ANXIETY

ANXIETY - Mitzi Wasik, PharmD, BCPS
BASICS
DESCRIPTION (1)
A common acute or chronic, fearful emotion with associated physical symptoms. DSM-IV-R recognizes the following subtypes
• Acute situational anxiety: Response to recent stressful event, usually transient symptoms
• Generalized anxiety disorder (GAD): Persistent underlying anxiety or adjustment disorder with anxious mood and significant symptoms of motor tension, autonomic hyperactivity, and hypervigilance, lasting >6 months
• Panic disorder (PD): Recurrent unexpected attacks with at least one attack (or more) associated with persistent concern about additional attacks, worries about implications of the attack (losing control, having a heart attack), or a significant change in behavior related to the attack; often leads to agoraphobia
• Social phobia (Social Anxiety Disorder): Marked and persistent fear and avoidance of performance or social situations in which the person is exposed to unfamiliar people or scrutiny
• System(s) Affected: Nervous
GENERAL PREVENTION (2)
• Cognitive behavior therapy
• Management of stress, to extent possible
• Relaxation techniques
• Meditation
EPIDEMIOLOGY (3)
Predominant sex: Female > Male (2:1)
Incidence
• 15.7 million Americans suffer from anxiety disorders every year, 30 million will suffer at some point in their lives
• 30% of patients suffering from anxiety seek treatment.
Prevalence
• 12-month prevalence rate
- Panic disorder:1.3-1.7%
- Generalized anxiety disorder
 All ages12.1-12.7%
- Social phobia: 1.7-3.7%
• Onset can occur anytime in life, from adolescent to adulthood
- Women >age 45 are most frequently affected
RISK FACTORS
Social and financial problems, medical illness, family history, lack of social support
Genetics
Panic disorder: Increased concordance in monozygotic versus dizygotic twins
ETIOLOGY
• Panic disorder, social phobia, and obsessive compulsive disorder are associated with genetic factors.
• Mediated by abnormalities of neurotransmitter systems (serotonin, norepinephrine, and gamma-aminobutyric acid [GABA])
ASSOCIATED CONDITIONS
• Depression (commonly)
• Agoraphobia
• Alcohol or substance abuse
• Somatoform disorders


DIAGNOSIS
(1,4)
SIGNS AND SYMPTOMS
History
Symptoms must occur for more days than not for 6 months
Physical Exam
• 3 (or more) criteria are required for diagnosis of GAD. Only one required in children
- Restlessness or feeling keyed up or on edge
- Easily fatigued
- Difficulty concentrating or mind going blank
- Irritability
- Muscle tension
- Sleep disturbances (difficulty falling or staying asleep)
- Difficulty controlling worry
• Persistent worry must cause significant distress, impairment in social, occupational, or other areas of functioning
• Nonspecific signs and symptoms that may be present with different subtypesunrealistic or excessive anxiety or worry, sense of impending doom, nervousness, instability, tachycardia, palpitations, systolic click murmur, hyperventilation, choking sensation, sighing respiration, nausea or abdominal distress, paresthesias, diaphoresis, dizziness or syncope, flushing, muscle tension, tremulousness, restlessness, headache, backaches, and muscle spasm
TESTS
EEG, ECG, etc.
Lab
Laboratory tests are often normal. See Differential Diagnosis for conditions to rule out.
Imaging
Usually none
Diagnostic Procedures/Surgery
Psychologic testing
• Anxiety Disorders Interview Schedule (ADIS), Hamilton's Anxiety Scale (HAM-A), Clinical Global Impression Scale (CGI), DSM-IV-R criteria
DIFFERENTIAL DIAGNOSIS
• Cardiovascular
- Ischemic heart disease, valvular heart disease, cardiomyopathies, myocarditis, arrhythmias, mitral valve prolapse (most symptomatic cases are associated with panic disorder), congestive heart failure, or myocardial infarction
• Respiratory
- Asthma, chronic obstructive pulmonary disease, pulmonary embolism, or pneumonia
• CNS
- Stroke, seizures, dementia, migraine, Parkinson disease, neoplasms
• Metabolic and hormonal
- Hyperthyroidism, pheochromocytoma, adrenal insufficiency, Cushing syndrome, hypokalemia, hypoglycemia, hyperparathyroidism
• Nutritional
- Thiamine, pyridoxine, or folate deficiency, iron deficiency anemia
• Drug-induced anxiety
- Alcohol, sympathomimetics (cocaine, amphetamines, caffeine)
• Withdrawal
- Alcohol, sedative-hypnotics
• Other
- Other psychiatric comorbidities
TREATMENT
GENERAL MEASURES
• Appropriate health care: Outpatient
• Based on careful workup and identification of etiology and subtype of anxiety disorders
• Identify coexistent substance abuse.
• Counseling or psychotherapy along with medications, biofeedback in selected cases
• Serial office visits
Diet
• Limit caffeine intake.
• Avoid alcohol (drug interactions).
Activity
Physical exercise
SPECIAL THERAPY
Complementary and Alternative Medicine
Kava was previously used but is no longer in favor due to liver toxicities.
MEDICATION (DRUGS) (3,5,6,7,8)
First Line
• Conditions
- Acute situational anxiety: Short-term (up to 1 month) treatment with benzodiazepines (2)[B]
- Generalized anxiety disorder
- Escitalopram (Lexapro) 10 mg/day titrated by 10 mg every week to a max of 20 mg/day (10 mg/day max) (1)[A]
- Paroxetine (Paxil) 10 mg daily titrated by 10 mg a week to a max 50 mg/day (20 mg/day most effective dose); (10 mg/day) (1)[A]
- Venlafaxine (Effexor XR) 37.5-75 mg titrated to a max of 225 mg/day (1)[A]
- Imipramine (Tofranil) 50 mg/day (max 200 mg/day, 100 mg in elderly) (1)[A]
- Fluoxetine (Prozac) 10 mg daily up to max of 20-40 mg/day (2)[C]
- Sertraline (Zoloft) 25 mg daily up to max of 200 mg/day (2)[B]
- Buspirone (Buspar) 20-30 mg/day divided b.i.d. to t.i.d. (max 60 mg/day) (1)[A]
• Panic disorder and social phobia: SSRIs, TCAs (e.g., imipramine), buproprion, trazodone, and beta-blockers (2)[B]
Second Line
• Generalized anxiety disorder
- Hydroxyzine 50-100 mg q6h (max 400 mg/day) (1) [A]
• BZDs (short-term use) (1)[A]
- Alprazolam (Xanax) 0.25 mg b.i.d. to t.i.d. increase by 0.25 mg, if needed
- Clonazepam (Klonopin) 0.5 mg t.i.d. to maximum of 1.5-4.5 mg per day
- Diazepam (Valium) 2-5 mg b.i.d. increase by 2 mg if needed
- Lorazepam (Ativan) 0.5 mg b.i.d. to t.i.d. increase by 0.5 mg if needed (response, if any, is slow, often 4-6 weeks)
• Panic disorder
- BZDs may be used short term until TCA or SSRI takes effect (2-3 weeks)
- BZDs may be helpful for initial control of symptoms until the SSRIs or TCAs are effective.
ALERT
Pediatric Considerations
• Reduced dosage of medications in adolescent
• Anxiety often comorbidly exists with ADHD
Geriatric Considerations
• Reduced dosage of medications
• Avoid TCAs and long-acting benzodiazepines.
Pregnancy Considerations
• BZDs: Contraindicated in 1st trimester of pregnancy, and with caution later in pregnancy and during lactation. May cause lethargy and weight loss in nursing infants; avoid breast-feeding if the mother is taking benzodiazepines chronically or in high doses.
• SSRIs: Taper and discontinue, if possible, in 1st trimester; may be used later in pregnancy (except paroxetine Class D).
• Precautions:
- BZDs: Advanced age, renal insufficiency, suicidal tendency, open-angle glaucoma. Sudden discontinuation increases the risk of seizures, especially with alprazolam.
- BZDs with short half-lives (e.g., alprazolam) increase the potential for dependency and protracted withdrawal symptoms; use with caution when patients with severe panic disorder are taking other CNS sedatives or with patients who have a history of substance abuse/dependence.
- Buspirone: Hepatic and/or renal dysfunction
- TCAs: Advanced age, glaucoma, benign prostate hypertrophy, hyperthyroidism, cardiovascular disease, liver disease, urinary retention, MAO inhibitor treatment
• Significant possible interactions
- BZDs (CYP inhibitors/inducers): Cimetidine, ethanol, oral contraceptives, disulfiram, levodopa, rifampin
- Buspirone: MAO inhibitors
- TCAs: Amphetamines, barbiturates, guanethidine, clonidine, epinephrine, ethanol, norepinephrine, MAO inhibitors, propoxyphene, allow 14-day washout period before starting MAOIs after TCA d/c
- SSRIs: MAO inhibitors (may cause fatal serotonin syndrome), may raise serum levels of other medications
FOLLOW-UP
PROGNOSIS
With active treatment, excellent results can often be obtained.
COMPLICATIONS
• Impaired social/occupational functioning
• Drug dependence (benzodiazepines)
• Alcohol dependence
PATIENT MONITORING
• Watch for and treat associated psychiatric disorders.
• Monitor mental status on benzodiazepines and avoid drug dependence.
• Monitor blood pressure, heart rate, and anticholinergic side effects on TCAs.
• Monitor for suicidality with SSRIs, venlafaxine, and imipramine.
REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association, 2000:429-484.
2. Rickels K, Moira R. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry. 2002;63(suppl 14):9-16.
3. Lepine J. The epidemiology of anxiety disorders: Prevalence and societal costs. J Clin Psychiatry. 2002;63(suppl 14):4-8.
4. Kirkwood C, Melton S, Pharmacotherapy: A pathophysiologic approach. In: Anxiety Disorders I: Generalized Anxiety, Panic, and Social Anxiety Disorders. 6th ed. New York, NY; McGraw Hill: 2005.
5. Rickels K, Rynn M, Iyengar M, et al. Remission of generalized anxiety disorder: A review of the paroxetine clinical trials database. J Clin Psychiatry. 2006;67(1):41-47.
6. Goodman WK, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: Pooled results from double-blind, placebo-controlled trials. J Affect Disord. 2005;87(2-3):161-167.
7. Mitte K, Noack P, Steil R, Hautzinger M. A meta-analytic review of the efficacy of drug treatment in generalized anxiety disorder. J Clin Psychopharmacol. 2005;25(2):141-150.
8. Briggs G. Drugs In Pregnancy And Lactation: A Reference Guide to Fetal and Neonatal Risk. 7th ed. Philadelphia, PA: Lippincott Williams  Wilkins; 2005.
ADDITIONAL READING
• Medline Plus, www.medlineplus.gov
• Mayo Clinic, www.mayoclinic.com
MISCELLANEOUS
Abbreviations: DSM-IV-R, Diagnostic and Statistical Manual of Mental Disorders, 4th edition Text Revision; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; CYP, cytochrome P450 enzymes; BZD, benzodiazepine