Treatment Resistant Generalized Anxiety Disorder

Treatment Resistant Generalized Anxiety Disorder

  1. •Anxiety refers to a state of anticipation of alarming future events, whereas fear is a result of perceived imminent threat. The former is the same distressing experience of dread and foreboding as the latter, except that it derives from an unknown internal stimulus or is inappropriate to the reality of the current situation. Anxiety is manifested in the physical, affective, cognitive, and behavioral domains.
  2. •Individuals with GAD commonly present with excessive and disproportionately high levels of anxiety, fear, or worry for most days over at least a 6-mo period in a number of areas. The worrying must be greater than would be expected given the situation, and it must cause significant interference in functioning. The subjective anxiety must be accompanied by at least three somatic symptoms in adults and one in children (e.g., restlessness, irritability, sleep disturbance, muscle tension, difficulty concentrating, or fatigue). GAD cannot be diagnosed if it occurs only in the context of an active mood, such as depression, or if the anxiety is better explained by another active anxiety disorder, such as PTSD or panic disorder. These disorders are often misdiagnosed as “treatment resistant” GAD.

Etiology & Risk Factors

  • •Hypotheses include models based on neurotransmitters (catecholamines, indolamines) and developmental psychology (e.g., behavioral inhibition, neuroticism, and harm avoidance).
  • •Prevalence increases with a family history, increase in stress, history of physical or emotional trauma, and medical illness.

Clinical Features

Presenting Signs and Symptoms

  • •Report of being “anxious” all of their lives
  • •Excessive worry, usually regarding family, finances, work, or health
  • •Sleep disturbance, particularly early insomnia
  • •Muscle tension (typically in the muscles of neck and shoulders) or headache
  • •Difficulty concentrating
  • •Daytime fatigue
  • •Gastrointestinal symptoms compatible with irritable bowel syndrome (one third of patients)
  • •Physical symptoms are the usual reason for seeking medical attention
  • •Comorbid psychiatric illness (e.g., dysthymia or major depression) and substance abuse (e.g., alcohol abuse) are frequent

 Diagnosis

  • •When diagnosing treatment resistant GAD, it is imperative to rule out selected medical causes/contributing factors.
  • •Screening tests may enhance detection. A screening tool often used in primary care is the GAD-2. It asks, “During the past month, have you been bothered a lot by:
    • 1.“Nerves or feeling anxious or on edge?”
    • 2.“Worrying about a lot of different things?” The response to each question is given a score of 0 (not at all), 1 (several days), 2 (more than half of the days), 3 (nearly every day).
  • •A score of ≥3 has a sensitivity of 86% and a specificity of 83% for detecting GAD. A simple 7-item in-office case finding instrument, the GAD-7, includes additional questions to assess symptom severity and can be used to monitor symptoms.

Selected Medical Causes of Anxiety

From Stern TA et al: Massachusetts General Hospital handbook of general hospital psychiatry, ed 7, 2018, Elsevier.

Endocrine
1.Adrenal cortical hyperplasia (Cushing disease)
2.Adrenal cortical insufficiency (Addison disease)
3.Adrenal tumors
4.Carcinoid syndrome
5.Cushing syndrome
6.Diabetes mellitus
7.Hyperparathyroidism
8.Hyperthyroidism
9.Hypoglycemia
10.Hypothyroidism
11.Insulinoma
12.Menopause
13.Ovarian dysfunction
14.Pancreatic carcinoma
15.Pheochromocytoma
16.Pituitary disorders
17.Premenstrual syndrome
18.Testicular deficiency
Drug-Related
Intoxication
1.Analgesics
2.Antibiotics
3.Anticholinergics
4.Anticonvulsants
5.Antidepressants
6.Antihistamines
7.Antihypertensives
8.Antiinflammatory agents
9.Antiparkinsonian agents
10.Aspirin
11.Caffeine
12.Chemotherapy agents
13.Cocaine
14.Digitalis
15.Hallucinogens
16.Neuroleptics
17.Steroids
18.Sympathomimetics
19.Thyroid supplements
20.Tobacco
Withdrawal
1.Ethanol
2.Narcotics
3.Sedative-hypnotics
Cardiovascular and Circulatory
1.Anemia
2.Cerebral anoxia
3.Cerebral insufficiency
4.Congestive heart failure
5.Coronary insufficiency
6.Dysrhythmias
7.Hyperdynamic β-adrenergic state
8.Hypovolemia
9.Mitral valve prolapse
10.Myocardial infarction
11.Type A behavior
Respiratory
1.Asthma
2.Hyperventilation
3.Hypoxia
4.Pneumonia
5.Pneumothorax
6.Pulmonary edema
7.Pulmonary embolus
Immunologic-collagen Vascular
1.Anaphylaxis
2.Polyarteritis nodosa
3.Rheumatoid arthritis
4.Systemic lupus erythematosus
5.Temporal arteritis
Metabolic
1.Acidosis
2.Acute intermittent porphyria
3.Electrolyte abnormalities
4.Hyperthermia
5.Pernicious anemia
6.Wilson disease
Neurologic
1.Brain tumors (especially in the third ventricle)
2.Cerebral syphilis
3.Cerebrovascular disorders
4.Combined systemic disease
5.Encephalopathies (toxic, metabolic, infectious)
6.Epilepsy (especially temporal lobe epilepsy)
7.Essential tremor
8.Huntington’s disease
9.Intracranial mass lesion
10.Migraine headaches
11.Multiple sclerosis
12.Myasthenia gravis
13.Organic brain syndrome
14.Pain
15.Polyneuritis
16.Postconcussive syndrome
17.Postencephalitic disorders
18.Posterolateral sclerosis
19.Vertigo (including Ménière disease and other vestibular dysfunction)
Gastrointestinal
1.Colitis
2.Esophageal dysmotility
3.Peptic ulcer
Infectious disease
1.Acquired immunodeficiency syndrome
2.Atypical viral pneumonia
3.Brucellosis
4.Malaria
5.Mononucleosis
6.Tuberculosis
7.Viral hepatitis
Miscellaneous
1.Nephritis
2.Nutritional disorders
3.Other malignancies (e.g., oat cell carcinoma)

History & Physical Examination

  • •The possible physical symptoms of anxiety reflect autonomic arousal and include an array of bodily perturbations.
  • •The anxious state ranges from edginess and unease to terror and panic. Cognitively, the experience is one of worry, apprehension, and thoughts concerned with emotional or bodily danger. Behaviorally, anxiety triggers a multitude of responses concerned with diminishing or avoiding the distress.

Physical Signs and Symptoms of Anxiety

From Stern TA et al: Massachusetts General Hospital handbook of general hospital psychiatry, ed 7, 2018, Elsevier.

1.Anorexia
2.“Butterflies” in stomach
3.Chest pain or tightness
4.Diaphoresis
5.Diarrhea
6.Dizziness
7.Dry mouth
8.Dyspnea
9.Faintness
10.Flushing
11.Headache
12.Hyperventilation
13.Light-headedness
14.Muscle tension
15.Nausea
16.Pallor
17.Palpitations
18.Paresthesias
19.Sexual dysfunction
20.Shortness of breath
21.Stomach pain
22.Tachycardia
23.Tremulousness
24.Urinary frequency
25.Vomiting

Laboratory Tests

  • •Thyroid profile
  • •Electrolyte measures, including calcium
  • •Toxicology screen
  • •ECG
  • •Acute cases: Possible monitoring and cardiac enzymes to rule out arrhythmia or ischemia

Differential Diagnosis

  • •Anxiety symptoms may be the principal manifestation of an underlying medical illness. 
  • •Of patients referred for psychiatric treatment, 5% to 42% have been reported as having an underlying medical illness responsible for their distress, with depression and anxiety as frequent complaints. 
  • •Of reported cases of medical illnesses causing anxiety symptoms, 25% have been secondary to neurologic problems; 25% to endocrinologic causes; 12% to circulatory, rheumatoid, or collagen vascular disorders and chronic infection; and 14% to miscellaneous other illnesses. 
  • •A most common cause of anxiety may be alcohol and drug use; the anxiety results from either intoxication or, more typically, withdrawal states. 
  • •Medical illnesses that may generate or exacerbate anxiety symptoms.
  • •Iatrogenic cause should be suspected if anxiety follows recent changes in medication.
  • •If patients are in acute distress, the possibility of another cause, including another anxiety disorder such as panic disorder, should be considered.

How is this treated?

First-Line Treatment

  • •Cognitive-behavioral therapy
  • •SSRIs and SNRIs (e.g., venlafaxine and duloxetine) are effective typical first-line treatment. Particularly useful if comorbid depression present.

Pharmacologic Therapy

  • •Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).
  • •Benzodiazepines can be effective under close supervision; however, they have fallen out of favor as a first-line treatment given their potential for functional impairment, abuse, and dependence. Drug selection is based on pharmacokinetic properties, which determine the rapidity of onset of effect, the degree of accumulation with multidosing, the rapidity of offset of clinical effect, and the risk of drug discontinuation syndrome.
  • •Sedating antidepressants, such as mirtazapine, may also be useful for initial insomnia secondary to anxious ruminations.
  • •Buspirone can be effective with minimal potential for tolerance or abuse. May be less effective in patients with previous benzodiazepine exposure and may require a high-dose titration.

Nonpharmacologic & Supportive Care

  • •Cognitive-behavioral therapy
  • •Acceptance and commitment therapy
  • •Relaxation training and meditative approaches
  • •Biofeedback
  • •Psychodynamic psychotherapy

Persistent or Recurrent Disease 

  • •Anticonvulsants (including valproate, gabapentin, topiramate, and lamotrigine) are increasingly being studied and used for a range of anxiety disorders, with some (e.g., gabapentin) administered as an alternative to benzodiazepines because of their sedating properties and tolerability.
  • •β-Blocking drugs, such as propranolol hydrochloride, have proved useful in alleviating some of the peripheral autonomic symptoms of anxiety (such as tremor and tachycardia). Although of second-line or third-line importance in treating panic attacks or more cognitively experienced symptoms (e.g., worry), β-blockers are often impressively useful in the performance-anxiety subtype of social phobia and when persistent peripheral symptoms (somatic anxiety) predominate. Agents, such as atenolol, that are less able to cross the blood–brain barrier than propranolol may have advantages for patients who experience fatigue or dysphoria when taking propranolol. Effective doses vary, and treatment requires upward titration from low initial doses. 
  • •CBT for anxiety disorders brings to bear an array of cognitive restructuring, exposure, and symptom management techniques that target the core fears and behavioral pattern characterizing each anxiety disorder. Cognitive interventions include a variety of procedures to challenge and restructure the inaccurate and maladaptive cognitions that increase anxiety and help maintain anxiety disorders. Procedures range from informational discussions, self-monitoring, and Socratic questioning to the construction of behavioral experiments in which patients can directly examine the veracity of anxiogenic expectations. A reliance on corrective experiences also lies at the heart of exposure interventions that provide patients with opportunities to extinguish learned fears, by directly confronting (in a hierarchical fashion) feared events and sensations. Symptom management techniques typically include relaxation and breathing retraining procedures to help eliminate anxiogenic bodily reactions. In addition, training in problem-solving or social skills may be necessary to eliminate behavioral deficits that help maintain anxiety disorders. Similarly, couples sessions may be required to change family patterns that help maintain avoidant or other anxiety-related behaviors. 

Follow-Up

Referral

  • •For refractory symptoms
  • •For comorbid psychiatric conditions

Disposition

  • •GAD is chronic with periodic exacerbations.
  • •Treatment is given to reduce level of symptoms and improve functioning. Suicide risk is higher than in the general population.

Pearls & Considerations

When evaluating treatment resistant GAD is important to rule out PTSD, panic disorder, and other psychiatric illnesses. Work up should also rule out medical disorders that mimic GAD and may interfere with treatment of GAD.

References

  • 1. Glass S.P., Pollack M.H., Otto M.W., Wittman C.W., Rosenbaum J.F.: Anxious patients. In Stern TA (eds): Massachusetts General Hospital handbook of general hospital psychiatry., ed 7 2018. Elsevier,
  • 2. Hall R.C.W.: Anxiety. RCW hall psychiatric presentations of medical illness: somatopsychic disorders. 1980. SP Medical & Scientific Books, New York pp. 13-35.
  • 3. Hall R.C., Gardner E.R., Popkin M.K., et al.: Unrecognized physical illness prompting psychiatric admission: a prospective study. Am J Psychiatry 1981; 138 (5): pp. 629-635.
  • 4. Cavanaugh S., Wettstein R.: Prevalence of psychiatric morbidity in medical populations. Psychiatry Update 1984; 3: pp. 187-215.
  • 5. Cameron O.G.: The differential diagnosis of anxiety. Psychiatric and medical disorders. Psychiatr Clin North Am 1985; 8 (1): pp. 3-23.
  • 6. Altunoz U., et al.: Clinical characteristics of generalized anxiety disorder: older vs. young adults. 2018; 72: pp. 97-102.
  • 7. McEvoy P.M., et al.: Group metacognitive therapy for repetitive negative thinking in primary and non-primary generalized anxiety disorder: an effectiveness trial. J Affect Disord 2015; 175: pp. 124-132
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