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, other mental health disorders, chronic physical illness, and a history of abuse or trauma. Clinical presentation includes fatigue, low concentration, restlessness, irritability, and sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. 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 reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

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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 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:
    • Female 
    • Family history
    • Comorbid mental health disorders
    • Other chronic physical disorders (arthritis, GI disorders)
    • History of abuse/trauma
  • 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 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 and GABA
      •  Increase in norepinephrine
    • ↑ Glucose 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, 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 
  • 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 often present with various somatic symptoms; a specific nonpsychiatric diagnosis is rarely found.
  • Components:
    • Cognition:
      • Overestimating the danger
      • Poor coping skills
    • Behaviors:
      • Avoidance
      • Being distracted
      • Seeking reassurance
    • Symptoms or complaints:
      • Muscle aches (e.g., neck, back, shoulder pains)
      • Poor sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep
      • Fatigue (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 Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism) and other mental disorders

Assessment

  • Workup if there are physical signs and symptoms suggestive of an underlying disease:
    • CBC
    • Thyroid 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. Normal Electrocardiogram (ECG)
    • Toxicology
  • Screening tools:
    • GAD 7-item scale: 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

  • CBT has the most evidence for efficacy in treating GAD. 
  • Psychodynamic therapy may uncover sources or issues linked to the patient’s anxiety. 
  • Supportive 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 offers reassurance and comfort.

Nonmedical interventions

  • Exercise 
  • Diet modifications such as limiting caffeine intake

Medications

  • Medication is selected based on availability, patient tolerance to side effects, other comorbidities, and treatment history.
  • Antidepressants (selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)) are the 1st-line treatment.
    • Highest amount of evidence for efficacy 
    • Little risk of abuse
    • SSRIs: e.g., sertraline, citalopram, and paroxetine 
    • SNRIs: e.g., venlafaxine and duloxetine
  • 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 or diazepam) are preferred. 
    • Buspirone: slow action and weaker anxiolytic effect than benzodiazepines 
    • Pregabalin: has shown some efficacy (used in Europe)
    • Tricyclic antidepressants Tricyclic antidepressants 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 (TCAs): less acceptable tolerability and can cause arrhythmias
    • Hydroxyzine: 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) and CBT
Panic disorder Recurrent and unexpected abrupt surges (within minutes) of intense fear or discomfort ≥ 1 month
  • Acute attack: BZD
  • Maintenance: SSRIs, CBT
Specific phobia Unreasonable fear of a certain object or situations ≥ 6 months
  • 1st line: CBT
  • Medication has an insignificant role.
Social phobia ( 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
  • 1st line: SSRIs or CBT
  • Performance-only subtype: beta-blockers or BZD
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 ≥ 6 months 1st line: SSRIs or CBT
Separation anxiety disorder Anxiety arises from the fear of being separated from attachment 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 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 or amphetamine
  • Withdrawal from alcohol or BZD
  • Medications such as beta-2 agonists (albuterol) or levothyroxine

Differential Diagnosis

  • Intoxication (cocaine or amphetamines): patients with cocaine use disorder Cocaine use disorder Cocaine use disorder is a substance use disorder defined by pathologic consumption of the recreational drug cocaine. Cocaine is an indirect sympathomimetic that blocks the reuptake of dopamine, serotonin, and norepinephrine from the synaptic cleft. This process causes stimulant effects on the body and mind such as euphoria and increased energy. Cocaine Use Disorder or amphetamine use disorder Amphetamine use disorder Amphetamine use disorder (AUD) is a condition characterized by pathologic use of psychostimulants. Amphetamines produce their effect by increasing the release and blocking the reuptake of neurotransmitters (dopamine, norepinephrine, serotonin). Medically, they are used for the treatment of ADHD and narcolepsy. Amphetamine Use Disorder are predisposed to anxiety when they are intoxicated with either substance. Symptoms include agitation, psychosis, hemodynamic instability ( hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. 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 Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, psychosis, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Withdrawals from alcohol and anxiolytics are distinguished from GAD by history taking, physical exam, and urine toxicology screen. 
  • Major depressive disorder Major depressive disorder Major depressive disorder (MDD), commonly called depression, is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of ≥ 2 weeks. Major depressive disorder has the highest lifetime prevalence among all psychiatric disorders. Major Depressive Disorder: a disorder marked by depressed mood, sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of 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 may develop agoraphobia, which is the fear of being in places or situations where leaving or escape 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) that are time consuming and cause severe distress. Symptoms are relieved partially by the performance of repetitive actions (known as compulsions). 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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