Generalised Anxiety Disorder

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Original Editors - Ellen Baumann from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description

According to Goodman and Fuller, anxiety can be defined as a heightened emotional state of concern, worry, or apprehension. It can lead to physiologic arousal causing an increase in heart rate and sweat gland activity.

Anxiety is a normal feeling to encounter; however when one experiences excessive worry, tension, and anxious feelings on a daily basis then he/she may have generalized anxiety disorder (GAD). This disorder is diagnosed with a person demonstrates anxious feelings and constant worry over daily activities for a six-month time frame. GAD can be considered primary or seconary depending on the onset. If GAD occurs early in life without out any other diagnoses, than it is considered primary. However if GAD develops later in life and there are other diosrders present, it is considered secondary in nature. 

Prevalence

Generalized Anxiety Disorder affects nearly 6.8 million American adults. GAD is a gradually progressing disorder and can occur at any point throughout the lifespan, however is most often occurs between childhood and midlife. Women are two times more likely to develop GAD than men. Other factors that correlate to an increased prevalence of GAD include being older than 24 years of age, separated, widowed, divorced, unemployed, or being a homemaker.

GAD is one of the most common anxiety disorders seen by physicians and these patients are frequesnt users of the healthcare system. In a review article written by Katzman titled Current Consideration in the Treatment of Generalized Anxiety Disorder found that in a recent survey, "patients who sought help from mental health services in the past year had a 50% chance of having GAD." Patients who have been diagnosied with GAD are also at a greater risk for suicide or suicide attempts.

Characteristics/Clinical Presentation

There are many characteristics/symptoms assosciated with generalized anxiety disorder. The most common include: 

• Constant worrying and excessive anxiety (about small or large concerns)
  
• Difficulty concentrating
  
• Excessive sweating
• Palpitations or rapid heart beat
• Chest Pain
• Shortness of breath
• Stomach/intestinal symptoms
• Nausea or diarrhea
• Fatigue
• Irritability
• Muslce tension/ muslce aches
• Headaches
• Restlessness/ feeling 'on edge'
• Trembling or easily startled
• Sleep disturbance: difficulty falling asleep, staying asleep, or restless, unsatisfying sleep

Anxiety disocrders are often associated with depression and substance abuse. 

Goodman and Snyder state that "anxiety amplifies physical symptoms." The text also states that anxiety increases muslce tension. This increase in tension can reduce blood flow and oxygen to the tissue and in turn cause a buildup of celluar metabolites. This statement demonstrates that musculoskeletal complaints (headaches, back pain, muslce tension/aches, and fatigue) can be caused from anxiety-caused tension or heightened sensitivity to pain.

People who have a general anxiety disorder place an increased attention on physical and emotional pain. This increased focus can be in the form of the person noticing pain more or interpreting the pain as more significant. Goodman and Fuller state that disability, pain behavior (limping and facial grimacing), and the seeking of medication could develop with anxiety diosrders. Physical, behavioral, cognitive, and/or psychologic symptoms may be present.

The autonomic nervous system can refer pain to the somatic systems of the body. These symptoms incluse chest pain, pelvic pain, dyspnea, palpatations, parasthesia, and possible digestive, bowel, or bladder disorders.

Goodman and Fuller explain that anxiety can become self-generating. This can be expalined in that the symptoms of anxiety reinforce the reaction and in turn cause a 'spiral effect'. Certain items can stimulate the spiral effect and trigger anxiety disorderes; these include caffeine, cocaine, or other stimulant drugs, medications containting caffiene, and even stimulants used for the treatment of asthma.

Associated Co-morbidities

Co-morbidies play an essential role in describing and understanding general anxiety diosrders. The conditions of GAD may not be recognized as an emotional problem until the secondary disorder/ co-morbidity develops. Hoyer et al. states that epidemiological studies have found high rates of co-morbidity in GAD.  

Generalized anxiety disorder is most often associated with other disorders which can include other anxiety disorders, depression, and substance abuse. GAD can also lead to or worsen pre-existing conditions such as insomnia, digestive or bowel problems, headaches, and bruxism (teeth grinding).

Other associated anxiety disorders can include panic disorder, phobias, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), or adjustment disorder with anxious mood (those with an organic illness).

In a study of GAD in young women, Hoyer et al found that the timing of the co-morbidities can either appear later in the course of the general anxiety disorder or they may appear early in the developmental stages of the disorder. 

Co-morbidities that may be associated with GAD include: Major Depressive Disorder, Dysthymia, Specific (simple) Phobia, Social Phobia (social anxiety disorder), Agoraphobia, Panic Disorder, Mania, Substance abuse, Alcohol use/dependence, Drug abuse/dependence.

Medications

See Medical Management section for current use of medications to help treat GAD.

Diagnostic Tests/Lab Tests/Lab Values

There are two main diagnostic tools used for generalized anxiety disorder: in Europe, the International Statistical Classification of Diseases- 10th revision (ICD-10) and in the United States the Diagnostic and Statistical Manual for Mental Disorders- Fourth Edition (DSM-IV).

According to Katzman, the criteria for generalized anxiety disorder include:

ICD-10 Criteria:

• For a diagnosis of GAD, patient must have anxiety that is generalized and persistent but not restricted to, or even strongly predominating in, any particular environmental circumstances, i.e. it is 'free-floating'. Dominant symptoms are variable but include persistent nervousness, trembling, muscular tensions and epigastric discomfort. Fears that the pateint or a relative will shortly become ill or have an accident are often expressed.

DSM-IV criteria:

• For a diagnosis of GAD, patient must have excessive anxiety and worry for 6 months, plus have three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or sleep disturbance.

Goodman and Snyder suggest that during the subjective examination of a patient, one may want to ask specific questions regarding anxiety/depression.

• Have you been under a lot of stress lately?
• Are you having some trouble coping with life in general and/or life's tensions?
• Do you feel exhausted or overwhelmed mentally or physically?
• Does your mind go blank or do you have trouble concentrating?
• Do you have trouble sleeping at night (difficulty getting to sleep, staying asleep, restless sleep, feel exhaused upon awakening)? Do you have trouble focusing during the day?
• Do you worry about finances, work, or life in general?
• Do you get any enjoyment in life?
• Do you feel keyed yo or restless? Irritable and jumpy? On edge most of the time?
• Do you have an general sense of dread or unknown fears?
• Do you have any of these symptoms: a racing heart, dizziness, tingling, muscle or joint pains?

The authors also list qustions specific to Asian patient/clients:

• Do you feel you are having any imbalance of yin and yang?
• Is your chi (internal energy) low?
• Do you believe it is your destiny to have this condition or your destiny not to have this condition? (This is a fatalism versus well-being approach to illness.)

Causes

The exact cause of Generalized Anxiety Disorder is not fully understood. According to the Mayo Clinic, GAD may be caused by brain chemicals (neurotransitters) and their natural fluxuation. These neurotransmitters include serotonin, dopamine, and norepinephrine. There is also evidence that genitics play a role in the development of GAD. Other possible causes include environment and stress levels.

Systemic Involvement

The symptoms of anxiety can manifest in several ways incorporating physcial, behavioral, cognitive, and psychologic aspects of life.

Physical: 

• Increased signing
• Increased blood pressure
• Tachycardia
• Shortness of breath
• Dizziness
• Lump in throat
• Muscle tension
• Dry mouth
• Diarrhea
• Nausea
• Clammy hands
• Profuse sweating
• Restlessness, pacing, irritability, difficulty concentrating
• Chest pain
• Headache
• Low back pain
• Myalgia (which consists of muscle pain, tension, or tenderness)
• Arthralgia (joint pain)
• Abdominal distress
• Irritable bowel syndromw (IBS)
  

Behavioral:

• Hyperalertness
• Irritability
• Uncertainty
• Apprehension
• Difficulty with memory or concentration
• Sleep disturbance
  

Cognitive:

• Fear of losing mind
• Fear of losing control
  

Psychologic:

• Phobias
• Obsessive-compulsive behavior

Anxiety can also affect the systemic systems throughout the body. These can include:

• Cardiopulmonary System: Chest pain, tachycardia, increased blood pressure, increased sighing respirations, shortness of breath
  
• Musculoskeletal System: Muscle tension, myalgia, arthralgia, low back pain
  
• Gastrointestinal System: Lump in throat, diarrhea, nausea, irritable bowel syndrome (IBS)
• Neurologic System: Dizziness, difficulty concentrating and making decisions, problems with memory
  
• General/ multiple system involvment: Fatigue, sleep disturbances, dry mouth, sweating, clammy hands, headache
  

There are screening tools that can differential between systeminc involvement versus psychogenic symptoms. These include the McGill Pain Questionnaire, Illness Behavior Syndrome and Symptom Magnification, and Waddell's Nonorganic Signs.

According to Goodman and Snyder, to help differentiate between these two sources (systemic and psychogenic) of symptoms, series of questions can be asked to the patient.

• Do you have trouble sleeping at night?
• Do you have trouble focusing during the day?
• Do you worry about finances, work, or life in general?
• Do you feel a sense of dread or worry without cause?
• Do you ever feel happy?
• Do you have a fear in being in groups of people? Fear of flying? Public speaking?
• Do you have a racingheart, unexplained dizziness, or unexpected tingling in your face or fingers?
• Do you wake up in the morining with your jaw clenched or feeling sore mucles and joints?
• Are you irritable or jumpy most of the time?

Medical Management (current best evidence)

When beginning a treatment program for a patient with generalized anxiety disorder many factors must be considered. These factors include patient education, patient preference, treatment success/failure history, and the patient's co-morbidities.

It is important to educate the patient that anxiety is a medical condition that has the ability to be managed. The patient needs to understand how his/her lifestyle and internal thoughts can play a role in the management of anxiety. The patient's preference in the treatment techniques plays a major role in the management and remission of GAD. The patient needs to engage in their treatment and must be willing to make modification of their lifestyle and internal thoughts. A patient's co-morbidities also plays a role in treatment, as they might have pre-exisitng disorder that can be affecting their anxiety. Anxiety can be affect numerous systems throughout the body; therefore it is important to realize that the treatment of anxiety can also help with the associated disorders/pain throughout the body.

There are four different guideline committees that have listed their recomendations for the treatment of patients with generalized anxiety disorder. These committees consist of the World Federation of Societies of Biological Psychiatry (2002), the British Association for Psychopharmacology (2005), the National Institute for Health and Clinical Excellence (2004), and the Acnadian Psychiatric Association (2006). The focus of acute treatment for patients who experience GAD is to improve symptoms; with the primary long-term goal of remission ("the complete resoulution of both symptoms and functional impairment.") Based on the guidelines for treatment from the committees, the first stage of pharmacotherapy should include an antidepressant, such as a selective serotonin reuptake inhibitor (SSRI) or a serotonin noradrenaline reuptake inhibitor (SNRI).

First- line treatment:

Selective Serotonin Reuptake Inhibitors:

• The two common SSRI used in the treatment of GAD include paroxetine (Paxil) and escitalopram (Lexapro). Sertraline (Zoloft) can be considered a treatment option, however it is not currently licensed for GAD.
  
• All of these pharmacological interventions were studied in randomized, double-blinded, placebo controlled environments. As reported by Katzman, each SSRI showed effective treatment of GAD (with paroxetine demonstrating long-term treatment as well). These drugs helped patients achieve greater remission of their anxiety disorder when comapred to a placebo.
  
• How they work: the exact mechanism of action has not yet been determined; however the current thought is that the SSRIs involve a down-regulation of noradrenergic receptors. An advantage to these drugs is the potential for long term usage for treatment of GAD without the worry of abuse or tolerance.

Serotonin Noradrenalin (Norepinephrine) Reuptake Inhibitors:

• Two common SNRI used in the treatment of GAD include duloxetine (Cymbalta) and venlafaxine (Effexor).
• The pharmacological intervention was performed on a group of subjects in a double-blind experimental study. It was found that both duloxetine and venlafaxine produced significant improvements in anxiety when compared to those who received placebo only treatment.
  
• However, it was found that adverse side effects were significanly greater in the venlafaxine group, but not found within the duloxetine group.
• How they work: this group of medications is for the treatment of antidepression (and anxiety) which increases the levels of serotonin and norepinephrine. This increase is a result of the inhibition their reabsorbtion into the cells within the brain. The mechanism in which this occurs is not full understood; however it is believed that these higher levels enhance the neurotransmission (sending of the nerve impulses) and therefore improve and elevate mood.
  

It has been reported that SSRIs and SNRIs have "efficacy limitations, such as lack of resonse in many patients, a 2- to 4- week delay before the onset of symptom relief, lack of full remission, ans risk of relapse."

Second- line treatment:

Benzodiazepines:

• This classification of medication offers a rapid relief of anxiety symptoms for a patient. 
  
• Mechamism of action occurs by the interaction with the "receptors activated by the neuroinhibitory transmitter, GABA. In doing so, they promote binding of GABA to GABA subunit receptors (GABA A) and enhance chloride ion influx."
• They are not effective in resolving depression that is often associated/accompaned with GAD.
• Long-term use is not recommended due to concerns of dependence.
• Short to Intermediate acting agents include: oxazepam (Serax), alprazolam, lorazepam (Ativan). Loger acting agents include: diazepam (Valium), chlordiazepoxide (Librium), and clorazepate (Tranxene).

Buspirone:

• The generic name is referred to as Buspar. This drug is an azapirone and has been shoe effective in the treatment of anxiety over a placebo; however, it may not be as effective as benzodiazepines.
• The mechanism of action is mediated through serotoninergic activity (specifically as an agonist of the serotonin receptor subtype 5-hydroxytryptamine-1A.)
• It is classified as a nonaddictive, nonsedating alternative to the benzodiazepines. It is not considered a first-line treatment due to the one-to three-week delay in relief of symptoms, the short half-life (which results in dosing two to three times per day), and the decreased impact on the comorbiditiy of depression.

Pregabalin:

• This drug is currenly only recommended to those pateints who are intolerant to SSRIs or SNRIs or who do not receive full remission from SSRIs or SNRIs.
• "The mechanism of action is caused by inhibition of the release of excitatory neurotransmitters" and "the onset of action occured within the first week".
• In patients, this drug "has been shown to relieve psychic and somatic symptoms of anxiety" in a manner similar to benzodiazepines (lorazepan and alprazolam) and SNRIs (venlafaxine).
• This drug has not been FDA approved for the treatment of GAD (however it is approved in Europe).

Other Possible Medical Management:

Beta Blockers:

• Beta Blockers are used to treat patients with certain heart conditions. However this drug can also be used to help prevent the physical symptoms of certain anxiety disorders (usually a type of phobia).
• An example is propranolol (Inderal) is used to lower the heart rate that is often accompainied with anxiety.

Physical Therapy Management (current best evidence)

Physical therapists cannot directly cure anxiety, as is effects neurotransmitteres within the brain. However physical therapists need to be aware of the symptoms of anxiety due to the fact that more and more patients are being diagnosed with generalized anxiety disorder.

Alternative/Holistic Management (current best evidence)

Psychological Counseling:

Cognitive Behavioral Therapy (CBT):

• CBT involves addressing the irrational thinking patterns in how patients behave and feel. In many patients CBT has been shown to decrease the symptoms associated with GAD. CBT treatment includes numerous sessions with a trained mental health professional as well as an awareness of the principles of this therapy.
  
• According to an article written by Kavan in the American Academy of Family Physicians, "CBT addresses the role of irrational thinking in how patients feel and behave. CBT for GAD typically includes patient self-monitoring of worring or related symptoms; cognitive restructuring, including evaluating and reconsidering interpretive and predictive thoughts/worries; relaxation training; and rehersal of coping skills." This will in turn help patients understand the triggers of their anxiety and patterns of counterproductive thinking. In these therapy interventions, patients try to exchange the unnecessary worrying and thoughts with more practical problem-solving approach. These patients should also incorporate self-calming techniques (including deep brathing, relaxation, and exercise) into their daily life. This will help reduce arousal and give them a sense of control over their anxious symptoms.
  

Complemantary and Altermative Medicine (CAM) Interventions:

Herbal Supplements:

• One type of herb that has been researched for the treatment of anxiety is kava extract (Piper methysticum). There has been a cochrane systematice review and a meta-analysis that have shown kava to treat anxiety over a placebo. Kava cannot be recommended to patients due to the associated risk of hepatotoxicity.
• Other types of herbs that have been used in the treatment of anxiety include valerian, St. John wort, and passionflower. However these herbs lack research to support their effectiveness and safety.

Aromatherapy:

• There has not been many research articles pertaining to aromatherapy and anxiety. However in one small, non-controlled study of aromatherapy combined with massage, it was found that anxiety and mood improved over an eight month time frame. In another larger study of cancer patients with massage and aromatherapy, it was found that anxiety was decreased after a two week period; however these results disapperared by week ten.
• These studies did not include a control group and therefore readers cannot distinguish between the effects massage and aromatherapy on treatment of anxiety.

Meditation:

• A meditation based stress management program has been shown to help in the treatment of anxiety. However a recent Cochrane systematic review did not prove mediation to be effect over conventional treatments for anxiety.
• A "mindfulness-based cognitive therapy" has also been shown to decrease the symptoms related to anxiety.

Acupuncture:

• There have been no direct studies relating to GAD and accupuncture; however there have been studies that have been performed on patients with posttraumatice stress symdrome. A small study demonstrated positive results of acupuncture in these patients.
  

Differential Diagnosis

Kavan, Elsasser, and Barone created a differential diagnosis table within their article titled Generalized Anxiety Disorder: Practical Assessment and Management.

Cardiopulmonary Disease:

• Angina pectoris
  
• Cardiac arrythmia
  
• Cardiomyopathy
  
• Congestive heart failure
  
• Hyper/hypotension
  
• Mitral valve prolapse
  
• Myocardial infarction
  
• Recurrent pulmonary embolism
  

Endocrine Disorders:

• Hypercortisolism (Cushing syndrome)
  
• Hyperthyroidism (throtoxicosis)
  
• Hypoglycemis
  
• Hypoparathyroidism
  
• Hypothyroidism
  
• Phechromocytoma
  

Metabolic Conditions:

• Acidosis
  
• Electrolyte abnormalities
  
• Pernicious Anemia
  

Neurologic Disorders:

• Encephalitis
  
• Narcolepsy
• Neoplasms
• Parkinson disease
• Seizure
• Vestibular dysfunction (labyrinthitis, Meniere disease)

Nutritional Deficiencies:

• Folate
• Pyridoxine
• Vitamin B-12

Psychiatric Disorders:

• Adjustment disorder (with anxiety, with anxiety and depressed mood)
  
• Depression
• Other anxiety disorders: panic disorder, social anxiety disorder, substance-induced anxiety disorder, anxiety disorder casued by a general medical condition
  

Respiratory:

• Asthma
  
• Chronic obstructive pulmonary disease (COPD)
  
• Hypoxia
  
• Pnemonia
  

Other Disorders:

• Acute hyperventilation syndrome
  
• Acute intermittent porphyria
  
• Chronic fatigue syndrome
  
• Wilson disease
  

Within this same article, the authors list anxiety-inducing medications and substances which include:

Medication/substance usage:	Medication/substance Withdrawal:
Amphetamines	Alcohol
Anticholinergics	Anticholinergics
Beta-adrenergic agonists	Anxiolytic (e.g. benzodiazepines)
Caffine	Barbiturates
Cannabis	Beta blockers
Clonidine (Catapres)	Caffine
Cocaine	Cocaine
Corticosteroids	Hypnotics
Digoxin toxicity	Nicotine
Ephedrine and decongestants	Opiates
Hallucinogens	Sedatives
Herbal medicine (e.g. ginseng)
Methylphenidate (Ritalin)
Neuroleptics
Reserpine
Selective serotonin reuptake inhibitors (SSRI)
Sympathomimetics
Theophylline toxicity
Thyroxine and levothyroxine

Case Reports

add links to case studies here (case studies should be added on new pages using the case study template)

Generalized anxiety disorder and clinical worry episodes in young women

The impact of generalized anxiety disorder and stressful life events onrisk for major depressive episodes

Resources

National Institue of Mental Health

Mayo Clinic

RxList: The Internet Drug Index

Recent Related Research (from Pubmed)

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References

see adding references tutorial.