Generalized anxiety disorder

Generalized anxiety disorder
Video explanation
Specialty Psychiatry
Frequency 4% at some point[1]

Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry, that is, apprehensive expectation about events or activities.[2] This excessive worry often interferes with daily functioning, as individuals with GAD typically anticipate disaster, and are overly concerned about everyday matters such as health issues, money, death, family problems, friendship problems, interpersonal relationship problems, or work difficulties.[3][4] Individuals may exhibit a variety of physical symptoms, including feeling tired, fidgeting, headaches, numbness in hands and feet, muscle tension, difficulty swallowing, upset stomach, vomiting, diarrhea, breathing difficulty, difficulty concentrating, trembling, irritability, sweating, restlessness, insomnia, hot flashes, rashes, and inability to fully control the anxiety (ICD-10).[5] These symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD.[2][3]

Standardized rating scales such as GAD-7 can be used to assess severity of GAD symptoms.[6] GAD is the most common cause of disability in the workplace in the United States.[7]

In a given year, approximately two percent of American adults and European adults experience GAD.[8][9] Globally about 4% are affected at some point in their life.[1] GAD is seen in women twice as much as men. GAD is also common in individuals with a history of substance abuse and a family history of the disorder.[10] Once GAD develops, it may become chronic, but can be managed or eliminated with proper treatment.[11]

Causes

Genetics

About a third of the variance for generalized anxiety disorder has been attributed to genes.[12] Individuals with a genetic predisposition for GAD are more likely to develop GAD, especially in response to a life stressor.[13]

Substance-induced

Long-term use of benzodiazepines can worsen underlying anxiety,[14][15] with evidence that reduction of benzodiazepines can lead to a lessening of anxiety symptoms.[16] Similarly, long-term alcohol use is associated with anxiety disorders,[17] with evidence that prolonged abstinence can result in a disappearance of anxiety symptoms.[18] However, it can take up to two years for anxiety symptoms to return to baseline in about a quarter of people recovering from alcoholism.[19]

In one study in 1988–90, illness in approximately half of patients attending mental health services at British hospital psychiatric clinic, for conditions including anxiety disorders such as panic disorder or social phobia, was determined to be the result of alcohol or benzodiazepine dependence. In these patients, anxiety symptoms, while worsening initially during the withdrawal phase, disappeared with abstinence from benzodiazepines or alcohol. Sometimes anxiety pre-existed alcohol or benzodiazepine dependence, but the dependence was acting to keep the anxiety disorders going and often progressively making them worse. Recovery from benzodiazepines tends to take a lot longer than recovery from alcohol, but people can regain their previous good health.[19]

Tobacco smoking has been established as a risk factor for developing anxiety disorders.[20]

Excessive caffeine usage has been linked to anxiety.[21]

Mechanisms

Amygdala

Generalized anxiety disorder has been linked to disrupted functional connectivity of the amygdala and its processing of fear and anxiety.[22] Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). The basolateral complex processes the sensory-related fear memories and communicates their threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices.

Another area, the adjacent central nucleus of the amygdala, controls species-specific fear responses in its connections to the brainstem, hypothalamus and cerebellum areas. In those with generalized anxiety disorder, these connections seem less functionally distinct, and there is greater gray matter in the central nucleus. Another difference is that the amygdala areas have decreased connectivity with the insula and cingulate areas that control general stimulus salience, while having greater connectivity with the parietal cortex and prefrontal cortex circuits that underlie executive functions.[22] The latter suggests a compensation strategy for dysfunctional amygdala processing of anxiety. This is consistent with cognitive theories that suggest the use in this disorder of attempts to reduce the involvement of emotions with compensatory cognitive strategies.[22]

Diagnosis

DSM-5 criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders DSM-5 (2013),[2] published by the American Psychiatric Association, are paraphrased as follows:[2]

  1. Too much anxiety or worry over more than six months. This is present most of the time in regards to many activities.
  2. Inability to manage these symptoms
  3. At least three of the following occur:
    Note: Only one item is required in children.
    1. Restlessness
    2. Tires easily
    3. Problems concentrating
    4. Irritability
    5. Muscle tension.
    6. Problems with sleep
  4. Symptoms result in problems with functioning.
  5. Symptoms are not due to medications, drugs, other physical health problems
  6. Symptoms do not fit better with another psychiatric problem such as panic disorder

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders (2004); minor changes include wording of diagnostic criteria.[23]

ICD-10 criteria

ICD-10 Generalized anxiety disorder "F41.1"[24]
Note: For children different criteria may be applied (see F93.80).

  1. A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
  2. At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).
    Autonomic arousal symptoms
    (1) Palpitations or pounding heart, or accelerated heart rate.
    (2) Sweating.
    (3) Trembling or shaking.
    (4) Dry mouth (not due to medication or dehydration).
    Symptoms concerning chest and abdomen
    (5) Difficulty breathing.
    (6) Feeling of choking.
    (7) Chest pain or discomfort.
    (8) Nausea or abdominal distress (e.g. churning in the stomach).
    Symptoms concerning brain and mind
    (9) Feeling dizzy, unsteady, faint or light-headed.
    (10) Feelings that objects are unreal (derealization), or that one's self is distant or "not really here" (depersonalization).
    (11) Fear of losing control, going crazy, or passing out.
    (12) Fear of dying.
    General symptoms
    (13) Hot flashes or cold chills.
    (14) Numbness or tingling sensations.
    Symptoms of tension
    (15) Muscle tension or aches and pains.
    (16) Restlessness and inability to relax.
    (17) Feeling keyed up, or on edge, or of mental tension.
    (18) A sensation of a lump in the throat or difficulty with swallowing.
    Other non-specific symptoms
    (19) Exaggerated response to minor surprises or being startled.
    (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.
    (21) Persistent irritability.
    (22) Difficulty getting to sleep because of worrying.
  3. The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
  4. Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.[5]

History of diagnosis

The American Psychiatric Association first introduced GAD as a diagnosis in the DSM-III in 1980. Prior to the introduction of this diagnosis, GAD was presented as one of the two core components of anxiety neurosis, the other being panic. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualized as an aspect of major depression instead of an independent disorder.[25] Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R.[26] Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer.[27] The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis.[25] Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring "often."[28] The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics.[26] It has been stated that the constant changes in the diagnostic features of the disorder have made it difficult for researchers to identify the biological and psychological underpinnings of the disorder making it difficult to create specialized medications for the disorder. This has led to the continuation of GAD being medicated heavily with SSRIs.[26]

Prevention

Mental disorders are difficult to prevent, but many techniques are available to help relieve and manage anxiety. Many sufferers have found ease by relaxation exercises, deep breathing practice and meditation.[29] Additionally, avoidance of caffeine may prevent GAD.[30] Avoiding nicotine also can decrease the risk for the development of anxiety disorders including generalized anxiety disorder.[31]

Treatment

Meta-analysis indicates that both cognitive behavioral therapy (CBT) and medications (such as SSRIs) have been shown to be effective in reducing anxiety. A comparison of overall outcomes of CBT and medication on anxiety did not show statistically significant differences (i.e. they were equally effective in treating anxiety). However, CBT is significantly more effective in reducing depression severity, and its effects are more likely to be maintained in the long term, whereas the effectiveness of pharmacologic treatment tends to lessen if medication is discontinued.[32] A combination of both CBT and medication is generally seen as the most desirable approach to treatment.[33] Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Therapy

Generalized anxiety disorder is based on psychological components that include cognitive avoidance, positive worry beliefs, ineffective problem-solving and emotional processing, interpersonal issues, previous trauma, intolerance of uncertainty, negative problem orientation, ineffective coping, emotional hyperarousal, poor understanding of emotions, negative cognitive reactions to emotions, maladaptive emotion management and regulation, experiential avoidance, and behavioral restriction.[34] To combat the previous cognitive and emotional aspects of GAD, psychologists often include some of the following key treatment components in their intervention plan; self-monitoring, relaxation techniques, self-control desensitization, gradual stimulus control, cognitive restructuring, worry outcome monitoring, present-moment focus, expectancy-free living, problem-solving techniques, processing of core fears, socialization, discussion and reframing of worry beliefs, emotional skills training, experiential exposure, psychoeducation, mindfulness and acceptance exercises.[34] There exist behavioral, cognitive, and a combination of both treatments for GAD that focus on some of those key components.

Among the cognitive–behavioral orientated psychotherapies the two main treatments are cognitive behavioral therapy and acceptance and commitment therapy (ACT).[35] Intolerance of uncertainty therapy and motivational interviewing are two new treatments for GAD that are used as either stand-alone treatments or additional strategies that may enhance CBT.[36]

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT) is a psychological method of treatment for GAD that involves a therapist working with the patient to understand how thoughts and feelings influence behaviour.[37] Elements of the therapy include exposure strategies to allow the patient to confront their anxieties gradually and feel more comfortable in anxiety-provoking situations, as well as to practice the skills they have learned. CBT can be used alone or in conjunction with medication.[38]

Components of CBT for GAD includes psychoeducation, self-monitoring, stimulus control techniques, relaxation, self-control desensitization, cognitive restructuring, worry exposure, worry behavior modification, and problem-solving. The first step in the treatment of GAD is informing of the patient about the issues and the plan of the solution. The purpose of psychoeducation is to provide some relief, destigmatization of the disorder, motivating, and accomplishing participation by making the patient understand the program of treatment. The purpose of this component is to identify cues that provoke the anxiety. Stimulus control intervention refers to minimizing the stimulus conditions under which worrying occurs. Relaxation techniques lower the patients' stress and thus increase attention to alternatives in feared situations (other than worrying). Deep breathing exercise, progressive muscle relaxation, and applied relaxation fall under the scope of relaxation techniques.[36]

Self-control desensitization involves patients being deeply relaxed before vividly imagining themselves in situations that usually make them anxious and worry until internal anxiety cues are triggered. Patients then imagine themselves coping with the situation and decreasing their anxious response. If anxiety diminishes, they then enter a deeper relaxed state and turn off the scene. The purpose of cognitive restructuring is to shift from a worrisome outlook to a more functional and adaptive perception of the world, the future, and the self. It involves Socratic questioning that leads patients to think through their worries and anxieties so they can realize that alternative interpretations and feelings are more accurate. It also involves behavioral experiments that actually test the validity of both the negative and alternative thoughts in real-life situations. In CBT for GAD, patients also engage in worry exposure exercises during which they are asked to imagine themselves exposed to images of the most feared outcomes. Then they engage in response-prevention instruction that prevents them from avoiding the image and motivates alternative outcomes to the feared stimulus. The goals of worry exposure are habituation and reinterpretation of the meaning of the feared stimulus. Worry behavior prevention requires patients to monitor the behaviors that caused them worry and are then asked to prevent themselves from engaging in them. Instead, they are encouraged to use other coping mechanisms learned earlier in the treatment. Finally, problem solving focuses on dealing with current problems through a problem-solving approach: (1) definition of the problem, (2) formulation of goals, (3) creation of alternative solutions, (4) decision-making, and (5) implementing and verifying the solutions.[36]

There is little debate regarding the effectiveness of CBT for GAD. However, there is still room for improvement because only about 50% of those who complete treatments achieve higher functioning or recovery after treatment. Therefore, there's a need for enhancement of current components of CBT.[36] CBT usually helps one-third of the patients substantially, whilst another third does not respond at all to treatment.[39]

Acceptance and commitment therapy

Acceptance and commitment therapy (ACT) is a behavioral treatment based on acceptance-based models. ACT is designed with the purpose to target three therapeutic goals: (1) reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations; (2) decreasing a person's literal response to their thoughts (e.g., understanding that thinking "I'm hopeless" does not mean that the person's life is truly hopeless), and (3) increasing the person's ability to keep commitments to changing their behaviors. These goals are attained by switching the person's attempt to control events to working towards changing their behavior and focusing on valued directions and goals in their lives as well as committing to behaviors that help the individual accomplish those personal goals.[40] This psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a nonjudgmental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviors that enact personal values.[41] Like many other psychological therapies, ACT works best in combination with pharmacology treatments.

Intolerance of uncertainty therapy

Intolerance of uncertainty therapy (IUT) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. IUT is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. IUT is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioral exposure. Studies have shown support for the efficacy of this therapy with GAD patients with continued improvements in follow-up periods.[36]

Motivational interviewing

A promising innovative approach to improving recovery rates for the treatment of GAD is to combine CBT with motivational interviewing (MI). Motivational interviewing is a strategy centered on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. MI contains four key elements: (1) express empathy, (2) heighten dissonance between behaviors that are not desired and values that are not consistent with those behaviors, (3) move with resistance rather than direct confrontation, and (4) encourage self-efficacy. It is based on asking open-ended questions and listening carefully and reflectively to patients' answers, eliciting "change talk", and talking with patients about the pros and cons of change. Some studies have shown the combination of CBT with MI more effective than CBT alone.[36]

Medications

An international review of psychiatrists' management of patients with generalized anxiety disorder (GAD) reported that the preferred first-line pharmacological treatments of GAD were selective serotonin reuptake inhibitors (SSRIs) (80%), followed by serotonin–norepinephrine reuptake inhibitors (SNRIs) (43%), and pregabalin (35%). Preferred second-line treatments were SNRIs (41%) and pregabalin (36%).[42]

Selective serotonin reuptake inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[38] These are the preferred first line of treatment.[42] SSRIs used for this purpose include escitalopram[43] and paroxetine.[44]

Common side effects include nausea, sexual dysfunction, headache, diarrhea, constipation, restlessness, increased risk of suicide in young adults and adolescents,[45] among others. Overdose of an SSRI can result in serotonin syndrome.

Benzodiazepines

Benzodiazepines are most often prescribed to patients with Generalized Anxiety Disorder. Research suggests that these drugs give some relief, at least in the short term. However, they carry some risks, mainly impairment of both cognitive and motor functioning, and psychological and physical dependence that makes it difficult for patients to stop taking them. It has been noted that people taking benzodiazepines are not as alert on their job or at school. Additionally, these drugs may impair driving and they are often associated with falls in the elderly, resulting in hip fractures. These shortcomings make the use of benzodiazepines optimal only for short-term relief of anxiety.[46] CBT and medication are of comparable efficacy in the short-term but CBT has advantages over medication in the longer term.[47]

Benzodiazepines (or "benzos") are fast-acting hypnotic sedatives that are also used to treat GAD and other anxiety disorders.[38] Benzodiazepines are prescribed for generalized anxiety disorder and show beneficial effects in the short term. Popular Benzodiazepines for GAD include alprazolam, lorazepam and clonazepam. The World Council of Anxiety does not recommend the long-term use of benzodiazepines because they are associated with the development of tolerance, psychomotor impairment, cognitive and memory impairments, physical dependence and a withdrawal syndrome.[48][49] Side effects include drowsiness, reduced motor coordination and problems with equilibrioception.

Pregabalin and gabapentin

Pregabalin (Lyrica) acts on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate, norepinephrine and substance P. Its therapeutic effect appears after 1 week of use and is similar in effectiveness to lorazepam, alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance and additionally, unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. It also has a low potential for abuse and dependency and may be preferred over the benzodiazepines for these reasons.[50][51] The anxiolytic effects of pregabalin appear rapidly after administration, similar to the benzodiazepines, which gives pregabalin an advantage over many anxiolytic medications such as antidepressants.[52]

Gabapentin (Neurontin), a closely related drug to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD,[53] though unlike pregabalin, it has not been approved specifically for this indication. Nonetheless, it is likely to be of similar usefulness in the management of this condition, and by virtue of being off-patent, it has the advantage of being significantly less expensive in comparison.[54] In accordance, gabapentin is frequently prescribed off-label to treat GAD.[55]

Other psychiatric drugs

Other drugs

Comorbidity

GAD and depression

In the National Comorbidity Survey (2005), 58 percent of patients diagnosed with major depression were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2 percent, and with panic disorder, 9.9 percent. Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4 percent of patients with social phobia, 9.4 percent with agoraphobia, and 2.3 percent with panic disorder. A longitudinal cohort study found 12% of the 972 participants had GAD comorbid with MDD.[56] Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone.[57] In addition, social function and quality of life are more greatly impaired.

For many, the symptoms of both depression and anxiety are not severe enough (i.e. are subsyndromal) to justify a primary diagnosis of either major depressive disorder (MDD) or an anxiety disorder. However, dysthymia is the most prevalent comorbid diagnosis of GAD clients. Patients can also be categorized as having mixed anxiety-depressive disorder, and they are at significantly increased risk of developing full-blown depression or anxiety.

GAD and substance use disorders

Those with GAD have a lifetime comorbidity prevalence of 30% to 35% with alcohol use disorder and 25% to 30% for another substance use disorder.[58] People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities.[58] A study found that GAD was the primary disorder in slightly more than half of the 18 participants that were comorbid with alcohol use disorder.[59]

Other comorbidities

In addition to coexisting with depression, research shows that GAD often coexists with conditions associated with stress, such as irritable bowel syndrome.[60] Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain, cardiac events and interpersonal problems.[61]

Further research suggests that about 20 to 40 percent of individuals with attention deficit hyperactivity disorder have comorbid anxiety disorders, with GAD being the most prevalent.[62]

The World Health Organization's Global Burden of Disease project did not include generalized anxiety disorders.[63] In lieu of global statistics, here are some prevalence rates from around the world:

The usual age of onset is variable, from childhood to late adulthood, with the median age of onset being approximately 31[65] and mean age of onset is 32.7.[66] Most studies find that GAD is associated with an earlier and more gradual onset than the other anxiety disorders.[67] The prevalence of GAD in children is approximately 3%; the prevalence in adolescents is reported as high as 10.8%.[68] When GAD appears in children and adolescents, it typically begins around 8 to 9 years of age.[69]

Populations with a higher rate of diagnosis of GAD are individuals that are traditionally oppressed. This includes individuals with low and middle socio-economic status, separated, divorced, and widowed individuals. Women are twice as likely to develop GAD as men. This is primarily because women are more likely than men to live in poverty, be subject to discrimination, and be sexually and physically abused.[70] African Americans have significantly higher odds of enduring GAD and the disorder often manifests itself in different patterns.[71][72] Other populations that are more diagnosed with GAD are those who live alone, those with a low level of education, and the unemployed.[73] GAD is also common in the elderly population.[74]

Compared to the general population, patients with internalizing disorders such as depression, generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD) have higher mortality rates, but die of the same age-related diseases as the population, such as heart disease, cerebrovascular disease and cancer.[75]

Comorbidity and treatment

A study on comorbidity of GAD and other depressive disorders has shown that treatment is not more or less effective when there is some sort of comorbidity of another disorder.[76] The severity of symptoms did not affect the outcome of the treatment process in these cases.

See also

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