Generalized anxiety disorder

Genetics, family, and environment The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists a hereditary basis for GAD, but the exact nature of this hereditary basis is not fully understood. structural changes in the brain related to GAD, The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who have anxiety disorders, including GAD).). When GAD is considered among all anxiety disorders (e.g., panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30–40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. Thus, strained or stressful social relationships, as evidenced by abusive partners, display some association with the emergence of anxiety as a symptom of GAD. Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g., in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include: • PACAP (A54G polymorphism): remission after 6-month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013)) • HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to six months of Venlafaxine treatment (Lohoff et al. (2013)) • SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to six months of Venlafaxine treatment (Lohoff et al. (2013)) Problematic digital media use == Pathophysiology ==

The pathophysiology of GAD is an active and ongoing area of research, often involving the intersection of genetics and neurological structures. Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). propose that false alarms (unnecessary worry) are less costly than failing to detect real threats. As a result, having a relatively low threshold for perceiving danger may have historically conferred survival benefits. In individuals with GAD, however, this adaptive threshold appears to be set too low or activated too often, generating pervasive worry about routine events and relatively minor stressors. Empirical work supports the idea that GAD involves heightened reactivity in brain regions associated with threat detection, including the amygdala. Researchers have also found links between GAD and elevated inflammation markers, suggesting a possible physiological correlate for the chronic anxiety seen in the disorder. Although anxiety's defensive functions may have been advantageous in unpredictable environments, modern contexts can render this vigilance maladaptive when it persists as near-constant worry and avoidance. This view places GAD at the extreme end of a continuum, where otherwise beneficial anxiety responses overshoot, leading to significant distress and functional impairment. ==Diagnosis==

DSM-5 criteria The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ICD-10 criteria The 10th revision of the International Statistical Classification of Diseases (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows: See ICD-10 F41.1 Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80). ==Treatment==

Traditional treatment modalities broadly fall into two categories, i.e., psychotherapeutic and pharmacological intervention. Treatment modalities can, and often are, utilized concurrently so that an individual may pursue psychotherapy and pharmacological therapy. Both cognitive behavioral therapy (CBT) and medications (e.g., SSRIs) have been shown to be effective in reducing anxiety. A combination of both CBT and medication is generally seen as the most desirable approach to treatment. Psychotherapy Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behavior. Cognitive behavioral therapy Cognitive behavioral therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and integrates the cognitive and behavioral therapeutic approaches. progressive relaxation, Psychodynamic therapy Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual to explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. which has greater effectiveness than imaginal exposure in regards to generalized anxiety disorder. The aim of in vivo exposure treatment is to promote emotional regulation using systematic and controlled therapeutic exposure to traumatic stimuli. Exposure is used to promote fear tolerance. Exposure therapy is also a preferred method for children who struggle with anxiety. Children typically prefer using a group format for exposure therapy treatment. This allows for peer learning and the opportunity to develop social skills. Behavioral therapy Behavioral therapy is a therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g., one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioral therapy enables an individual to re-learn conditioned responses (behaviors) and to thereby challenge behaviors that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviors. 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. Intolerance of uncertainty therapy Intolerance of uncertainty (IU) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. Intolerance of uncertainty therapy (IUT) is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients develop the ability to tolerate, cope with, and accept uncertainty in their lives 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 in GAD patients with continued improvements in follow-up periods. 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. The primary goal of EFT is assisting individuals in living with their vulnerable emotions and overcoming avoidance so that adaptive experiences such as compassion and protective anger can be generated in response to the emotional needs that are embedded in core emotional vulnerability. Sandplay therapy Sandplay therapy (SPT) is an intervention based on nonverbal therapeutic practices. The main objective of SPT is to allow the individual the ability to work through their emotional problems from childhood traumas (CT) through play using sand and toy figures. Although the therapy is mainly focused on nonverbal cues, verbal cues are also observed and documented during the rehabilitation process of the individual. SPT allows a multi-sensory experience through a safe and protected space, allowing the individual the opportunity to regulate their mind and emotions. This therapeutic practice is offered to both adults and children. Other forms of psychological therapy • Relaxation techniques (e.g., relaxing imagery, meditational relaxation) • Mindfulness-based stress reduction (MBSR) • Supportive therapy: This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness. Pharmacotherapy Medications that have been studied were reviewed in a recent network meta-analysis that compared all studied medications with placebo and also with each other and another compared the rates of remission between different medications. Benzodiazepines (BZs) have been used to treat anxiety starting in the 1960s. There is a risk of dependence and tolerance to benzodiazepines. BZs have a number of effects that make them a good option for treating anxiety including anxiolytic, hypnotic (sleep-inducing), muscle relaxant, anticonvulsant, and amnestic (impair short-term memory) properties. Other medications that have been used or evaluated for treating GAD include: • SSRIs • Citalopram • Tiagabine SSRIs increase serotonin levels through inhibition of serotonin reuptake receptors. FDA approved SSRIs used for this purpose include escitalopram and paroxetine. 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. Common side effects include nausea, sexual dysfunction, headache, diarrhea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than in escitalopram and sertraline. In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding. These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS. FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor). While SNRIs have similar efficacy as SSRIs, many psychiatrists prefer to use SSRIs first in the treatment of Generalized Anxiety Disorder. 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. Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness. In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure. Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering. 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. 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. Pregabalin and gabapentin Pregabalin (Lyrica) is effective for treating GAD. It 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 one 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 misuse and dependency and may be preferred over the benzodiazepines for these reasons. 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. Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD, 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. In accordance, gabapentin is frequently prescribed off-label to treat GAD. Complementary and alternative medicines studied for potential in treating GAD Complementary and alternative medicines (CAMs) are widely used by individuals with GAD despite having no evidence or varied evidence regarding efficacy. • Lavender (Lavandula angustifolia) extracts: Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation. Lifestyle Lifestyle factors including: stress management, stress reduction, relaxation, sleep hygiene, and caffeine and alcohol reduction can influence anxiety levels. Physical activity has been shown to have a positive impact, whereas low physical activity may be a risk factor for anxiety disorders. Engaging in physical activity appears to significantly reduce the risk of developing anxiety symptoms and disorders, though limitations in study quality and consistency highlight the need for further research. Substances and GAD Certain substances or the withdrawal from certain substances have been implicated in promoting the experience of anxiety. and excessive caffeine use has been linked to aggravating and maintaining anxiety. ==Comorbidity==

Depression A longitudinal cohort study found 12% of 972 participants had GAD comorbid with major depressive disorder. 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. 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, though this is an unstable diagnosis that typically either goes away or shifts to a different diagnosis later on. Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, ranging from genetic pleiotropy (i.e., GAD and nonbipolar depression might represent different phenotypic expressions of a common etiology ) to impaired executive control or sleep problems and fatigue as potential bridging mechanisms between the two disorders. Both disorders are found to precede each other or help the other develop. In 32% of anxiety cases, depression was seen to begin before or concurrently, while in 37% of depression cases, anxiety was seen to begin before or concurrently. Within 72% of anxiety cases, a history of depression was found. Compared to the general population, patients with internalizing disorders such as depression, generalized anxiety disorder, 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. A comorbidity between GAD and attention deficit hyperactivity disorder (ADHD) has been observed. Anxiety disorders and major depressive disorder occur in a minority of individuals with ADHD, but more often than in the general population. Further research suggests that about 20 to 40 percent of individuals with ADHD have comorbid anxiety disorders, with GAD being the most prevalent. 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. People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities. == Epidemiology ==

GAD is often estimated to affect approximately 3–6% of adults and 5% of children and adolescents. Although estimates have varied to suggest a GAD prevalence of 3% in children and 10.8% in adolescents. When GAD manifests in children and adolescents, it typically begins around 8 to 9 years of age. Estimates regarding prevalence of GAD or lifetime risk (i.e., lifetime morbid risk [LMR]) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g., DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. However, the risk of developing GAD at any point in life has been estimated at 9.0%. and among those with low socioeconomic status. It has been suggested that greater prevalence of GAD in women may be because women are more likely than men to live in poverty, are more frequently the subject of discrimination, and be sexually and physically abused more often than men. In regard to the first incidence of GAD in an individual's life course, a first manifestation of GAD usually occurs between the late teenage years and the early twenties and mean age of onset being 32.7. However, GAD can begin or reoccur at any point in life. United States United States: Approximately 3.1 percent of people age 18 and over in a given year (9.5 million). Other • Australia: 3 percent of adults • Canada: 2.5 percent • Italy: 2.9 percent • Taiwan: 0.4 percent == 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. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since the comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to six months or longer. The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. 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 several different topics. 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. ==See also==