Combining research approaches to advance our understanding of drug addiction

Drug addiction is a complex behavior, likely to be influenced by various genes, environmental factors, and gene-gene and gene-environment interactions. Various aspects of addiction are studied by different disciplines. Animal studies are increasing insight into brain regions and genes associated with addiction. Epidemiologic studies are establishing the factors increasing risk for initiation and continuation of substance use. Twin and adoption studies are increasing our understanding of the complex mechanisms involved in substance use, including comorbidity and gene environment interaction. Finally, molecular genetic studies in humans are starting to yield some converging findings. It is argued and illustrated with examples that greater awareness of progress in other disciplines can speed up our understanding of the complex processes involved in addiction. This should help our ability to identify who is at increased risk of becoming addicted and the development of prevention and intervention strategies targeted at an individual’s specific needs.     

The genetics of alcoholism and alcohol abuse

Twin studies have established that there are substantial genetic influences on alcoholism (0.5-0.6) in both men and women. Our knowledge of behaviors predisposing to alcoholism, including anxiety and impulsivity, is advancing rapidly through animal and human studies. Although alcoholism is often comorbid with other substance abuse and psychiatric disorders, recent studies have shown that, with the exception of nicotine, the heritability of alcoholism is largely substance-specific. Increasing understanding of the neurobioligy of addiction has identified neural pathways in which genetic variation at candidate genes could influence vulnerability. Some functional variants of these genes have been identified. Recent linkage analyses in humans and rodents have pointed to genomic regions harboring genes that influence alcoholism. Refinement of clinical phenotypes and use of intermediate phenotypes will improve chances of gene identification. All these advances in the understanding of the genetics of alcoholism should facilitate the development of more accurately targeted therapies using molecular diagnostic approaches.     

Genetic studies in Alzheimer's disease

Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.     

Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes

Comorbid substance abuse disorders have emerged as one of the greatest obstacles to the effective treatment of persons with schizophrenia. Estimates of the prevalence of such comorbidity vary, but as many as half of persons with schizophrenia may suffer from a comorbid drug or alcohol disorder. Younger age, male gender, and lower educational attainment are associated with greater risk for addiction. Persons with schizophrenia and comorbid addiction tend to have an earlier onset of schizophrenia than do those without comorbid addiction. Research does not support a link between specific symptoms of schizophrenia and choice of abused drugs. Rather, drug choice is correlated with the pattern of ambient drug use in the community. Comorbid substance disorders are associated with a variety of poorer outcomes, including increased psychotic symptoms, poorer treatment compliance, violence, housing instability and homelessness, medical problems (including human immunodeficiency virus infection), poor money management, and greater use of crisis-oriented services that result in higher costs of care. Considerable progress has been made over the past decade in understanding the need to integrate substance abuse treatment and mental health treatment to provide more effective care for this population.     

Impact of ADHD and its treatment on substance abuse in adults

Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance abuse in adults. Additional psychiatric comorbidity increases this risk. ADHD is associated with different characteristics of substance abuse: substance abuse transitions more rapidly to dependence, and lasts longer in adults with ADHD than those without ADHD. Self-medication may be a factor in the high rate of substance abuse in adults with ADHD. While previous concerns arose whether stimulant therapy would increase the ultimate risk for substance abuse, recent studies have indicated that pharmacologic treatment appears to reduce the risk of substance abuse in individuals with ADHD. When treating adults with ADHD and substance abuse, clinicians should assess the relative severity of the substance abuse, the symptoms of ADHD, and any other comorbid disorders. Generally, stabilizing or addressing the substance abuse should be the first priority when treating an adult with substance abuse and ADHD. Treatment for adults with ADHD and substance abuse should include a combination of addiction treatment/psychotherapy and pharmacotherapy. The clinician should begin pharmacotherapy with medications that have little likelihood of diversion or low liability, such as bupropion and atomoxetine, and, if necessary, progress to the stimulants. Careful monitoring of patients during treatment is necessary to ensure compliance with the treatment plan.     

Risk factors for suicidal ideation in a population of community-recruited female cocaine users

Introduction

Suicide, as the 11th leading cause of death in America, is a significant public health concern. Previous studies have shown that drug users are a population at especially high risk for suicidal ideation (SI). Although most people who think about killing themselves do not ultimately commit suicide, identifying those at risk for such thoughts is important.

Methods

In this analysis, data from a sample of 462 cocaine-using women (87% African American) recruited using street outreach methods for a National Institute on Drug Abuse–funded study were examined to identify risk factors for lifetime SI. Sociodemographic factors, adverse childhood experiences, sexual behaviors, psychiatric comorbidities, and drug abuse and dependence were examined as potential risk factors using both bivariate and logistic regression analysis.

Results

Fifty percent of the sample met at least one criterion for lifetime SI, and 32% of the sample reported a lifetime suicide attempt. In the final logistic regression model, childhood physical abuse, childhood sexual abuse, rape after the age of 15 years, posttraumatic stress disorder, and number of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, depression criteria met emerged as significant independent predictors of lifetime SI.

Conclusion

These findings identify important risk factors for SI among female substance abusers in community settings.     

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research

Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.     

Genome-Wide Association Studies of Alcohol Dependence and Substance Use Disorders

Genome-wide association studies (GWAS) currently represent the most systematic approach to genetic research into complex disorders. They can detect associations of common variants in genomic regions in the absence of an a priori assumption. Most of the GWAS of addiction performed to date have focused on alcohol dependence or smoking behavior. Four GWAS of alcohol dependence have been published thus far, and only two single nucleotide polymorphisms have received modest support of replication in a subsequent study. Many more GWAS have been conducted for smoking behavior. One large, single GWAS and meta-analyses of the phenotype “smoking quantity” have generated convincing evidence for the contribution of variants in genes for cholinergic nicotinic receptor subunits. This article focuses on GWAS of alcohol addiction and provides an overview of GWAS of other substance abuse disorders.     

Comments on risk for schizophrenia

Recent developments have significantly furthered understanding of genetic and environmental factors affecting risk for schizophrenia. Environmental effects, such as immigration, living in a city, and substance abuse have been found to be associated with later schizophrenia. Although the highest risk for schizophrenia is still having a monozygotic twin with schizophrenia (50%), the candidate genes claimed to be associated to date only yield a very small excess risk and all of these effects (environmental and genetics) increase the risk for schizophrenia by only 2-3 fold. Thus, given the low prevalence of the disorder in the general population (0.5-1%), they are not practical in predicting future illness. One possible strategy to make the currently known risk factors for schizophrenia more useful clinically is based on findings indicating that many of the genetic and environmental risks cited above are not specific for schizophrenia, but increase risk for psychopathology in general. As up to 50% of the general population will be affected during their lifetime by a condition defined in DSM IV as psychopathology, due to this much higher base rate, factors increasing risk by 2-3 fold might become clinically relevant.     

Molecular genetics of addiction vulnerability

Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances. to mnemonic processes that are likely to include those involved in substance dependence, and to the volumes of brain gray matter in regions that are likely to contribute to mnemonic/ cognitive and to addictive processes. The working idea that these three heritable phenotypes are likely to share some of the same complex genetic underpinnings is presented. This review contains association-based molecular genetic studies of addiction that largely derive from my laboratory and their fit with linkage data from other laboratories. These combined results now identify many of the loci and genes that contain allelic variants that are likely to provide the heritable components of human addiction vulnerability. These data are also likely to have broad implications for neurotherapeutics. Drugs with potential abuse liabilities are widely used for indications that include pain, anxiety, sleep, seizure, and attentional disorders. There is increasing nonmedical use of these prescribed substances. Increasing information about addiction vulnerability gene variants should help to improve management of risks of dependence in individuals who receive such therapeutics. In addition, since mnemonic components that correlate well with individual differences in brain regional volumes are likely to play major roles in addiction processes, many addiction vulnerability genes are also good candidates to contribute to individual differences in mnemonic processes. Recently elucidation of addiction-associated haplotypes for the “cell adhesion” Nr-CAM gene illustrate several of these points.     

Genetics of alcohol dependence

Twin, family, and adoption studies have consistently shown that genetic factors play an important role in the pathogenesis of alcohol dependence. Numerous studies have aimed to identify genes that contribute to susceptibility to alcohol dependence. Whole-genome linkage studies have identified several chromosomal regions that are linked with alcohol dependence. Association studies have also identified genes associated with alcohol dependence. Alcohol-metabolizing enzymes, such as alcohol dehydrogenase-1B and aldehyde dehydrogenase-2, are the most well-established genes that have polymorphisms associated with the risk for alcohol dependence. Polymorphisms in gamma-aminobutyric acid receptor genes are also reported to be associated with alcohol dependence. The polymorphism of opioid receptor mu 1 gene is of interest because it alters the treatment effects of naltrexone. Several genes related to neural transmission have been reported to be associated with alcohol dependence, but results are inconsistent among studies. One reason for these inconsistent results is the great heterogeneity of alcohol dependence. Classifying alcohol dependence into homogeneous phenotypes is a good strategy to solve this problem. Recently, several genome-wide association studies have been reported. Genome-wide association studies enable hypothesis-free genome mapping of vulnerability-contributing genes and are expected to add data to identify genes associated with the susceptibility to alcohol dependence. Knowledge of the genetic basis of alcohol dependence is growing and leads to a better understanding of the biological mechanisms of addiction, which can help with strategies to prevent and treat this disease.     

Determinants of Substance Abuse in a Population of Children and Adolescents Involved with the Child Welfare System

Substance abuse is an important health issue facing children involved with child welfare, but little is known about the associated factors. The purpose of this study was to build on findings from the Canadian Incidence Study of Reported Child Abuse and Neglect-2003 and use a national sample of 10–15 year old children to examine the factors associated with substance abuse for all investigations and substantiated investigations of maltreatment. Our findings showed that almost 14% of all investigated children were abusing substances and that this proportion was even greater among those whose investigation of maltreatment had been substantiated (almost 16%). The severity of the experienced maltreatment, in addition to behavioural factors, was found to be associated with substance abuse. While the pathways to substance abuse are complex, understanding the risk factors associated with substance abuse in this population are important for targeted interventions for prevention and treatment.     

Family-Based Association Analysis of Serotonin Genes in Pathological Gambling Disorder: Evidence of Vulnerability Risk in the 5HT-2A Receptor Gene

Pathological gambling (PG) has become a growing public health problem in many countries around the world. PG is an impulse control disorder and its behavior and psychopathology present similarities with substance abuse disorders. Evidence from twin studies supports a significant genetic predisposition to PG, but the precise genetic loci still remain unclear. The present study investigates the allele and genotype distribution of polymorphisms of the serotonin transporter, serotonin receptor 1B and 2A genes in 140 sib-pairs discordant for the diagnosis of PG. A significant association of the C/C genotype of the serotonin receptor 2A T102C (rs 6313) polymorphism and the PG phenotype was observed [OR?=?1.7 (1.1–3.4)]. This preliminary result is consistent with the hypothesis that the serotonin system is associated with addiction behavior and similar results have been reported for nicotine and alcohol dependence.     

Outcome predictors in substance use disorders.

Given the heterogeneous nature of substance abuse, it is notable that several predictors of response are independent of the primary drug of abuse or the treatment setting [208]. Although the strength of the relationship of predictor to outcome varies, the following factors have been identified consistently: severity of dependence or withdrawal; psychiatric comorbidity; substance-related problems; motivation (abstinence commitment); length of treatment; negative affective states; cognitive factors; personality traits and disorders; coping skills; multiple substance abuse; contingency contracting or coercion; genetic factors; sleep architecture; urges and craving; self-efficacy; and economic and social factors. Although it is well known that severity of dependence (including polysubstance abuse), serious psychiatric comorbidity, and social problems are associated with poor treatment response, only recently has research examined the efficacy of intervention strategies that specifically address these problems. Adequate treatment of psychiatric comorbidity and improvement in social, economic, and family functioning lead to better treatment outcomes. The development of specific techniques to enhance self-efficacy, motivation, coping skills, and functioning in the community are concrete examples of how the identification of factors associated with positive outcomes has led to the development of new treatments. Despite significant accomplishments, the field is left with many unanswered questions. Although several biologic markers, such as neuroendocrine response and sleep architecture, show promise as outcome predictors, it is not known whether these are critical factors in the initiation of substance use or its progression to dependence. Determining whether biologic markers are epiphenomena reflecting the amount and duration of substance abuse or are fundamental to the pathophysiology of dependence is a matter of urgent concern. With some exceptions, identification of biologic predictors has not led to innovative therapies. One of these exceptions is the development of naltrexone for the treatment of alcoholism, which was based in a solid theoretical rationale and followed by hypothesis-driven experiments. Similar opportunities should emerge from current basic science and clinical research. The application of pharmacogenetic techniques to the field of addiction also holds great promise. As future studies are undertaken, researchers and clinicians must be mindful that differences in outcome predictors across drugs of abuse and treatments may emerge as subgroups of individuals with addictive disorders and new therapies are identified. There is already evidence that early onset alcoholism is associated with poor response under some circumstances, yet may be a predictor of response to targeted pharmacotherapy with ondansetron [64, 112]. As the ability to subtype disorders based on meaningful biologic differences grows, it is anticipated that several relevant outcome predictors that are specific for pharmacotherapy will emerge.     

缩小精神病生物学模型与社会心理学模型研究间的差距

Summary

Paul Bebbington’s recent Special Article provides an excellent synthesis of recent advances in psychosocial research on psychosis. However, we doubt that a model based solely on social epidemiology and cognitive theory can totally describe psychosis, and to be fair, Bebbington does not suggest that it does. A complete model must also incorporate what we have learned from non-social epidemiology, neuroscience, and genetics. Evidence indicates that both the social risk factors that interest Bebbington and biological risk factors, such as abuse of stimulants and cannabis, can provoke psychotic symptoms by dysregulating striatal dopamine. The role of neurodevelopmental deviance also needs to be considered in the etiology of schizophrenia-like psychosis. Moreover, the striking advances in our understanding of the genetic architecture of psychosis open an exciting door into studies examining gene-environment correlation and gene-environment interaction. In short, Bebbington demonstrates the value of cognitive and social researchers talking to each other, but the occasional chat with the more biologically inclined could produce a more comprehensive model.

 

      

Genetic vulnerability to drug abuse.

Addiction to various substances, including drugs and alcohol, probably arises from a combination of environmental and genetic factors. The genetic vulnerability to drug addiction is supported by several familial, adoption and twin studies. However, as in other mental disorders, the genetic vulnerability to drug addiction appears complex: these disorders do not follow the rules of Mendelian inheritance. Instead, they are probably influenced by multiple susceptibility genes, each of which contributes to the disorder. The more genes necessary for a disorder, the harder it is to detect any of them. This difficulty is magnified by the role of environmental factors. Association studies using the candidate gene approach can identify susceptibility genes for drug abuse supported by the pathophysiological hypothesis of the illness. This review will focus on the clinical and molecular genetic studies in drug abuse.     

Do Child Abuse and Maltreatment Increase Risk of Schizophrenia?

Introduction

IntroductionaaAlthough childhood abuse is a recognised risk factor for depression, post-traumatic stress disorder, and substance misuse, its role in the aetiology of psychotic disorder remained controversial. This is in part because the putative effect of childhood trauma on psychosis has been mostly evaluated by small, cross sectional, uncontrolled studies that raised methodological issues.

Methods

Papers concerning the association between childhood trauma and psychotic disorders (to November, 2011) were identified using a comprehensive search of PubMed, Psychinfo, and Scopus and analysing reference list of relevant papers. A narrative synthesis was used to summarise results.

Results

An association between childhood abuse and psychotic symptoms was consistently reported by large cross sectional surveys with an effect ranging from 1.7 to 15. However, we cannot conclude that the relationship is causal as lack of longitudinal studies prevent us from fully excluding alternative explanations such as reverse causality. Gender, cannabis use, and depressive and post-traumatic stress disorder symptoms appear to moderate the effect of childhood trauma on psychotic disorders. However, specificity of childhood abuse in psychotic disorders and, particularly, in schizophrenia has not been demonstrated.

Conclusion

Although the association between childhood abuse and psychosis has been replicated, the etiological role of such early adversity has yet to be fully clarified. So far none of the studies reported support the hypothesis that childhood abuse is either sufficient or necessary to develop a psychotic disorder. It seems likely that any effect of childhood abuse on schizophrenia needs to be understood in terms of genetic susceptibility and interaction with other environmental risk factors.     

The epidemiology of mood disorders

This review provides an overview of the epidemiology, risk factors, and genetic epidemiology of mood disorders in adults and children. The magnitude and impact of mood disorders in the community outweighs that of most other chronic diseases. Although there is substantial knowledge regarding the sociodemographic risk factors for mood disorders, our understanding of the pathogenesis and classification still is evolving. Comorbidity of mood disorders with anxiety disorders and substance abuse has been documented widely. Whereas substance abuse and mood disorders seem to be independent etiologically, anxiety and mood disorders result from partially common etiologic factors. The results of family, twin, and adoption studies reveal that a positive family history is the most potent risk factor for mood disorders, particularly bipolar disorder. However, the specific factors that are transmitted in families still are unknown. The two areas that will inform future genetic research include phenomenologic studies that refine the validity of the current phenotypic classification of mood disorders, and application of study designs to elucidate specific factors that may explain the familial transmission of these disorders.     

Prégabaline et risque d’addiction : une nouvelle demande de soin ?

PurposePregabalin (PRG) is a gamma-aminobutyric acid (GABA) analogue used for treatment of epilepsy, neuropathic pain, generalised anxiety disorder and currently being studied for other indications. Supported by the results of case studies and a limited number of studies, there is an ongoing debate about the addictive potential of PRG. However, evidence is scarce and no definitive assessment on the potential for abuse and dependence to PRG is available. The objective of our study was to identify the number of cases of abuse or dependence to PRG published and to study potential risk factors of addiction to PRG.MethodsWe have identified on PubMed and ScienceDirect published case studies of PRG abuse or dependence and analysed these cases on the basis of several clinical parameters.ResultsA total of 118 cases of PRG abuse or dependence were identified, including 21 isolated cases (mean age 33 years, 67 % men). The mean daily dose of PRG was 2,9 g. Current or past polydrug abuse was present in the majority of cases. Psychiatric diagnoses, other than substance-related disorders, were reported in as many patients, and almost all patients experienced withdrawal symptoms when PRG was discontinued.ConclusionCurrent literature suggests an important and growing concern for the abuse of PRG. Male sex, psychiatric and/or addiction history, including opioid addiction, may be potential risk factors for the development of addictive behaviours associated with PRG.     

Wnt signaling networks in autism spectrum disorder and intellectual disability

Background

Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).

Abstract

Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.

Conclusions

We will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.