Anxiety disorder (AD) is commonly comorbid with other mental illness. It could be a state or trait, controversially. Evidence for an association between alcoholism and anxiety has emerged from clinical studies of patients with alcoholism, and those of patients with anxiety disorders. Alcohol dependence (or abuse) as well as bipolar disorder (BP) is usually comorbid with anxiety disorder and/or depressive disorder, which often coexist and are difficult to distinguish from one another. However, in Han Chinese population, the comorbidity rate either with alcoholism or bipolar disorder was not reported as much high as reported in Caucasians, this finding of comorbidity between anxiety/depressive disorders and alcohol dependence (or abuse) or/and bipolar disorders, possibly at the genetic level, makes the differentiation of their categorical diagnoses in the association study vitally important.
- mental illness
Feinstein  started to draw attention on patients with one or more than one diagnosable disease and defined “Comorbidity” as “
Regardless of types of anxiety disorder (AD), anxiety is one of the most prevalent of all psychiatric disorders in other mental illnesses, such as mood disorders and alcoholism. Different types of mental illnesses commonly comorbid with AD as well as the ethnic role will be reviewed. The comorbidity has gained increasing prominence in psychiatry and psychology in the past few decades . A distinction between two types of comorbidity has been drawn a decade ago by Angold et al. .
Reiger et al.  reported that approximately 15% of people suffered from AD, according to Diagnostic and Statistical Manual-3rd edition (DSM-III) during their lifetime. Keith et al. (1991) compared the prevalence of AD, including subtypes between community and the institute prevalence rates, and found the lifetime rate of AD was 15% overall, 16% in nursing home residents, 28% in prisoners, and 51% in patients in mental hospitals. Further, Robins et al.  studied the prevalence of AD and found that phobia is the most common AD (Figure 1).
As the more specific and classified the AD was studied, simple phobia was reported as the most common comorbidity, up to nearly 50%. Approximately 13% of people reported symptoms matching the DSM criteria, and social anxiety disorder was in the second place of highest reported disorder of anxiety. Post-traumatic stress disorder (PTSD), often goes unrecognized, but its prevalence reached 20% in victims of war trauma.
However, the more commonly recognized disorders, such as generalized anxiety disorder (GAD) and panic disorder (PD), have the lower lifetime prevalence rates of approximately 5 and 3.5%, respectively. Another often underdiagnosed disorder, obsession-compulsive disorder (OCD), is found in 2.5% of the population. Interestingly, a recent study found very little change in the prevalence of mental disorders, including specific anxiety disorders, since 1990 .
Because of high recognition and high prevalence rate, researchers started to explore whether AD is a genetic-related psychiatric disorder. Therefore, genetic risk factors are being studied; researchers have found genetic predisposition for two broad groups of anxiety disorders: a panic-generalized anxiety-agoraphobia group and a specific phobia group . More clinically important risk factors include comorbid substance abuse and family history. Weissman et al.  conducted a 20-year study in the offspring of depressed parents and found a three-fold increase in ADs, including greater substance abuse, younger onset, and more significant physical health concerns.
Although a genetic predisposition for developing an AD is likely , environmental stressors clearly play a role in varying degrees. All of the disorders are affected in some way by external cues and how they are proceeded and reacted to. Research has also shown that patients suffering from anxiety are generally more sensitive to physiologic changes than nonanxious patients, and panic disorder sufferers are even more sensitive to these than the GAD patients. Objective testing, however, reveals that physiologic changes between anxious and nonanxious patients are comparable. This heightened sensitivity leads to diminished autonomic flexibility, which may be the result of faulty central information processing in anxiety-prone persons .
The neuroanatomical foundation of anxiety may be related to the influence of the septohippocampal system in the brain on learning and memory . Patients with AD manifest impaired divided attention , verbal learning, verbal recall , visual learning and memory , episodic memory and executive function , and cognitive information processing .
2. Anxiety disorder as comorbidity
2.1. Anxiety disorder as comorbidity in bipolar disorders
Prior to year 2000, there were few studies on bipolar disorder II (BPII) and little research into the differences between BPI and BPII patients. More and more studies have been conducted to distinguish between the subdivisions of bipolar disorders (BPI and BPII). Genetically, there was an association with the interaction between
Anxiety disorders have been reported as a common comorbidity in BP [23–28], the life time prevalence was reported by National Institute of Mental Health (NIMH) as 51.2% [29, 30], and current anxiety disorders in 31% of the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) . The National Comorbidity Survey reports that approximately 90% (BPI: 86–92%; BPII: 89%) of bipolar patients comorbid with AD [31–33]. More often, comorbid with panic disorder (PD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) either in the community or in primary care and psychiatric settings has been reported [30, 32, 34, 35]. There is a growing body of research evidence that bipolar depressives have comparable if not higher rates of comorbid anxiety disorders than unipolar depressives [23, 24, 26–28, 36]. Accordingly, anxiety comorbidity could be a fundamental feature of bipolar disorder . Recent studies reported that among all bipolar disorders, BPII has higher comorbidity with AD than does BPI [23, 25, 26, 28, 38].
Other important aspects to be borne in mind are recognition and prognosis. Compared to noncomorbid BP, BP patients with AD are susceptible to a higher risk of suicidal behavior , substance abuse [30, 40, 41], lower psychosocial performance  and has a more frequent family history of mental illness . Moreover, the AD comorbidity can complicate the course of illness and pharmacological treatment strategies . Not only the high comorbidity between BP and AD has been noticed, but the types of AD comorbidity in BP could also complicate the recognition of BPI and BPII and predict the prognosis. Patients with BP and AD are susceptible to higher risk of suicidal behaviour , substance abuse [30, 40, 41], lower psychosocial performance , and a more frequent family history of mental illness than BP patients without AD . Moreover, the AD comorbidity would complicate the course of illness and pharmacological treatment strategies .
A number of studies [23–26, 44] have shown bipolar disorder to be highly comorbid with anxiety disorder; a prevalent rate of 51.2% was reported by the National Institute of Mental Health (NIMH) [30, 45]. BP is most frequently associated with panic disorder (PD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), whether in the community, in primary care, or in psychiatric settings [30, 32, 34, 35]. The National Comorbidity Survey reports that approximately 90% of BP patients (BP-I: 86–92%; BP-II: 89%) have at least one comorbid AD [31–33].
There is a growing body of research evidence that individuals with bipolar depression have comparable if not higher rates of comorbid ADs than do individuals with unipolar depression [23, 24, 26, 27, 36, 44]. Anxiety comorbidity is, then, a fundamental feature of BP . Moreover, established studies [23, 25, 26, 38, 44] show that BP-II is more often comorbid with AD than is BPI. The BP patients with AD comorbidity have been pointed out to have worse prognosis, such as shortened euthymia, delayed remission, and rapid cycling. The AD comorbidity worsens BP patients’ episode and their response to treatment, and increases their suicidal behavior. Previous researchers have also pointed out a higher possibility of comorbidity with substance use disorder in BP patient comorbid with AD (BP
2.2. Anxiety disorder as comorbidity in bipolar disorders of ethnics
Chang et al.  found that the anxiety disorder comorbidity rate in both BPI (26.7%) and BPII (39.0%) were lower in Han Chinese in Taiwan than in Western populations (more than 50% in BPI and BPII) [26, 30]. There was no significant difference in the gender-based distribution of anxiety disorder in our patients, which agrees with one study  but disagrees with others [34, 59, 60] that report a higher prevalence in women than in men. One reason may be that lower prevalence of a disease shows a greater statistical meaning for fixed heritability and a fixed number of trait loci . Therefore, the lower anxiety disorder comorbidity rate not only is more easy for researchers to look at the genetic factor of AD high comorbid with BP but also may decrease psychosocial, cultural, and other confounding factors. Those factors and their interaction might increase the prevalence rate of mental illness, especially anxiety disorder. In addition, a higher comorbidity rate with BPII than with BPI was found which agreed with most of large-sample epidemiological studies [23, 25, 26, 28, 38]. Patients with BP and co-occurring anxiety symptoms or anxiety disorders are susceptible to higher rates of depressive episodes , which may explain the higher comorbidity rate in patients with BPII than with BPI.
For further investigation of the AD subtypes with BP, Chang et al.  found that the highest AD comorbidity in both subtypes of BP patients was GAD instead of PD or OCD, the major AD comorbidities in the western BP populations. Wittchen et al.  reported that the highest rate of comorbidity of GAD was associated with major depressive disorder (62.4%) and the lowest with BP (10.5%). One of the possible reasons may be due to ethnic differences or the genetic heterogeneity of anxiety disorder and depressive disorder like BPII. A higher occurrence of GAD with BPII was found in Chang et al. (2012)’s study, which is similar to previous studies showing higher occurrence of GAD with MDD [63, 64]. This gender difference in BPII could be derived from the high GAD-associated depression. However, the causal relationship should be further investigated. The other reason could be that the same diagnostic criteria of BPI and BPII except the duration might not be appropriate, the redefinition of the diagnostic criteria after more different ethnic BP subtype studies are suggested.
Chang et al.  have reported a relatively low rate of anxiety-disorder comorbidity in both BP subtypes in Han Chinese population in Taiwan, implying an ethnic possibility. Because of this low anxiety-disorder comorbidity in BP population in Taiwan, it was easier to identify BP patients with/without comorbidities to study the influence of anxiety-disorder comorbidity on neuropsychiatric performance. Although causal relationship between the comorbid anxiety disorders in BPI and BPII is not yet clear, additional studies are required, and the ethnic differences are suggested to be taken into account.
BPII patients with anxiety-disorder comorbidity also showed more substance abuse and dependence, suicide attempts, and personality disorders than did BPI patients [23, 25, 26, 28, 30, 57, 65]. After excluding the comorbidity of anxiety disorder, BPI and BPII patients have similar suicide rates, suggesting that AD comorbidity increases the risk of suicide in BPII . The risk of suicide in Han Chinese BP patients in Taiwan may be lower than western BP populations, but it needs further study to confirm.
Anxiety disorders occur most frequently during depressive episodes in patients with BP , except for those in the depressive state, anxiety disorder would often present during subsyndromal states . Boylan et al.  reported that about 32% of their BP patients had more than two comorbid anxiety disorders. The lower incidence in BPI patients (21.9%) and a similar incidence in BPII patients (33.8%) were found. This finding implies that BP patients with multiple anxiety-disorder comorbidities may have a more severe psychopathology and a worse prognosis, even with what is currently considered as appropriate treatment . In addition, anxiety disorder may be a predisposing factor for BP. Long-term follow-up studies are needed to confirm whether some anxiety-disorder comorbidities are in remission during the inter-episode stage or increase in intensity as symptoms of depression worsen.
2.3 Genetic aspect in comorbidity with anxiety disorder in bipolar disorders
Relative genetic factor between BP and AD was proposed , but no definite susceptibility gene for BP has been identified. One possible explanation could be neither subtypes of BP nor comorbidities were differentiated in most studies [71–73]. The contribution of genetic factors to the etiology of BP has also been reported from studies on family, twin, and adoption [72, 74]. From the twin studies, the inheritance for bipolar disorder overall is around 85% [75, 76]. The distinction between BPI and BPII may be associated with different genetic categories [21, 77–79]. Knowing the association between AD comorbidity and BP at the genetic level may improve our understanding more in this mental illness.
Dopaminergic dysfunction has been implicated in the pathogenesis of bipolar disorder, especially the dopamine D2 receptor gene (
In the midbrain-hindbrain regions, another important role in the development of dopaminergic neuron, brain-derived neurotrophic factor (BDNF), in which the
2.4. The DRD2 gene associated with ALDH2 in bipolar II disorder with anxiety disorder
There is an increased risk of mental disorder among relatives of anxiety neurotics from family studies . Therefore, if the
Brain-imaging study  shows that healthy controls with an
Enzymes that function in the metabolic breakdown of acetaldehyde are considered as the
Wang et al.  revealed the relationship among
2.5. The DRD3 gene and BDNF gene associated with bipolar subtypes with/out anxiety disorder
Chang et al.  investigated the association between
Takahashi et al.  has reported the effect of the
There have been some reports about that the Met heterozygotes compared to the Val homozygotes of the
For the results in the BPI, a main effect of
Chang et al.  have provided initial evidence of the involvement of dopaminergic pathway with
The results in Chang et al.’s study  not only replicated Lohoff et al.  finding that the positive association was between the Val allele and the BPI patients, but also related to the AD comorbidity. However, a disagreement was noticed between this study and previous findings of association between the Met allele with anxiety disorders [121, 122], indicating the possible ethnic variation. Moreover, the major subtype of AD comorbidity in the Han Chinese BPI and BPII was general anxiety disorder  while PD or OCD was the higher comorbidity with the BP in the western population [30, 32, 34, 35]. The genotype distribution of the
3. Anxiety disorder as comorbidity in alcoholism of ethnics
3.1. The relationship between DRD2 gene and ALDH2 gene in anxiety-depression alcoholism
Several studies in alcohol detoxification have been reported that the
Since ALDH2 is a crucial enzyme for ethanol catabolism which might also play an important role in dopamine catabolism and risk for alcoholism, the involvement of the
3.2. Interaction between personality traits and genes in anxiety-depressive alcoholism
Cloninger has hypothesized of lower novelty seeking and higher harm avoidance in type I alcoholism compared with healthy volunteers. Later, Huang et al.  and Huang et al.  have proved that anxiety-depressive alcohol dependence (ANX/DEPALC) could be a genetically well-defined subtype of alcoholism linking to
Further analysis with stratification of the
Wang et al.  provided preliminary evidence that comorbid BP-II+AD might be one of the subtypes of BPII. The
Previous studies provided initial evidence of the involvement of dopaminergic pathway as well as serotonin system in the pathogenesis of bipolar disorder [110, 113, 134, 135]. However, whether the interaction of these genes leads to dysfunctional dopaminergic signaling or serotonin regulation and to what extent these genes would affect the etiology of bipolar disorder with AD comorbidity still require further clarification. Moreover, AD playing the role of comorbidity in BP and alcoholism showed relatively lower prevalence rate in Han Chinese while compared to previous studies conducted in Western population. This finding implied an ethnic possibility which has been supported in some studies with genetic investigation. Moreover, in both BP and ALC with AD comorbidity have been reported to have relationship with dopaminergic genes as well as serotonin-related genes, the
AD: anxiety disorder
ALDH2: aldehyde dehydrogenase 2
ANX/DEP ALC: anxiety/depression alcoholism
BDNF: brain-derived neurotrophic factor
BP: bipolar disorder
DOPAC: 3,4-dihydroxyphenylacetic acid
DRD2: dopamine D2 receptor
DRD3: dopamine D3 receptor
GAD: generalized anxiety disorder
PTSD: post-traumatic stress disorder
PD: panic disorder
OCD: obsession compulsive disorder
MAOA: monoamine oxidase A