Dual disorder patients are characterized by a highly variable and phenotypically complex presentation. Recent research suggests that impairments within a limited number of functional neurobiological dimensions may play a central role in the vulnerability for development of dual disorders. Specifically impairments in the central regulatory role of the hippocampus and brain circuitries underlying behavioural control and stress regulation may be proposed as “trans-disease”, i.e. processes that occur across a range of disorders, making findings from one disorder relevant to the other disorders. This line of thinking may open up new ways of exploring not only the pathogenesis of dual disorders, but most importantly, may provide new targets for both treatment and prevention interventions for these patients.

5.1 Introduction

Addictive behaviours, defined as compulsive drug seeking and drug use despite of negative consequences, are highly prevalent disorders in the general population worldwide. Of importance, their clinical manifestation (“phenotype”) is highly variable depending on multiple, genetic, and environmental factors (e.g. availability and local culture concerning use of psychoactive substances). In contrast with their phenotypical heterogeneity, a common hallmark among many patients suffering from severe addictions is the very high rate of psychiatric comorbidity (Reissner et al. 2012). Indeed, rates of comorbidity are far higher than can be expected, by pure chance, based upon the relative risks and prevalence of different individual psychiatric disorders.

Different hypotheses on causal pathways have been put forward to explain this excess in comorbidity (Moggi 2005). Many of these are explored in depth in the subsequent, disorder-oriented chapters within this book. However, although all these different causal models are of importance, they basically come down to two separate theories. On the one-hand models, having some form of a self-medication hypothesis at their basis. On the other-hand models that suggest that common neurobiological vulnerabilities underlie both psychiatric disorders and addictions. Evidence in support of the self-medication hypothesis has remained up to now limited and inconsistently supported by the data. In contrast, evidence is accumulating that impairments in (common) neurobiological processes might be underlying the susceptibility of individuals to develop (comorbid) substance use and psychiatric disorders.

5.2 Neurobiological Pathways Involved in Addictive Disorders

Although it is beyond the scope of this textbook to provide a comprehensive overview on the neurobiology of addiction [see for review (Volkow and Baler 2014)], some essential elements need to be noted. A wealth of evidence indicates substantial commonalities among the different substance use disorders categories, including non-chemical addictive behaviours. These findings weaken the hypothesis that different addictions represent discrete disorders. Non drug-specific mechanisms (e.g. the neurobiological processes underlying drug-related reinforcement) represent a commonality of many drug effects. These mechanisms involve dopaminergic and other major neurobiological systems, despite differences in routes of administration, biotransformation pathways and primary neurochemical targets of the different psychoactive substances (Vanyukov et al. 2012). This commonality is clinically reflected by the high prevalence of comorbidity between types of addictions (e.g. alcohol and nicotine) and the highly frequent switching from one substance to another in the course of addictive disorders (e.g. heroine to alcohol).

Depending on the focus and the neurobiological level studied, addiction has been characterized as a disorder of the brain, learning, memory, neuronal maturation and neuroplasticity, homeostatic regulation, and compulsion. In addition, genetic association studies have shown that the genes that are associated to variations in risks of developing addictive behavioural are not unique for a specific drug or drug categories of abuse (Vanyukov et al. 2012). In addition, neurobiological characteristics associated with risk for addiction are found not only in the “disease” affected individuals, but are also, often in a lesser degree, in unaffected family members.

Of importance, within the context of dual disorders, is that evidence is accumulating that the same neurobiological factors that carry risk of addictive disorders, may also be involved in the pathogenesis of other psychiatric disorders, thus representing a common underlying vulnerability to develop both addictive (chemical and behavioural) and other mental disorders.

5.3 Vulnerabilities in Neurobiological Pathways: A Common Underground for Comorbidity?

From a neurobiological perspective, vulnerabilities underlying both major forms of mental illnesses and addictions are intimately inter-related and in some aspects inseparable pathogenic disease processes (Chambers 2007, 2013). This is paralleled by their clinical presentations where mental disorders and addictions often unfold as intertwined chronic conditions punctuated by episodes of relapse and recovery in psychiatric and/or addiction symptoms. Symptomatic exacerbations of these dual disorders, “relapses”, are associated with novel or destabilizing environmental contexts, psychological stress, and exposure to addictive drugs and/or associated cues.

Although the research field is as yet in full development and the complexities of neural circuitries are far from being fully understood, some neurobiological hypotheses are taking shape.

5.3.1 Hippocampal Neurogenesis

Within the context of pathogenesis of dual disorders, the hippocampus might take up a central position. Animal and human studies reveal abnormal or maladaptive hippocampal neurogenic activity in the pathogenesis of a range of psychiatric disorders. These disorders, including schizophrenia, post-traumatic stress disorder (PTSD), mood disorders, and some personality disorders (cluster B) are all highly comorbid with substance use disorders (Kessler 2004). Although these disorders involve many different symptom domains and etiologic and developmental aspects, they do share three hippocampus-related attributes: (1) disturbance in Hypothalamic–pituitary–adrenocortical (HPA) axis regulation and stress-reactivity, (2) hippocampal atrophy, and (3) disturbances in hippocampal learning and memory (Chambers 2007, 2013). Loss of hippocampal network vitality (due to deficits in neurogenesis) impairs not only learning and memory but also the hippocampal feedback regulation of the HPA axis activity affecting negatively stress resilience. Alternatively, (chronic) repeated surges of corticosteroids can further impair hippocampal neurogenesis and functionality, a mechanism that overall induces a vicious circle of further impairment. In addition, and highly relevant in the context of dual disorders, all addictive drugs when used chronically, share a capacity to reduce hippocampal neurogenic activity (Chambers 2013; Noonan et al. 2010).

Importantly, whatever its initial cause, animal studies show that the suppression of hippocampal neurogenesis has important addiction enhancing effects both to the initiation (increase of self-administration) as to the continuation (diminished extinction of drug seeking). Moreover, suppression of hippocampal neurogenic proliferation has been shown to enhance substance-primed reinstatement of drug seeking in animals that have previously been extinguished from drug-seeking behaviour (Chambers 2013).

Taken together, there is growing evidence, admittedly largely based upon animal studies, supporting a central role for hippocampal dysfunction in the pathogenesis of psychiatric disorders, addictions, and their comorbidity. This model allows explaining how low states of hippocampal neurogenesis, whether generated by underlying mental illness, prior addictive drug exposure or by their combination, evokes changes in corticostriatal circuitry function. These changes enhance learning associated with drug reinforcement, at the expense of learning and maintaining more adaptive natural-reward focused behaviours (Chambers 2013). Moreover other aspects of hippocampus-dependent learning, i.e. memory are impaired in the process. In addition, given the deleterious effects of chronic substance use on the hippocampal functionality and its associated deregulation of stress mechanisms, pathogenesis of dual disorders might have the character of a vicious circle aggravating the pathogenic factors during the course of the disorders. These mechanisms may explain how addictive drug use typically worsens rather than improves psychiatric symptoms. This finding provides further support to the hypothesis that dual disorders represent disease synergy rather than reflect self-medication process.

5.3.2 Externalizing and Internalizing Dimensions of Psychiatric Disorders

In addition to a proposed central role of the “hippocampus” hypothesis, other related neurobiological factors can be identified underlying the vulnerability to dual disorders. Based upon epidemiological data, Kessler and colleagues (Kessler et al. 2011) suggest categorizing psychiatric disorders in two broad categories—internalizing and externalizing disorders. Specific phobia and obsessive compulsive disorder are considered the most characteristic internalizing disorders while hyperactivity disorder and oppositional-defiant disorder are typical examples of externalizing disorders (Kessler et al. 2011). Of importance, both broad categories of disorders are characterized by a high comorbidity with other disorders within the same categories. Interestingly, although substance use disorders are positioned within the externalizing spectrum, comorbidity with SUD is found in disorders from both internalizing and externalizing categories. Thus, these two pathways, associating SUD with internalizing and externalizing disorders respectively may reflect common underlying neurobiological vulnerabilities.

5.3.2.1 Impulse Regulation and the Externalizing Spectrum

Impairments in self-regulation and inhibitory control have been proposed as central to various stages of substance abuse such as increasing susceptibility to initial use, transition to dependence, maintenance, and relapse (Goldstein and Volkow 2011). Converging evidence (structural and functional neuroimaging, electrophysiological) points to the involvement (hypo-functionality) of the pre-supplementary motor area (pre-SME) in dorsomedial prefrontal cortex (dmPFC) and the right ventrolateral PFC encompassing the anterior insula and inferior frontal gyrus in response inhibition (Morein-Zamir et al. 2013). Although these findings may reflect a consequence of the neurotoxicity associated with chronic substance abuse, pre-existing genetic and environmental vulnerabilities likely interact with short- and long-term effects of substance use on behaviour and brain to produce these deficits. Evidence suggests that impaired response regulation and control are present in individuals with a family history of drug and alcohol dependence. Moreover, these characteristics when found in childhood predict an early age of onset of addictive disorders (Tarter et al. 2003). Of importance, these impairments of regulatory control, as reflected by abnormalities in both structural and functional brain circuitries, are also a hallmark of other psychiatric often, developmental disorders (e.g. ADHD, ODD, conduct disorder).

In addition to response inhibition, efficient executive control requires monitoring for errors or conflicting response plans. These functions are particularly impaired in addictive behaviours. Key region suggested here is the anterior cingulate cortex (ACC). ACC hypo activity has been reported in users of different substances of abuse (Morein-Zamir et al. 2013). Deficient error and conflict monitoring associated with ACC hypo activation could play a role in drug abuse development, maintenance, and relapse (Connolly et al. 2012). Again, impairments in error/conflict monitoring are not typical for SUD, but a hallmark of many other “externalizing” disorders such as borderline and antisocial personality disorder, ADHD (Brazil et al. 2009; de Bruijn et al. 2006; Shiels and Hawk 2010).

Taken together, clinical features of behavioural under-control and their neurobiological correlates may represent a common underlying vulnerability to develop a wide range of externalizing comorbid disorders, e.g. CD, ADHD, and SUD. This hypothesis is supported by longitudinal studies relating these features in children with an increased risk on a broad area of disinhibited behavioural disorders (e.g. sexual risk behaviour, SUD) (Vanyukov et al. 2012). Of importance, this opens up a window of opportunity for potential treatments and prevention. Indeed, behavioural and pharmacological treatment, improving behavioural control might help to regain control over substance use in established SUD patients and if applied early in life, diminishes the risk in impulsive children to develop behavioural and substance use disorders later in life.

5.3.2.2 Internalizing Disorders

Brain-Stress Systems

The concept of stress refers to processes aimed at the perception, appraisal and response to (potentially) harmful or threatening stimuli. Brain regions such as the amygdala, hippocampus, insula, orbitofrontal cortex, and anterior cingulate (“limbic circuitry”) are all involved in the appraisal of stressful stimuli. Other regions, such as the locus coeruleus, hypothalamus, thalamus, and striatum are involved in the physiological and emotional responses. Although developed as highly important adaptive mechanisms, abnormalities with stress processing are at the base of many psychiatric disorders and symptoms. Specifically, chronic stress and early childhood adversities can have profound effects on many (“trans-disease”) psychiatric disorders and their potential co-occurrence.

Early Childhood Adversity

Epidemiological studies have shown that people who experience chronic, early childhood adversity (ECA) have a greater likelihood of developing and phenotypically shaping addictive and other psychiatric disorders (Benjet et al. 2013). In analysing the data of the adolescent participants in the National Comorbidity Survey (NCS-A), McLaughlin and colleagues showed that ECA is associated with a substantial proportion of child–adolescent onset of psychiatric disorders, including more than 40 % of onsets of behaviour disorders and one-third of onset of substance use disorders. A finding reflected in animal research where ECA consistently has been associated with both an increase in self-administration of substances and a higher likelihood of developing addictive and other behavioural and mood-regulation disorders. Multiple hypotheses have been suggested to explain this association. The two most substantiated are on the one hand the so-called self-medication hypothesis and on the other hand changes in neurobiological pathways induced by early, chronic or repetitive stress. As indicated earlier, self-medication refers to the process of alleviating the pain of trauma, negative experiences both within the context of trauma and possible associated psychiatric disorders (e.g. Post Traumatic Stress Disorder, PTSD, Mood Disorders, MD). On the other hand, ECA can induce changes in neurobiological and neurohormonal pathways ultimately altering learning, reward, craving, and self-regulation (impulsivity) mechanisms through stress allostasis (Benjet et al. 2013). The concept of allostatic load proposes that the process of achieving stability through alteration of neural, neuroendocrinal, and immune mechanisms, while adaptive in the short run, becomes overloaded and ultimately maladaptive with chronic stress (McEwen 2000).

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Tags: Co-occurring Addictive and Psychiatric Disorders

Dec 3, 2016 | Posted by admin in PSYCHOLOGY | Comments Off

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The Pathogenesis of Dual Disorders: Neurobiological Perspectives

5. The Pathogenesis of Dual Disorders: Neurobiological Perspectives

5.1 Introduction

5.2 Neurobiological Pathways Involved in Addictive Disorders