CMN 552
Module 2 Primary Study Guide
Sadock, Chapter 14
Section 14.1
DSM-5 Modifications in Anxiety Disorders
The major subtypes of anxiety disorders in the DSM-5 include panic disorder (with or without
agoraphobia), agoraphobia (without a history of panic disorder), specific phobia, social phobia, and generalized
anxiety disorder (GAD). Revisions to the classification of anxiety disorders in the DSM-involve removing
obsessive- compulsive disorder and posttraumatic disorder have been subsumed under newly created “obsessive-
compulsive and related disorders” and “trauma- and stressor-related disorders” categories, respectively. Therefore,
both obsessive–compulsive disorder and posttraumatic stress disorder are not considered in this chapter. Other
modifications to the proposed DSM-5 anxiety disorders category include the addition of separation anxiety disorder
(contained under Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence in the DSMIV), the
identification of agoraphobia as a distinct and codable disorder (Diagnosed only with reference to panic disorder in
the DSM-IV), minor revisions to criterion language to enhance clarity, objectivity, and consistency across the
anxiety disorders, and the relabeling of social phobia as social anxiety disorder (SAD). As such, the term “social
phobia” will now be replaced with “social anxiety disorder.”
Section 14.2
PANIC DISORDER AND THE PANIC ATTACK SPECIFIER
Differential Diagnosis, Etiology, Course, and Treatment
Once full criteria have been met, the disorder tends to be chronic, though the course is often fluctuating.
Even after treatment to the point of remission, the rate of relapse is high. For example, naturalistic studies often
demonstrate a >50 percent relapse rate within 12 months of discontinuing an effective antidepressant.
Agoraphobia: Epidemiology
Similar to Panic Disorder, more women than men have agoraphobia and the age of onset peaks in the late
teens to early twenties. Agoraphobia in the absence of Panic Disorder is considered to be rarer than agoraphobia
with comorbid Panic Disorder. However, there is some variability in the prevalence data. The measured prevalence
of agoraphobia in specific clinical settings may evolve as the DSM-5’s recognition of agoraphobia without Panic
Disorder will spur clinicians to screen and consider the disorder more frequently, even in patients who do not present
with panic attacks. Other anxiety disorders are seen alongside agoraphobia in comorbidity rates that often exceed 50
percent. Comorbid depressive disorders are seen in 33 to 52 percent of cases, with some suggestion that the presence
of comorbid panic attacks increases the risk of comorbid depressive episodes.
Social Anxiety Disorder: Differential Diagnosis, Etiology, Course,
Treatment
, As mentioned above, Avoidant Personality Disorder (described in more detail elsewhere in this book) has
been the subject of debate over whether it is distinct from Social Anxiety Disorder, with the DSM-5 separating the
two. Social Anxiety Disorder has a high comorbidity with other anxiety and affective disorders, as well. The use of
illicit anxiolytics and sedatives leads to the relatively high rate of comorbid substance use disorders. The
comorbidity between Social Anxiety Disorder and Selective Mutism is discussed elsewhere in this chapter. Social
Anxiety Disorder is a common comorbidity in children with an Autism Spectrum diagnosis and also appears at rates
above population baseline in patients with Schizophrenia. Risk factors for Social Anxiety Disorder include female
gender, family history, and childhood signs of behavioral inhibition. There is insufficient data on specific genetic
factors mediating the increased familial risk, but parenting styles may also contribute to this familiarity. The Mini-
Social Phobia Inventory (Mini-SPIN) is an appropriate screening tool for adults. One could see how agoraphobia
could be confused with Social Anxiety Disorder or PTSD, though the context-dependent fears in the same situation
would be different. For example, a patient with Social Anxiety Disorder might dislike a crowded party because they
feel that everybody is looking at them and judging them. A patient with agoraphobia might avoid the same crowded
party out of concern that, were they to develop anxiety, it would be difficult to sprint for the exit. A patient with
PTSD might find that their desire for hypervigilance is overwhelmed by the multiple stimuli in a crowded room.
There is a markedly increased rate of suicide attempt amongst patients with Social Anxiety Disorder. This,
along with the significant functional impairment associated with this disorder, should motivate clinicians to pursue
aggressive treatment for these patients. CBT has demonstrated efficacy for Social Anxiety Disorder. The first-line
pharmacologic treatments are serotonergic agents, but other, PRN medications, especially for the performance
subtype (beta blockers), have been used effectively. Social Anxiety Disorder is a chronic condition, with a high rate
of symptom re-emergence after symptom remission is achieved via selective serotonin reuptake inhibitors (SSRIs),
for example. However, durable remission, even after cessation of CBT and/or antidepressants, has been seen in a
small proportion of patients.
Epidemiology
Social Anxiety Disorder is more common than some of the other disorders described in this section, with a
cross-national prevalence rate of 2 to 3 percent. It is more common in women than in men, has peak onset in the
early teenage years (often associated with the move to junior high school or high school, or some other increase in
social context complexity), and is associated with an increased risk of depressive episodes. AKA late teens to early
20s
SPECIFIC PHOBIA
Definition, Diagnosis, and Clinical Features
Specific Phobias are fears of specific objects or situations, such as spiders or blood, that go beyond the true
threat of the stimulus and cause avoidance and functional impairment (Table 14.2–2). The patient is fearful nearly
every time they are confronted with the phobic stimulus. The phobia, by rule, lasts longer than 6 months. Many
patients have multiple phobic stimuli, in which case each would be coded separately. ICD-10 has specific codes for
phobias of animals, natural environment (heights, storms, water), fear of blood, fear of injections, fear of
transfusions, fear of other medical care, fear of injury, fear of a specific situation (elevators, airplanes, enclosed
spaces, etc.), and fear of other (anything that does not fit into one the above).
Differential Diagnosis, Etiology, Course, and Treatment
As was articulated previously, delineating between the context- dependent phobias can be a challenge when
getting a history from any specific patient. Though some patients develop a Specific Phobia only after a traumatic
event involving a threatening phobic stimulus, these patients, by definition, do not develop the breadth of symptoms
that meet the criteria for PTSD. Similarly, patients can develop a Specific Phobia to an event following a panic
attack, but Panic Disorder requires that at least some panic attacks that are unexpected, rather than just coming from
a known phobic stimulus. As articulated previously, agoraphobia and Specific Phobia may be difficult to distinguish
if the phobic stimulus is in a specific, public location. However, patients with agoraphobia ought to fear multiple
public situations. Moreover, patients with agoraphobia specifically fear the panic or shame that can develop in
public situations.
Some Specific Phobias, such as animal phobias, have a unique age of onset, suggesting a nontraumatic
etiology perhaps more based in evolutionary preparedness. Other Specific Phobias, such as blood- injury illness
,phobia, have a unique physiology (i.e., bradycardia and hypotension as opposed to the usual tachycardia and
hypertensive reaction) and a greater rate of familiality that suggest still another distinct etiology.
There is a genetic component, but heritability does not seem specific for the type of Specific Phobia, but
rather for the general risk of developing some kind of Specific Phobia. For many phobias, environmental factors,
such as trauma, may be more important. As with other anxiety disorders, cognitive factors and conditioning may
also play a role.
While the course of specific phobia may be especially chronic, there are effective treatments. Patients often
recognize that their anxiety exceeds the true threat of the stimulus and this insight can often motivate a patient to
pursue therapy. The treatment of choice for Specific Phobia is a behavioral therapy series that includes exposure-
based, systematic desensitization. There are small, placebo- controlled studies involving serotonergic antidepressants
or atypical antipsychotics, but the data is very limited. There is ongoing work on augmenting exposure-based
psychotherapy with d-cycloserine, though the data requires ongoing interpretation and study replication to avoid
harm via administration of this medication in the wrong context. There is very little long-term data on the durability
of remission in pharmacologic studies.
Generalized Anxiety Disorder: Epidemiology
GAD is characterized by an uncontrollable worry, more days than not, lasting greater than 6 months, and
causing significant impairment.
GAD has a lifetime prevalence rate of 5 percent, often begins in the late teens, and is more common in women as
men. The high lifetime psychiatric comorbidity has led some to view GAD as a prodromal or residual phase of a
major depression, though there is insufficient empirical support for this view. Other common comorbidities include
other anxiety spectrum disorders and substance use disorders.
Separation Anxiety Disorder: History/Comparative Nosology
The epidemiologic evidence documenting a high rate of onset occurring after 18 years old has led to a
removal of the age-of-onset restriction in the DSM-5. The inclusion of the adult-onset formulation has moved
Separation Anxiety Disorder from DSM-IV’s “Disorders Usually First Diagnosed in Infancy, Childhood or
Adolescence” to DSM-5’s “Anxiety Disorders.” As noted with Selective Mutism, the prominent symptom of worry
ties Separation Anxiety Disorder to the other, classical diagnoses in the Anxiety Disorders section.
‘
Section 14.3
Medical Symptoms/Disorders
Community samples have strongly confirmed the high magnitude of comorbidity of anxiety disorders with
several medical conditions that had been described in clinical samples. There is a growing body of evidence for
specific patterns of associations between anxiety disorders and a range of medical disorders including respiratory
conditions, cardiovascular diseases, gastrointestinal disorders, metabolic diseases, and musculoskeletal disorders.
For example, in the Australian National Survey of Health and Wellbeing, there was a two-fold greater rates of
physical conditions among those with anxiety disorders compared to those without anxiety. Similar to other mental
disorders, comorbid anxiety with physical disorders are associated with substantially greater disability than anxiety
disorders alone.
Investigation of comorbidity of physical disorders and anxiety is complicated by the role of physical
symptoms as a core feature of panic disorder and GAD. There is now evidence that anxiety disorders may represent
the initial manifestations of several physical conditions, and there are also numerous physical conditions that lead to
anxiety-like symptoms. In adults, anxiety disorders, particularly GAD and panic, are associated with cardiovascular
risk factors and diseases. For example, analyses of data from electronic medical records and direct interviews
regarding medical and mental disorders in the large Philadelphia Neurodevelopmental Cohort (PNC) revealed that
asthma was the only medical condition specifically associated with anxiety disorders in childhood and adolescence.
This link has been confirmed in a population based birth cohort study in Australia that found that youth with more
severe and persistent asthma at age 5 years were more likely to have anxiety problems from ages 5 to 17 years.
Therefore, some of the other comorbid physical disorders associated with anxiety may not emerge until later in life.
Similar to adults, rates of anxiety disorder in the PNC increased with the severity of aggregate physical conditions,
suggesting that physical–mental comorbidity is associated with greater impairment of both conditions. Prospective
documentation of the evolution of anxiety disorders and physical conditions will be critical to the understanding of
, the explanations for comorbidity.
Section 14.4
Genetic Epidemiology
Genetic epidemiology seeks to understand how diseases and their risk factors are distributed in families.
First, family studies compare rates of illness in relatives of those who have the condition (case probands) with rates
in relatives of healthy controls. Higher rates in the former group of relatives, as parameterized by a relative risk (RR)
or odds ratio (OR) greater than 1.0, suggest familial aggregation. Next, one relies on either adoption studies (not
available for ADs) or twin studies to differentiate genetic from within-family environment as sources of aggregation.
Twin studies compare resemblance for a condition between members of a twin pair using the fact that identical
(monozygotic [MZ]) twins share 100 percent of their genetic sequence while nonidentical (dizygotic [DZ]) twins
share, on average, only 50 percent, like any two siblings. One commonly used measure of twin resemblance is the
proband-wise concordance, that is, the proportion of co-twins of affected index twins who are also affected. If
average concordance for MZ pairs is greater than that for DZ pairs, this is evidence for a genetic component to
family resemblance. With larger twin samples, one may also estimate the proportion of individual differences due to
the effects of genetic factors (heritability). For conditions with substantial heritability, gene finding (linkage or
association) studies are undertaken to identify which specific genes contribute to risk.
A 2001 meta-analysis summarized findings across extant family and twin studies for various adult ADs.
Those results suggest an overall moderate level of familial aggregation (OR = 4 to 6) and heritability (30 to 50
percent) across the ADs. This means that, on average, first-degree relatives (FDRs) of someone affected by an AD
are four to six times more likely to develop one than a random individual. Fifty percent heritability means that
genetic and nongenetic factors are about equally responsible for the etiology of Ads (half and half). Few family
studies have been published since then, as it is now well established that all ADs aggregate in families. More twin
studies have been conducted, however, with emphasis on the etiology of comorbidity or developmental risk. The
results of that meta-analysis will be referred to and augmented with data from more recent studies, where available.
Molecular Genetics: Linkage & Candidate Gene Association
Two main approaches have been applied to identify susceptibility genes in human studies: linkage and
association studies. Linkage studies are performed in family pedigrees with several affected individuals to identify
chromosomal loci likely to harbor a gene influencing a biologic trait or condition. While effective for identifying
highly penetrant genes of large effect seen in classic Mendelian disorders, linkage has, with few exceptions, not been
successful for most complex phenotypes encountered in medicine, including ADs. Several linkage studies have been
performed for ADs, with few consistent findings between studies. Suggestive evidence for linkage to PD has been
reported for regions on chromosomes 4q, 9q, 13q, 14q, and 22q. A more recent PD genome-wide linkage scan
conducted in the isolated population of the Faroe Islands found an association of the amiloride sensitive cation
channel 1 (ACCN1) gene, previously supported by animal studies. However, this association was not replicate in an
independent sample. A reanalysis of several PD linkage studies supported linkage on chromosomes 4q and 7p. A
Yale University group conducted linkage analyses of phobic disorder in a set of pedigrees ascertained for PD,
reporting linkage on chromosome 3q for agoraphobia, 14q for specific phobia, and 16q for social phobia. There are
no published linkage scans for GAD. A meta-analysis of 162 families with panic or other ADs found suggestive
evidence for linkage on chromosomes 1, 5, 15, and 16. Of note, these AD linkage results moderately but
significantly correlated with those for neuroticism, also examined in that study.
Association studies allow one to test specific genetic markers for their contribution to a phenotype. They
include case-control comparisons in unrelated individuals or family-based transmission tests. To date, most
association studies of ADs have focused on candidate genes, which have to be chosen using a priori knowledge,
either from their position under a linkage peak or by their purported biologic relevance for the pathophysiology of
the disease. Similar to depression, the most widely studied candidate genes for ADs are genes involved in
neurotransmitter systems (e.g., serotonin, norepinephrine, GABA, glutamate, and dopamine) or the stress response
system. A review summarizing more than 350 candidate gene findings for PD concluded that most of these results
were inconsistent, negative, or not clearly replicated. (This has been the case for most candidate gene studies in
psychiatry.) Failure to identify susceptibility loci may be due to differences in phenotypic assessment, heterogeneity
at the genetic level, underpowered studies with small sample sizes, and poor candidate gene selection. A systematic
Module 2 Primary Study Guide
Sadock, Chapter 14
Section 14.1
DSM-5 Modifications in Anxiety Disorders
The major subtypes of anxiety disorders in the DSM-5 include panic disorder (with or without
agoraphobia), agoraphobia (without a history of panic disorder), specific phobia, social phobia, and generalized
anxiety disorder (GAD). Revisions to the classification of anxiety disorders in the DSM-involve removing
obsessive- compulsive disorder and posttraumatic disorder have been subsumed under newly created “obsessive-
compulsive and related disorders” and “trauma- and stressor-related disorders” categories, respectively. Therefore,
both obsessive–compulsive disorder and posttraumatic stress disorder are not considered in this chapter. Other
modifications to the proposed DSM-5 anxiety disorders category include the addition of separation anxiety disorder
(contained under Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence in the DSMIV), the
identification of agoraphobia as a distinct and codable disorder (Diagnosed only with reference to panic disorder in
the DSM-IV), minor revisions to criterion language to enhance clarity, objectivity, and consistency across the
anxiety disorders, and the relabeling of social phobia as social anxiety disorder (SAD). As such, the term “social
phobia” will now be replaced with “social anxiety disorder.”
Section 14.2
PANIC DISORDER AND THE PANIC ATTACK SPECIFIER
Differential Diagnosis, Etiology, Course, and Treatment
Once full criteria have been met, the disorder tends to be chronic, though the course is often fluctuating.
Even after treatment to the point of remission, the rate of relapse is high. For example, naturalistic studies often
demonstrate a >50 percent relapse rate within 12 months of discontinuing an effective antidepressant.
Agoraphobia: Epidemiology
Similar to Panic Disorder, more women than men have agoraphobia and the age of onset peaks in the late
teens to early twenties. Agoraphobia in the absence of Panic Disorder is considered to be rarer than agoraphobia
with comorbid Panic Disorder. However, there is some variability in the prevalence data. The measured prevalence
of agoraphobia in specific clinical settings may evolve as the DSM-5’s recognition of agoraphobia without Panic
Disorder will spur clinicians to screen and consider the disorder more frequently, even in patients who do not present
with panic attacks. Other anxiety disorders are seen alongside agoraphobia in comorbidity rates that often exceed 50
percent. Comorbid depressive disorders are seen in 33 to 52 percent of cases, with some suggestion that the presence
of comorbid panic attacks increases the risk of comorbid depressive episodes.
Social Anxiety Disorder: Differential Diagnosis, Etiology, Course,
Treatment
, As mentioned above, Avoidant Personality Disorder (described in more detail elsewhere in this book) has
been the subject of debate over whether it is distinct from Social Anxiety Disorder, with the DSM-5 separating the
two. Social Anxiety Disorder has a high comorbidity with other anxiety and affective disorders, as well. The use of
illicit anxiolytics and sedatives leads to the relatively high rate of comorbid substance use disorders. The
comorbidity between Social Anxiety Disorder and Selective Mutism is discussed elsewhere in this chapter. Social
Anxiety Disorder is a common comorbidity in children with an Autism Spectrum diagnosis and also appears at rates
above population baseline in patients with Schizophrenia. Risk factors for Social Anxiety Disorder include female
gender, family history, and childhood signs of behavioral inhibition. There is insufficient data on specific genetic
factors mediating the increased familial risk, but parenting styles may also contribute to this familiarity. The Mini-
Social Phobia Inventory (Mini-SPIN) is an appropriate screening tool for adults. One could see how agoraphobia
could be confused with Social Anxiety Disorder or PTSD, though the context-dependent fears in the same situation
would be different. For example, a patient with Social Anxiety Disorder might dislike a crowded party because they
feel that everybody is looking at them and judging them. A patient with agoraphobia might avoid the same crowded
party out of concern that, were they to develop anxiety, it would be difficult to sprint for the exit. A patient with
PTSD might find that their desire for hypervigilance is overwhelmed by the multiple stimuli in a crowded room.
There is a markedly increased rate of suicide attempt amongst patients with Social Anxiety Disorder. This,
along with the significant functional impairment associated with this disorder, should motivate clinicians to pursue
aggressive treatment for these patients. CBT has demonstrated efficacy for Social Anxiety Disorder. The first-line
pharmacologic treatments are serotonergic agents, but other, PRN medications, especially for the performance
subtype (beta blockers), have been used effectively. Social Anxiety Disorder is a chronic condition, with a high rate
of symptom re-emergence after symptom remission is achieved via selective serotonin reuptake inhibitors (SSRIs),
for example. However, durable remission, even after cessation of CBT and/or antidepressants, has been seen in a
small proportion of patients.
Epidemiology
Social Anxiety Disorder is more common than some of the other disorders described in this section, with a
cross-national prevalence rate of 2 to 3 percent. It is more common in women than in men, has peak onset in the
early teenage years (often associated with the move to junior high school or high school, or some other increase in
social context complexity), and is associated with an increased risk of depressive episodes. AKA late teens to early
20s
SPECIFIC PHOBIA
Definition, Diagnosis, and Clinical Features
Specific Phobias are fears of specific objects or situations, such as spiders or blood, that go beyond the true
threat of the stimulus and cause avoidance and functional impairment (Table 14.2–2). The patient is fearful nearly
every time they are confronted with the phobic stimulus. The phobia, by rule, lasts longer than 6 months. Many
patients have multiple phobic stimuli, in which case each would be coded separately. ICD-10 has specific codes for
phobias of animals, natural environment (heights, storms, water), fear of blood, fear of injections, fear of
transfusions, fear of other medical care, fear of injury, fear of a specific situation (elevators, airplanes, enclosed
spaces, etc.), and fear of other (anything that does not fit into one the above).
Differential Diagnosis, Etiology, Course, and Treatment
As was articulated previously, delineating between the context- dependent phobias can be a challenge when
getting a history from any specific patient. Though some patients develop a Specific Phobia only after a traumatic
event involving a threatening phobic stimulus, these patients, by definition, do not develop the breadth of symptoms
that meet the criteria for PTSD. Similarly, patients can develop a Specific Phobia to an event following a panic
attack, but Panic Disorder requires that at least some panic attacks that are unexpected, rather than just coming from
a known phobic stimulus. As articulated previously, agoraphobia and Specific Phobia may be difficult to distinguish
if the phobic stimulus is in a specific, public location. However, patients with agoraphobia ought to fear multiple
public situations. Moreover, patients with agoraphobia specifically fear the panic or shame that can develop in
public situations.
Some Specific Phobias, such as animal phobias, have a unique age of onset, suggesting a nontraumatic
etiology perhaps more based in evolutionary preparedness. Other Specific Phobias, such as blood- injury illness
,phobia, have a unique physiology (i.e., bradycardia and hypotension as opposed to the usual tachycardia and
hypertensive reaction) and a greater rate of familiality that suggest still another distinct etiology.
There is a genetic component, but heritability does not seem specific for the type of Specific Phobia, but
rather for the general risk of developing some kind of Specific Phobia. For many phobias, environmental factors,
such as trauma, may be more important. As with other anxiety disorders, cognitive factors and conditioning may
also play a role.
While the course of specific phobia may be especially chronic, there are effective treatments. Patients often
recognize that their anxiety exceeds the true threat of the stimulus and this insight can often motivate a patient to
pursue therapy. The treatment of choice for Specific Phobia is a behavioral therapy series that includes exposure-
based, systematic desensitization. There are small, placebo- controlled studies involving serotonergic antidepressants
or atypical antipsychotics, but the data is very limited. There is ongoing work on augmenting exposure-based
psychotherapy with d-cycloserine, though the data requires ongoing interpretation and study replication to avoid
harm via administration of this medication in the wrong context. There is very little long-term data on the durability
of remission in pharmacologic studies.
Generalized Anxiety Disorder: Epidemiology
GAD is characterized by an uncontrollable worry, more days than not, lasting greater than 6 months, and
causing significant impairment.
GAD has a lifetime prevalence rate of 5 percent, often begins in the late teens, and is more common in women as
men. The high lifetime psychiatric comorbidity has led some to view GAD as a prodromal or residual phase of a
major depression, though there is insufficient empirical support for this view. Other common comorbidities include
other anxiety spectrum disorders and substance use disorders.
Separation Anxiety Disorder: History/Comparative Nosology
The epidemiologic evidence documenting a high rate of onset occurring after 18 years old has led to a
removal of the age-of-onset restriction in the DSM-5. The inclusion of the adult-onset formulation has moved
Separation Anxiety Disorder from DSM-IV’s “Disorders Usually First Diagnosed in Infancy, Childhood or
Adolescence” to DSM-5’s “Anxiety Disorders.” As noted with Selective Mutism, the prominent symptom of worry
ties Separation Anxiety Disorder to the other, classical diagnoses in the Anxiety Disorders section.
‘
Section 14.3
Medical Symptoms/Disorders
Community samples have strongly confirmed the high magnitude of comorbidity of anxiety disorders with
several medical conditions that had been described in clinical samples. There is a growing body of evidence for
specific patterns of associations between anxiety disorders and a range of medical disorders including respiratory
conditions, cardiovascular diseases, gastrointestinal disorders, metabolic diseases, and musculoskeletal disorders.
For example, in the Australian National Survey of Health and Wellbeing, there was a two-fold greater rates of
physical conditions among those with anxiety disorders compared to those without anxiety. Similar to other mental
disorders, comorbid anxiety with physical disorders are associated with substantially greater disability than anxiety
disorders alone.
Investigation of comorbidity of physical disorders and anxiety is complicated by the role of physical
symptoms as a core feature of panic disorder and GAD. There is now evidence that anxiety disorders may represent
the initial manifestations of several physical conditions, and there are also numerous physical conditions that lead to
anxiety-like symptoms. In adults, anxiety disorders, particularly GAD and panic, are associated with cardiovascular
risk factors and diseases. For example, analyses of data from electronic medical records and direct interviews
regarding medical and mental disorders in the large Philadelphia Neurodevelopmental Cohort (PNC) revealed that
asthma was the only medical condition specifically associated with anxiety disorders in childhood and adolescence.
This link has been confirmed in a population based birth cohort study in Australia that found that youth with more
severe and persistent asthma at age 5 years were more likely to have anxiety problems from ages 5 to 17 years.
Therefore, some of the other comorbid physical disorders associated with anxiety may not emerge until later in life.
Similar to adults, rates of anxiety disorder in the PNC increased with the severity of aggregate physical conditions,
suggesting that physical–mental comorbidity is associated with greater impairment of both conditions. Prospective
documentation of the evolution of anxiety disorders and physical conditions will be critical to the understanding of
, the explanations for comorbidity.
Section 14.4
Genetic Epidemiology
Genetic epidemiology seeks to understand how diseases and their risk factors are distributed in families.
First, family studies compare rates of illness in relatives of those who have the condition (case probands) with rates
in relatives of healthy controls. Higher rates in the former group of relatives, as parameterized by a relative risk (RR)
or odds ratio (OR) greater than 1.0, suggest familial aggregation. Next, one relies on either adoption studies (not
available for ADs) or twin studies to differentiate genetic from within-family environment as sources of aggregation.
Twin studies compare resemblance for a condition between members of a twin pair using the fact that identical
(monozygotic [MZ]) twins share 100 percent of their genetic sequence while nonidentical (dizygotic [DZ]) twins
share, on average, only 50 percent, like any two siblings. One commonly used measure of twin resemblance is the
proband-wise concordance, that is, the proportion of co-twins of affected index twins who are also affected. If
average concordance for MZ pairs is greater than that for DZ pairs, this is evidence for a genetic component to
family resemblance. With larger twin samples, one may also estimate the proportion of individual differences due to
the effects of genetic factors (heritability). For conditions with substantial heritability, gene finding (linkage or
association) studies are undertaken to identify which specific genes contribute to risk.
A 2001 meta-analysis summarized findings across extant family and twin studies for various adult ADs.
Those results suggest an overall moderate level of familial aggregation (OR = 4 to 6) and heritability (30 to 50
percent) across the ADs. This means that, on average, first-degree relatives (FDRs) of someone affected by an AD
are four to six times more likely to develop one than a random individual. Fifty percent heritability means that
genetic and nongenetic factors are about equally responsible for the etiology of Ads (half and half). Few family
studies have been published since then, as it is now well established that all ADs aggregate in families. More twin
studies have been conducted, however, with emphasis on the etiology of comorbidity or developmental risk. The
results of that meta-analysis will be referred to and augmented with data from more recent studies, where available.
Molecular Genetics: Linkage & Candidate Gene Association
Two main approaches have been applied to identify susceptibility genes in human studies: linkage and
association studies. Linkage studies are performed in family pedigrees with several affected individuals to identify
chromosomal loci likely to harbor a gene influencing a biologic trait or condition. While effective for identifying
highly penetrant genes of large effect seen in classic Mendelian disorders, linkage has, with few exceptions, not been
successful for most complex phenotypes encountered in medicine, including ADs. Several linkage studies have been
performed for ADs, with few consistent findings between studies. Suggestive evidence for linkage to PD has been
reported for regions on chromosomes 4q, 9q, 13q, 14q, and 22q. A more recent PD genome-wide linkage scan
conducted in the isolated population of the Faroe Islands found an association of the amiloride sensitive cation
channel 1 (ACCN1) gene, previously supported by animal studies. However, this association was not replicate in an
independent sample. A reanalysis of several PD linkage studies supported linkage on chromosomes 4q and 7p. A
Yale University group conducted linkage analyses of phobic disorder in a set of pedigrees ascertained for PD,
reporting linkage on chromosome 3q for agoraphobia, 14q for specific phobia, and 16q for social phobia. There are
no published linkage scans for GAD. A meta-analysis of 162 families with panic or other ADs found suggestive
evidence for linkage on chromosomes 1, 5, 15, and 16. Of note, these AD linkage results moderately but
significantly correlated with those for neuroticism, also examined in that study.
Association studies allow one to test specific genetic markers for their contribution to a phenotype. They
include case-control comparisons in unrelated individuals or family-based transmission tests. To date, most
association studies of ADs have focused on candidate genes, which have to be chosen using a priori knowledge,
either from their position under a linkage peak or by their purported biologic relevance for the pathophysiology of
the disease. Similar to depression, the most widely studied candidate genes for ADs are genes involved in
neurotransmitter systems (e.g., serotonin, norepinephrine, GABA, glutamate, and dopamine) or the stress response
system. A review summarizing more than 350 candidate gene findings for PD concluded that most of these results
were inconsistent, negative, or not clearly replicated. (This has been the case for most candidate gene studies in
psychiatry.) Failure to identify susceptibility loci may be due to differences in phenotypic assessment, heterogeneity
at the genetic level, underpowered studies with small sample sizes, and poor candidate gene selection. A systematic
