Generalized Anxiety Disorder

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:
  • Female 
  • Family history Family History Adult Health Maintenance
  • Comorbid mental health disorders
  • Other chronic physical disorders ( arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, 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 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 use disorder

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:
    • Avoidance
    • Being distracted
    • Seeking reassurance Reassurance Clinician–Patient Relationship
  • 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 function tests Thyroid Function Tests Blood tests used to evaluate the functioning of the thyroid gland. Ion Channel Myopathy
  • 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 Screening Preoperative Care and monitoring symptom severity 
  • Hospital Anxiety and Depression Scale Scale Dermatologic Examination (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 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

• 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 Supportive psychotherapy Psychotherapy offers reassurance Reassurance Clinician–Patient Relationship and comfort.

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 reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants) and serotonin-norepinephrine reuptake inhibitors Serotonin-Norepinephrine Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)) are the 1st-line treatment.
  • Highest amount of evidence for efficacy 
  • Little risk of abuse
  • SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants: e.g., sertraline Sertraline A selective serotonin uptake inhibitor that is used in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants, citalopram Citalopram A furancarbonitrile that is one of the serotonin uptake inhibitors used as an antidepressant. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia in preference to tricyclic antidepressants, which aggravate dyskinesia. Serotonin Reuptake Inhibitors and Similar Antidepressants, and paroxetine Paroxetine A serotonin uptake inhibitor that is effective in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants 
  • SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants: e.g., venlafaxine Venlafaxine A cyclohexanol and phenylethylamine derivative that functions as a serotonin and noradrenaline reuptake inhibitor (SNRI) and is used as an antidepressant agent. Serotonin Reuptake Inhibitors and Similar Antidepressants and duloxetine Duloxetine A thiophene derivative and selective neurotransmitter uptake inhibitor for serotonin and noradrenaline (SNRI). It is an antidepressant agent and anxiolytic, and is also used for the treatment of pain in patients with diabetes mellitus and fibromyalgia. Serotonin Reuptake Inhibitors and Similar Antidepressants
• 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 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 
  • 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 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 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

Comparison with Other Anxiety Disorders

Differential Diagnosis

• Intoxication ( 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 amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants): patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 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 Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, 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 Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children), diaphoresis, and mydriasis Mydriasis Dilation of pupils to greater than 6 mm combined with failure of the pupils to constrict when stimulated with light. This condition may occur due to injury of the pupillary fibers in the oculomotor nerve, in acute angle-closure glaucoma, and in adie syndrome. Glaucoma. Acute intoxication is distinguished from GAD by history taking, physical exam, and urine toxicology screen. 
• Withdrawal (from alcohol or 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): patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance, anhedonia Anhedonia Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia). Schizophrenia, feelings of guilt or worthlessness, loss of energy, low concentration, weight or appetite changes, psychomotor retardation or agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, and suicidal ideation Suicidal ideation A risk factor for suicide attempts and completions, it is the most common of all suicidal behavior, but only a minority of ideators engage in overt self-harm. Suicide. These symptoms last for ≥ 2 weeks. Excessive worry is a common feature of 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 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 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, 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.