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Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months. Generalized anxiety disorder is more common in women. Among the risk factors are family history Family History Adult Health Maintenance, other mental health disorders, chronic physical illness, and a history of abuse or trauma. Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor includes fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, low concentration, restlessness, irritability, and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance. Diagnosis is clinical but if history suggests an underlying disease, laboratory tests are obtained. Treatment includes a combination of psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy (e.g., CBT) and medications such as selective serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants) and serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS- norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants).

Last updated: 29 Jun, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months.

  • Anxiety is a normal emotional state marked by intense, frequent, irrational, and unpleasant physical and mental arousal.
  • Anxiety is a response to an unknown threat, while fear is a response to a known threat.

Epidemiology

  • Lifetime prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of GAD in the United States: 5.1%–11.9 %.
  • More common in women than in men (2:1)
  • Although onset is in late adolescence/early adulthood, those with GAD usually receive diagnosis and treatment later in life.

Pathophysiology

Risk factors

  • General:
  • Late-onset GAD risk factors:
    • Poverty
    • Recent adverse events
    • Parental loss or separation
  • GAD is the most likely condition to coexist with another psychiatric disorder:
    • Other anxiety disorders such as phobias Phobias Neurological Examination or panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder 
    • PTSD PTSD Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD) 
    • Depressive disorders 
    • Substance abuse

Pathogenesis

  • Exact etiology is still unknown. 
  • Biologic:
    • Genetic factors predispose individuals to GAD.
    • Abnormalities in neurotransmitters:
      •  Decrease in serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS and GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS
      •  Increase in norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS
    • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance metabolism in the cortex, limbic system Limbic system The limbic system is a neuronal network that mediates emotion and motivation, while also playing a role in learning and memory. The extended neural network is vital to numerous basic psychological functions and plays an invaluable role in processing and responding to environmental stimuli. Limbic System: Anatomy, and basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy 
  • Stress and traumatic events

Clinical Presentation and Diagnosis

Clinical features

  • Main hallmark is excessive worry and anxiety about different subjects accompanied by restlessness or physical tension for more than 6 months. 
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship often present with various somatic symptoms Somatic symptoms Major Depressive Disorder; a specific nonpsychiatric diagnosis is rarely found.
  • Components:
    • Cognition:
      • Overestimating the danger
      • Poor coping skills
    • Behaviors:
    • Symptoms or complaints:
      • Muscle aches (e.g., neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, back, shoulder pains)
      • Poor sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep
      • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia (feeling physically and emotionally drained)
      • Restlessness (trouble relaxing)
      • Poor concentration (mind going blank)
      • Irritability or being easily annoyed
  • Course: chronic, fluctuating, and with gradual onset
  • Exclusion of substance use or other medical conditions (e.g., hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism) and other mental disorders

Assessment

  • Workup if there are physical signs and symptoms suggestive of an underlying disease:
    • CBC
    • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function tests
    • Chemistry panel
    • ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG)
    • Toxicology
  • Screening Screening Preoperative Care tools:
    • GAD 7-item scale Scale Dermatologic Examination: for screening and monitoring symptom severity 
    • Hospital Anxiety and Depression Scale (HADS): widely used for assessment and monitoring of anxiety and depression severity

Management

The gold standard for management of GAD is a combination of psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy and pharmacotherapy.

Psychotherapy

Nonmedical interventions

  • Exercise 
  • Diet modifications such as limiting caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants intake

Medications

  • Medication is selected based on availability, patient tolerance Tolerance Pharmacokinetics and Pharmacodynamics to side effects, other comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus, and treatment history.
  • Antidepressants (selective serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants) and serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)) are the 1st-line treatment.
  • 2nd line: 
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (BZD):
      • Usually avoided due to high risk of misuse
      • If used, administer only on an as-needed basis for a short period of time.
      • Those with longer duration of action ( clonazepam Clonazepam An anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures. The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses. Benzodiazepines or diazepam Diazepam A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. Benzodiazepines) are preferred. 
    • Buspirone: slow action and weaker anxiolytic effect than benzodiazepines 
    • Pregabalin Pregabalin A gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia. Second-Generation Anticonvulsant Drugs: has shown some efficacy (used in Europe)
    • Tricyclic antidepressants ( TCAs TCAs Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants): less acceptable tolerability and can cause arrhythmias
    • Hydroxyzine Hydroxyzine A histamine h1 receptor antagonist that is effective in the treatment of chronic urticaria, dermatitis, and histamine-mediated pruritus. Unlike its major metabolite cetirizine, it does cause drowsiness. It is also effective as an antiemetic, for relief of anxiety and tension, and as a sedative. Antihistamines: short-term or immediate control of symptoms

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Comparison with Other Anxiety Disorders

Table: Comparison of anxiety disorders
Condition Most important features Duration Treatment
Generalized anxiety disorder Chronic multiple worries, usually about issues, events, or activities ≥ 6 months Combination of antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants) and CBT
Panic disorder Recurrent and unexpected abrupt surges (within minutes) of intense fear or discomfort ≥ 1 month
Specific phobia Phobia A phobia can be defined as an irrational fear that results in avoidance of the feared subject, activity, or situation. Social Anxiety Disorder Unreasonable fear of a certain object or situations ≥ 6 months
  • 1st line: CBT
  • Medication has an insignificant role.
Social phobia Social phobia Anxiety disorder characterized by the persistent and irrational fear, anxiety, or avoidance of social or performance situations. Social Anxiety Disorder ( social anxiety disorder Social anxiety disorder Social anxiety disorder, or social phobia, is a psychiatric illness marked by fear and avoidance of social interactions due to concerns about embarrassment. The disorder usually occurs in more than one social situation for more than 6 months and leads to a significant decline in function. Social Anxiety Disorder) Fear or avoidance of social interactions due to concerns about being embarrassed ≥ 6 months
Agoraphobia Agoraphobia Agoraphobia is fear or anxiety in a situation that would be difficult to leave or to obtain help in the event that one develops panic-like symptoms. Situations include being in public or open spaces, lines, crowds, or public transport. Agoraphobia Fear of being in situations or places where it is difficult to leave or escape Escape With constant immune mechanisms holding unstable tumor cells in equilibrium, tumor-cell variants may emerge. These cancer cells may express fewer antigens on their surfaces or lose their MHC class I expression.Variants may also protect themselves from T-cell attack via expression of IC molecules on their surfaces, like normal cells.Creation of an immunosuppressive state in the microenvironment is another way to grow without immunologic interference. Cancer Immunotherapy ≥ 6 months 1st line: SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants or CBT
Separation anxiety disorder Anxiety arises from the fear of being separated from attachment Attachment The binding of virus particles to virus receptors on the host cell surface, facilitating virus entry into the cell. Virology figures. ≥ 1 month
  • 1st line: CBT
  • Medications can be used if CBT alone fails.
Illness anxiety disorder Illness Anxiety Disorder Illness anxiety disorder, formerly known as hypochondriasis, is a chronic condition characterized by a prolonged and exaggerated concern about one’s health and possible illness. Patients fear or are convinced that they have a disease and interpret minor or normal bodily symptoms as signs of a serious medical condition. Illness Anxiety Disorder Anxiety arises from concerns about having or acquiring a certain illness. ≥ 6 months
  • Schedule regular Regular Insulin followup visits.
  • Avoid doing unnecessary diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests.
  • Avoid referrals.
  • CBT and antidepressants if these measures fail
Substance- or drug-induced anxiety disorder
  • Intoxication with cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics or amphetamine
  • Withdrawal from alcohol or BZD
  • Medications such as beta-2 agonists ( albuterol Albuterol A short-acting beta-2 adrenergic agonist that is primarily used as a bronchodilator agent to treat asthma. Sympathomimetic Drugs) or levothyroxine Levothyroxine Thyroid Replacement Therapy

Differential Diagnosis

  • Intoxication (cocaine or amphetamines): patients with cocaine use disorder or amphetamine use disorder are predisposed to anxiety when they are intoxicated with either substance. Symptoms include agitation, psychosis, hemodynamic instability (hypertension, tachycardia), diaphoresis, and mydriasis. Acute intoxication is distinguished from GAD by history taking, physical exam, and urine toxicology screen. 
  • Withdrawal (from alcohol or benzodiazepines): patients with alcohol use disorder or anxiolytic use disorder are at an increased risk of withdrawal if they discontinue their substance use abruptly. Symptoms include worsening of initial anxiety, insomnia, psychosis, and seizures. Withdrawals from alcohol and anxiolytics are distinguished from GAD by history taking, physical exam, and urine toxicology screen. 
  • Major depressive disorder: a disorder marked by depressed mood, sleep disturbance, anhedonia, feelings of guilt or worthlessness, loss of energy, low concentration, weight or appetite changes, psychomotor retardation or agitation, and suicidal ideation. These symptoms last for ≥ 2 weeks. Excessive worry is a common feature of major depressive disorder and a diagnosis of GAD may be made alongside MDD if anxiety symptoms are sufficiently severe. 
  • Panic disorder: a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. Unlike GAD, these time-limited panic attacks present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Fear of dying or “going crazy” can occur. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may develop agoraphobia, which is the fear of being in places or situations where leaving or escape Escape With constant immune mechanisms holding unstable tumor cells in equilibrium, tumor-cell variants may emerge. These cancer cells may express fewer antigens on their surfaces or lose their MHC class I expression.Variants may also protect themselves from T-cell attack via expression of IC molecules on their surfaces, like normal cells.Creation of an immunosuppressive state in the microenvironment is another way to grow without immunologic interference. Cancer Immunotherapy is difficult. 
  • Obsessive-compulsive disorder Obsessive-compulsive disorder Obsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment. Obsessive-compulsive Disorder (OCD) ( OCD OCD Obsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment. Obsessive-compulsive Disorder (OCD)): a condition characterized by recurring intrusive thoughts, feelings, or sensations (known as obsessions Obsessions Recurrent thoughts, images, or urges that are intrusive and recognized as unwanted, causing significant anxiety and distress . Obsessive-compulsive Disorder (OCD)) that are time consuming and cause severe distress. Symptoms are relieved partially by the performance of repetitive actions (known as compulsions Compulsions Repetitive behaviors or mental acts that the individual is driven to perform in relation to an obsession. Obsessive-compulsive Disorder (OCD)). Detailed history taking will reveal that the excessive worry from GAD comes from upcoming issues, while in OCD OCD Obsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment. Obsessive-compulsive Disorder (OCD) the worry is more inappropriate and consists of intrusive ideas.

References

  1. Baldwin, D. (2021). Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis. UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/generalized-anxiety-disorder-in-adults-epidemiology-pathogenesis-clinical-manifestations-course-assessment-and-diagnosis
  2. Craske, M. (2021). Approach to treating generalized anxiety disorder in adults. UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/approach-to-treating-generalized-anxiety-disorder-in-adults
  3. Dave, P. (2017). Clinical management of anxiety disorders. https://www.researchgate.net/publication/348489972_Clinical_Management_of_Anxiety_Disorders
  4. Grant, J. (2021). Overview of anxiety disorders. https://www.researchgate.net/publication/348435567_Overview_of_Anxiety_Disorders
  5. Palkar, P. (2020). Neurobiology of anxiety disorders. https://www.researchgate.net/publication/341407589_Neurobiology_of_Anxiety_Disorders
  6. Sadock, B. J., Sadock, V. A., & Ruiz, P. (2014). Kaplan and Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry (11th ed.). Chapter 9, Anxiety Disorders, pages 387-417. Philadelphia, PA: Lippincott Williams and Wilkins.

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