Generalized anxiety disorder

Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities.[2] This excessive worry often interferes with daily functioning, and sufferers 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, vomiting, diarrhea, breathing difficulty, trembling, irritability, restlessness, sleeping difficulties, sweating and rashes.[5]

These symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD.[2][3] GAD is also common in individuals with a history of substance abuse and a family history of the disorder.[6] Standardized rating scales such as GAD-7 can be used to assess severity of GAD symptoms.[7]

Medications which have been found to be useful include duloxetine, pregabalin, venlafaxine, and escitalopram.[8]

In a given year, approximately two percent of American adults and European adults experience GAD.[9][10] Globally about 4% are affected at some point in their life.[1] GAD is seen in women twice as much as men.[11]

Generalized anxiety disorder
SpecialtyPsychiatry
TreatmentBehavioral therapy, medications
Frequency3-5% (lifetime prevalence) [1]

Risk factors

Genetics

Genes are attributed to about a third of general anxiety disorder's variance.[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 diminishment 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 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 could progressively make 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] Neurotransmitter systems, inflammation, oxidative stress, mitochondria dysfunction and neurogenesis are affected by exposure to cigarette smoke which are all pathways thought to be associated with GAD.[21]

Excessive caffeine use has also been linked to aggravating and maintaining anxiety.[22] This is due to overactivation of the sympathetic nervous system[23]

Gender

Women are twice as likely to develop GAD as men. It has been suggested that this is primarily because women are more likely than men to live in poverty, be subject to discrimination, and be sexually and physically abused.[24]

Other

Populations with a higher rate of diagnosis of GAD includes individuals with low and middle socio-economic status and those who are separated, divorced, unemployed, widowed or have low levels of education.[25]

African Americans have higher odds of having GAD and the disorder often manifests itself in different patterns.[26][27]

GAD is also common in the elderly population.[28]

Low self esteem, disrupted family environments and sexual abuse also increase the risk of GAD.

Pathophysiology

Amygdala small
Amygdala

Generalized anxiety disorder has been linked to disrupted functional connectivity of the amygdala and its processing of fear and anxiety.[29] 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.[29] 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.[29]

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.[30]

ICD-10 criteria

ICD-10 Generalized anxiety disorder "F41.1"[31] 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]

Prevention

Increased core temperature can help to relax muscles.[32]

Foods high in Omega-3 including Oily Fish such as Salmon and Mackerel reduce the inflammatory response and so helps to increase serotonin availability.[33]

Many people have found ease by relaxation exercises, deep breathing practice, and meditation.[34]

Additionally, avoidance of caffeine may prevent GAD.[35]

Avoiding nicotine also can decrease the risk for the development of anxiety disorders including generalized anxiety disorder.[36]

Treatment

Once GAD develops, it is possible for it become chronic, but can be managed or eliminated with proper treatment.[37]

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.[38] A combination of both CBT and medication is generally seen as the most desirable approach to treatment.[39] Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Lifestyle

Lifestyle factors including: stress management, stress reduction, relaxation, exercise, sleep hygiene, caffeine, and alcohol can influence the persistence of anxiety. Stress is a factor that can trigger anxiety. Therefore, keeping stress levels low through stress management, stress reduction, and relaxation may be beneficial. Physical activity has shown to have a positive impact whereas low physical activity may be a risk factor for anxiety disorders.[40]

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.[41] 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.[41] 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).[42] 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.[43]

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT) appears to be useful in the treatment of generalized anxiety disorder.[44] 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.[43] CBT usually helps one-third of the patients substantially, whilst another third does not respond at all to treatment.[45]

CBT is a psychological method of treatment that involves a therapist working with the person to understand how thoughts and feelings influence behaviour.[46] 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.[47]

Albert Ellis is one such notable cognitive theorist, and practitioner who coined the term "maladaptive assumptions."[48] These maladaptive assumptions, negatively incorporated in a client's thought patterns, may serve to disrupt the ability to engage in healthy interactions.[48] Frequent use of such maladaptive assumption such as, "It is awful and catastrophic when things are not the way one would very much like them to be" may provoke further anxiety over the course of events.[48] Thus rational-emotive therapy, a form of cognitive behavioral therapy, may be implemented to counter clients' maladaptive assumptions, and educate them about the part excessive worrying plays in resulting cognitive interpretations across a span of social situations.

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.[43]

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.[43]

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.[49] 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.[50] 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.[43]

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 to be more effective than CBT alone.[43]

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%).[51]

Selective serotonin reuptake inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[47] These are the preferred first line of treatment.[51] These increase serotonin levels through inhibition of serotonin reuptake receptors.[52]

FDA approved SSRIs used for this purpose include escitalopram[53] and paroxetine.[54] However, guidelines suggest using sertraline first due to its cost-effectiveness compared to other SSRIs used for generalized anxiety disorder and a lower risk of withdrawal compared to SNRIs. If sertraline is found to be ineffective, then it is recommended to try another SSRI or SNRI.[55]

Common side effects include nausea, sexual dysfunction, headache, diarrhea, constipation, restlessness, increased risk of suicide in young adults and adolescents,[56] among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than escitalopram and sertraline.[57] In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding.[55] Overdose of an SSRI or concomitant use with another agent that causes increased levels of serotonin can result in serotonin syndrome, which can be life threatening.

Serotonin norepinephrine reuptake inhibitors

First line pharmaceutical treatments for GAD also include serotonin-norepinephrine reuptake inhibitors (SNRIs).[58] These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS.[59]

FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor).[60][61] While SNRIs have similar efficacy as SSRIs,[62] many psychiatrists prefer to use SSRIs first in the treatment of Generalized Anxiety Disorder.[63][64][65][60] The slightly higher preference for SSRIs over SNRIs as a first choice for treatment of anxiety disorders may have been influenced by the observation of poorer tolerability of the SNRIs in comparison to SSRIs in systematic reviews of studies of depressed patients.[66][67][68] Duloxetine is also indicated for the treatment of chronic musculoskeletal pain and neuropathic pain associated with diabetes mellitus,[69] and may be a good option for patients with both conditions.[65]

Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness.[70] In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure.[71][70] Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering.[69][72] Like other serotonergic agents, SNRIs have the potential to cause serotonin syndrome, a potentially fatal systemic response to serotonergic excess that causes symptoms including agitation, restlessness, confusion, tachycardia, hypertension, mydriasis, ataxia, myoclonus, muscle rigidity, diaphoresis, diarrhea, headache, shivering, goose bumps, high fever, seizures, arrhythmia and unconsciousness.[73] SNRIs like SSRIs carry a black box warning for suicidal ideation, but it is generally considered that the risk of suicide in untreated depression is far higher than the risk of suicide when depression is properly treated.[74]

Benzodiazepines

Benzodiazepines are most often prescribed to people with generalized anxiety disorder. Research suggests that these medications 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 medications 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.[75] CBT and medication are of comparable efficacy in the short-term but CBT has advantages over medication in the longer term.[76]

Benzodiazepines (or "benzos") are fast-acting hypnotic sedatives that are also used to treat GAD and other anxiety disorders.[47] 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.[77][78] 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.[79][80] The anxiolytic effects of pregabalin appear to persist for at least six months continuous use, suggesting tolerance is less of a concern; this gives pregabalin an advantage over certain anxiolytic medications such as benzodiazepines.[81]

Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD,[82] 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.[83] In accordance, gabapentin is frequently prescribed off-label to treat GAD.[84]

Other psychiatric medications

Other medications

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.[86] 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.[87] 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.

Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, including genetic pleiotropy, meaning that GAD and nonbipolar depression might represent different phenotypic expressions of a common etiology.[88]

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.[89] People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities.[89] 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.[90]

Other comorbidities

GAD often coexists with conditions associated with stress, such as muscle tension and irritable bowel syndrome.[91]

Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain and interpersonal problems.[92]

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.[93]

Comorbidity and treatment

Therapy has been shown to have equal efficacy in patents with GAD and patients with GAD and comorbid disorders. Patients with comorbid disorders have more severe symptoms when starting therapy but demonstrated a greater improvement than patients with simple GAD.

Pharmacological approaches i.e. the use of Antidepressants must be adapted for different comorbidities. For example, Serotonin Reuptake inhibitors and short acting Benzodiazepines (BZDs) are used for depression and anxiety. However, for patients with anxiety and substance abuse, BZDs should be avoided due to their abuse liability.[94] CBT has been found an effective treatment since it improves symptoms of GAD and substance abuse.

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.[95]

History

The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder.[88] 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.[96] Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R.[97] 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.[98] The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis.[96] Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring "often".[99] 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.[97] It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.[97]

Epidemiology

4% are affected at some point in their life.[1] GAD is seen in women twice as much as men.

USA

GAD is the most common cause of disability in the workplace in the United States.[100]

United States: approx. 3.1 percent of people age 18 and over in a given year (9.5 million)[9]

UK

5.9 percent of adults were affected by GAD in 2019.[101]

Other

  • Australia: 3 percent of adults[102]
  • Canada: 2.5 percent [103]
  • Italy: 2.9 percent[104]
  • Taiwan: 0.4 percent[104]

The usual age of onset is variable, from childhood to late adulthood, with the median age of onset being approximately 31[105] and mean age of onset is 32.7.[106] Most studies find that GAD is associated with an earlier and more gradual onset than the other anxiety disorders.[107] The prevalence of GAD in children is approximately 3%; the prevalence in adolescents is reported as high as 10.8%.[108] When GAD appears in children and adolescents, it typically begins around 8 to 9 years of age.[109]

See also

References

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Further reading

  • Brown, T. A., O'Leary, T .A., & Barlow, D. H. (2001). "Generalised anxiety disorder". In D. H. Barlow (ed.), Clinical handbook of psychological disorders: A step-by-step treatment manual (3rd ed.). New York: Guilford Press.
  • Barlow, D. H., & Durand, V. M. (2005). Abnormal psychology: An integrative approach. Australia; Belmont, Calif.: Wadsworth.
  • Tyrer, Peter; Baldwin, David (2006). "Generalised anxiety disorder". The Lancet. 368 (9553): 2156–66. doi:10.1016/S0140-6736(06)69865-6. PMID 17174708.

External links

External resources
Affective spectrum

The affective spectrum is a spectrum of affective disorders (mood disorders). It is a grouping of related psychiatric and medical disorders which may accompany bipolar, unipolar, and schizoaffective disorders at statistically higher rates than would normally be expected. These disorders are identified by a common positive response to the same types of pharmacologic treatments. They also aggregate strongly in families and may therefore share common heritable underlying physiologic anomalies.

Affective spectrum disorders include:

Attention deficit hyperactivity disorder

Bipolar disorder

Body dysmorphic disorder

Bulimia nervosa and other eating disorders

Cataplexy

Dysthymia

Generalized anxiety disorder

Hypersexuality

Irritable bowel syndrome

Impulse-control disorders

Kleptomania

Migraine

Major depressive disorder

Obsessive-compulsive disorder

Oppositional defiant disorder

Panic disorder

Posttraumatic stress disorder

Premenstrual dysphoric disorder

Social anxiety disorder

FibromyalgiaThe following may also be part of the spectrum accompanying affective disorders.

Chronic pain

Intermittent explosive disorder

Pathological gambling

Personality disorder

Pyromania

Substance abuse and addiction (includes alcoholism)

TrichotillomaniaAlso, there are now studies linking heart disease.Many of the terms above overlap. The American Psychiatric Association's definitions of these terms can be found in the Diagnostic and Statistical Manual of Mental Disorders (DSM).

Anxiety disorder

Anxiety disorders are a group of mental disorders characterized by significant feelings of anxiety and fear. Anxiety is a worry about future events, and fear is a reaction to current events. These feelings may cause physical symptoms, such as a fast heart rate and shakiness. There are several anxiety disorders, including generalized anxiety disorder, specific phobia, social anxiety disorder, separation anxiety disorder, agoraphobia, panic disorder, and selective mutism. The disorder differs by what results in the symptoms. People often have more than one anxiety disorder.The cause of anxiety disorders is a combination of genetic and environmental factors. Risk factors include a history of child abuse, family history of mental disorders, and poverty. Anxiety disorders often occur with other mental disorders, particularly major depressive disorder, personality disorder, and substance use disorder. To be diagnosed symptoms typically need to be present for at least 6 months, be more than what would be expected for the situation, and decrease functioning. Other problems that may result in similar symptoms include hyperthyroidism; heart disease; caffeine, alcohol, or cannabis use; and withdrawal from certain drugs, among others.Without treatment, anxiety disorders tend to remain. Treatment may include lifestyle changes, counselling, and medications. Counselling is typically with a type of cognitive behavioral therapy. Medications, such as antidepressants, benzodiazepines, or beta blockers, may improve symptoms.About 12% of people are affected by an anxiety disorder in a given year, and between 5% and 30% are affected over a lifetime. They occur in females about twice as often as in males, and generally begin before age 25 years. The most common are specific phobias, which affect nearly 12%, and social anxiety disorder, which affects 10%. Phobias mainly affect people between the ages of 15 and 35, and become less common after age 55. Rates appear to be higher in the United States and Europe.

Coluracetam

Coluracetam (INN) (code name BCI-540; formerly MKC-231) is a nootropic agent of the racetam family. It was initially developed and tested by the Mitsubishi Tanabe Pharma Corporation for Alzheimer's disease. After the drug failed to reach endpoints in its clinical trials it was in-licensed by BrainCells Inc for investigations into major depressive disorder (MDD), which was preceded by being awarded a "Qualifying Therapeutic Discovery Program Grant" by the state of California. Findings from phase IIa clinical trials have suggested that it would be a potential medication for comorbid MDD with generalized anxiety disorder (GAD). BrainCells Inc is currently out-licensing the drug for this purpose. It may also have potential use in prevention and treatment of ischemic retinopathy and retinal and optic nerve injury.Coluracetam has been shown to reverse the loss of choline acetyltransferase production in the medial septal nucleus of rats exposed to phencyclidine (PCP), and is considered a potential therapeutic drug for schizophrenia.

Daily Assessment of Symptoms – Anxiety

The Daily Assessment of Symptoms – Anxiety (DAS-A) questionnaire was specifically developed to detect reduction of anxiety symptoms in patients with Generalized Anxiety Disorder (GAD) during the first week of treatment. The original version of the instrument was designed for use in clinical trials assessing new pharmaceutical treatments for patients with GAD. The instrument is able to detect symptom changes within 24 hours of treatment. Currently,[2009] this is the only GAD specific tool validated to assess symptom improvement sooner than one week following treatment initiation.

Dissociative disorder not otherwise specified

Dissociative disorder not otherwise specified (DDNOS) is a mental health diagnosis for pathological dissociation that matches the DSM-5 criteria for a dissociative disorder, but does not fit the full criteria for any of the specifically identified subtypes, which include dissociative identity disorder, dissociative amnesia, and depersonalization/derealization disorder, and the reasons why the previous diagnoses weren't met are specified. "Unspecified dissociative disorder" is given when the clinician doesn't give a reason. The International Statistical Classification of Diseases and Related Health Problems (ICD-10) refers to the diagnosis as "Other dissociative and conversion disorders".Examples of DDNOS include chronic and recurrent syndromes of mixed dissociative symptoms, identity disturbance due to prolonged and intense coercive persuasion, disorders similar to dissociative identity disorder, acute dissociative reactions to stressful events, and dissociative trance.DDNOS is the most common dissociative disorder and is diagnosed in 40% of dissociative disorder cases. It is often co-morbid with other mental illnesses such as complex posttraumatic stress disorder, major depressive disorder, generalized anxiety disorder, personality disorders, substance use disorders, and eating disorders.

Duloxetine

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, and neuropathic pain. It is taken by mouth.Common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating. Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. It is a serotonin–norepinephrine reuptake inhibitor. How it works is not entirely clear.Duloxetine was approved for medical use in the United States in 2004. It is available as a generic medication. In the United States the wholesale cost per dose is about 0.20 USD as of 2018. In 2016 it was the 48th most prescribed medication in the United States with more than 15 million prescriptions.

Epix Pharmaceuticals

Epix Pharmaceuticals Inc (formerly Predix Pharmaceuticals Inc) was a pharmaceutical company based in Lexington, Massachusetts.

Its products included the following agents:

PRX-00023—5-HT1A receptor full agonist (later discovered to be an antagonist): for major depression and generalized anxiety disorder

PRX-03140—5-HT4 receptor partial agonist: for Alzheimer's disease

PRX-07034—5-HT6 receptor antagonist: for obesity and cognitive impairment associated with Alzheimer's disease and schizophrenia

PRX-08066—5-HT2B receptor antagonist: for pulmonary hypertension associated with chronic obstructive pulmonary diseaseAs of July 2009, the company was in the process of asset liquidation due to insufficient funds to stay afloat.

Exposure therapy

Exposure therapy is a technique in behavior therapy to treat anxiety disorders. Exposure therapy involves exposing the target patient to the anxiety source or its context without the intention to cause any danger. Doing so is thought to help them overcome their anxiety or distress. Procedurally, it is similar to the fear extinction paradigm developed studying laboratory rodents. Numerous studies have demonstrated its effectiveness in the treatment of disorders such as generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, PTSD, and specific phobias.

Fabre-Kramer Pharmaceuticals

Fabre-Kramer Pharmaceuticals is a pharmaceutical company that specializes in the development of psychotropic drugs. Products in their current development pipeline include gepirone and FKB01MD for major depression, gepirone and FKW00GA for generalized anxiety disorder, gepirone for hypoactive sexual desire disorder, FKF02SC for schizophrenia, and FKK01PD for Parkinson's disease.The company has also conducted clinical studies on a gepirone extended release formulation for major depression.

Generalized Anxiety Disorder 7

Generalized Anxiety Disorder 7 (GAD-7) is a self-reported questionnaire for screening and severity measuring of generalized anxiety disorder (GAD).

GAD-7 has seven items, which measure severity of various signs of GAD according to reported response categories with assigned points (see below). Assessment is indicated by the total score, which made up by adding together the scores for the scale all seven items.GAD-7 is a sensitive self-administrated test to assess generalized anxiety disorder, normally used in outpatient and primary care settings for referral to psychiatrist pending outcome. However, it cannot be used as replacement for clinical assessment and additional evaluation should be used to confirm a diagnosis of GAD.The scale uses a normative system of scoring as shown below - [bullet points of answer options and points assigned] - with question at the end qualitatively describing severity of the patient's anxiety over the past 2 weeks.

Not at all (0 points)

Several days (1 point)

More than half the days (2 points)

Nearly every day (3 points)

Glemanserin

Glemanserin (INN) (developmental code name MDL-11,939) is a drug which acts as a potent and selective 5-HT2A receptor antagonist. The first truly selective 5-HT2A ligand to be discovered, glemanserin resulted in the development of the widely used and even more potent and selective 5-HT2A receptor antagonist volinanserin (MDL-100,907), which is a fluorinated analogue. Though it was largely superseded in scientific research by volinanserin, glemanserin was investigated clinically for the treatment of generalized anxiety disorder. However, it was ultimately found to be ineffective and was not marketed.

Imagabalin

Imagabalin (INN, USAN; PD-332,334) is a drug which acts as a ligand for the α2δ subunit of the voltage-dependent calcium channel, with some selectivity for the α2δ1 subunit over α2δ2. Under development by Pfizer as a pharmaceutical medication, it has demonstrated preclinical efficacy of anxiolytic, analgesic, hypnotic, and anticonvulsant-like activity and is currently in phase III clinical trials for the treatment of generalized anxiety disorder.

Lesopitron

Lesopitron (E-4424) is a selective full agonist of the 5-HT1A receptor which is structurally related to the azapirones. In 2001 it was under development by Esteve as an anxiolytic for the treatment of generalized anxiety disorder (GAD). It made it to phase II clinical trials but was apparently discontinued as no new information on lesopitron has surfaced since.

List of investigational anxiolytics

This is a list of investigational anxiolytics, or anxiolytics that are currently under development for clinical use but are not yet approved. Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

Naluzotan

Naluzotan (INN, USAN; PRX-00023) is a serotonergic drug of the phenylpiperazine class that was under investigation by EPIX Pharmaceuticals Inc for the treatment of generalized anxiety disorder and major depressive disorder. It acts as a selective and potent 5-HT1A receptor partial agonist, readily stimulating prolactin responses, though it has also been found to bind to and activate the σ receptor. Naluzotan was well tolerated in clinical trials, with more patients in the control group dropping out due to adverse effects than in the active group in one study. The most frequently reported side effect was headache in 15% of patients (compared to 10% for placebo). In addition, naluzotan demonstrated significant antidepressant and anxiolytic effects as per the HAM-D and MADRS and the HAM-A, respectively, in some trials, but in others it did not. In the end it was not found to be significantly superior enough to placebo and development was stopped.

Phobophobia

Phobophobia is the fear of phobia(s) and, more specifically, of the internal sensations associated with that phobia and anxiety, which binds it closely to other anxiety disorders, especially with generalized anxiety disorders (free floating fears) and panic attacks. It is a condition in which anxiety disorders are maintained in an extended way, which combined with the psychological fear generated by phobophobia of encountering the feared phobia would ultimately lead to the intensifying of the effects of the feared phobia that the patient might have developed, such as agoraphobia, and specially with it, and making them susceptible to having an extreme fear of panicking. Phobophobia comes in between the stress the patient might be experiencing and the phobia that the patient has developed as well as the effects on his life, or in other words, it is a bridge between anxiety/panic the patient might be experiencing and the type of phobia he/she fears, creating an intense and extreme predisposition to the feared phobia. Nevertheless, phobophobia is not necessarily developed as part of other phobias, but can be an important factor for maintaining them.Phobophobia differentiates itself from other kind of phobias by the fact that there is no environmental stimulus per se, but rather internal dreadful sensations similar to psychological symptoms of panic attacks. The psychological state of the mind creates an anxious response that has itself a conditioned stimuli leading to further anxiety, resulting in a vicious cycle. Phobophobia is a fear experienced before actually experiencing the fear of the feared phobias its somatic sensations that precede it, which is preceded by generalized anxiety disorders and can generate panic attacks. Like all the phobias, the patients avoids the feared phobia in order to avoid the fear of it.

Pregabalin

Pregabalin, marketed under the brand name Lyrica among others, is a medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, and generalized anxiety disorder. Its use in epilepsy is as an add-on therapy for partial seizures. When used before surgery, it improves pain but results in greater sedation and visual disturbances. It is taken by mouth.Common side effects include headache, dizziness, sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problem with vision, and weight gain. Serious side effects may include angioedema, drug misuse, and an increased suicide risk. When pregabalin is taken at high doses over a long period of time, addiction may occur, but if taken at usual doses the risk is low. Use during pregnancy or breastfeeding is of unclear safety. Pregabalin is a gabapentinoid and acts by inhibiting certain calcium channels.Pregabalin was approved for medical use in the United States in 2004. It was developed as a successor to gabapentin. It is available as a generic medication in a number of countries but not the United States as of 2018. In the US the wholesale costs is about US$450 per month as of 2019. While in the United Kingdom a similar dose costs the NHS about £6. In 2016, it was the 83rd most prescribed medication in the United States with more than 9 million prescriptions. In the US, Pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970.

Sympatholytic

A sympatholytic (or sympathoplegic) drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS). They are indicated for various functions; for example, they may be used as antihypertensives. They are also used to treat anxiety, such as generalized anxiety disorder, panic disorder and PTSD.

Worry

Worry refers to the thoughts, images, emotions, and actions of a negative nature in a repetitive, uncontrollable manner that results from a proactive cognitive risk analysis made to avoid or solve anticipated potential threats and their potential consequences. Worry is described as a response to a moderate challenge for when the subject has inadequate skills. Worry turns to be problematic if one has been excessively apprehensive more days than not for at least six months.

Mental and behavioral disorders (F00–F99 & 290–319)

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