Download Co-Occurring Mental and Substance Use Disorders

Reviews and Overviews
Co-Occurring Mental and Substance Use Disorders:
The Neurobiological Effects of Chronic Stress
Kathleen T. Brady, M.D., Ph.D.
Rajita Sinha, Ph.D.
The high rate of co-occurrence of substance use disorders and other psychiatric
disorders is well established. The population of people with co-occurring disorders
is heterogeneous, and the prevalence of
comorbidity differs by diagnostic group.
One of the overarching issues in the area
of comorbidity is the nature of the connection between psychiatric disorders
and substance use disorders. The rapid
development of technical advances in the
neurosciences has led to a better understanding of the molecular biology, neurotransmitter systems, and neural circuitry involved in mental illness and
substance use disorders. The authors discuss the neurobiological interface between substance use disorders and other
psychiatric disorders with an emphasis on
emerging data concerning four psychiatric disorders that commonly co-occur
with substance use disorders: depression/
mood disorders, posttraumatic stress disorder, attention deficit hyperactivity disorder, and schizophrenia. Better understanding of the connection between
substance use disorders and psychiatric
disorders could have a profound effect on
prevention and treatment.
(Am J Psychiatry 2005; 162:1483–1493)
T
he high rate of co-occurrence of substance use disorders and other psychiatric disorders is well established (1,
2). The implications of comorbidity are far-reaching and
raise important questions that are unlikely to have simple
answers. One of the overarching issues is the question of
why substance use and other mental disorders so often
co-occur. Are there genetic mediators and/or neurobiological connections between these disorders that drive the
comorbidity? Do different psychiatric disorders have differing relationships with various substances of abuse? Better understanding of the connection between substance
use disorder and mental illness could have a profound effect on both prevention and treatment.
In this article, we focus on four psychiatric disorders—
depression/mood disorders, posttraumatic stress disorder
(PTSD), attention deficit hyperactivity disorder (ADHD),
and schizophrenia—because research concerning the
neurobiological and mechanistic connections between
these disorders and substance use disorders is particularly active. With the rapid development of technical advances in the neurosciences, the amount of information
concerning the molecular biology, neurotransmitter systems, and neural circuitry involved in mental illness and
substance use disorders has increased dramatically. In
this article, we conceptualize chronic distress as a central
construct underlying the association of each of these four
psychiatric disorders with substance use disorders and
examine emerging neurobiological findings within this
framework.
Am J Psychiatry 162:8, August 2005
Prevalence: Epidemiological
and Clinical Perspectives
Epidemiological surveys in the 1990s emphasized the
prevalence of comorbid psychiatric and substance use disorders in community samples of adults (1, 3, 4). In the Epidemiologic Catchment Area study (3), an estimated 45% of
individuals with alcohol use disorders and 72% of individuals with drug use disorders had at least one co-occurring
psychiatric disorder. In the National Comorbidity Study
(1), approximately 78% of alcohol-dependent men and
86% of alcohol-dependent women met the criteria for a
lifetime diagnosis of another psychiatric disorder, including drug dependence. The risk relationship appears to be
reciprocal, with psychiatric disorder predicting increased
risk of later substance use and vice versa. A study involving
a subset of National Comorbidity Study subjects found that
active psychiatric disorders predicted an increased risk for
the first onset of daily smoking and progression to nicotine
dependence (5). Comorbidity is greater in individuals who
are dependent on illicit drugs, compared to alcohol-dependent individuals, and individuals with multiple dependencies experience the highest rates of psychiatric comorbidity (6). Because acute intoxication and withdrawal
from drugs of abuse can mimic symptoms of psychiatric
disorders, the overlap of symptoms can be problematic in
making an accurate diagnosis of a psychiatric disorder in
an individual with a substance use disorder. This difficulty
may account for some of the high comorbidity rates reported in epidemiological studies, which are not generally
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designed to tease apart substance-related and independent psychiatric symptoms. Despite this caveat, even conservative estimates suggest a high rate of comorbidity between psychiatric disorders and substance use disorders.
Etiological Relationships:
Theoretical Perspective
Although convincing data support a strong association
between a variety of psychiatric disorders and substance
use disorders, the nature of the relationship is complex
and may vary depending on the disorder in question and
substance that is used. Several theories have been proposed to explain the high co-occurrence. Certain psychiatric disorders may be risk factors for development of substance use disorders or may modify the course of
substance use disorders. One of the more overarching theories of addiction is that drugs and their specific psychotropic effects are used to cope with emotional distress (7).
Psychiatric disorders have been conceptualized as chronic
distress states associated with neurobiological alterations
in brain stress circuits (8–10). On the other hand, chronic
drug use is associated with neuroadaptations in brain reward pathways that produce secondary psychiatric symptoms during acute and protracted withdrawal states (10).
With increasing severity of addiction, neuroadaptations in
stress and reward circuits occur, and these changes may
underlie the increasing emotional distress often associated with substance use disorders (11, 12).
A growing body of evidence from basic science and
translational studies implicates common neurobiological
pathways and abnormalities involved in addiction and a
number of psychiatric disorders. Within a neurobiological
framework, at least two hypotheses can be postulated to
explain comorbidity: 1) addiction and other psychiatric
disorders are different symptomatic expressions of similar
preexisting neurobiological abnormalities, and 2) repeated
drug administration, through neuroadaptation, leads to
biological changes that have common elements with the
abnormalities mediating certain psychiatric disorders (13).
One of the bridging constructs between psychiatric and
substance use disorders is the role of stress in the development and relapse of substance use disorders and other
psychiatric disorders. Figure 1 provides a heuristic model
of the relationship between chronic distress states, substance use disorders, and psychiatric comorbidity. Although the model conceptualizes chronic distress as the
bridging construct, various genetic and environmental
vulnerability factors contribute to the development of the
distress states, as noted in Figure 1. Additional research on
these factors will contribute to a more specific understanding of the mechanisms underlying the associations
between psychiatric and substance use disorders.
Corticotropin-releasing factor (CRF), one of the key hormones involved in the stress response, has been implicated in the pathophysiology of anxiety, affective, and ad-
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dictive disorders (8, 14). Preclinical evidence suggests that
CRF and noradrenergic pathways are involved in stressinduced reinstatement of drug-seeking behavior in drugdependent laboratory animals (15). Stress stimuli that activate CRF circuits are also known to potentiate mesolimbic dopaminergic reward pathways in laboratory animals
(16). Similarly, human laboratory studies have shown that
emotional stress and negative affect states increase drug
craving in drug-dependent individuals (17, 18). Evidence
of an association between severity of depressive symptoms in patients with major depression and the subjective
reinforcing effect of an acute dose of dextroamphetamine
(19) suggests dysregulation of reward systems with increasing levels of distress in major depression. In animal
models, early life stress and chronic stress result in longterm changes in stress responses (20). Such changes can
alter the sensitivity of the dopamine system to stress and
can increase susceptibility to self-administration of substances of abuse (16, 21, 22).
Corticolimbic dopamine and noradrenergic pathways
modulate prefrontal cortical function under conditions of
increasing cognitive or emotional demand, including persistent distress states, tasks involving high levels of cognitive challenge, and working memory tasks (23, 24). Glutamatergic and γ-aminobutyric acid (GABA)-ergic pathways
are also important in modulating prefrontal cortical function (25).
It is important to note that different substances of abuse
have widely varying effects on neurobiological systems.
Cocaine and amphetamines have a stimulating effect on
catecholaminergic systems. Opioid analgesic drugs act
through a complex system of opioid receptors, and nicotine acts through specific nicotinic receptors distributed
throughout the central and peripheral nervous systems.
GABA-ergic and glutamatergic systems are particularly
important in acute intoxication and withdrawal from alcohol and benzodiazepines. Clearly, the effects of acute intoxication and withdrawal differ for each of these drugs,
and the effect on psychiatric disorders also differs by drug.
It is interesting to note, however, that there appear to be
common neurobiological pathways operating across substances of abuse. Dopamine activity in the nucleus accumbens has been implicated in the mechanism of reinforcement for almost all drugs of abuse (26). Furthermore,
drugs of abuse activate the CRF/hypothalamic-pituitaryadrenal (HPA) axis during use/abuse, and alterations in
the CRF/HPA and noradrenergic systems during acute
withdrawal/abstinence are also well documented (11, 12,
26). Some animal models of reinstatement (i.e., stressinduced reinstatement, cue-induced reinstatement) operate across substances of abuse, also arguing for some common mechanisms.
In the following sections, we review emerging data that
shed light on the neurobiological connections between
various substance use disorders and the four psychiatric
disorders considered here (depression/mood disorders,
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KATHLEEN T. BRADY AND RAJITA SINHA
FIGURE 1. Schematic Model of Chronic Distress and Perpetuation of Psychiatric Symptoms and Drug Use in Individuals
With Comorbid Disordersa
Genetic and Environmental
Vulnerability Factors
Experimental
drug use
Family and social influences
Genetic/family history factors
Individual differences in initial
response to substances
Specific personality traits
Early life trauma
Poor frontal (executive) functioning
A
B
Chronic Distress
(associated with severity of psychiatric symptoms and drug use)
Repeated stress
exposure
Frequency of
drug use
Maladaptive Response Selection
C
Altered corticotropin-releasing
factor and hypothalamicpituitary-adrenal circuits
Altered reward pathways –
increased drug craving
Poor behavioral/cognitive coping
Neuroadaptations in
stress and reward
circuits in the brain
a
Regular and
chronic drug
use pattern
Various genetic and environmental vulnerability factors contribute to the development of psychiatric/emotional distress (A) and to drug abuse
(B). Chronic distress is a common construct underlying both the disabling psychiatric symptoms associated with specific psychiatric disorders
and the increasing distress associated with severity of substance use disorder. Chronic distress states are associated with selection of maladaptive responses, such as drug use, in order to attain desired goals or homeostasis. Maladaptive response selection mechanisms are associated
with alterations in various neurotransmitter systems (including corticotropin-releasing factor and hypothalamic-pituitary-adrenal circuits), increased levels of stress-induced drug craving, and poor adaptive coping, representing neuroadaptations in the stress and reward circuits (C).
This mechanism contributes to the escalation of drug use to the chronic levels characteristic of dependence, supporting a feed-forward loop
that leads to greater alterations in stress and reward systems. These alterations perpetuate chronic distress and susceptibility to repeated stress
exposures, thereby promoting a cycle of distress and drug use in individuals with comorbid disorders (adapted from Sinha [12]).
PTSD, ADHD, and schizophrenia). Figure 2 summarizes
the neurobiological evidence cited in the following sections and identifies the overlapping neurotransmitter systems and associated brain regions.
Depression
and Substance Use Disorders
Epidemiological studies reported rates of comorbidity of
major depression with nicotine, alcohol, and illicit drug
abuse ranging from 32% to 54% (1, 27, 28). Individuals with
major depression are more likely to develop substance use
disorders, and individuals with substance use disorders are
at greater risk for the development of major depression,
compared to the general population (27–29). Clinical similarities exist between major depression and substance use
disorders. Depressive symptoms are commonly reported
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during acute and chronic withdrawal from drugs of abuse.
Irritability, sleep difficulties, anxiety, and trouble with attention/concentration are associated with both protracted
withdrawal states and major depression.
Neurobiological similarities between major depression
and substance use disorders likely contribute to both
symptom overlap and high rates of comorbidity (13). Substantial data indicate that extrahypothalamic CRF and
HPA axis abnormalities (8) and alterations in catecholamine, serotonin, GABA, and glutamate systems are associated with major depression (30, 31). Neuroadaptations
associated with chronic drug abuse are associated with
alterations in these neurotransmitter systems, especially
during acute withdrawal states (13). CRF/HPA response
during acute drug withdrawal has a positive association
with withdrawal-related distress and with depressive
symptoms (32, 33). In addition, a growing amount of evihttp://ajp.psychiatryonline.org
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FIGURE 2. Central Systems/Pathways Involved in the Comorbidity of Psychiatric and Substance Use Disorders
Primary
Neurochemical
Systems
Corticotropin-releasing
factor (CRF)
Effects in Primary
Brain Regions
Activity in frontallimbic circuits
Similar imaging findings in major
depression and substance use disorder
Activity in anterior
cingulate
Common alterations in stress response
in major depression and substance
use disorder
Activity in amygdala
Smoking-related MAO inhibition
contributes to the antidepressant
effect of smoking in major depression.
Depression
Serotonergic
Hypothalamic/
extrahypothalamic
Glutamatergic
Dopaminergic
Posttraumatic
stress disorder
(PTSD)
Hypothalamic-pituitaryadrenal axis
Extrahypothalamic CRF
Noradrenergic system
Dopaminergic system
Attention deficit
hyperactivity disorder
(ADHD)
Disorder Comorbid With Substance Use Disorders
Monoamine oxidase
(MAO) activity
Noradrenergic system
MAO-A and MAO-B
levels in the brain
in smoking
Amygdala activation
during PTSD symptom
provacation/cue
presentation in
substance use
disorders
Frontal and prefrontal
cortical dysfunction
CSF CRF and norepinephrine in
substance withdrawl and PTSD
“Feed-forward” system of progressive
augmentation of stress response
Poor performance on prefrontal
cortical-related tasks such as selfmonitoring and behavioral and
motor control
Catecholamine input to prefrontal
cortex leading to reduced ADHD
symptoms and reduced drug seeking
in animal models
Dopaminergic system
Prefrontal cortical and
hippocampal/cortical
dysfunction
Schizophrenia
Glutamatergic system
dence indicates that the neurobiological alterations associated with acute withdrawal last for varying time periods
and contribute to drug craving and relapse in substance
use disorders (12). In a recent study (34), individuals with
substance use disorders, both with and without depressive symptoms, were found to have significantly lower
ACTH and cortisol response to CRF stimulation, compared to healthy subjects. These findings are consistent
with studies of abstinent smokers, alcoholic subjects, and
subjects with polysubstance dependence in which a
blunted cortisol response to standard psychological stressors was demonstrated (12). Blunted cortisol and prolactin responses to d-fenfluramine challenge in abstinent
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Key Interactions
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Dysregulated neural integration of
dopamine/glutamate in nucleus
accumbens leading to reduced
inhibitory control of dopamine
release
Nicotine administration improves
deficits in inhibitory gating of the
P-50 evoked response to repeated
auditory stimuli and deficits in
smooth pursuit eye movement
dysfunction and is associated with
impairment in visuospatial working
memory.
heroin-dependent individuals with and without depression have also been reported (35). Blunted peripheral
stress hormone responses may be a marker for increased
HPA axis activity (36, 37).
Evidence of altered neuroendocrine response to stress
challenges in substance use disorders is consistent with
clinical observations that individuals with substance use
disorder have difficulty managing stressful situations and
emotional distress states and often relapse in the face of
stressful situations (12, 38). In laboratory studies, stress
and negative affect states increase drug craving and emotional distress in abstinent substance-dependent individuals (17, 39–41). These changes are accompanied by physAm J Psychiatry 162:8, August 2005
KATHLEEN T. BRADY AND RAJITA SINHA
iological arousal (18), and this finding suggests that drugcraving states that are marked by increased levels of anxiety and distress are accompanied by biological stress responses. Increased distress-related drug craving is associated with vulnerability to continued drug use and relapse
(12, 42), and this association suggests a mechanistic connection between depressive symptoms and substance use
disorders.
In other studies, specific associations between monoamine oxidase (MAO) activity in smoking and major depression have been examined. MAO (with A and B subtypes), an enzyme involved in oxidizing serotonin, norepinephrine, and dopamine in the brain, has long been associated with negative mood and depression. For example,
MAO inhibitors are known to have antidepressant properties. It is interesting to note that smokers show reduced
MAO-A and MAO-B levels in the brain, compared to nonsmokers and former smokers (43, 44). These findings provide some support for the notion that smoking may have
antidepressant effects through inhibition of MAO-A and
MAO-B activity and suggest a pharmacological explanation for the high rates of smoking reported among individuals with major depression.
Recent findings from neuroimaging studies implicate
similar alterations in frontal-limbic brain circuitry in substance use disorders and major depression. Reduced frontal metabolism and hypoactivity of the anterior cingulate
have been reported in individuals with substance use disorders (45, 46). Significant reduction in dopamine D2 receptors, particularly in frontal-striatal regions, has been
noted in cocaine- and alcohol-dependent individuals,
compared to healthy subjects (45). Reduced frontal-limbic
metabolism has also been found in subjects with major
depression, relative to healthy subjects (47). Such findings
are consistent with postmortem studies showing reduced
cell density and gray matter volume in individuals with a
diagnosis of major depression (48). Furthermore, amygdala hyperactivity and anterior cingulate hypoactivity are
associated with major depression (47), and studies of individuals with substance use disorders indicate activation in
the amygdala associated with cue-induced drug craving
(49, 50). Under conditions of distress, cocaine-dependent
subjects exhibited decreased activity in frontal regions
such as the medial prefrontal cortex and the anterior cingulate, similar to that seen with negative mood in subjects
with major depression (51, 52). Similarly, a recent study
(53) reported lower levels of glucose metabolism in the anterior cingulate and insula, but higher levels in the orbitofrontal region, amygdala, middle and posterior cingulate,
and ventral striatum in methamphetamine abusers with
severe mood and anxiety symptoms, compared to healthy
subjects.
In conclusion, neuroendocrine and neuroimaging studies indicate dysregulation in frontal-limbic systems associated with stress and reward pathways in both major depression and substance use disorders. This common
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dysregulation is likely to contribute to the high rate of comorbidity of these illnesses. Evidence concerning negative
affect and stress-related drug seeking/craving provides additional insight into emotional distress states and drug use
in drug-experienced individuals. A better understanding of
these connections will contribute to the development of
new treatments for major depression, substance use disorders, and the comorbidity of these disorders.
PTSD and Substance Use Disorders
The high prevalence of the comorbidity of substance
use disorders and PTSD has been reported in a number of
studies. Initial reports focused on veterans with PTSD, of
whom 64%–84% met the criteria for a lifetime alcohol use
disorder and 40%–44% met the criteria for a lifetime drug
use disorder, including nicotine dependence (54, 55). In
civilian populations with PTSD, estimates of the lifetime
prevalence of substance use disorders range from 22% to
43% (56, 57), far higher than the estimates for substance
use disorders in the general population.
As in other comorbidities, PTSD and substance use disorders have a number of connecting pathways. Substance
intoxication may heighten the likelihood of exposure to
trauma, hence the likelihood of developing PTSD. Furthermore, chronic substance use and withdrawal may increase anxiety/arousal states, making it more likely that
individuals with substance use disorders will develop
PTSD after trauma exposure. On the other hand, PTSD
could increase the risk of developing a substance use disorder, because individuals may abuse substances in an attempt to relieve symptoms of PTSD. Substance use could
also exacerbate symptoms and/or prolong the course of
PTSD by preventing habituation to traumatic memories.
These pathways are not mutually exclusive, and new evidence is emerging concerning the neurobiological underpinnings of potential causal pathways. In one recent study
(58), individuals who had experienced any trauma and developed PTSD had an increased risk for the development
of drug dependence, particularly nicotine dependence,
but not alcohol dependence. This finding suggests specificity between substance of abuse and psychopathology.
The HPA axis, extrahypothalamic CRF, and the noradrenergic system are all intimately involved in the stress response, PTSD, and the pathophysiology of substance use
disorders. Evidence is accumulating to support a role for
CRF in mediating the effects of stress in increasing self-administration of drugs. Studies in rats have also demonstrated that withdrawal from chronic cocaine (59) or alcohol administration (60) in rats is associated with increases
in CRF in the hypothalamus, amygdala, and basal forebrain. Elevated CSF CRF has been found in humans during alcohol withdrawal (61). Two studies examining CSF
concentrations of CRF have demonstrated higher levels in
individuals with PTSD, compared to healthy subjects (62,
63). This finding is of particular interest because elevated
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brain CRF levels, especially in the amygdala, potentiate
fear-related behavioral responses (64). As such, elevated
levels of CRF may mediate both the symptoms of hyperarousal and the increased risk for substance use disorders
in PTSD. Increased CRF may enhance the reinforcing
properties of some drugs, worsen the severity of withdrawal symptoms, and exacerbate symptoms of PTSD.
Evidence implicating abnormalities in noradrenergic
systems has been found for both PTSD and substance use
disorders. Individuals with PTSD have elevated urinary excretion of both norepinephrine and epinephrine and elevated plasma levels of norepinephrine (65). Markers of
noradrenergic activity are increased in both alcohol and
opioid withdrawal (66–68). Brain CRF and noradrenergic
systems modulate each other in a number of ways. Stress
increases CRF in the locus ceruleus (69), and intraventricular administration of CRF increases norepinephrine
turnover in the hypothalamus, hippocampus, and prefrontal cortex (70). In the amygdala, norepinephrine stimulates the release of CRF (71). Koob and colleagues (72, 73)
hypothesized that interactions between CRF and the noradrenergic systems can function as a “feed-forward” system, with progressive augmentation of the stress response
with repeated stress exposure. Specifically, substance use
or withdrawal or other stress may stimulate CRF release in
the locus ceruleus, leading to the release of norepinephrine
in the cortex, which would, in turn, stimulate the release of
CRF in the hypothalamus and amygdala. This interaction
could help to explain the attempt to self-medicate PTSD
symptoms with substances of abuse, the worsening of
PTSD symptoms during substance withdrawal, and the increase in vulnerability to the development of PTSD in traumatized individuals with substance use disorders.
Neuroimaging studies have shed light on the connection between PTSD, other anxiety disorders, and substance use disorders. Amygdala activation occurs during
symptom provocation in PTSD, panic disorder, and social
phobia (74). As mentioned earlier, increased amygdalar
blood flow is also seen in cocaine-dependent individuals
presented with cocaine-related cues (50, 75).
ADHD Spectrum
and Substance Use Disorders
Substantial evidence suggests that ADHD, conduct disorder, and oppositional defiant disorder co-occur at high
rates among children and adolescents. This group of disorders, conceptualized as externalizing disorders, is associated with shared genetic and environmental risk factors
(76–78). Externalizing disorders are commonly comorbid
with substance use disorders in adolescents, with prevalence estimates ranging from 30%–50% (79). Adolescents
with comorbid substance use disorder and ADHD, conduct disorder, and/or oppositional defiant disorder have
an earlier age at onset and a more severe course of substance use disorder (80–82). Research has identified ge-
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netic, neurobiological, and psychosocial risk factors that
contribute to the core pathophysiology in the development of comorbid ADHD and substance use disorders.
Externalizing disorders are characterized by behavioral
disinhibition and personality traits such as aggression,
high levels of impulsivity, and poor self-control (77, 78,
83). Substantial evidence suggests that externalizing disorders are associated with problems in higher-order “executive” (frontal) cognitive function. In fact, ADHD has
often been characterized as a disorder of frontal and prefrontal cortex dysfunction (23, 71). Children with ADHD,
conduct disorder, oppositional defiant disorder, and earlyonset substance use disorder showed poor performance
on neuropsychological tests of abilities involving the prefrontal cortex, including planning, attention, cognitive
flexibility, working memory, self-monitoring, and behavioral and motor control (71).
In a large twin study that examined P3 amplitude—a robust electrophysiological marker with a strong genetic basis—lower P3 amplitude was associated with presence of
ADHD, conduct disorder, oppositional defiant disorder,
and substance use disorder in adolescent boys (78). Lower
P3 amplitude at age 17 years predicted development of
substance use disorder at age 20 years. Although genetic
factors contribute to the development of comorbid ADHD,
conduct disorder, and oppositional defiant disorder, a single shared environmental factor, identified as parent-child
conflict (i.e., negative social interactions between parents
and children), accounts for an even larger proportion of
the variance (84). Negative parent-child interactions, high
levels of negative affect, and emotional distress are also
known to increase the risk of substance use disorder in adolescents (85). These data suggest that coping with high
levels of family conflict may play an important role in the
development of both ADHD and substance use disorders.
Preclinical research has demonstrated that dopamine
and norepinephrine modulate prefrontal cortical function
(23, 86) and that stress impairs prefrontal cortical function
(86, 87). Evidence from brain imaging studies indicates
that the prefrontal cortex and anterior cingulate cortex
play important roles in cognitive conflict monitoring (88,
89) and self-regulation processing (90, 91). Difficulties in
response inhibition and self-regulation are core symptoms of externalizing disorders (78, 83). Compared to
healthy subjects, boys with comorbid ADHD, conduct disorder, and oppositional defiant disorder show greater behavioral aggression, heart rate reactivity, and higher levels
of anger in a laboratory-induced provocation paradigm
(92). Furthermore, in boys with externalizing symptoms,
lower cortisol levels and the personality traits of low levels
of self-control and harm avoidance are associated with the
development of substance use disorders (93, 94). Thus,
consistent with preclinical evidence indicating that stress
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KATHLEEN T. BRADY AND RAJITA SINHA
stance use disorders have poor stress-related coping and
poor self-regulation.
The prefrontal cortex and anterior cingulate cortex are
also important in regulating behavior related to future rewards. Primate studies have shown that the prefrontal cortex and anterior cingulate cortex are involved in assessing
reward expectancy (95) and motor responses based on future reward (96). These data are consistent with the critical
role of the prefrontal cortex in drug self-administration
and in the reinforcement and reinstatement of drug use
(97, 98). Children with ADHD and conduct disorder show
disinhibited physiological and behavioral responses during reward-related cognitive tasks (99, 100). These findings are consistent with decreased prefrontal cortical and
striatal activity and increased activity in posterior and sensory cortices in ADHD (101, 102) that is normalized by
chronic methylphenidate treatment (103). Preliminary
findings indicated that decreasing catecholamine input to
the prefrontal cortex by means of α2-adrenergic agonists
such as guanfacine, which inhibit norepinephrine centrally, enhances prefrontal cortical function and decreases
ADHD symptoms (104). It is interesting to note that other
α2-adrenergic agonists, such as clonidine and lofexidine,
attenuate stress-induced reinstatement of drug-seeking
behavior in laboratory models (105, 106). To the extent
that stress and reward dysfunction contribute to prefrontal cortical deficits in ADHD and substance use disorders,
α2-adrenergic agonists may be beneficial in addressing
this comorbidity.
Schizophrenia
and Substance Use Disorders
Recent studies have demonstrated that up to 50% of individuals with schizophrenia have either alcohol or illicit
drug dependence and more than 70% are nicotine dependent (2, 107, 108). In addition to having the expected adverse medical consequences, substance use in schizophrenic patients is associated with poor social function,
symptom exacerbation, frequent hospitalization, medication noncompliance, and poor treatment response (109,
110). Schizophrenia and substance use are connected by
multiple potential links, including genetic vulnerability,
medication side effects, negative symptoms, and psychosocial factors. Self-medication has been commonly invoked to explain the high comorbidity. Specifically, selfmedication of negative symptoms, such as social withdrawal and apathy, and drug use in the attempt to decrease
discomfort from the side effects of typical antipsychotic
medications have been suggested as explanations for the
high prevalence of substance use disorders in individuals
with schizophrenia. Although these factors may play some
role, advances in neurobiology suggest that the neuropathology of schizophrenia affects the neural circuitry mediating drug reward, leading to an increased vulnerability to
addiction. Specifically, Chambers and colleagues (111) hyAm J Psychiatry 162:8, August 2005
pothesized that abnormalities in hippocampal-cortical
function in schizophrenia impair the inhibitory hippocampal projections to the nucleus accumbens, resulting in
reduced inhibitory control over dopamine-mediated functional hyperresponsivity to dopamine release. In this model,
dysregulated neural integration of dopamine and glutamate in the nucleus accumbens resulting from frontal and
hippocampal dysfunction could lead, in subjects without
prior drug exposure, to neural and motivational changes
similar to those in long-term substance use. Thus, the predilection of schizophrenic patients to substance use disorders may be a primary disease symptom.
Recent studies focused on the neurobiological interface
between schizophrenia substance use disorders support
this hypothesis. In one study (112), magnetic resonance
images in groups of subjects with schizophrenia, schizophrenia plus alcohol dependence, and alcohol dependence only were compared with those from a matched
control group. Gray matter deficits were found in all three
patient groups, but were greatest in the group with comorbidity. The most prominent deficits were in the prefrontal
and anterior superior temporal regions, indicating that
comorbidity compounded the prominent prefrontal cortical deficits that are present independently in schizophrenia and alcohol dependence. Lifetime alcohol consumption in subjects with comorbidity was approximately five
times less than that in the alcohol-dependent subjects, yet
the subjects with comorbidity exhibited the full detrimental effects of alcohol, which suggests an interactive effect.
One area of particular interest is nicotine dependence
and schizophrenia. It has been estimated that 70%–90% of
individuals with chronic schizophrenia are nicotine dependent (113). Nicotine interacts with many of the same
central pathways involved in schizophrenia, including the
dopaminergic and glutamatergic pathways in the mesolimbic areas. Several abnormalities associated with
schizophrenia are improved with nicotine administration,
including deficits in the inhibitory gating of the P-50
evoked response to repeated auditory stimuli (114) and
deficits in smooth pursuit eye movement dysfunction
(115). George and colleagues (116) found deficits in visuospatial working memory in schizophrenic and nonschizophrenic individuals with nicotine dependence. With increasing periods of abstinence, the nonschizophrenic
smokers had improvements in visuospatial working memory, whereas the schizophrenic smokers experienced further impairment in visuospatial working memory. The authors postulated that the high rates of cigarette smoking in
schizophrenic patients may be related to the effects of
smoking in alleviating some of the cognitive dysfunction
associated with the presumed hypofunctionality of cortical
dopamine systems in schizophrenia. In a recent study of
more than 14,000 adolescents followed over a 4–16-year
period, adolescents who smoked more than 10 cigarettes/
day at the initial evaluation were significantly more likely
to be hospitalized for schizophrenia during the follow-up
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period (117). These findings suggest that smoking might
constitute self-medication of premorbid symptoms, might
reflect an intrinsic, disease-related disorder of nicotinic
transmission, or might play a causative role in the development of schizophrenia through chronic activation of mesolimbic dopaminergic neurotransmission in vulnerable
individuals. The development of novel approaches based
on nicotinic receptor mechanisms may have implications
for both prevention and treatment of schizophrenia.
Data from small, largely uncontrolled studies suggest
that treatment with clozapine and other atypical antipsychotics may be associated with decreases in substance
abuse in schizophrenic patients. Although the data are
limited, this favorable response to atypical agents is consistent with the theory that dysfunction of the brain reward system leads to an increased vulnerability to addictions in schizophrenia (118). Typical antipsychotic agents
are potent antagonists of D 2 receptors. Although this
blockade may initially decrease the reinforcing properties
of some substances of abuse, with chronic use there may
be enhancement of the substances’ reinforcing properties.
Studies in rodents demonstrated that chronic treatment
with haloperidol increased the reinforcing properties of
cocaine, presumably through up-regulation of the
postsynaptic dopamine receptor secondary to chronic
blockade (119). In contrast, atypical agents, such as clozapine, have varied actions on a number of neurotransmitter
systems and are much weaker D2 antagonists. It is possible
that these agents have a normalizing effect on the signal
detection capabilities of the mesocorticolimbic reward
circuitry, and this action may explain the association with
decreased substance use.
Conclusions
Although the nature of the relationship between psychiatric disorders and substance use disorders is complex and
multifaceted, there are likely to be unifying constructs.
Neuroadaptations in brain stress and reward pathways associated with chronic stress may predispose or unmask a
vulnerability to psychiatric disorders, substance use disorders, or both. Dysfunction in the prefrontal cortex and
frontal cortex associated with deficits in self-monitoring
and behavioral control are evident in ADHD, other externalizing disorders, and substance use disorders. Emerging
evidence suggests that abnormalities of glutamatergic
function in schizophrenia and other psychiatric disorders
may mediate vulnerability to the development of substance use disorders.
Although the focus of this article has been on neurobiological connections between psychiatric and substance
use disorders, it is important to note that these connections constitute just one facet of a complex issue. Further
exploration of overlapping neural circuitry and mechanistic relationships will be essential in guiding treatment and
prevention efforts. However, improvement in our under-
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standing of co-occurring disorders will be useful only if
there is a treatment system in place to implement these
findings. Clearly, change at public policy levels will be necessary to maximize the benefits derived from the findings
of neurobiological explorations in order to improve the
lives of individuals with comorbidity.
Received Oct. 8, 2004; revision received Jan. 12, 2005; accepted
Jan. 27, 2005. From the Clinical Neuroscience Division, Institute of
Psychiatry and Behavioral Sciences, Medical University of South Carolina; and Connecticut Mental Health Center, Yale University School of
Medicine, New Haven, Conn. Address correspondence and reprint requests to Dr. Brady, Clinical Neuroscience Division, Institute of Psychiatry and Behavioral Sciences, Medical University of South Carolina,
69 President St., Charleston, SC 29425; [email protected] (e-mail).
Supported by grant 1 P50 AR-049551 from the National Institute of
Arthritis and Musculoskeletal and Skin Diseases, grants 5 M01 RR01070-26 and M01 RR-00125 from the National Center for Research
Resources, and grants K24 DA-00435-04, 1 P50 DA-016556, and K02DA-017232 from the National Institute on Drug Abuse.
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