Clinical management of alcohol withdrawal

It has been well known for a number of years that abrupt withdrawal from alcohol following chronic use is associated with adverse consequences, ranging from mild tremors to withdrawal seizures. The overall purposes of treating alcohol withdrawal (AW) are to relieve patient discomfort, to prevent the development of more serious withdrawal symptoms, and to initiate long-term alcohol rehabilitation. Several areas of controversy exist in the clinical management of AW, including the optimal treatment setting, the need for pharmacologic management, and the most appropriate agent to prescribe when medication is deemed necessary. This article reviews the clinical features, general management, and treatment of AW.     

Personality and alcohol dependence

In this study, groups of ‘alcoholic’ subjects were independently rated as to their degree of dependence by a technique previously validated. The two groups of moderately and severely dependent subjects were then given the 101-item EPQ. In keeping with other similar studies, the data suggested that high N, high P and low E in men were related to the Clinical Alcohol Personality. Further analysis of these and other data suggest that whilst raised N scores may be a spurious artefact which is a consequence of heavy alcohol consumption, the E and P findings may reflect stable predispositions. There were no sex differences, but there was a major group difference on P, with both severely dependent men and women scoring significantly higher than their less dependent counterparts.     

Personality and the genetic risk for alcohol dependence

The extent to which the genetic risk for alcohol dependence (AD) and conduct disorder (CD) and their common genetic risk overlap with genetic factors contributing to variation in dimensions of personality was examined in a study of 6,453 individuals from 3,383 adult male and female same-sex and unlike-sex twin pairs from the Australian Twin Registry. The associations between the personality dimensions of positive emotionality, negative emotionality, and AD and CD risk were modest, whereas the associations between behavioral undercontrol and AD and CD risk were substantially higher. Genetic influences contributing to variation in behavioral undercontrol accounted for about 40% of the genetic variation in AD and CD risk and about 90% of the common genetic risk for AD and CD. These results suggest that genetic factors contributing to variation in dimensions of personality, particularly behavioral undercontrol, account for a substantial proportion of the genetic diathesis for AD and most of the common genetic diathesis for AD and CD among both men and women.     

Role of serotonin and serotonin-selective pharmacotherapy in alcohol dependence

The majority of studies that have examined the usefulness of pharmacotherapies selective for serotonin (5-hydroxytryptamine; 5-HT) as a treatment for alcohol dependence have been standard, double-blind clinical trials that include patients with a variety of clinical presentations. Almost all of the early studies evaluated heavy social drinkers and found only a modest advantage for 5-HT pharmacotherapies in reducing the number of drinks per day. Also, the advantage of these pharmacotherapies was observed primarily when these agents were given at higher daily dosages than suggested prescribing practices for use as an antidepressant. The few studies that evaluated treatment-seeking patients found that 5-HT pharmacotherapies were not instrumental in reducing drinking rates compared with placebo. These results led to a dampening of enthusiasm for use of these agents in treating alcohol dependence. However, more recent investigations have begun to target subgroups with potential abnormalities in 5-HT neurotransmission. The thinking is that these medications should be most useful in alcohol-dependent individuals who have more clearly delineated suggestive signs of 5-HT dysfunction, such as concomitant depression or anxiety. Although few results are available to date, there is growing evidence to suggest that alcohol-dependent subgroups are differentially responsive to 5-HT pharmacotherapies with respect to drinking-related outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic effects that were reported in the earlier studies, which included large heterogeneous patient groups. Further investigations are needed to confirm these initial optimistic results.     

Tobacco use, alcohol dependence, and cognitive performance

Chronic alcohol abuse has long been associated with a mild, generalized pattern of cognitive decrements. However, it is important to note that problem drinking rarely occurs in isolation from abuse of other drugs. For people dependent upon alcohol, tobacco is one of the mostly commonly coabused substances. Recent research suggests that individuals with alcohol dependency may gravitate toward tobacco use, in part, because of the positive effects of nicotine on aspects of cognitive performance that may be compromised as a consequence of chronic alcohol misuse. In this article, the author focuses on the effects of nicotine on behavioral and electrophysiological indexes of cognitive performance, and the impact of these effects on alcohol-related cognitive decrements. The author discusses implications of these findings in the context of treatment and recovery of people with alcoholism.     

Correlation of physical and psychological aspects in alcohol and drug dependence

Dependence to alcohol and drug must be consistently viewed as the consequence of a combination of physical and psychological elements. This is substantiated both philosophically and by taking issue with dualist concepts as well as those which absolutize the psychological aspect. The medical definition of dependence as an illness should be adhered to, whilst at the same time recognizing that psychological and social factors play a determining role.     

Electrolyte disorders, EEG changes and epileptic seizures in alcohol withdrawal delirium

For 180 patients suffering alcohol-withdrawal induced delirium, electrolytic concentration in the serum of Na, K, Ca, and Mg was determined in the early withdrawal phase, and the electroencephalograms of 95 delirium patients evaluated in respect of local and diffuse changes and epileptic activity, and compared in delirium patients with and without initial seizures. Delirium patients who had initial seizures suffered significantly longer-lasting periods of delirium and significantly more frequent electrolytic changes in the form of hypomagnesemia and hypopotassemia (hypokalemia). There was no significant difference in the EEG changes. A temporary metabolic disorder in the initial phase of the two-phase withdrawal process should be assumed to be the cause of seizures during alcohol withdrawal, and the pathogenetic significance of hypomagnesemia and hypopotassemia should be taken into consideration.     

Current status of knowledge on the changes in the hypothalamo-hypophyseo-adrenal cortex system and their effects in chronic alcohol use and withdrawal

The results of investigations into the changes in the function of the hypothalamus-hypophysis-renal gland system in chronic alcoholics are collated. The review shows that the activity of the hypothalamus-hypophysis-renal gland system is below-normal in at least some alcoholics, but due to conflicting results, it is not possible to decide whether the hypofunction of the adrenal gland is a primary of a secondary effect. The interrelationship between glucocorticosteroids and catecholamines is described and its importance for the adaptability of the organism is stressed. On the basis of the review it may seem advisable to introduce corticosteroid treatment into the therapeutic schema for delerious alcoholic patients and also to apply it on patients with the alcohol withdrawal syndrome if tests show that the function of their hypothalamus-hypophysis-renal gland systems is impaired.     

Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

It is widely recognized that posttraumatic stress disorder (PTSD) is a common consequence of trauma exposure, and women are at particularly high risk, with some but not all studies finding that women develop PTSD at twice the rate of men, despite greater trauma exposure in men (Breslau et al. 1998; Tanielian et al. 2008). Although some have suggested that greater exposure to interpersonal violence may contribute to higher rates of PTSD in women, other evidence implicates sex differences in the neurobiological mechanisms that are involved in fear conditioning and extinction. Enhanced fear conditioning and diminished extinction of conditioned fear have been associated with higher levels of endogenous estrogen in women, as well as the development and maintenance of PTSD in both sexes (Orr et al. 2000; Milad et al. 2009b; Glover et al. 2012). Furthermore, as one of the most empirically supported treatments for PTSD is prolonged exposure therapy, which is largely based on fear extinction principles and the success of extinction learning (Rothbaum and Davis 2003), a clear understanding of the individual factors impacting fear conditioning and extinction is critical.Although some of the studies examining sex differences in fear conditioning are inconsistent (Guimaraes et al. 1991; Zorawski et al. 2005; Milad et al. 2006), an increasing body of evidence from rodent and human studies supports the existence of sex differences in fear extinction learning and recall (Maren et al. 1994; Pryce et al. 1999; Milad et al. 2009a; Merz et al. 2013). One possible explanation for the lack of consistent findings in the fear conditioning literature may be related to potential floor effects associated with subclinical impairment of nonclinical samples, as most laboratory studies examining sex differences were conducted in healthy humans. Another explanation that is gaining substantial support is the impact of hormones that differ between the sexes, among individuals, and even within individuals across time (Quirk and Mueller 2008; Lebron-Milad and Milad 2012; Arevalo et al. 2015; Hwang et al. 2015; Herrera et al. 2017; Maeng et al. 2017; Antov and Stockhorst 2018).The available literature indicates that estradiol, the primary estrogen in women during the childbearing years, is also present at overall lower concentrations in males and plays a large role in the fear conditioning and extinction differences observed between men and women (Gupta et al. 2001; Jasnow et al. 2006; Chang et al. 2009; Milad et al. 2009a, 2010; Zeidan et al. 2011; Maddox et al. 2018; Matsumoto et al. 2018; Carvalho et al. 2021). In both sexes, estradiol plays a variety of important functions in the brain, including the regulation of oxidative stress, inflammation, and gene expression, as well as in cognitive functions such as learning and memory (Hammoud et al. 2020). Estrogen receptors are found throughout brain regions that are important for fear conditioning and extinction processes (e.g., the amygdala, ventromedial prefrontal cortex, and hippocampus), likely via enhancements to learning and memory (Milad et al. 2008; Quirk and Mueller 2008; Lebron-Milad and Milad 2012). In women, as peripheral levels of estradiol vary over the course of the menstrual cycle, so do levels of estradiol in the brain (Arevalo et al. 2015). Estradiol has been shown to enhance memory consolidation across stages of fear conditioning, extinction, and retention (Lebron-Milad and Milad 2012). Most relevant to learning in PTSD, women with high levels of estradiol demonstrate enhanced memory formation in the presence of stress exposure (Herrera et al. 2017; Antov and Stockhorst 2018). In animal and human models, higher estradiol levels appear to facilitate acquisition of fear conditioning and extinction (Maeng et al. 2017). For example, women with high endogenous estradiol levels have enhanced responses in fear circuitry during fear conditioning, extinction, and recall as compared with men (Hwang et al. 2015). When phase of menstrual cycle has been taken into account, differences have been observed in conditioned fear responses and severity of PTSD symptoms. Specifically, when women are in the midluteal phase of the menstrual cycle (higher endogenous estradiol), they demonstrate a stronger positive relationship between SCR during fear conditioning and PTSD symptoms than women in the early follicular phase of menstruation (lower endogenous estradiol) (Carpenter et al. 2022). In the complimentary literature on the startle response, low-estradiol women demonstrated reduced discrimination between CS+ and CS− during fear conditioning and reduced inhibition of fear-potentiated startle during extinction and extinction recall, indicating less successful learning than their high-estradiol counterparts (Glover et al. 2012, 2013; Armbruster et al. 2018). This literature suggests that higher levels of estradiol relate to enhanced acquisition of associations between an unconditioned stimulus (UCS) and a conditioned stimulus (CS) during fear conditioning and enhanced extinction of this association during the extinction phase due to greater memory consolidation.A variety of factors can account for hormone differences in women, including menstrual phase, age, and use of hormonal birth control. Approximately 11%–20% of women aged 20–39 yr use oral contraceptives (OCs) (Daniels and Abma 2020). Commonly used OCs directly affect estradiol levels and hormonal fluctuation associated with the menstrual cycle. However, hormonal contraceptives (HCs) have received little attention in the fear conditioning literature. At the time of writing, we were unable to locate studies examining the impact of other HCs on fear conditioning circuitry, although these forms of birth control are increasingly popular among women, and evidence suggests that a variety of HCs has impacts on brain structure, function, and cognitive processes (Brønnick et al. 2020). Literature suggests that estradiol levels in women on HCs are typically low, similar to those of women in the early follicular phase of menstruation (Brynhildsen 2014). Although Hwang et al. (2015) did not demonstrate an effect of HCs on fear conditioning, many HCs contain ethinyl estradiol, which is synthetic estrogen that binds to estrogen receptors at high levels. Further research is needed to determine whether synthetic estrogen present in HCs impacts fear conditioning and fear extinction and contributes to associated sex differences, particularly in a highly sensitized population such as those with PTSD. In the current study, differences in fear conditioning, extinction, and retention were examined in women on hormonal birth control and in the early follicular phase of the menstrual cycle as compared with men to determine whether the synthetic hormones present in HCs confer any enhancement to these processes over and above women off of birth control with theoretically low levels of endogenous estradiol.Fear conditioning is measured by assessing the differential SCR to a conditioned stimulus (CS+) paired with an unconditioned stimulus (shock; UCS) and a stimulus unpaired with a shock (CS−). Greater acquisition of fear conditioning is evidenced by greater SCR response to the CS+ when compared with the CS−. Fear extinction refers to repeated exposure to the CS in the absence of the US, which results in diminishing reactivity to previously conditioned stimuli due to an inhibitory neural link that is formed (Myers and Davis 2007). Extinction is therefore operationalized by reduced discrimination of responding to the CS+ and CS− over time, and its retention is evidenced by a maintenance of low differential SCR in response to presentation of CS+ and CS− cues at follow-up.In previous work, our group examined sex differences in skin conductance responses to a fear conditioning paradigm in men and women with PTSD (Inslicht et al. 2013). In that sample, women were premenopausal and underwent conditioning during the follicular phase of the menstrual cycle. We found that women had greater differential fear acquisition compared with men. Other work has indicated that the effects of endogenous gonadal hormones on fear extinction are moderated by PTSD diagnosis, such that women with PTSD demonstrated impaired fear extinction during the midluteal phase of menstruation but not during the early follicular phase (Pineles et al. 2016b). The current study examines the effect of sex, HC use, and PTSD severity on fear conditioning, fear extinction, and extinction retention in medically healthy trauma-exposed premenopausal women on or off HCs and age-matched men across a range of PTSD symptom severity. We used a validated laboratory conditioning paradigm (Inslicht et al. 2021) that occurred over several days in which fear acquisition was separated from extinction by 72 h to avoid influencing consolidation of fear conditioning, and extinction retention was evaluated 1 wk after the fear extinction session to provide a test of durability of extinction over time.Given evidence for impaired fear extinction in PTSD, we hypothesized that participants high in PTSD (men and women combined) would have decreased fear extinction learning and extinction retention compared with those with low PTSD symptom scores. As estradiol appears to enhance learning during stress in women, we predicted that women on HCs would demonstrate higher differential SCR during acquisition and lower differential SCR during extinction and extinction retention than naturally cycling women in the early follicular phase of menstruation and men. Finally, we predicted a PTSD × sex interaction effect for extinction learning and retention; women on HCs with high levels of current PTSD would have enhanced acquisition but decreased extinction learning and retention compared with women with low levels of current PTSD and men.     

The neurobiology of the stress-resistant brain

The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences of acute, repeated, and chronic stressor exposure on health and disease. Session IV entitled "The neurobiology of the stress-resistant brain" explored how we can intervene to promote stress resistance and stress resilience. Four scientists, who explore this topic from unique and convergent perspectives, presented their experimental results derived from studies in rat (Fleshner and Maier), non-human primates (Lyons), and human (Raskind). Summaries of each presentation, supporting publications, and overall take-home messages from the session are presented.     

Group-as-a-whole concepts and the therapeutic milieu on the inpatient psychiatric unit

This paper focuses on large group process on the inpatient psychiatric unit. General systems theory and group-as-a-whole concepts are used to understand the dynamics of the therapeutic milieu. Using this information as a tool, the therapist can make various interventions on an individual and group level that will help patients understand and deal with their own psychopathology. Another benefit of this process is that it will develop a community on the psychiatric unit where patients help each other to get well. Three clinical examples are used to illustrate the relevance of this concept. With the advent of short-term psychiatric hospitalization, the therapeutic milieu has shown a drastic decline. Emphasis has been placed on the individual as opposed to the group and a valuable therapeutic tool has been lost. Using a group-as-a-whole concept can help reverse this trend and make the milieu on the inpatient psychiatric unit instrumental in the recovery of the patient.     

The neurobiology of learning and memory

The study of memory is a great challenge, perhaps the greatest in biological sciences. Memory involves changes in a tiny fraction of an extremely large pool of elements, a conclusion that makes the task of finding those changes using current technologies formidable. What can be done about this roadblock to neurological investigations of learning? One response that has become particularly productive in recent years is to study learning or learning-like phenomena in relatively simple "model" systems. The idea is to extract basic principles from these models in which molecular and anatomical details can be studied and then to use these in analyzing learning in higher regions of the brain. In this article we discuss current progress and emerging concepts derived from the simple system approach using animal models.     

A suicide peak after weekends and holidays in patients with alcohol dependence

This paper analyzes the variation of suicide by day of the week in alcohol dependence, with public holidays taken into consideration. From 1949 through 1969, 1,312 patients with alcohol dependence were admitted to the Department of Psychiatry in Lund. By 1997, a total of 102 (99 men) alcoholic patients had taken their own life. Suicide victims with severe depression and other diagnoses were compared. There was a suicide peak on the first two days after weekends and holidays in patients with alcohol dependence (p < .05). Alcohol withdrawal is proposed as a contributor to the suicide peak.     

Current concepts on the neurobiology of Attention-Deficit/Hyperactivity Disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) is an early onset, clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. In contrast to the widespread acceptance of ADHD as a childhood diagnosis, Its prevalence In adults and its implications for clinical practice remain a source of controversy. Throughout the lifecycle, a key clinical feature observed in ADHD patients is comorbidity with Conduct Depressive, Bipolar, and Anxiety disorders. Family studies consistently support the assertion that ADHD runs in families. Heritability data from twin studies of ADHD attribute about 80 percent of the etiology of ADHD to genetic factors. Adoption studies of ADHD also implicate genes in its etiology. Molecular genetic data are bolstered by considerations suggesting that DRD4 and DAT genes may be relevant for ADHD. Independently of genes, prenatal exposure to nicotine and psychosocial adversity have also been identified as risk factors for ADHD. Structural and functional imaging studies consistently implicate catecholamine-rich fronto-subcortical systems in the pathophysiology of ADHD. The effectiveness of stimulants, along with animal models of hyperactivity, point to catecholamine disruption as at least one source of ADHD brain dysfunction. Although not entirely sufficient, changes in dopaminergic and noradrenergic function appear necessary for the clinical efficacy of pharmacological treatments for ADHD, providing support for the hypothesis that alteration of monoaminergic transmission in critical brain regions may be the basis for therapeutic action in ADHD.     

Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians

Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant *2 allele was protective against alcohol dependence, and possession of a 2nd *2 allele did not offer significant additional protection. The protective effects of these 2 gene polymorphisms were independent. Diagnostic criteria, recruitment strategy, and Japanese ethnicity moderated the effect of ALDH2*2. Recruitment strategy and gender moderated the effect of ADH1B*2. These findings highlight the importance of methodological issues and potential gene-gene and gene-environment interactions that must be considered when examining relationships between genetic polymorphisms and phenotypes.     

Acute effects of alcohol on memory: Impact of emotional context and serial position

Although the amnestic effects of alcohol in humans are well known, its effects on emotional memory are unclear. In this study, using a randomized double-blind placebo-controlled design, we examine narrative emotional episodic memory in healthy human female volunteers (n = 32) who received either a single dose of alcohol (0.6 g/kg), or a placebo and then viewed neutral story elements presented in either a neutral or emotional context. Memory was tested for gist and detail of the neutral elements 3 days later in a surprise recognition test. Since alcohol modulates GABAergic neurotransmission and may exert its effects on emotion through the limbic system, we predicted that acute alcohol treatment would reduce the expected emotional memory-advantage for gist, leaving detail memory relatively unaffected. Furthermore, given previous findings showing that ‘primacy’ memory is enhanced by physiological arousal, we predicted that reduced arousal produced by alcohol would have the opposite effect and impair primacy memory relative to the middle or ‘recency’ sections of the narrative. Emotional arousal was expected to oppose this effect, so impaired primacy memory following alcohol was only expected in the neutral version of the narrative. Although there was a main effect of story phase (though not of story version), contrary to expectations, alcohol impaired primacy memory for emotionally encoded neutral material. The results suggest that under certain circumstances emotional context or physiological arousal make memories labile and susceptible to disruption through pharmacological manipulation during encoding.