Neurobiology of comorbid post-traumatic stress disorder and
alcohol-use disorder
N. W. Gilpin
†,‡,*
and J. L. Weiner
§
†
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans,
LA, USA
‡
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New
Orleans, LA, USA
§
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem,
NC, USA
Abstract
Post-traumatic stress disorder (PTSD) and alcohol-use disorder (AUD) are highly comorbid in
humans. Although we have some understanding of the structural and functional brain changes that
define each of these disorders, and how those changes contribute to the behavioral symptoms that
define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be
due in part to a scarcity of adequate animal models for examining this research question. The goal
of this review is to summarize the current state-of-the-science on comorbid PTSD and AUD. We
summarize epidemiological data documenting the prevalence of this comorbidity, review what is
known about the potential neurobiological basis for the frequent co-occurrence of PTSD and AUD
and discuss successes and failures of past and current treatment strategies. We also review animal
models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the
human condition, and we discuss the strengths and weaknesses of each model. We conclude by
discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1)
highlight the need for better animal models of the comorbid condition and better clinical trial
design, (2) emphasize the need for examination of subpopulation effects and individual differences
and (3) urge cross-talk between basic and clinical researchers that is reflected in collaborative
work with forward and reverse translational impact.
Keywords
Alcohol dependence; alcohol use disorder (AUD); alcoholism; post-traumatic stress disorder
(PTSD); comorbid PTSD and AUD; amygdala; mesolimbic reward circuit; prefrontal cortex;
hippocampus; norepinephrine
*
Corresponding author: N. W. Gilpin, PhD, Department of Physiology, Louisiana State University Health Sciences Center, 1901
Perdido Street, New Orleans, LA 70112, USA. ngilpi@lsuhsc.edu.
HHS Public Access
Author manuscript
Genes Brain Behav
. Author manuscript; available in PMC 2018 January 01.
Published in final edited form as:
Genes Brain Behav
. 2017 January ; 16(1): 15–43. doi:10.1111/gbb.12349.
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Comorbid PTSD and AUD
It has long been recognized that exposure to traumatic events can elicit, in some individuals,
the emergence of a spectrum of debilitating and enduring anxiety-related symptoms, but the
term post-traumatic stress disorder (PSTD) was not officially recognized as an anxiety
disorder until the 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-III). This term replaced other labels such as ‘shell shock’ and ‘war neurosis’ that had
appeared in the literature for hundreds of years (Crocq & Crocq 2000; Trimble 1985). This
change was prompted by the acknowledgment that the etiological agent that triggered the
symptoms was outside the afflicted individual rather than merely a reflection of some
personal weakness or failing, a realization that slowly began to reduce the stigma associated
with this disorder. Revisions to the diagnostic criteria of PTSD continued until the latest
edition of the DSM (DSM-V) which recognized that, although anxiogenic symptoms are a
cornerstone of PTSD, this disease is better described by a new category of mental illnesses,
termed trauma- or stressor-related disorders, in which exposure to a traumatic or otherwise
adverse environmental event precedes the onset of each disorder. The diagnostic criteria of
PTSD include four clusters of symptoms: intrusion, avoidance, negative alterations in
cognitions and mood and alterations in arousal and reactivity (Guina
et al.
2016). Individuals
suffering from these disorders often re-experience a previously traumatic event, make
significant efforts to avoid internal or external reminders of the trauma and exhibit
hyperarousal in response to relatively neutral stimuli. These revisions to the diagnostic
criteria of PTSD are largely evidence-based and have helped to stimulate a much-needed
increase in research directed at this debilitating disorder. This is especially critical and
timely because the latest estimates using the DSM-V diagnostic criteria indicate that the
current past year PTSD prevalence was 4.7% and the lifetime prevalence rate was 8.3
(Kilpatrick 2003).
The diagnostic criteria for alcohol-use disorder (AUD) have also evolved with each iteration
of the DSM. In the latest edition (DSM-V), alcohol dependence and abuse have been
replaced by a single disease. Alcohol use disorder (AUD), with the diagnosis severity
dictated by the expression of a pathological set of behaviors related to the use of alcohol
(Hasin
et al.
2013). These behaviors fall into four main categories including impaired control
(e.g. drinking more than intended), social impairment (e.g. drinking behavior negatively
impacts work, family, etc.), risky use (e.g. driving while intoxicated) and altered physiology
(e.g. tolerance and withdrawal). As with PTSD, the prevalence of AUD is high. In the United
States, data from the 2012–2013 National Epidemiologic Survey on Alcohol and Related
Conditions III using the revised DSM-V criteria showed that the 12-month and lifetime
prevalence of AUD were 13.9% and 29.1%, respectively (Grant
et al.
2015a).
Epidemiology of comorbid PTSD and AUD
Despite the high incidence of AUD in the general population, individuals with PTSD are at
even higher risk of developing AUD. Although an anecdotal connection between these
disorders had long been appreciated, numerous clinical and epidemiological studies have
consistently documented a strong association between PTSD and AUD (Blanco
et al.
2013;
Debell
et al.
2014; Jacobson
et al.
2008; Shorter
et al.
2015). For example, a large
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retrospective review of the lifetime co-occurrence of DSM-III-R alcohol dependence and
other psychiatric disorders from the US National Comorbidity Study reported that PTSD
was associated with a three-fold increase in risk of developing AUD (Kessler
et al.
1997).
Other studies have reported that the lifetime prevalence of any substance-use disorder (SUD)
was twice as high in persons with PTSD vs. those not suffering from this disorder (Shorter
et
al.
2015) and that alcohol is the most commonly abused drug in PTSD patients (Jacobsen
et
al.
2001). Indeed, a recent study examined the relationship between the frequency of
childhood physical, sexual and emotional abuse and the development of substance use and
PTSD in an urban, civilian population. Not only was the lifetime prevalence of substance
dependence very high in these individuals (e.g. alcohol: 39%; cocaine: 34%), but also a
strong correlation was noted between the levels of childhood abuse and both the prevalence
of AUD and current PTSD symptoms (Khoury 2010). Interestingly, more recent data suggest
that scoring high on a measure of resilience characteristics such as tenacity, strong self-
efficacy and emotional/cognitive control under pressure may reduce the risk of substance
misuse and PTSD in this ‘at-risk’ population (Wingo 2014).
Despite the high prevalence of comorbid PTSD/AUD in the civilian population, the situation
is even more dire for military personnel. First, the prevalence of PTSD in military and
veteran populations may be twice that observed in the civilian population (Gates
et al.
2012;
Ramchand
et al.
2010). Similarly, military personnel are disproportionately impacted by the
adverse effects of alcohol. Recent surveys show that rates of alcohol misuse range from 18%
to 35% for soldiers returning from Operation Iraqi or Enduring Freedom (Hoge
et al.
2004;
Wilk
et al.
2010). Other data on military personnel that served in Iraq and Afghanistan found
that the baseline prevalence of binge drinking among Reserve or National Guard personnel
was 53.6% and the incidence of alcohol-related problems was 11.9% (Jacobson
et al.
2008).
Moreover, individuals who reported combat experience had higher rates of new-onset heavy
drinking, binge drinking and alcohol-related problems than those not exposed to combat
(Jacobson
et al.
2008). Not surprisingly, the rates of comorbid PTSD and AUD are
extremely high in military personnel. The Veterans Administration reported that almost 70%
of veterans hospitalized for PTSD also suffered from a comorbid SUD, with alcohol being
the most commonly abused drug Kulka
et al.
1988 and a more recent study found that
almost 50% of actively serving or National Guard Infantry personnel deployed to Iraq that
screened positive for PTSD also met diagnostic criteria for alcohol misuse (Thomas
et al.
2010). Importantly, as noted earlier, the diagnostic criteria for PTSD and AUD have recently
been revised. Therefore, new epidemiological studies are needed to obtain estimates of the
prevalence of the comorbid condition in the general population and at-risk groups using
these revised criteria.
Despite the notion that high rates of comorbidity between PTSD and AUD reflect an attempt
by the individual to self-medicate the negative affective state that emerges in trauma and
stressor-related disorders, there is also a growing appreciation that all of these disorders may
actually share common neural substrates (Enman
et al.
2014). Although a number of
behavioral and pharmacological treatments are available for both PTSD and AUD, these
interventions are frequently ineffective and individuals who suffer from this dual diagnosis
are particularly ill-served by current treatment options (Ipser 2015; Najavits 2013; Sofuoglu
2014). As such, there is a great deal of interest in gaining a better understanding of the
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neurobiological substrates underlying this comorbidity. However, progress has been
hampered, to some extent, by a lack of animal models that engender a behavioral phenotype
that reflects the human comorbid condition. The overarching goal of this review is to
summarize the current state of research on the comorbidity between PTSD and AUD. This
article will summarize the epidemiological evidence documenting the prevalence of this
comorbidity and review the neurobiological basis for the frequent co-occurrence of these
disorders. Current treatment options will also be discussed. This review will also summarize
the literature on available animal models, highlighting where the models parallel the human
condition, and discuss the strengths and weaknesses of each model. Collectively, this
summary may provide guidance for future work directed at improving animal models and
developing more effective treatments for comorbid PTSD and AUD. As this article will
focus primarily on the literature related to the comorbidity between PTSD and AUD, for
manuscripts focused solely on the epidemiology, neurobiology and treatment of each
disorder alone, the interested reader is directed to the following PTSD (Admon
et al.
2013b;
Atwoli
et al.
2015; Hoskins
et al.
2015; Pitman
et al.
2012) and AUD reviews (Batman &
Miles 2015; Koob 2013; Samochowiec
et al.
2014; Tabakoff & Hoffman 2013; Zindel &
Kranzler 2014).
Temporal expression of PTSD and AUD
Although relatively few studies have addressed the order of onset of PTSD and AUD, there
is a general consensus that PTSD precedes the onset of AUD (Chilcoat & Breslau 1998;
Epstein
et al.
1998; Jacobsen
et al.
2001; Kessler
et al.
1995, although see Cottler
et al.
1992). For example, a recent longitudinal study in a cohort of National Guard troops that
were screened pre- and post-deployment to Iraq found no effect of pre-deployment alcohol
status on the onset of PTSD; however, initial PTSD symptoms significantly increased the
risk of screening positive for new-onset alcohol dependence (Kline
et al.
2014). These
findings lend empirical support to the notion that individuals with PTSD may misuse alcohol
in an attempt to alleviate the anxiogenic and hyperarousal symptoms associated with this
disorder. Recent work has also highlighted an alarming increase in the prevalence of
pediatric PTSD, which may further increase the likelihood of developing AUD following a
PTSD diagnosis (Makley & Falcone 2010).
Risk factors of comorbid PTSD and AUD
As highlighted above, there is compelling evidence that active military personnel and
veterans are at increased risk for comorbid PTSD and AUD diagnoses. Are there other risk
factors associated with this dual diagnosis? Several studies have noted that exposure to a
wide range of early life stressors increases risk for the development of PTSD alone and
AUD alone, and that childhood adversity represents an even greater risk factor for the
development of comorbid PTSD and AUD. For example, data from the National Survey of
Adolescents reported that a history of interpersonal violence was a stronger risk factor for
the dual diagnosis of PTSD and AUD than for either non-comorbid diagnoses (Kilpatrick
et
al.
2013). In a study of alcohol-dependent men with comorbid PTSD, a history of emotional
abuse in childhood was found to contribute to impaired quality of life (Evren
et al.
2011). A
more recent analysis of data from the National Epidemiological Survey on Alcohol and
Related Conditions confirmed this relationship, finding that individuals with comorbid
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PTSD and AUD were more likely to have suffered childhood adversities than those with
only one of these conditions (Blanco
et al.
2013).
There is also evidence that stressors such as lower socioeconomic status and traumatic life
events may place adult victims at greater risk of developing comorbid PTSD and AUD
(Riggs
et al.
2003; Ullman
et al.
2006).
Sex, gender and comorbid PTSD/AUD
Epidemiological studies consistently find that women are more than twice as likely than men
to be diagnosed with PTSD over their lifetime (Breslau
et al.
1997; Kessler
et al.
1995; Olff
et al.
2007). In contrast, AUD rates are almost twice as high in men (Erol & Karpyak 2015;
Nelson
et al.
1998). Given this dichotomy, it may not be surprising that the data on whether
men or women are at greater risk for the development of comorbid PTSD and AUD are
mixed. Several studies have reported higher prevalence of comorbid PTSD and AUD in men
(Conway
et al.
2006; Kozaric-Kovacic
et al.
2000), whereas others cite slightly higher or
comparable rates of comorbidity in women and men (Kessler
et al.
1995, 1997; Pietrzak
et
al.
2012). One complicating factor may be that the type of trauma experienced could
influence the likelihood of developing comorbid PTSD and AUD. For example, while sexual
assault is a well-established risk factor for PTSD, one study found that the nature of the
assault impacts the probability of also developing AUD (Goldstein 2011). While rape
victims in this study had a significantly higher incidence of PTSD than non-victims, women
who experienced drug/alcohol-facilitated rape (i.e. were incapacitated) with or without
forcible rape were even more likely to develop AUD than those who experienced forcible
rape alone. Other studies have also begun to identify a variety of correlates that may predict
the comorbid condition. For example, among a group of sexual assault survivors who were
all diagnosed with PTSD, women who believed that drinking could reduce distress, had less
education, or had a history of other traumas were more likely to also suffer from comorbid
drinking problems (Ullman 2006). Collectively, these studies suggest that gender likely
influences the prevalence of comorbid PTSD and AUD; however, considerable additional
research will be needed to better understand the factors that moderate this relationship.
Consequences of comorbid PTSD and AUD
Many studies have examined how the dual diagnosis of PTSD and AUD influences the
trajectory and prognosis of these disorders. Here, the literature consistently illustrates that
the dual diagnosis of PTSD and AUD exacerbates the symptoms of each disorder. For
example, in patients with PTSD, heavy alcohol drinking increases the number (Behar 1987)
and severity of PTSD symptoms (Bremner
et al.
1996; Jacobsen
et al.
2001; Saladin
et al.
1995) and prolongs the course of illness (Bremner
et al.
1996; Yehuda
et al.
1995). One
particularly troubling study looked at suicidal ideation and attempts in patients with PTSD
and either comorbid major depressive disorder or alcohol dependence. While comorbid
depression was not related to suicidal thoughts and actions, PTSD patients with comorbid
alcohol dependence showed higher suicidal ideation and suicide attempts (Rojas
et al.
2014).
Similarly, individuals with comorbid PTSD show an earlier onset of AUD symptoms
(Driessen
et al.
2008), poorer physical and mental health (Evren
et al.
2011) and a much
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