Comorbidity of anxiety and mood disorder is quite common, with some research suggesting that as many as 60% of individuals with an anxiety disorder also meet criteria for major depressive disorder [12]. As noted above, individuals with both anxiety and mood disorders, compared to individuals with only one disorder, show greater functional impairment, lower quality of life, and poorer treatment outcomes.
In the next section, we will briefly review comorbidity between mood disorders and anxiety disorders and discuss the impact of these comorbidities.
Epidemiology and Impact
The majority of existing work has primarily focused on the comorbid relationship between depression and the range of anxiety disorders. For instance, the National Comorbidity Survey-Replication (NCS-R) indicates that, among those with panic disorder (PD), upwards of 80% of individuals meet diagnostic criteria for another psychiatric disorder. About 35% of those individuals meet criteria for major depressive disorder (MDD), 14% for bipolar disorder, and 10% for dysthymia [12]. Similar rates of comorbidity have been observed among individuals with social anxiety disorder (SAD), where the NCS-R found that 37% of those indi- viduals with SAD also met criteria for MDD [12]. The highest observed comor- bidity between anxiety and mood exists between generalized anxiety disorder (GAD) and MDD, where upwards of 60% of individuals with GAD also met cri- teria for MDD [13, 14].
These high rates of anxiety/mood comorbidity are associated with a number of negative clinical outcomes such as suicidality and substance use. For instance, pre- vious research among individuals with comorbid panic disorder and major depres- sive disorder found that suicide attempts were increased among this group compared to those with one disorder [15]. Additional research suggests that the rate of suicide attempts is more than double among individuals with comorbid PD and MDD com-
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pared to those with only one disorder [16]. Similar cross-sectional and longitudinal results were found with SAD and MDD, where comorbid diagnosis of SAD and MDD in adolescence was associated with greater likelihood of later substance abuse and suicide attempt compared to those with only one disorder [17]. What’s more, those with comorbid GAD and MDD reported more functional impairment than those with only one disorder [18].
These observed comorbidities have a significant impact on treatment response rates. Recent research found that having any anxiety disorder comorbidly with MDD was associated with a chronic and more severe course of treatment compared to those individuals with only anxiety disorders [19]. Examining specific anxiety disorders found that both comorbid SAD and MDD and comorbid GAD and MDD were associated with poorer response to treatment than individuals with a single disorder [20, 21].
Key Clinical Features
Although anxiety and mood disorders represent distinct diagnostic categories, there are a number of overlapping features of anxiety and mood disorders that complicate assessment and treatment planning. The most pertinent example of this is between GAD and MDD [22, 23]. Between these two disorders, there are some distinct symptom domains but also a number of overlapping symptoms, including irritabil- ity, restlessness, difficulty concentrating, trouble sleeping, and fatigue [1]. In clini- cal practice, however, these differences may be even more subtle. For instance, nausea associated with GAD may be associated with poor appetite, which is a symptom of MDD. Careful consideration of the presenting symptoms, diagnoses, and their overlap may be of critical importance to determine if an individual is pre- senting with GAD, MDD, or both.
Family and Genetics
Genome-wide association studies suggest that the heritability of psychiatric dis- orders is explained by large numbers of genes that each contribute a small increased risk for the development of certain disorders [24]. Therefore, genetic differences in isolation are not thought to cause psychiatric disorders but instead are thought to increase one’s risk and vulnerability to the development of the disorder. A number of genetic risk factors have been identified to be shared across anxiety and depression, suggesting that this overlap in genetic suscepti- bility may contribute to the high rate of comorbidity among these classes of disorders [24, 25]. Therefore, inheriting certain genetic factors may make one more likely to develop anxiety as well as depression. Twin studies show support for a shared genetic vulnerability between anxiety and depression with some
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genetic factors influencing general liability to initializing disorders (i.e., anxiety and mood disorders; [26, 27]). Additionally, family studies further support a shared genetic vulnerability between anxiety and depression. Offspring of par- ents with an anxiety disorder show an increased risk for developing a depressive disorder compared to offspring of nonpsychiatric controls, and offspring of par- ents with MDD show increased risk for developing an anxiety disorder [27–29].
These increased risks suggest a shared hereditable factor between anxiety and mood disorders.
Studies examining shared genetic risk factors between anxiety and mood dis- orders have identified several target genes including the Glutamate decarboxylase 1 gene and the catechol-O-methyltransferase (COMT) gene. These genes code for enzymes that help regulate the activity of a number of different neurotransmitters including gamma-aminobutyric acid (GABA), dopamine, epinephrine, and nor- epinephrine [30–32]. Overall, these genes have been associated with individual differences in trait neuroticism, reactivity and structural differences in the amyg- dala, and increased susceptibility across anxiety disorders and MDD ([25, 30, 31, 33]; Hettema et al. 2015). Meta-analyses examining variations of 5-HTTLPR, the promotor region of the serotonin transporter gene 5-HTT, have shown mixed and inconclusive results in their association with both anxiety and mood disorders (i.e., [34–36]). More recent research has focused on how shared genetic vulnera- bilities may interact with shared environmental factors to increase one’s risk for developing comorbid anxiety and depression.
Environmental Risk
In addition to genetic risk factors, certain environmental factors also increase sus- ceptibility to anxiety and depression. As discussed previously, in a study of 1033 pairs of female twins, the nonfamilial environmental risk factors for anxiety and depression played an etiological role and showed modest overlap [23]. Furthermore, parenting behaviors, including parent rejection and control, have been linked to the intergenerational transmission of anxiety and depression [37]. Importantly, both anxious and depressed mothers show less warmth and more controlling parental behaviors [38]. Additionally, anxiety and depression are also associated with inse- cure attachment in early childhood [39].
Childhood trauma is thought to play a role in the development of anxiety and mood disorders. For example, emotional neglect in childhood is specifically asso- ciated with depressive disorder, dysthymia, and social phobia in adulthood [40].
Maladaptive emotion regulation strategies appear to mediate the relationship between childhood trauma and adulthood depression and anxiety symptoms [41].
Furthermore, additional research suggests that early life trauma interacts with genetic risk factors and increases the sensitivity of the neuroendocrine stress response system, putting individuals at heightened risk for anxiety and depression development following additional exposure to stress later in life [42–44].
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Psychological stressors in adulthood, such as trauma or loss, are another environ- mental risk factor associated with both anxiety and depression.
Biomarkers
Anxiety and depression also show a number of shared biological markers that are thought to contribute to their development and high rates of comorbidity. The amyg- dala plays a role in emotional memory formation and retrieval [45]. Overactivation of the amygdala is evident in both anxiety and mood disorders [46–48]. Amygdala activation has been shown to decrease in response to successful treatment with anti- depressants for depression and cognitive behavioral therapy for anxiety [45, 49].
The prefrontal cortex, which plays a role in emotional processing, is another brain region that has shown reliable dysregulation in anxiety and depression [45].
Prefrontal cortex dysfunction has been shown to be present during resting states as well as during emotional-cognitive tasks in anxious and depressed individuals [50].
Research also shows dysfunction in the connectivity between the prefrontal cortex and amygdala in depression and anxiety such that the prefrontal cortex does not show a compensatory increase in modulation in the presence of amygdala hyperac- tivity [51, 52]. This suggests possible impairment in top-down cognitive control over emotional responses in both anxiety and depression.
Findings have been mixed regarding brain-derived neurotrophic factor (BDNF) as a shared biomarker for anxiety and depression. Depressed individuals consis- tently show lower plasma and serum BDNF protein levels compared to healthy controls, and plasma BDNF levels normalize after antidepressant treatment [53, 54]. In contrast, studies of serum levels of BDNF in anxiety disorders have been somewhat inconsistent and suggest that lower BDNF protein levels are only seen in female individuals with anxiety disorders compared to female healthy controls [55].
While these findings are consistent with the preclinical literature that suggest gen- der plays a role in the association between BDNF and anxiety disorders, further research is warranted to better understand if BDNF is a shared biomarker for anxi- ety and mood disorders.
Cognitive and Personality Correlates
A number of different personality traits including neuroticism, anxiety sensitivity, and behavioral inhibition have been shown to play a role in both anxiety and depres- sion, potentially contributing to their high comorbidity rate. Neuroticism is defined as a disposition to anxiety and emotional instability with a tendency to stay in nega- tive mood states [56]. High scores of neuroticism are associated with increased risk for developing depression and anxiety [57, 58]. In a 10-year longitudinal study
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examining neuroticism from adolescence to young adulthood, the group with higher absolute neuroticism levels showed a significant increased risk for developing depression and anxiety disorders compared to those with moderate neuroticism lev- els [59]. Furthermore, while scores of neuroticism are associated with depressive and anxiety disorder development in isolation, comorbid depression and anxiety show particularly high neuroticism [60]. In a 3-year longitudinal study of adoles- cents, Zinbarg et al. [61] found that neuroticism significantly predicted the onset of unipolar mood disorders and the onset of anxiety disorders. However, neuroticism most strongly predicted the onset of comorbid unipolar mood disorders and anxiety disorders [61].
Anxiety sensitivity, or the tendency to perceive anxious states as aversive or harmful [62], has also been shown to play a role in both anxiety and depression.
Anxiety sensitivity has three components including fear of bodily sensations, fear of loss of cognitive control, and fear of publicly observable symptoms. The fear of loss of cognitive control shows strong, nonredundant associations with GAD, dimen- sional depression scores, and secondary diagnoses of MDD in a study of individuals with anxiety disorders with and without comorbid depression [63]. In a study on treatment-seeking individuals with anxiety and mood disorders, fear of publicly observable symptoms showed unique associations with SAD, GAD, and MDD, while fear of bodily sensations showed unique associations with SAD, PD, and specific phobia [64]. Additionally, both GAD and MDD are associated with low distress tolerance, or the ability to tolerate aversive emotional states, which may be another factor contributing to their high comorbidity [65].
Behavioral inhibition, a temperament characterized by the tendency to feel dis- tress toward or withdrawn from unfamiliar situations, is another personality corre- late of anxiety and depression, potentially contributing to their comorbidity.
Behavioral inhibition is associated with both anxiety and depression in children and in young adults [66, 67]. Behavioral inhibition in childhood predicts later anxiety disorder development, with children remaining inhibited over timing being at the highest risk for anxiety disorders [68]. Furthermore, in a study examining the chil- dren of individuals with panic disorder, MDD, and comorbid PD and MDD, behav- ioral inhibition was more prevalent among the children of parents with comorbid MDD and PD than either disorder alone [69].
Anxiety and mood disorders have shown other common associations with per- sonality traits. While negative affectivity seems to be a shared personality correlate across the anxiety and mood disorders, low positive affectivity has been linked to both depression and social anxiety disorder [22]. Furthermore, intolerance of uncer- tainty was originally thought to be a specific risk factor for GAD, but a meta- analysis by Gentes and Ruscio [70] found intolerance of uncertainty to show comparable associations to both GAD and MDD. Furthermore, anxiety and mood disorders have shown associations with low conscientiousness, and dysthymia disorder and social phobia, specifically, have been linked to low extraversion [71]. There are many overlapping cognitive and personality correlates for anxiety and mood disor- ders, which may contribute to the high comorbidity seen between these two classes of disorders. Furthermore, these cognitive and personality vulnerabilities are
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thought to interact with both genetic and environmental factors, altogether contrib- uting to an increased risk for comorbid anxiety and depression.
In summary, the onset of anxiety disorders often precedes the onset of mood disorders. The development of an anxiety disorder in childhood is associated with a two- to threefold increased risk for depression and anxiety disorders in adulthood [72]. Additionally, the presence of more than one anxiety disorder, severe impair- ment from an anxiety disorder, and comorbid panic attacks have all been associated with a significantly increased risk for developing MDD [73]. Furthermore, respond- ing to anxiety symptoms with rumination and hopeless cognitions has also been associated with an increased risk for depressive symptom. Therefore, anxiety disor- ders and anxiety response styles may be additional risk factors for the development of depression, helping to account for their high comorbidity rate [73–75].
Treatment Considerations
A number of studies have examined best practices for treating these comorbidities, with some suggesting treating them sequentially and others suggesting treating them concurrently [11, 76, 77]. However, results are largely inconclusive, suggest- ing further research in the area must be conducted. Therefore, having a greater understanding of anxiety and its comorbidity with mood disorders, substance use disorders, and physical health problems is critical to ultimately improve assessment and treatment targets for this vulnerable population.
Existing treatments, including both pharmacotherapy and psychotherapy, have shown efficacy for treating anxiety and mood disorders alone. While these treat- ments do overlap, treating anxiety and mood disorders when they are comorbid may be associated with treatment complications. In terms of medications, selective sero- tonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the first-line treatments for anxiety and mood disorders (see Chap. 13).
Other medications, such as tricyclic antidepressants and monoamine oxidase inhibi- tors, are also treatment options, but are typically not used as first-line treatments due to their side effect profiles [5]. SSRIs and SNRIs have been shown to be effective for both the treatment of anxiety and mood disorders, but limited research suggests that dual-action drugs, such as SNRIs, may, in fact, be more effective for comorbid anxiety and mood disorders [78]. Some clinical guidelines suggest that, for indi- viduals with comorbid anxiety and mood disorders, medications should be initiated at half the dose needed for the depressive symptoms because some individuals with anxiety may be hypersensitive to the initial effects of the antidepressants [79].
Psychotherapy, alone or in conjunction with pharmacotherapy, may also be par- ticularly useful for individuals with comorbid anxiety and mood disorders. Cognitive behavioral therapy (CBT) is a well-established, efficacious treatment for anxiety and mood disorders, and research has consistently shown that CBT is more effective at reducing anxiety and depressive symptoms than waitlist control [80]. CBT works for both anxiety and mood disorders by challenging automatic negative thoughts,
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exposing individuals to feared stimuli, and increasing engagement in pleasurable activities. However, despite the efficacy of CBT for anxiety and mood disorders individually, there still remains some debate as to the best way to treat these disor- ders when they appear comorbidly. One example of CBT that may be particularly useful for comorbid anxiety and mood disorders is the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders [81, 82]. This treatment uses all of the established techniques of CBT, but instead of targeting the disorder itself, it targets the shared underlying vulnerability factors that are thought to maintain dis- orders. Given the considerable overlap between symptoms of anxiety and mood disorders, this approach may represent a more efficient and effective strategy for treating comorbid anxiety and mood disorders.
Mindfulness-based approaches, such as mindfulness-based stress reduction (MBSR; [83]), as well as acceptance and commitment therapy (ACT; [84]), may be additional efficacious strategies for the treatment of these comorbidities.
Mindfulness-based treatments emphasize experiencing emotions nonjudgmentally and have been shown to be effective for anxiety and mood disorders individually;
adapting these for individuals with comorbid anxiety and mood disorders may be important. ACT functions similarly, but targeting experiential avoidance and having individuals confront uncomfortable emotions head on, which is applicable to both anxiety and mood disorders.
Currently, pharmacotherapies, such as SSRIs and SNRIs, as well as psychothera- pies such as CBT, are the first-line treatments for comorbid anxiety and mood disor- ders. However, novel strategies are currently being investigated that may augment or replace currently existing treatments. In terms of additional biological targets, ket- amine, an NMDA agonist, has shown rapid and large effects for reducing anxiety and depressive symptoms among individuals with chronic mood and anxiety disorders [85]. Additionally, deep brain stimulation has been shown to reduce both depressive and anxiety symptoms among individuals with chronic, intractable depression [86].
Further, while research is highly limited, near-infrared light photobiomodulation has shown preliminary results to reduce both anxiety and depressive symptoms [87], yet rigorous randomized controlled trials are pending.
Additional novel strategies have focused on non-pharmacological interven- tions, some of which may prove useful as adjuncts to existing treatments.
Specifically, brief computer-based interventions may be particularly useful. For example, attention bias modification (ABM) targets threat-related attention biases observed in anxiety and mood disorders that are often not targets in CBT [88].
Some preliminary work has shown the ABM reduced anxiety in a clinical popula- tion [89], but research has yet to determine if ABM is superior to pharmacotherapy or psychotherapy. More recent work has examined ABM as an adjunct to standard CBT for anxiety disorders, but studies examining these approaches have been met with mixed results. One study examining CBT plus attention bias training (com- pared to CBT with placebo) found overall reductions in anxiety symptoms, but these reductions did not differ by treatment group [90]. However, in a second simi- lar study, but using a group CBT format, clinician-rated anxiety symptoms signifi- cantly reduced in the CBT + attention training group compared to placebo [91].
Along with attention, deficits in cognitive control have been similarly observed
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among individuals with anxiety and mood disorders. Cognitive control has been shown to be a targetable and malleable factor in treatment [92], and some research among individuals with depression showed that targeting cognitive control reduced depressive symptoms [93]. However, no research has examined the impact of tar- geting cognitive control for individuals with comorbid anxiety and mood disorders.
Future Directions
Calling into question the diagnostic validity of the current diagnostic system (DSM-5), the high rates of comorbidity among mood and anxiety disorders sug- gest that they may be alternative clinical manifestations of the same underlying pathophysiological process instead of distinct entities [94, 95]. If etiological research stays within the constraints of the DSM-5 diagnostic categories, poten- tially important mechanistic overlaps between disorders could be overlooked [94]. Therefore, the National Institute of Mental Health has created the Research Domain Criteria (RDoC) initiative which aims to explore biological, neurologi- cal, and psychological etiological mechanisms that span current DSM-5 diagno- ses [94, 96]. As RDoC research informs and transforms the classification of psychiatric disorders, changes to the classification system that are informed by etiological understanding may better account for the co-occurrence of mood and anxiety disorders [97]. Nevertheless, within the current diagnostic system, it remains important to identify comorbid anxiety and mood disorders within clini- cal practice [98]. This identification allows for appropriate treatment approaches to be taken in order to optimize outcomes.