) with completed consecutive measurements were analyzed. Poor sleep quality was associated with increased self-reported aggression (ß = 1.08; 95% CI, 0.38-1.78). This association was positively confounded by general psychopathology, indicating that sleep quality is specifically related to self-reported aggression instead of being part of general psychopathology (adjusted ß = 1.18; 95% CI, 0.39-1.97). Poor sleep quality was not associated with changes in self-reported impulsivity, clinician-rated impulsivity or clinician-rated hostility in this population. CONCLUSION: Poor sleep quality was associated with an increase in self-reported aggression over one year in male forensic psychiatric patients. Early evaluation and treatment of sleep problems in (forensic) psychiatric patients may play an important role in reducing the risk of aggressive behavior.

Poor Sleep and Its Relation to Impulsivity in Patients with Antisocial or Borderline Personality Disorders.

Studies investigating sleep and personality disorders consistently demonstrate a relation between personality disorders characterized by behavioral disinhibition and/or emotional dysregulation (traditionally termed cluster B personality disorders) and poor sleep. This finding is in line with previous studies associating insomnia with impulsive behavior, since this is a core characteristic of both antisocial and borderline personality disorder. The current study investigates a group (n = 112) of forensic psychiatric inpatients with antisocial or borderline personality disorder or traits thereof. Subjective sleep characteristics and impulsivity were assessed with the Pittsburgh Sleep Quality Index, the Sleep Diagnosis List, and the Barratt Impulsiveness Scale, respectively. More than half of the patients (53.6%) report poor sleep quality and 22.3% appears to suffer from severe chronic insomnia. Both poor sleep quality and chronic insomnia are significantly associated with self-reported impulsivity, in particular with attentional impulsiveness. This association was not significantly influenced by comorbid disorders. Actively treating sleep problems in these patients may not only improve sleep quality, mental health, and physical well-being, but may also have impact on impulsivity-related health risks by increasing self-control.

[Violent women: a multicentre study of the characteristics of female forensic psychiatric patients]. / Gewelddadige vrouwen: een multi-centeronderzoek naar kenmerken van vrouwelijke forensisch psychiatrische patiënten.

BACKGROUND: Violence perpetrated by women has attracted more and more attention in the past few years. However, there is lack of background information about women admitted to forensic psychiatric hospitals and about risk factors for recidivism. AIM: To conduct a multicenter study which will give more insight into female psychiatric patients and which will probably have implications for psychodiagnostics, risk assessment and treatment in (forensic) psychiatric settings. METHOD: We coded the files of 297 women who, between 1984 and 2013, had been admitted to one of four Dutch forensic psychiatric facilities by reason of violent delinquent behaviour. We used an extensive coding list and several risk assessment tools including the recently developed Female Additional Manual (fam) for women. RESULTS: The general picture that emerged was one of severely traumatised women with complex pathology and a high level of comorbidity. Many of the women had experienced previous treatment failures and had caused many incidents during treatment. CONCLUSION: Female forensic psychiatric patients are a complex group that deserves more specific attention. Attention for traumas from the past, intensive supervision in relationships and training for staff in dealing with, for instance, manipulative behaviour are the most important implications from this study.

Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology.

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.

Acute effects of melatonin on spontaneous and picrotoxin-evoked sleep-wake behaviour in the rat.

Various studies indicate that exogenous melatonin has hypnotic properties in humans, which may be mediated by its influence on the circadian timing system or direct sleep-promoting actions, e.g. through a modulation of GABAergic transmission. The aim of the present placebo-controlled study was to examine the effects of melatonin on sleep in rats and the contribution of gamma-aminobutyric acid (GABA)A receptors. Sleep-wake behaviour was assessed in nine rats after intraperitoneal (i.p.) administration of pharmacological doses of melatonin (5 and 10 mg kg(-1)) and after combined administration of the GABAA receptor antagonist picrotoxin (1.5 mg kg(-1)) and melatonin (10 mg kg(-1)). To prevent chronobiotic effects, melatonin was delivered in the middle of the light period. Neither doses of melatonin exerted significant effects on brain temperature, sleep architecture or sleep electroencephalogram (EEG). Moreover, melatonin failed to attenuate the picrotoxin-induced promotion of wakefulness. These observations indicate that melatonin hardly influences sleep-wake behaviour in rats.

The GABA(A) agonist gaboxadol improves the quality of post-nap sleep.

RATIONALE: Previous studies demonstrated that gaboxadol, a selective GABA(A) agonist, increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions. OBJECTIVE: Because the hypnotic actions of drugs may be more readily demonstrated under conditions of poor sleep quality, we investigated the influence of gaboxadol on postnap sleep. METHODS: In a randomized, placebo-controlled cross-over study using a late afternoon nap model, we assessed the effects of a single oral dose of 20 mg gaboxadol on disturbed nighttime sleep in young, healthy subjects. RESULTS: Comparisons of visually scored sleep parameters between baseline and placebo postnap nights showed that the nap prolonged sleep latency, decreased total sleep time and SWS and attenuated delta, theta and alpha activity in the EEG within non-REM sleep. Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly decreased intermittent wakefulness, increased total sleep time and SWS and enhanced delta and theta activity in the non-REM EEG. Furthermore, gaboxadol increased subjective sleep quality. CONCLUSIONS: These data show that gaboxadol counteracts the disrupting effects of a nap on subsequent sleep and suggest that, in addition to promoting deep sleep and sleep maintenance, gaboxadol is able to facilitate sleep initiation and thus, exhibits significant hypnotic actions under conditions in which sleep quality is experimentally reduced.

The influence of subchronic administration of the neurosteroid allopregnanolone on sleep in the rat.

The endogenous neurosteroid allopregnanolone has recently been demonstrated to have somnogenic properties that are very similar to those of other agonistic modulators of GABA(A) receptors, especially of short-acting benzodiazepines. Short-acting benzodiazepines are established to rapidly lose their hypnotic effect upon repeated administration. To investigate the tolerance potential of allopregnanolone, we assessed sleep-wake behavior in rats during subchronic treatment (once daily for five days) with placebo or 15 mg/kg allopregnanolone (n = 8 each). The sleep patterns of the placebo and allopregnanolone group did not differ significantly before and after treatment. Throughout the entire treatment period the allopregnanolone group exhibited shorter non-rapid eye movement sleep (non-REMS) latencies, prolonged REMS latencies, longer non-REMS episodes, more pre-REMS and less low-frequency, but higher spindle activity in the electroencephalogram (EEG) within non-REMS than the placebo group. The lack of tolerance effects suggests that allopregnanolone may be an efficacious modulator of sleep-wake behavior over longer time periods than most drugs targeting the benzodiazepine binding site of the GABA(A) receptor.

Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects.

Aging is associated with a dramatic decrease in sleep intensity and continuity. The selective GABA(A) receptor agonist gaboxadol has been shown to increase non-REM sleep and the duration of the non-REM episodes in rats and sleep efficiency in young subjects and to enhance low-frequency activity in the electroencephalogram (EEG) within non-REM sleep in both rats and humans. In this double-blind, placebo-controlled study, we investigated the influence of an oral dose of 15 mg of gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol, prolactin, growth hormone) in 10 healthy elderly subjects (6 women). Compared with placebo, gaboxadol did not affect endocrine activity but significantly reduced perceived sleep latency, elevated self-estimated total sleep time, and increased sleep efficiency by decreasing intermittent wakefulness and powerfully augmented low-frequency activity in the EEG within non-REM sleep. These findings indicate that gaboxadol is able to increase sleep consolidation and non-REM sleep intensity, without disrupting REM sleep, in elderly individuals and that these effects are not mediated by a modulation of hormone secretion.

The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects.

Aging is associated with a dramatic decrease in slow wave sleep (SWS) and sleep consolidation. Previous studies revealed that various GABA(A) agonists and the GABA uptake inhibitor tiagabine augment slow frequency components in the EEG within non-REM sleep, and thus promote deep sleep in young individuals and/or rats. In the present double-blind, placebo-controlled study, we assessed the effect of a single oral dose of 5 mg tiagabine on nocturnal sleep in ten healthy elderly volunteers (6 females). During the placebo night the subjects displayed a low sleep efficiency, due to high amounts of intermittent wakefulness, and little SWS. Tiagabine significantly increased sleep efficiency, tendentially decreased wakefulness and prominently increased both SWS and low-frequency activity in the EEG within non-REM sleep. The present findings demonstrate that tiagabine increases sleep quality in aged subjects. Moreover, the effects of tiagabine closely match those evoked by the GABA(A) agonist gaboxadol in young subjects and indicate that such compounds may have prospects in the treatment of sleep disturbances, particularly of those commonly occurring in the elderly.

Sleep changes induced by lipopolysaccharide in the rat are influenced by age.

In mammals, aging is associated with immune senescense. To examine whether the sleep changes occurring during immune challenge are affected by age, we assessed sleep alterations induced by the administration of lipopolysaccharide (LPS) in young and middle-aged rats. During vehicle, the middle-aged rats exhibited less pre-rapid eye movement sleep (pre-REMS) as well as REMS, due to a smaller number and shorter duration of REMS episodes, than young rats. LPS elevated body temperature, increased non-REMS, and suppressed both pre-REMS and REMS in the young as well as in the middle-aged rats. However, in the young animals, LPS significantly enhanced slow-wave activity in the electroencephalogram (EEG) within non-REMS, reflecting an increase in sleep intensity. In contrast, LPS attenuated EEG power in most frequency bands in the older animals. This finding indicates age-related changes in the modulation of sleep by LPS.

Diurnal variations in lipopolysaccharide-induced sleep, sickness behavior and changes in corticosterone levels in the rat.

Inoculation of rats with microorganisms or microbial constituents that activate host defense promotes non-rapid eye movement sleep (non-REMS) and suppresses REMS. In this study, we evaluated circadian influences on the effects of lipopolysaccharide (LPS) on sleep, sickness behavior and plasma corticosterone levels in the rat. Three sets of experiments were performed. In each, the animals were intraperitoneally injected with vehicle for LPS (30 microg/kg) during 2 consecutive days, at the beginning of either the circadian rest or the activity phase. In experiment 1, sleep-wake behavior and brain temperature were recorded, and in experiment 2, core body temperature, locomotor activity as well as food and water intake. In experiment 3, corticosterone blood levels were measured. The results show that LPS-evoked changes in temperature, sleep and other behavioral parameters depend markedly on the time of day LPS is administered. However, a direct comparison of the LPS data demonstrates that, except for sleep parameters, the absolute time course of the assessed parameters was rather similar between the rest and activity phases. These findings suggest that LPS evokes a state characterized by high temperature and low vigilance, which is reached independently of the circadian phase.

High doses of systemic DHEA-sulfate do not affect sleep structure and elicit moderate changes in non-REM sleep EEG in rats.

The hormone dehydroepiandrosterone (DHEA) and its metabolite DHEA-sulfate (DHEAS) occur in huge quantities in the plasma as well as in the brain of vertebrates. To investigate whether DHEAS modulates sleep-wake behavior, we assessed the sleep response to three doses (25, 50, and 100 mg/kg) of intraperitoneally administered DHEAS, mixed with oil, in 8 rats. DHEAS injections produced dose-dependent and long-lasting elevations in the plasma levels of both DHEAS and DHEA. DHEAS administration did not affect sleep time and architecture but exerted persistent effects on the electroencephalogram (EEG) within non-rapid eye movement sleep: 50 mg/kg DHEAS significantly augmented EEG power in the frequency range of sleep spindles, and 100 mg/kg DHEAS depressed EEG power in the slow-wave frequency bands. The findings indicate that DHEAS changes the sleep EEG in a dose-dependent way, possibly through a modulation of GABA- and glutamate-induced currents.

gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats.

Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.

Sleep and Its Modulation by Drugs That Affect GABA(A) Receptor Function.

Most sleeping pills are made up of chemical compounds that are ligands for allosteric modulatory binding sites on the GABA(A) receptor. Polysomnographic studies demonstrate that these hypnotics effectively increase the ability to fall and to stay asleep, but disrupt the physiological sleep profile (typical electroencephalograms (EEG) for the awake state and the different states of sleep are shown). Hence, there is an urgent need for sleep-promoting substances with a different mechanism of action. GABA analogues are one class of promising molecules.

Assessment of neuroleptic-like properties of progesterone.

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders. Because the administration of this steroid might be of therapeutic value in psychiatric disturbances, we investigated the behavioral properties of progesterone in the rat to assess putative neuroleptic-like properties of this steroid. Progesterone administration dose-dependently increased the EEG activity during wakefulness in the 10- to 30-Hz frequency bands and decreased locomotor activity. While no anxiolytic activity could be detected in the plus maze, the highest dose of progesterone (90 mg/kg) exerted an inhibitory effect on the conditioned avoidance response. In contrast to haloperidol (0.5 mg/kg), progesterone neither produced catalepsy nor antagonized amphetamine-induced stereotypy. However, both progesterone (10, 30 and 90 mg/kg) and haloperidol (0.1 mg/kg) effectively restored the disruption of the prepulse inhibition (PPI) of the acoustic startle response (ASR) that was evoked by apomorphine (2 mg/kg). In contrast, allopregnanolone (10 mg/kg), one of the main metabolites of progesterone, did not significantly antagonize the effect of apomorphine on the PPI. This behavioral profile of progesterone is compatible with the sedative properties of its metabolite allopregnanolone via the GABAA receptor, but also with the possibility that progesterone itself shares some properties with atypical antipsychotics, which may be relevant for the development and treatment of psychotic disturbances.

Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists.

This paper reviews the sleep effects of systemically administered agonistic modulators of GABAA receptors, including barbiturates, benzodiazepines, zolpidem, zopiclone and neuroactive steroids, and the selective GABAA agonists muscimol and THIP. To assess the involvement of GABAA receptors in the physiologic regulation of sleep, the article emphasizes the hypnotic properties shared by agonistic modulators and by the selective agonists of the GABAA receptor complex. In both rats and normal sleeping individuals, agonistic modulators are able to reduce sleep latency, increase sleep continuity, and promote non-rapid-eye-movement (NREM) sleep as well as the occurrence of spindles. Furthermore, nearly all of these compounds have been shown to attenuate slow-wave activity (SWA) and to suppress the occurrence of REM sleep. In the same species, GABAA agonist(s) do not seem to affect sleep latency or REM sleep time, but may increase sleep continuity and NREM sleep and augment SWA while depressing spindle activity in humans. The distinct sleep effects of GABAA agonists may be due to their unspecific stimulation of GABAA receptors throughout the brain, and to the fact that they are poor substrates for uptake and probably exert more tonic effects than liberated GABA. If so, the involvement of GABAA receptors in the various aspects of sleep can be inferred more accurately from the hypnotic effects of agonistic modulators. This implies that an activation of GABAA receptors plays a crucial role in the initiation and maintenance of NREM sleep and in the generation of sleep spindles, but disrupts the processes underlying slow EEG components and the triggering of REM sleep.

The GABA(A) receptor antagonist picrotoxin attenuates most sleep changes induced by progesterone.

Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABA(A) receptor functioning. To assess the involvement of GABA(A) receptors, we investigated the sleep responses to one dose of the GABA(A) antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (< or = 8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABA(A) receptors play an important role in the sleep effects of progesterone.