Who among the following is most likely to be diagnosed with generalized anxiety disorder?

Anxiety

Anxiety can manifest in many forms following TBI, variably resembling diagnoses of generalized anxiety disorder (GAD), panic disorder, phobias, obsessive–compulsive disorder (OCD), or posttraumatic stress disorder (PTSD) found in the DSM-V (Hiott and Labbate, 2002; Mallya et al., 2015). Some have hypothesized a role for injury to the mesial temporal lobe, including the amygdala, and compromised top-down PFC functioning in the pathophysiology of posttraumatic anxiety (Hoffman and Harrison, 2009).

The rate of GAD after TBI is estimated to be ~ 15%–24%, substantially higher than that found in the general population (Fann et al., 1995; Diaz et al., 2012). The rates of OCD following TBI range between 1% and 5%, similar to rates in the general population (Hiott and Labbate, 2002). At least one study suggests that panic disorder is common after TBI, occurring in roughly 9%, several times higher than rates in the general population (Deb et al., 1999a,b; Hiott and Labbate, 2002). The rates of PTSD has been found to vary widely, ranging from 12%–30% in mild–moderate TBI to 3%–23% in severe TBI (Zatzick et al., 2010; Tanev et al., 2014; Alway et al., 2016a,b). Discussion of PTSD, TBI, their overlapping symptomatology, and psychopharmacologic management is complex and covered more thoroughly in other reviews (Bahraini et al., 2014; Tanev et al., 2014).

Following TBI, anxiety is often most marked shortly after injury, due to the stress of the injurious event itself as well as initial adjustment to any deficits. Thereafter, anxiety is often multifactorial, representing biologic, psychologic, and social insults (Fann and Jakupcak, 2013). Interestingly, some evidence suggests an inverse relationship between injury severity and anxiety disorders, with milder injuries associated with greater likelihood of PTSD, social phobia, panic disorder, and agoraphobia (Van Reekum et al., 2000; Hiott and Labbate, 2002; Bryant et al., 2010). Some caution that anxiety disorders in TBI can often be overlooked when symptoms are not obvious or the symptoms are taken as a “normal response” to the injury (Hiott and Labbate, 2002). As was the case for depression, posttraumatic anxiety disorders are also significantly undertreated, with only half of patients receiving appropriate treatment (Whelan-Goodinson et al., 2009).

Regarding pharmacotherapy, to date no controlled trials have been performed. In the general psychiatric population, SSRIs or SNRIs are again often used first-line, given their efficacy and tolerability in the treatment of GAD, OCD, panic, phobias, or PTSD. As frequently practiced in general psychiatry, it may be worthwhile trialing a second SSRI or SNRI agent before another medication class. Buspirone, a drug that acts as a partial 5-HT1A receptor agonist, D2 antagonist, and α2 antagonist, is another viable treatment option, though data here too is lacking. Also notable with buspirone is that some of the common side effects—light-headedness and dizziness—can be problematic for the TBI population.

Benzodiazepines, while highly effective in the short term, are generally to be avoided, if possible, among those with TBI. Benzodiazepines are sedating, associated with attentional and memory impairments with both short- and long-term use (Barker et al., 2004a,b), and can cause behavioral disinhibition. Animal models raise additional concern that benzodiazepines may lead to a delayed or truncated recovery (Schallert et al., 1986). These agents furthermore have addictive potential, which may be especially problematic for individuals with TBI, given their high premorbid and postinjury rates of substance use disorders.

If benzodiazepines are nevertheless indicated, for example, when used as a bridge until SSRIs or SNRIs become therapeutic, some recommend use of shorter-acting agents such as lorazepam, which carry a reduced likelihood of cognitive and sedative side effects. Long-acting agents such as clonazepam may be preferable in other cases due to their lower likelihood of addiction or abuse.

Comorbidity

Many studies report very high rates of comorbidity for patients with a principal diagnosis of GAD. Sanderson, Di Nardo, Rapee & Barlow (1990b) report that 91% of their GAD patient sample had an additional DSM-III-R diagnosis. In a similar study, de Ruiter, Ruken, Garssen, van Schaik & Kraai-maat (1989) report a comorbidity rate of 67% for GAD. In these studies, the most common additional diagnoses were Social Phobia, Panic Disorder, Dysthymic Disorder and Specific Phobia. When comparing GAD and Panic Disorder, Noyes and colleagues (1992) report that Specific Phobia was a more common secondary diagnosis for GAD subjects. In a large-scale study involving 468 anxiety disorder patients, Moras, Di Nardo, Brown & Barlow (1991, cited in Brown & Barlow, 1992) report that GAD and Panic Disorder with Agoraphobia were the principal diagnostic categories that had the highest comorbidity rates.

High rates of comorbidity for GAD as a secondary disorder have also recently been reported. In their extensive study, Moras et al. (1991, cited in Brown & Barlow, 1992) found that GAD was the most common additional diagnosis (23%) at the clinical level (at least moderate severity). In a study of patients with a principal diagnosis of Major Depression or Dysthymia, Sanderson, Beck and Beck (1990a) report that GAD and Social Phobia were the two most common additional diagnoses. Brown and Barlow (1992) suggest that further research on comorbidity is of the utmost importance for diagnostic classification and treatment outcome. Considering the high rate of comorbidity of GAD, these considerations become all the more important.

Co-morbidity

Co-morbidity in GAD is high, with “pure” cases of GAD found infrequently in both community and clinical samples. The NCS-R found that 85% of individuals with a diagnosis of GAD in the past 12 months met criteria for another co-occurring psychiatric condition.135 In mental health settings, 80% to 90% of patients with current GAD also have at least one other concurrent psychiatric disorder,137 with similar rates reported in primary medical settings.138 High rates of co-morbidity in GAD appear across the life span, including in children and adolescents139 and in the elderly.140

Considerable attention has been paid to the relationship between GAD and depression. According to data from the original NCS, 39% of people meeting criteria for a current diagnosis of GAD also had current MDD, and 22% met criteria for dysthymia.141 Similar co-morbidity rates of depressive disorders have been reported in clinical samples. For instance, in the Harvard/Brown Anxiety Disorders Research Program study, 54% of patients with GAD had either current MDD or dysthymia.142 Other work has demonstrated that between 35% and 50% of patients with current MDD also meet criteria for GAD.137

Aside from the commonly reported co-morbidities of GAD and the depressive disorders, GAD also displays high rates of co-morbidity with the other anxiety disorders, most notably SAD and specific phobias. Furthermore, similar to other anxiety-related conditions, GAD frequently co-occurs with substance use disorders, most typically alcohol dependence. However, unlike other anxiety disorders (such as SAD and PD) where alcohol use appears to serve a self-medication purpose, alcohol dependence typically precedes the onset of GAD.130,143

GAD is common in patients who are treated in medical settings with unexplained somatic complaints,144 and some evidence suggests that GAD may frequently precede the onset of somatic symptoms.145 These findings are not surprising given previous research that highlights the pervasiveness of somatic symptoms (most notably muscle tension) in people with GAD, and suggest that physicians in primary care must be vigilant to the potential psychological underpinnings of those problems. It is notable that GAD is the least common anxiety disorder reported in mental health settings, but is the most common anxiety disorder in primary care settings146 and in patients with chronic medical conditions.147 GAD is commonly associated with numerous physical problems (including chest pain, chronic fatigue syndrome, irritable bowel syndrome, and tension headaches), and chronic medical illnesses (such as hypertension and heart disease). Research also suggests that co-morbidity in GAD increases the burden on health care. For instance, GAD patients with co-morbid psychiatric conditions were shown to have higher medical utilization compared to patients with GAD alone, in that there were higher costs of laboratory tests, hospitalization, and medication; further, they demonstrated greater rates of absenteeism from work.130

In general, co-morbid GAD has a poorer prognosis in terms of impairment, course of illness, and treatment response. For example, the NCS demonstrated that people with co-morbid GAD and a mood disorder reported greater interference with life activities and more interpersonal problems.148 Similarly, Wittchen and colleagues134 found that patients with GAD and MDD were slightly more impaired than patients with pure GAD or pure depression. In other work, greater social disability was reported by patients in a primary care setting meeting criteria for both GAD and another psychiatric disorder (46%) compared to patients with GAD alone (25%) and somatic disorders without a psychiatric diagnosis (20%).146 The remission rate for GAD with a co-morbid disorder appears to be about half the annual remission rate of GAD alone.132,149 Treatment response is also delayed in patients for whom GAD represents a co-morbid condition. One study found that in patients with MDD, treatment response to either nortriptyline or interpersonal psychotherapy was delayed when GAD was present.150 Similarly, in GAD patients receiving psychotherapy, the presence of a co-occurring Axis I condition predicted worse outcome.151 It is promising, however, that in GAD patients with some co-morbid disorders (e.g., SAD) receiving psychotherapy, a significant decrease in co-morbidity was observed,152 while GAD symptoms were reduced following psychotherapy for PD.153

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by excessive and persistent worries that the individual feels are uncontrollable. The worry must be experienced more days than not for at least 6 months, and focus on multiple topics. The diagnosis of GAD also requires at least three of the following: restlessness, fatigue, difficulty in concentrating, irritability, muscle tension, or sleep disturbance. Finally, the individual must experience marked distress or impairment in functioning due to these symptoms.

Those with GAD worry about common concerns, such as work, health, and finances, but the degree of worry is excessive, given the actual likelihood or impact of the event. Further, those with GAD feel as if they cannot stop worrying even if they want to. Often, the worries interfere with other tasks because the person is unable to focus on other tasks due to worrying, or engages in reassurance-seeking behaviors such as calling home to make sure everyone is okay.

The lifetime prevalence rate for GAD is ∼5%, and the disorder is more common in women than in men. Often, people with GAD report worries as far back as they can remember, and describe their worry as a personality trait.

II Generalized Anxiety Disorder and Social Anxiety Disorder

Generalized anxiety disorder (GAD) is a common and impairing anxiety disorder, with an estimated 12-month prevalence of 1.7%–3.4% (being more prevalent in older adults) (Wittchen et al., 2011). Diagnosis of GAD requires the presence of psychological and physical anxiety symptoms for at least 6 months, these symptoms not being “understandable” as deriving from another condition. ICD-10 criteria (World Health Organization, 1993) emphasize symptoms of tension, worrying and apprehension, whereas DSM-5 criteria (American Psychiatric Association, 2013) emphasize multiple, distressing, and uncontrollable worries. Earlier versions of DSM diagnostic criteria were based on the presence of symptoms for at least 1 month and had low interrater reliability (Di Nardo et al., 1983; Mannuzza et al., 1989), but the subsequent stipulations of a 6-month duration and perception of uncontrollable worry have enhanced the overall reliability of diagnosis (Brown et al., 2001). However, there are persisting concerns about diagnostic validity, such as the distinction from major depression and the threshold for symptom severity (Brown et al., 2001; Brown, Chorpita, & Barlow, 1998), and a more dimensional approach based on measuring worry, distress, and other symptoms might help delineate the condition (Gordon & Heimberg, 2011; Rutter & Brown, 2015). Symptom severity is usually assessed through observer-rated scales, such as the Hamilton Rating Scale for Anxiety (HAMA) (Hamilton, 1959): a HAMA score of less than 9 may correspond to symptom remission, whereas a score of 24 or more indicates anxiety symptoms of at least moderate intensity (Bandelow et al., 2006), HAMA scores being strongly correlated with self-rated impairments (Stein et al., 2009).

Selective serotonin reuptake inhibitor (SSRI) prescription is the usual first-line pharmacological treatment in GAD, based on efficacy, tolerability, and safety in randomized controlled trials. Response rates are often high, but only approximately one-half of patients enter symptom remission after 2–3 months of treatment (Baldwin, Huusom, & Mæhlum, 2006). The intensity of coexisting depressive symptoms often reduces with treatment, even with anxiolytic drugs that have no efficacy in major depressive episodes (Baldwin et al., 2015; Stein et al., 2008). Response is more likely in patients whose symptoms have reduced in intensity within the initial 2 weeks of treatment (Baldwin et al., 2009, 2012a). The comparative efficacy and tolerability of differing pharmacological treatments are uncertain (Baldwin et al., 2011). Sustained treatment is usually needed as GAD is often episodic, or waxes and wanes, over long periods (Angst et al., 2008). Relapse prevention studies have demonstrated the long-term efficacy of many pharmacological treatments, including some SSRIs (escitalopram and paroxetine) (Allgulander, Florea, & Trap Huusom, 2006; Stocchi et al., 2003) and the serotonin-norepinephrine reuptake inhibitors (SNRI) duloxetine and venlafaxine (Davidson et al., 2008; Hackett, White, & Salinas, 2000; Rickels et al., 2010) and also pregabalin (Feltner et al., 2008), quetiapine (Katzman et al., 2011), and agomelatine (Stein et al., 2012). Preclinical studies with the novel “multimodal” antidepressant vortioxetine suggested potential anxiolytic effects (Baldwin & Hanumanthaiah, 2015), and it reduces anxiety symptoms in depressed patients (Baldwin et al., 2016a): however, randomized placebo-controlled trials of acute treatment of GAD have produced inconsistent findings (Pae et al., 2015), despite its efficacy in preventing relapse (Baldwin, Loft, & Florea, 2012). The place of benzodiazepine anxiolytics is much debated although benzodiazepines are often prescribed in routine practice when treating patients with GAD (Baldwin et al., 2012b). There may be a role for careful prescribing of benzodiazepines in some patients, including in short-term treatment (up to 4 weeks) while waiting for an SSRI to become effective. There may also be a place for longer-term treatment, when patients have not responded to a series of interventions, including psychological approaches and sequential treatment courses with an SSRI, SNRI, pregabalin, and the 5-HT1A partial agonist buspirone (Baldwin et al., 2013).

Social anxiety disorder (SAD), also known as social phobia, has an estimated 12-month prevalence of 2.3% (Wittchen et al., 2011) and typically has an onset by adolescence and runs a prolonged course. The condition is characterized by marked, persistent, and unreasonable fear of being observed or evaluated negatively by other people, in social or performance situations, with accompanying physical and psychological anxiety symptoms (American Psychiatric Association, 2013; World Health Organization, 1993). Feared situations (such as speaking to unfamiliar people or eating in public) are avoided or endured with significant distress. It is often not recognized in primary medical care, but detection in psychologically distressed patients can be enhanced with screening questionnaires. The condition is often misconstrued as mere “shyness” but can be distinguished from uncomplicated shyness by the higher levels of personal distress, severe symptoms, and greater impairment. The generalized subtype (where anxiety is associated with many situations) is more disabling and shows greater comorbidity, although patients with the nongeneralized subtype (where anxiety is focused on a limited number of situations) can also be substantially impaired. Patients with SAD often present with symptoms arising from comorbid conditions (especially depression), rather than with anxiety symptoms and avoidance of social and performance situations. There are strong and possibly two-way associations between SAD and substance use disorders.

Medications with proven efficacy in acute treatment of SAD include most SSRIs (escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), venlafaxine, the monoamine oxidase inhibitors phenelzine and moclobemide, some benzodiazepines (bromazepam and clonazepam), some anticonvulsants (gabapentin and pregabalin), and olanzapine. Cognitive behavioral therapy (CBT) is the most well-established psychological treatment. Network metaanalysis of the comparative efficacy of pharmacological and psychological treatments indicates that SSRIs and venlafaxine are superior to pill placebo and CBT superior to “psychological placebo” (i.e., nonspecific psychological intervention) (Mayo-Wilson et al., 2014). As with GAD, prescription of an SSRI is usually regarded as first-line pharmacological treatment, based on efficacy, tolerability, and safety in randomized controlled trials (Baldwin et al., 2014). There is rather little evidence of a dose-response relationship in acute treatment (Baldwin et al., 2016b). Response is more likely in patients whose symptoms have reduced in intensity within the initial 2 weeks of treatment (Baldwin et al., 2009). Sustained treatment is usually needed, as SAD is typically a chronic condition, but relapse prevention studies demonstrating the long-term efficacy of pharmacological treatments (escitalopram, paroxetine, sertraline, and pregabalin) are limited (Blanco et al., 2013). Patients who make only a limited response to CBT may benefit if continued CBT is combined with medication, and those who respond only partly to pharmacological treatment may benefit if it is combined with CBT (Canton, Scott, & Glue, 2012). Combination of an SSRI (sertraline) with a benzodiazepine (clonazepam) has been found superior to continuing with sertraline monotherapy or switching to venlafaxine (Pollack et al., 2014).

Diagnosis

Diagnoses to consider in patients presenting with anxiety in the ED include:

Generalized anxiety disorder

Panic disorder

Social phobia (social anxiety disorder)

Acute stress disorder

PTSD (see Chapter 20)

Obsessive compulsive disorder

11.10.4.6 Intolerance of Uncertainty

Intolerance of uncertainty can be described as a dispositional characteristic resulting from negative beliefs about uncertainty and its implications (Dugas and Robichaud, 2007). This construct has been shown to be elevated in clinical populations compared to nonclinical controls, and is particularly high among individuals with a diagnosis of GAD (Ladouceur et al., 1999). It has been identified as a transdiagnostic mechanism of change, particularly in anxiety and related disorders (Rosser, 2019). Evidence for intolerance of uncertainty as a mechanism of exercise for mental health was not supported in a study that found no change following a single bout of aerobic exercise or stretching (LeBouthillier and Asmundson, 2015); however, in a subsequent study of four-week exercise interventions, intolerance of uncertainty decreased in a resistance training condition but not aerobic exercise condition (LeBouthillier and Asmundson, 2017). More studies are necessary to examine this as a potential mechanism of change.

Benzodiazepines

Benzodiazepines have a long history of use for GAD. Although none has been formally approved for the treatment of GAD by regulatory authorities, alprazolam was indicated by the US FDA “for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety.” While many physicians express horror at prescribing benzodiazepines, alprazolam continues to be the most frequently prescribed psychiatric medication in the USA and several other benzodiazepines are frequently prescribed for anxiety and GAD. They work quickly, effectively, have no hepatoxicity, have no sexual side-effects, have no activating effects in the first few weeks of use like antidepressants, do not cause nausea or headaches, and patients find them acceptable. They are ineffective for depression and, if stopped too rapidly after several weeks of continuous use, they have a very troublesome withdrawal syndrome. In high doses they can cause cognitive impairment and ataxia. Therefore they should never, ever be stopped quickly, but rather tapered very slowly over weeks rather than over days. This minimizes the disruption and the danger associated with the withdrawal syndrome. Benzodiazepines are associated with some abuse and dependence liability. The rates for DSM-III-R abuse and dependence in a large epidemiology sample were 0.6% for abuse and 0.5% for dependence (Hughes et al., 1991). A detailed review of benzodiazepines is available elsewhere (Sheehan and Raj, 2009).

7.08.4.4 Anxiety and Depression

The overlap between anxiety and depression is an issue of longstanding importance within psychology and psychiatry given the high rates of coexistence for these conditions regularly reported among younger adults (Cloninger, 1990; Copp, Schwiderski, & Robinson, 1990; Feldman, 1993). In fact, six-month prevalence data from the ECA survey documented that one-fifth of individuals with an anxiety disorder also had symptoms that met criteria for an affective disorder (Regier et al., 1990). Conversely, one-third of those assigned an affective disorder diagnosis also were given at least one anxiety disorder diagnosis (Regier et al., 1990). Given these high rates of coexistence, further understanding of the nature of this overlap is warranted among elderly people.

ECA data regarding the coexistence of anxiety and affective disorders were not presented separately for the elderly. Nonetheless, recent reviews have highlighted the significant overlap between these sets of diagnoses and symptoms in this segment of the population (Alexopoulos, 1991; Flint, 1994). With regard to data addressing coexistence of assigned diagnoses, it has been reported that over 90% of older adults from the community who reported symptoms appropriate for a diagnosis of GAD also met criteria for depression (Lindesay, Briggs, & Murphy, 1989). In this same community sample, almost 40% of individuals with a phobia diagnosis were also assigned a diagnosis of depression according to the International classification of disease (8th ed.)(ICD-8) criteria assessed via semi-structured interview. In another study conducted via retrospective chart review (Raj et al., 1993), 45% of elderly clinic patients with PD diagnosed according to DSM-III-R also met criteria for coexistent major depression. In an examination of 44 older adults with a principal DSM-III-R diagnosis of GAD (Beck et al., 1996a), approximately 15% met criteria for a coexistent affective disorder. When older adults with affective disorders have been evaluated, over one-third have met criteria for a coexistent anxiety disorder diagnosis (Alexopoulos, 1991). Thus, rates of overlap between anxiety and affective disorders among the elderly are high.

Other reports have addressed the degree of overlap between symptoms of anxiety and depression, rather than prevalence of coexistent disorders per se. In these studies, significant positive associations between symptoms of anxiety and depression have been observed in community samples of older adults (Lindesay et al., 1989; Ben-Arie, Swartz, & Dickman, 1987), institutionalized elderly people (Parmelee et al., 1992), and older clinic patients (Alexopoulos, 1991). In the authors' own investigation of older adults with GAD, higher levels of depressive symptoms were also evident relative to a matched control sample (Beck et al., 1996a). In a longitudinal study of 1070 older adults from the community, 702 of whom were interviewed twice over a three-year interval, Larkin et al. (1992) reported some covariance between anxiety and depressive symptoms assessed in the context of “neurotic” conditions. These data highlight further the significant overlap between anxiety and depression among the elderly, and may even be interpreted to support some indistinguishability among these two sets of symptoms (Beck & Stanley, 1997). However, data reviewed below attest to the ability of clinicians to differentiate and diagnose both types of disorders reliably among elderly samples (see Section 7.08.5).