GENERALISED ANXIETY DISORDER

Introduction
Background
Generalized anxiety disorder (GAD), previously termed overanxious disorder of childhood, is one of the most frequently encountered anxiety disorders. It has a 12-month prevalence ranging from 3-5% and a lifetime prevalence of 4-7% with a possible additional 4% that are subsyndromal in presentation.

Generalized anxiety disorder is commonly encountered in the primary care outpatient medical setting. It causes a persistent relapsing and debilitating functional disability due to the diversity of symptom presentation, including autonomic, musculoskeletal, gastrointestinal, and respiratory symptoms as well as psychological symptoms of anxiety, tension, and worry. When patients are asked about their quality of life, the reported impairment is comparable to that of major depression.

Long-term risks of generalized anxiety disorder include increased risk of medical complications from unnecessary and sometimes risky testing or invasive procedures and mortality from secondary depression due to increased risk of suicide and/or homicide.

Generalized anxiety disorder is characterized by persistent, excessive, unrealistic, and disabling worry in children, adolescents, and adults as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Changes from the prior category of overanxious disorder of childhood include that in children and adolescents only 1 symptom of anxiety is required such as restlessness, fatigue, difficulty concentrating, irritability, muscle aches, muscle tension, or sleep difficulties.1 Although fear and worry are common in healthy children, generalized anxiety disorder is diagnosed when the worrying significantly interferes with functioning.2

Typically, healthy infants and toddlers experience separation anxiety and fears of loud noises, being startled, strangers, monsters, and darkness. School-aged children may worry about bodily injury and natural disasters. In adolescents, worries and fears may include concerns about social acceptance, psychosexual development, and academic performance, typically involving test anxiety despite above average potential. In adults, worries generally include fear of poor job performance and performance anxiety.

In general, clinicians diagnose generalized anxiety disorder when fears and worries intensify with increasing age and result in impairment of functioning.3

A child with generalized anxiety disorder may frequently seek reassurance as to the safety of family members to the exclusion of participation in normative activities. Associated symptoms of perfectionistic behavior may cause procrastination in task completion such as an inability to complete school assignments.

Children especially can behave in a rigid fashion, because the lack of ability to control their worrying expresses itself in an intense need to maintain structure and regularity. The anxiety can interfere with cognitive function to the degree that underachievement may be a concern.4

Case study

A 10-year-old male presents problems at home and at school. He is restless and has trouble concentrating, especially in the evening, and he tosses and turns until he finally falls asleep. He spends much of his waking hours fretting even though he lives in a safe neighborhood with a stable family situation. He has not experienced or witnessed traumatic events. During the Mental Status Examination, you notice that when he hears loud noises, he becomes especially anxious. He reports that he "knows it's not true" but that he fears a catastrophe such as an airplane crash or an intruder when he hears loud noises. His teacher reports that he has academic potential but that he "wastes time" during the school day "unnecessarily" asking her repeatedly if he is "doing okay" on his assignments.
Pathophysiology
Currently, animal researchers have been looking at areas deep in the brain, such as the basolateral amygdala and the periaqueductal grey matter. Hyperresponsiveness of the amygdala may relate to reduced activation thresholds when responding to perceived social threat.5,6

Pediatric generalized anxiety disorder seems to be related to abnormally modulated learned fear responses.7

Impaired cognitive functioning is also a feature of generalized anxiety disorder for both pediatric and adult cases.8

Frequency
United States
More than 16 million Americans aged 18-54 years suffer from an anxiety disorder.
Prevalence rates of generalized anxiety disorder range from 2.9-4.6%.9
International
Worldwide prevalence rates of generalized anxiety disorder have been as high as 15%.10

Mortality/Morbidity
When generalized anxiety disorder is accompanied by comorbid depression or panic disorder, the risk significantly increases for death due to suicidality in both children and adolescents.11
Much attention has been paid to differences between cohorts of adults with anxiety disorders and suicide attempts.12
Significant comorbidity exists between generalized anxiety disorder and somatic disorders, such as asthma, irritable bowel disease, and chronic neck and back pain.13
Race
Currently, studies of racial rates of the prevalence of anxiety disorders do not specifically tease out generalized anxiety disorder incidence and prevalence.14

Sex
Although twice as many females as males report generalized anxiety disorder, males may be more vulnerable to developing generalized anxiety disorder related to stressful life events.15

Age
Generalized anxiety disorder is more common in adolescents; however, children and the elderly can also present with this disorder. In older individuals, a medical workup is more likely to yield a diagnosis of a treatable medical abnormality.16,17

Clinical
History
In children and adolescents, only one of the following is needed for a diagnosis of generalized anxiety disorder:1


Excessive anxiety and worry occurring more days than not for at least 6 months, affecting a number of different events or activities.
Difficulty controlling the worry.
One of the following symptoms in association with the worry (in adults, 3 of the following symptoms are required): restlessness, fatigue, impaired concentration (or mind going blank), irritability, muscle tension, or sleep disturbance (difficulty falling or staying asleep or restless, unsatisfying sleep).
The focus of the anxiety and worry are not confined to features of another Axis I diagnosis including worrying about having a panic attack (as in panic disorder), social embarrassment, or separation from caregiver.
Clinically significant distress or impairment experienced in multiple areas, such as social, school, or employment.
The disturbance is not due to the effects of a medication or substance or general medical conditions and does not occur exclusively during a mood disorder, a psychotic disorder, or associated with a pervasive developmental disorder.
In children and adolescents, parent and self-report measures, such as the Multidimensional Anxiety Scale for Children and the Screen for Child Anxiety Related Emotional Disorders, should be combined with obtaining a thorough family history for anxiety and mood disorders.18

Questionnaires can be helpful both to confirm diagnosis and help with monitoring response to treatment.19

In adults older than 50 years and in younger individuals, considering a differential diagnosis of physical conditions and medical abnormalities that may mimic or contribute to symptoms of generalized anxiety disorder is crucial. Screening medical tests should also be considered in children and adolescents, especially those at higher risk for comorbid diagnoses such as those with asthma, chronic pain syndromes, migraine headaches, seizure disorders, or economically disadvantaged environments.

Careful attention should be paid to obtaining a history for possible adverse reactions to prescribed medications, substance use/abuse and exposure to potential environmental toxins eg, caffeine, lead). In addition, physical examination should include vital signs and screening neurologic exams to rule out less common diagnoses such as hypoglycemia, pheochromocytoma, delirium, grain tumors, porphyrias, and cardiac arrhythmias.20,3

Screening measures, such as the GAD-7, in primary care settings can aid with diagnosis and treatment in a timely fashion.21


Physical
Typically, children and adults with generalized anxiety disorder also experience uncomfortable physical symptoms including rapid heartbeat, feeling short of breath, increased sweating, stomach cramping, a feeling of a lump in the throat or inability to swallow, frequent need to urinate, dry mouth, nausea, diarrhea, cold and/or clammy hands, headaches, or neck or backaches. A feeling of nervous tension is often accompanied by a feeling of shaking, trembling, twitching, or body aches. Often, children especially are not diagnosed or receive incorrect treatment and they may undergo unnecessary, invasive, or dangerous medical testing and inappropriate medication treatment for supposed presence of physical illnesses and, as a result, experience an increase in the intensity of fear and worry about their health status.22,23,24

Elements of the Mental Status Examination that should be assessed in generalized anxiety disorder include the following:



Query about suicidal/homicidal ideation or plan (Have you ever wished you were never born, thought you would be better off dead, wish to harm yourself or others, have a plan to harm yourself or others, or ever tried to kill yourself or seriously injure yourself or others?)
Formal testing of orientation/recall:
Does the patient respond when you call them by name (oriented to person)?
Is the patient oriented to place and time? When you ask what place, season, day, month, year is it, does the patient respond appropriately?
Does the patient have intact short- or long-term recall? Ask the patient to spell the word WORLD forward and backward, count backward from 100 by 7s, recall what he or she did to celebrate his or her birthday last year and the name of his or her first-grade teacher.

Causes
Causes of generalized anxiety disorder include genetic predisposition and environmental factors to encourage anxious behavior since generalized anxiety disorder can cluster in families. Parents can model anxious behaviors to their children. Stressful early life events such as early parental death can also place individuals at higher risk for generalized anxiety disorder. Chronic experiences of fear and learned helplessness may cause greater chronic cortisol activation and increased sympathetic tone.25,6

Traumatic experiences and abnormal prenatal hormonal exposures may also play a role the cause of this disorder.7,23,24

Current research is looking at anticipatory anxiety and whether the presence of alterations in amygdala and anterior cingulate cortex anticipatory activity functions may predict the likelihood of medications such as venlafaxine being effective treatments for generalized anxiety disorder.6

Differential Diagnoses
Alcoholism
Mental Disorders Secondary to General Medical Conditions

Anxiety Disorder, Separation Anxiety and School Refusal
Munchausen Syndrome

Anxiety Disorder, Social Phobia and Selective Mutism
Munchausen Syndrome by Proxy

Anxiety Disorder, Trichotillomania
Nicotine Addiction

Anxiety Disorders
Opioid Abuse

Asthma
Parasomnias

Brain tumor
Pheochromocytoma

Breathing-Related Sleep Disorder
Pheochromocytoma

Caffeine-Related Psychiatric Disorders
Phobic Disorders

Cocaine-Related Psychiatric Disorders
Posttraumatic Stress Disorder

Conversion Disorders
Premenstrual Dysphoric Disorder

Delirium
Primary Insomnia

Dementia Due to HIV Disease
Seizure disorder

Depression
Sleep Disorder, Geriatric

Dissociative Disorders
Sleep Disorders

Dysthymic Disorder
Social Phobia

Factitious Disorder
Somatoform Disorder, Somatization

Generalized Anxiety Disorder
Somatoform Disorders

Hyperthyroidism
Stimulants

Hypochondriasis
Substance-Induced Mood Disorders: Depression and Mania

Hypoglycemia
Suicide

Hypothyroidism
Tourette Syndrome

Menopause and Mood Disorders


Workup
Laboratory Studies
Prior to medication treatment, order testing for drugs of abuse, pregnancy, and screening tests for diabetes mellitus.
If pulse or blood pressure are abnormal then additional testing including cardiogram or Holter monitoring, blood tests of thyroid hormone and thyroid-stimulating hormone, and 24-hour urine screen for norepinephrine and epinephrine should be considered.3
Imaging Studies
If headache is a prominent feature, an EEG or MRI could be considered along with neurologic consultation to rule out seizures or brain tumor.



Other Tests
Before medication treatment, pregnancy testing in females of childbearing age is recommended.

Generalized Anxiety Disorder: Treatment & Medication
Author: Bettina E Bernstein, DO, Assistant Professor, Department of Psychiatry, Philadelphia College of Osteopathic Medicine; Private Practice at the Wynnewood House; Consultant, Child Guidance Resource Centers, Early Elementary Education Program, Clinical Affiliate, Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Dec 2, 2009

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Overview
Differential Diagnoses & Workup
Treatment & Medication
Follow-up
References
Keywords
Further Reading

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Medical Care
Successful treatment approaches generally involve medication combined with therapy. However, cognitive behavioral therapy (CBT) has been proven superior in placebo-controlled trials. Other therapies, such as relaxation therapy, supportive psychotherapy, or mindfulness therapy, have been used if CBT is not appropriate.26

CBT generally includes self reward as well as problem solving and can be as effective as medications, especially for children with mild generalized anxiety disorder.27

Combining CBT with medications is extremely helpful in resistant cases.28,29

Indications for hospitalization include the following:


Severe functional impairment (cannot meet own daily needs)
Suicide or homicide risk
Social skills deficits (The person is so preoccupied that he or she is unaware that his or her actions and behaviors have the potential to provoke others to cause harm.)
Emotional intelligence is a protective factor for suicidal behavior; thus, this should be assessed as part of the decision regarding need for a psychiatric hospitalization.23

Consultations
A Psychiatrist should be the primary clinician when medication treatment is attempted.
Social work consultation may be helpful if coping skills are markedly impaired.
Psychology consultation and testing is indicated if cognitive impairment is of concern or if the patient may be a candidate for CBT.
Cardiology consultation is indicated when symptoms include heart rate irregularity or abnormal blood pressure.
Neurology consultation is indicated when symptoms include headaches or visual field abnormalities, balance abnormalities, or mental status changes.
Endocrinology consultation is indicated when symptoms include heat or cold intolerance, problems with fluid balance, or mood swings due to cortisol abnormalities.
To reduce muscle tension, manual manipulation or massage therapy can be helpful in nonpharmacologic approaches. Treatment with a licensed practitioner is important as there have been cases of sexual abuse or battery with nonlicensed nonprofessionals.
Diet
Decreasing caffeine intake can be extremely helpful as can the use of some gentle herbal preparations in persons who do not have allergies or sensitivities to those agents.30

Activity
Exercise and social affiliativeness can be helpful in preventing secondary depression.

Medication
Psychoactive medications can be extremely helpful for treatment of resistant generalized anxiety disorder when part of a multifaceted treatment program, which usually includes cognitive behavior therapy.
The choice of medication often depends on factors such as side effect profile. Monoamine oxidase inhibitors (MAOIs), although extremely effective, have many food and drug interactions that frequently preclude their usage.
Generally, it is helpful to avoid medications that have significant addictive potential and can cause tolerance and the need for higher and higher dosage with the risk of overdosage or drug diversion because medication treatment is often needed for an extended time.
Refraining from consuming grapefruit and grapefruit juice while taking any of the classes of psychoactive medications is recommended as grapefruit and grapefruit juice have the potential to alter drug levels and potentially cause toxicity.
The lowest number of pills with the fewest refills should be prescribed to prevent overdose and the patient should be monitored closely, especially with the initiation of antidepressant therapy, to prevent or detect new-onset suicidal or homicidal ideation or plan of self-injurious behavior, especially with tricyclics, MAOIs, antihypertensives, and seizure medications due to their higher lethality.
All classes of the following medications are not considered recommended for use in pregnancy due to the risk of teratogenicity (pulmonary hypertension, birth defects) or acute neonatal withdrawal syndromes in the third trimester. Adverse effects from some of the antidepressants include serotonin syndrome and neuroleptic malignant syndrome.
Serotonin syndrome (SS) is a potentially life-threatening reaction caused by excessive serotonin causing fever, muscle stiffness, nausea, confusion, and hallucinations. Many medications can cause serotonin syndrome including SSRIs, SNRIs, TCAs, 5-HT agonists (sumatriptan, zolmitriptan), St. John's wort (herb), ginkgo biloba (herb), and tricyclic or heterocyclic antidepressants.
Neuroleptic malignant syndrome (NMS) can be idiopathic, genetic, or induced by drug-drug interactions; it consists of a potentially life-threatening abnormal muscle reaction including fever, muscle stiffness, confusion, hallucinations, and elevated CPK, which can progress to coma and death. Certain medications are associated with increased risk of NMS, especially if given with MAOIs or antidepressants, antipsychotics, lithium, tramadol, morphine, meperidine, or anticholinergic anesthesia.
Do not take an MAOIs within 2 weeks of taking any other class of antidepressants. Do not combine multiple antidepressants especially due to the risk of SS.
Antihypertensives are investigational agents currently in use for generalized anxiety disorder. Propranolol (Inderal) is a beta-blocker that may be extremely helpful in preventing posttraumatic stress disorder but should not be used in patients with asthma or those with documented hypersensitivity. Rebound hypertension or stroke is a risk if this medication is suddenly discontinued; therefore, this medication should be tapered before it is stopped. Not approved for use in children. Adult dosage range 10-80 mg. Because of the risk of hypotension, coma, or death, do not give with other medications that lower blood pressure.
Clonidine (Catapres) is an alpha blocker, also used as an investigational agent that has been used as second-line medication (not FDA approved) for ADHD, intermittent explosive disorder, and in the setting of insomnia and restlessness in individuals with pervasive developmental disorder/autistic spectrum disorder. Clonidine is not FDA approved for use in children.
The antituberculosis-antibiotic agent d-cycloserine has also been used in the investigational setting.
Herbal preparations are being used for the treatment of generalized anxiety. However, formulations like valerian are not proven effective by controlled studies. Risk for dependence and grogginess (use with caution if driving) as well as drug-drug interactions may be deleterious to health.
Passiflora has not been proven to be effective by controlled studies either; risk for dependance and grogginess (use with caution if driving) as well as drug-drug interactions may be deleterious to health.
Antidepressants
All antidepressants carry a risk of suicidal/homicidal ideation or self-injurious behavior, although meta-analyses have shown that the benefits of antidepressants in treating depression-related morbidity and preventing mortality may outweigh the risks when the patient is closely monitored.31 Antidepressants have a risk of exacerbating seizures in persons with uncontrolled seizure disorder.

Selective and nonselective serotonin reuptake inhibitors are generally used for generalized anxiety disorder, panic, posttraumatic stress disorder, depression, and social phobia.





Venlafaxine (Effexor)
FDA-approved for GAD in adults. May be helpful for other anxiety disorders.

DosingInteractionsContraindicationsPrecautionsAdult
37.5-300 mg ER PO qd

Pediatric
Pediatric dosage levels are not established;
For reasons not yet known, this medication is not preferred for those younger than 18 years because of a possible association with more adverse reactions including new-onset suicidal ideation;
See the FDA Web site for up-to-date information on this subject


DosingInteractionsContraindicationsPrecautionsCimetidine, MAOIs, sertraline, fluoxetine class I-C antiarrhythmics, TCAs, and phenothiazine may increase the effects of venlafaxine

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; patients currently taking MAOIs or who have taken them within 14 days of initiating therapy

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Patients on this medication may experience hypertension; fatal reaction may occur if venlafaxine is taken concurrently with a MAOI; exercise caution in patients with cardiovascular disorders; the sustained release formulation should not be divided, crushed, or placed in water



Desipramine (Norpramin)
Tricyclic antidepressant that has norepinephrine and serotonin reuptake inhibition properties. One of the oldest agents available for the treatment of depression and has established efficacy in the treatment of panic disorder. Elderly and adolescent patients may need lower dosing or slower titration.

DosingInteractionsContraindicationsPrecautionsAdult
75 mg/d PO in divided doses; increase gradually to 150-200 mg/d in divided or single dose; not to exceed 300 mg/d

Pediatric
<6 years: Not established
6-12 years: 10-25 mg/d PO or 1-5 mg/kg/d in divided doses hs; not to exceed 5 mg/kg/d
>12 years: 25-50 mg/d PO; gradually increase to 100 mg/d in single or divided doses; not to exceed 150 mg/d



DosingInteractionsContraindicationsPrecautionsDecreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates; levels may increase with concurrent use of stimulants


DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; narrow-angle glaucoma; recent postmyocardial infarction; current administration of MAOIs or fluoxetine or administration in the previous 2 wk

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Sudden death has been associated with desipramine, do not use unless other safer antidepressants have been tried with adequate doses and treatment duration (unwise to prescribe medication without a tertiary care mental health professional consultation); cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, and hyperthyroidism (patients receiving thyroid replacement) may occur



Trazodone (Desyrel)
Useful in the treatment of panic disorders. Antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.
In animals, selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor 5-HTP.


DosingInteractionsContraindicationsPrecautionsAdult
25-50 mg PO hs (very sedating) to maximum 250 mg/d
Maintenance: Once adequate response achieved, dosage may be gradually reduced with subsequent adjustment depending on response; keep dose at lowest effective level

Pediatric
<12 years: Not established
>12 years: Initially, administer 1.5-2 mg/kg/d PO in divided doses
Increase dose gradually q3-4d prn; not to exceed 6 mg/kg/d

DosingInteractionsContraindicationsPrecautionsTrazodone may enhance response to alcohol, barbiturates, and other CNS depressants; digoxin and phenytoin serum levels may increase in patients receiving trazodone concurrently; trazodone may decrease hypoprothrombinemic effects of warfarin

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Hypotension, including orthostatic hypotension and syncope, has occurred; may produce drowsiness, dizziness, or blurred vision; patients taking this medication should observe caution while driving or performing other tasks requiring alertness, coordination, or dexterity



Duloxetine (Cymbalta)
Potent inhibitor of neuronal serotonin and norepinephrine reuptake. Indicated for GAD.

DosingInteractionsContraindicationsPrecautionsAdult
30-60 mg PO qd

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMetabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase duloxetine blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels and toxicity; duloxetine moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines [eg, thioridazine], type 1C antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAOIs or triptans serotonin syndrome consisting of serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes including extreme agitation, delirium, and coma (see contraindications)

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; uncontrolled narrow-angle glaucoma; do not use within 14 d of stopping MAOI use (do not initiate MAOIs within 5 d of stopping duloxetine)

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing—do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; recommended not to prescribe to patients with substantial alcohol use or evidence of chronic liver disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating; may cause serotonin syndrome (ie, changes in mental status [agitation, hallucinations, coma], autonomic instability [tachycardia, labile blood pressure, hyperthermia], neuromuscular abnormalities [hyperreflexia, incoordination], and/or gastrointestinal tract symptoms



Escitalopram (Lexapro)
SSRI and S-enantiomer of citalopram. Used for the treatment of depression. Mechanism of action is thought to be potentiation of serotonergic activity in CNS resulting from inhibition of CNS neuronal reuptake of serotonin. Onset of depression relief may be obtained after 1-2 wk, which is sooner than other antidepressants.

DosingInteractionsContraindicationsPrecautionsAdult
10 mg PO qd initially; if needed, may increase to 20 mg/d after 1 wk



Pediatric
Not established



DosingInteractionsContraindicationsPrecautionsPrimarily metabolized by CYP450 3A4 and 2C19; coadministration with alcohol or other centrally acting drugs increases CNS depression; cimetidine increases AUC and maximum serum concentration; coadministration with sumatriptan and SSRIs has caused weakness and hyperreflexia

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; administration within 14 d of receiving MAOI

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution with history of seizures, mania, suicide; common adverse effects include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating, fatigue, and somnolence



Paroxetine (Paxil)
Alternative DOC. Potent selective inhibitor of neuronal serotonin reuptake. Also has a weak effect on norepinephrine and dopamine neuronal reuptake.
While numerous antidepressants are currently available, SSRIs provide many advantages over past antidepressants. MAOIs should be avoided in mood disorders with depressive features. MAOIs are lethal if patient relapses from abstinence and combines them with cocaine.

DosingInteractionsContraindicationsPrecautionsAdult
40 mg/d PO qd

Pediatric
<18 years: Not established
>18 years: Administer as in adults

DosingInteractionsContraindicationsPrecautionsInhibits CYP450 2D6 and thus may increase toxicity of 2D6 substrates (eg, phenothiazines, propafenone, flecainide and encainide, other SSRIs, tricyclic antidepressants); phenobarbital and phenytoin decrease effects of paroxetine; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity of paroxetine; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to using other SSRIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; concurrent administration with MAOIs, or administering within 14 days of discontinuing a MAOIs; coadministration with thioridazine or pimozide

DosingInteractionsContraindicationsPrecautionsPregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Caution in history of seizures, mania, renal disease, and cardiac disease; the controlled-release product should not exceed 50 mg/d for elderly or debilitated individuals, or those with severe renal or hepatic impairment; meta-analysis showed a higher frequency of suicidal behavior in adults (particularly young adults)



Fluoxetine (Prozac)
Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.

May cause more gastrointestinal adverse effects than other SSRIs now currently available, which is the reason it is not recommended as a first choice. May be given as a liquid and a capsule.

May give as 1 dose or divided doses. Presence of food does not appreciably alter levels of the medication. May take up to 4-6 weeks to achieve steady state levels of the medication as it has longest half-life (72 h).

Long half-life is both an advantage and a drawback. If it works well, an occasional missed dose is not a problem; if problems occur, eliminating all active metabolites takes a long time. The choice depends on adverse effects and drug interactions. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one over another at this point if dosing is started at a conservative level and advanced as tolerated.


DosingInteractionsContraindicationsPrecautionsAdult
5 mg/d PO initially; may advance by 5-mg increments q3-5d to 20 mg/d
Then, advance in this manner again after about 6 wk; for GAD, higher doses commonly used for other anxiety disorders or depressive disorders are usually not required


Pediatric
<18 years: Not established; 2 mg/d in young children or extremely anxious adolescents initially; may benefit from doses of 5-10 mg/d; rate of dosage advance should be more conservative than in adults
>18 years: Administer as in adults

DosingInteractionsContraindicationsPrecautionsInhibits CYP450 isoenzymes 2C9, 2C19, 2D6, and 3A4; increases toxicity of diazepam and trazodone by decreasing clearance; also increases toxicity of MAOIs, and highly protein-bound drugs; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to SSRIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; concurrently taking MAOIs or took them in the last 2 wk; coadministration with thioridazine

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Known or suspected history of mania or hypomania; caution in hepatic impairment and history of seizures; MAOIs should be discontinued at least 14 d before initiating fluoxetine therapy



Sertraline (Zoloft)
FDA approved for panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. May be helpful for other anxiety disorders.

DosingInteractionsContraindicationsPrecautionsAdult
50-200 mg PO qd; initiate at 25 mg/d and increase as tolerated, not to exceed 200 mg/d

Pediatric
25-100 mg PO qd

DosingInteractionsContraindicationsPrecautionsInhibits CYP450 isoenzymes 3A3/4, 2C9, 2C19, and 2D6, resulting in possible decreased clearance of isoenzyme substrates (eg, metoprolol, thioridazine, imipramine, haloperidol, phenytoin, barbiturates, glyburide, warfarin)
Increases toxicity of MAOIs, diazepam, tolbutamide, and warfarin; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to SSRIs


DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; do not use concurrently or within 2 wk of MAOIs

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in pre-existing seizure disorders, and in those who have experienced a recent myocardial infarction, have unstable heart disease, and hepatic or renal impairment; volume depletion or diuretic use may cause hyponatremia (especially in the elderly); difficulties with maintenance or initiation of sleep; history of pediatric or adult bipolar disorder in first-degree relative, as this medication may precipitate hypomania or frank mania/psychosis along with behavioral disinhibition



Fluvoxamine (Luvox)
Enhances serotonin activity due to selective reuptake inhibition at neuronal membrane. Does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer side effects than tricyclic antidepressants.

FDA approved for obsessive-compulsive disorder in those aged 8 years and older. May be helpful for other anxiety disorders.

DosingInteractionsContraindicationsPrecautionsAdult
25 mg PO qhs initially as single dose, increase dose in 50-mg increments q4-7d as tolerated until maximum therapeutic benefit achieved at lowest effective dose; divide total daily dose into 2 doses; if doses are unequal, administer larger dose hs; not to exceed 300 mg/d

Pediatric
<8 years: Not established
>8 years: 12.5 mg PO qhs initially as single dose, increase dose in 25-mg increments q4-7d as tolerated until maximum therapeutic benefit achieved at lowest effective dose; divide total daily doses higher than 50 mg into 2 doses; if doses are unequal, administer larger dose hs; not to exceed 200 mg/d


DosingInteractionsContraindicationsPrecautionsRisk of a hypertensive crisis increases in coadministration with MAOIs; fluvoxamine potentiates effect of triazolam and alprazolam and thus, when taking them concurrently, dose should be reduced by at least 50%; reduce also the dose of theophylline by one third, and monitor plasma levels if taking it concurrently with fluvoxamine; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity of fluvoxamine; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to SSRIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; patients currently receiving MAOIs or have taken them in past 2 wk; currently taking thioridazine, cisapride, or pimozide

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in liver dysfunction, cardiovascular disease, history of seizures, or suicidal tendencies



Mirtazapine (Remeron)
Increases availability of serotonin and norepinephrine.


DosingInteractionsContraindicationsPrecautionsAdult
15-45 mg/d PO


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMay increase effect of CNS depressants; concurrent administration with MAOI may trigger hypertensive crisis; concomitant administration with quinolone antibiotics, ketoconazole, or fluvoxamine may increase toxicity of mirtazapine

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; MAOI within 14 d

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May cause drowsiness; discontinue use if patient develops sore throat, fever, or other signs of infection; suicide ideation is inherent in depression and may persist until significant remission occurs; severe neutropenia reported in clinical trials



Nefazodone (Serzone)
Antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors. Withdrawn from the US due to liver impairment.

DosingInteractionsContraindicationsPrecautionsAdult
300-600 mg/d PO


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsDecreases effects of anticoagulants, oral hypoglycemics, diuretics, clonidine, methyldopa; increases effects of digoxin, carbamazepine, and MAOIs; toxicity of nefazodone may increase when used concurrently with amiodarone, cimetidine, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, zafirlukast, zileuton

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; use of MAOIs within previous 14 d of initiating treatment; concurrent use with astemizole, carbamazepine, cisapride or terfenadine

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in cardiac disease, cerebrovascular disease or seizures; discontinue therapy and reevaluate if priapism occurs



Bupropion (Wellbutrin)
Inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake. Also available in sustained-release preparations (Wellbutrin SR).

DosingInteractionsContraindicationsPrecautionsAdult
100-450 mg PO qd or 150-400 mg SR PO qd, initially; if initial dose ineffective and higher dose tolerated, increase gradually to maximum of 100 mg SR PO qid or 150 PO tid

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsCarbamazepine, cimetidine, phenytoin, and phenobarbital may decrease effects; toxicity increases with concurrent administration of levodopa and MAOIs; may cause hypertension; may increase risk of suicidal ideation or worsening depression

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; seizure disorder, anorexia nervosa, concurrent use with MAOIs or additional bupropion products

DosingInteractionsContraindicationsPrecautionsPregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Caution in renal or hepatic insufficiency; doses >450 mg/d significantly decrease seizure threshold



Imipramine (Tofranil)
Tricyclic antidepressant that has norepinephrine and serotonin reuptake inhibition properties. One of the oldest agents available for the treatment of depression and has established efficacy in the treatment of panic disorder. Elderly and adolescent patients may need lower dosing or slower titration.

DosingInteractionsContraindicationsPrecautionsAdult
Initial: 50-75 mg PO qd titrated gradually to 150 mg qd according to tolerance
Dose range: 75-300 mg PO qd, administered either hs or divided doses

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsIncreases toxicity of sympathomimetic agents such as isoproterenol and epinephrine by potentiating effects and inhibiting antihypertensive effects of clonidine; coadministration with or use within 2 wk of MAOIs or fluoxetine may cause serotonin syndrome or hypertensive crisis

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; narrow-angle glaucoma; in acute recovery phase following myocardial infarction; patients taking MAOIs or fluoxetine, or have taken them in the past 2 weeks

DosingInteractionsContraindicationsPrecautionsPregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
May impair mental or physical abilities required for performance of potentially hazardous tasks; caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, or receiving thyroid replacement



Selegiline (Emsam)
Irreversible MAOI. Has greater affinity for MAO-B compared with MAO-A; however, at antidepressant doses, inhibits both isoenzymes. MAO-A and MAO-B catabolize neurotransmitter amines in CNS (eg, norepinephrine, dopamine, serotonin). Indicated for treating major depressive disorder. At lowest strength (ie, 6 mg delivered over 24 h), may be used without the dietary restrictions required for oral MAOIs used to treat depression.

DosingInteractionsContraindicationsPrecautionsAdult
Starting dose: 6 mg/24 h patch; apply topically once q24h; remove previous day's patch when applying new patch

Dosage range: 6-12 mg/24 h; if dose increase is warranted, increase by 3 mg/24 h at >2-wk intervals; not to exceed 12 mg/24 h

Apply to dry, intact, nonoily, nonhairy skin on upper torso (ie, below neck and above waist), upper thigh, or outer surface of upper arm; avoid reapplication to same site on consecutive days


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsDo not coadminister with other drugs that cause or increase risk of serotonin syndrome (eg, SSRIs [fluoxetine, sertraline, paroxetine], SNRIs [venlafaxine, duloxetine], TCAs [imipramine, amitriptyline], MAOIs [isocarboxazid, phenelzine, tranylcypromine], mirtazapine, bupropion, meperidine, tramadol, methadone, propoxyphene, pentazocine, dextromethorphan, cyclobenzaprine, oral selegiline, St John's wort); do not ingest tyramine-containing foods and beverages (eg, aged cheese, wine, beer, dried or fermented meats [sausage], fava beans, soybean products, yeast extract, sauerkraut) with patches that release >6 mg/24 h or for 2 wk following discontinuation of patch; sympathomimetic amines (eg, cold products or appetite depressants containing pseudoephedrine, phenylephrine, phenylpropanolamine, or ephedrine) increase risk of hypertensive crisis; general or local anesthesia containing sympathomimetics or cocaine increases risk of hypertensive crisis (avoid elective surgery during treatment and for at least 10 d after discontinuing patch; if surgery is required immediately, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may be used cautiously); carbamazepine and oxcarbazepine may increase plasma levels; alcohol may increase mental and motor skills impairment

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; SSRIs, dual SNRIs, TCAs, bupropion, mirtazapine, meperidine and other analgesics, carbamazepine, oxcarbazepine, sympathomimetic amines

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May cause mild redness on skin at application site; may cause lightheadedness or postural hypotension secondary to decreased blood pressure; applying direct heat to patch may increase amount of drug absorbed from patch so avoid direct heat exposure (eg, heating pads, electric blankets, sauna, hot tubs, prolonged sunlight); as with all antidepressants, labeling includes a warning for risk of increased suicidality in children and adolescents; all patients with depression should be monitored closely for suicidality; rule out risk of bipolar disorder before initiating antidepressant therapy (treatment with antidepressant alone may precipitate a mixed/manic episode); may impair judgment, thinking, or motor skills



Phenelzine (Nardil)
Has demonstrated clear superiority over placebo in double-blind trials for treating specific symptoms of panic disorders. Usually reserved for patients who do not tolerate or respond to traditional cyclic or second-generation antidepressants.

DosingInteractionsContraindicationsPrecautionsAdult
15 mg PO tid initially; increase gradually to 60-90 mg/d prn during early phase of treatment; after maximum benefit, reduce dosage slowly over several weeks

Maintenance: 15 mg PO qd or qod; may continue taking medication for as long as required

Pediatric
<16 years: Not recommended
>16 years: Administer as in adults

DosingInteractionsContraindicationsPrecautionsElevated blood pressure reported in patients taking MAOIs who were then given buspirone (allow at least 10 d to elapse between discontinuation of MAOIs and institution of buspirone); may significantly increase hypotensive effect of antihypertensive drugs, including thiazide diuretics; concomitant administration of meperidine with MAOIs or during the 2 or 3 weeks following MAO therapy may cause serious reactions including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death; combination of MAOIs and dextromethorphan reported to cause brief episodes of psychosis or bizarre behavior; may potentiate effect of psychotropic agents; excessive amounts of caffeine may produce severe hypertension; serotonin syndrome may occur if coadministered or used within 14 days of discontinuing SSRI therapy; coadministration with dexmethylphenidate or methylphenidate may cause hypertensive crisis; selective 5-HT1 receptor agonists (eg, rizatriptan, sumatriptan) may increase risk of cardiac toxicity if administered within 2 weeks following the discontinuation of MAOIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; confirmed or suspected cerebrovascular defects; cardiovascular disease; hypertension; history of headache; history of liver disease or abnormal liver function tests; severe renal function impairment; severe or frequent headaches (headaches are first symptom of hypertensive reaction to drug); coadministration with sympathomimetics (including amphetamines); some CNS depressants (including narcotics [eg, meperidine] and alcohol); antihypertensive, diuretic, antihistaminic, sedative, or anesthetic drugs; bupropion; buspirone; dextromethorphan; cheese or other foods with a high tyramine content; excessive quantities of caffeine; and SSRIs

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Most important reaction associated with MAOIs is occurrence of hypertensive crises, which have sometimes been fatal, resulting from coadministration of MAOIs and certain drugs and foods; if hypertensive crisis occurs, discontinue MAOI and immediately institute therapy to lower blood pressure (phentolamine, available as Regitine, has been used and is recommended at a dosage of 5 mg IV to lower blood pressure); before prescribing, become completely familiar with full material on dosage, adverse reactions, and contraindications, as well as with principles of MAOI therapy and adverse reactions of this class of drugs; MAOIs can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia; use MAOIs with caution in hyperthyroid patients because may increase sensitivity to pressor amines



Tranylcypromine (Parnate)
Treats major depression. Binds irreversibly to MAO, thereby reducing monoamine breakdown and enhancing synaptic availability.

DosingInteractionsContraindicationsPrecautionsAdult
10 mg PO qd, titrate as tolerated; usual dose 30-60 mg/d PO in divided doses

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsElevated blood pressure reported in patients taking MAOIs who were then given buspirone (allow at least 10 d to elapse between discontinuation of MAOIs and institution of buspirone); may significantly increase hypotensive effect of antihypertensive drugs, including thiazide diuretics; concomitant administration of meperidine with MAOIs or during the 2 or 3 weeks following MAO therapy may cause serious reactions including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death; combination of MAOIs and dextromethorphan reported to cause brief episodes of psychosis or bizarre behavior; may potentiate effect of psychotropic agents; excessive amounts of caffeine may produce severe hypertension; serotonin syndrome may occur if coadministered or used within 14 days of discontinuing SSRI therapy; coadministration with dexmethylphenidate or methylphenidate may cause hypertensive crisis; Selective 5-HT1 receptor agonists (eg, rizatriptan, sumatriptan) may increase risk of cardiac toxicity if administered within 2 weeks following discontinuation of MAOIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; confirmed or suspected cerebrovascular defects; cardiovascular disease; hypertension; history of headache; history of liver disease or abnormal liver function tests; severe renal function impairment; severe or frequent headaches (headaches are first symptom of hypertensive reaction to drug); coadministration with sympathomimetics (including amphetamines); some CNS depressants (including narcotics [eg, meperidine] and alcohol); antihypertensive, diuretic, antihistaminic, sedative, or anesthetic drugs; bupropion; buspirone; dextromethorphan; cheese or other foods with a high tyramine content; excessive quantities of caffeine; and SSRIs

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Most important reaction associated with MAOIs is occurrence of hypertensive crises, which have sometimes been fatal, resulting from coadministration of MAOIs and certain drugs and foods; if hypertensive crisis occurs, discontinue MAOI and immediately institute therapy to lower blood pressure (phentolamine, available as Regitine, has been used and is recommended at a dosage of 5 mg IV to lower blood pressure); before prescribing, become completely familiar with full material on dosage, adverse reactions, and contraindications, as well as with principles of MAOI therapy and adverse reactions of this class of drugs; MAOIs can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia; use MAOIs with caution in hyperthyroid patients because may increase sensitivity to pressor amines



Isocarboxazid (Marplan)
Nonselective hydrazine MAOI demonstrated to inhibit MAO in the brain, heart, and liver. Mechanism by which MAOIs act as antidepressants is not fully understood but is thought to involve elevation of brain levels of biogenic amines. However, MAO is a complex enzyme system widely distributed throughout body, and drugs that inhibit MAO cause a number of clinical effects. Thus, it is unknown whether MAO inhibition, other pharmacologic actions, or interaction of both is responsible for the antidepressant effects observed.

DosingInteractionsContraindicationsPrecautionsAdult
10 mg PO bid; may increase q2-4d until therapeutic effect or maximum 80 mg/d achieved; usually 40 mg/d is effective

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsElevated blood pressure reported in patients taking MAOIs who were then given buspirone (allow at least 10 d to elapse between discontinuation of isocarboxazid and institution of buspirone); may significantly increase hypotensive effect of antihypertensive drugs, including thiazide diuretics; concomitant administration of meperidine with MAOIs or during the 2 or 3 weeks following MAO therapy may cause serious reactions including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death; combination of MAOIs and dextromethorphan reported to cause brief episodes of psychosis or bizarre behavior; may potentiate effect of psychotropic agents; excessive amounts of caffeine may produce severe hypertension; serotonin syndrome may occur if coadministered or used within 14 days of discontinuing SSRI therapy; coadministration with dexmethylphenidate or methylphenidate may cause hypertensive crisis; Selective 5-HT1 receptor agonists (eg, rizatriptan, sumatriptan) may increase risk of cardiac toxicity if administered within 2 weeks following the discontinuation of isocarboxazid

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; confirmed or suspected cerebrovascular defects; cardiovascular disease; hypertension; history of headache; pheochromocytoma (such tumors secrete pressor substances whose metabolism may be inhibited by isocarboxazid); history of liver disease or abnormal liver function tests; severe renal function impairment; severe or frequent headaches (headaches are first symptom of hypertensive reaction to drug); coadministration with sympathomimetics (including amphetamines); some CNS depressants (including narcotics [eg, meperidine] and alcohol); antihypertensive, diuretic, antihistaminic, sedative, or anesthetic drugs; bupropion; buspirone; dextromethorphan; cheese or other foods with a high tyramine content; excessive quantities of caffeine; and SSRIs

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Most important reaction associated with MAOIs is occurrence of hypertensive crises, which have sometimes been fatal, resulting from coadministration of MAOIs and certain drugs and foods; if hypertensive crisis occurs, discontinue isocarboxazid and immediately institute therapy to lower blood pressure (phentolamine, available as Regitine, has been used and is recommended at a dosage of 5 mg IV to lower blood pressure); before prescribing, become completely familiar with full material on dosage, adverse reactions, and contraindications, as well as with principles of MAOI therapy and adverse reactions of this class of drugs; MAOIs can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia; use isocarboxazid with caution in hyperthyroid patients because may increase sensitivity to pressor amines

Antianxiety agents
Benzodiazepines are sedative hypnotics metabolized by the liver. They work by increasing the actions of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain. It may depress all levels of the CNS, including the reticular activating system and limbic system and therefore can depress breathing, consciousness, and cause disinhibition.

Buspirone hydrochloride, a 5-HT 1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS, has a slow onset of anxiolytic effect and may take up to 2-3 weeks to work.





Lorazepam (Ativan)
Sedative hypnotic with short onset of effects and relatively long half-life.

By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

When patient needs to be sedated for longer than 24-hour period, this medication is excellent.

DosingInteractionsContraindicationsPrecautionsAdult
0.5-10 mg/d PO divided bid/tid

Pediatric
0.05 mg/kg/dose PO q4-8h

DosingInteractionsContraindicationsPrecautionsToxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; preexisting CNS depression, hypotension, and narrow angle glaucoma; reversal agents (eg, flumazenil) contraindicated when lorazepam used for life-threatening conditions (eg, control of intracranial pressure or status epilepticus)

DosingInteractionsContraindicationsPrecautionsPregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease



Alprazolam (Xanax)
For management of anxiety attacks. Binds receptors at several sites within the CNS, including the limbic system and reticular formation. Effects may be mediated through GABA receptor system.

DosingInteractionsContraindicationsPrecautionsAdult
0.25-4 mg PO qd or divided tid



Pediatric
<18 years: Not established
>18 years: Administer as in adults

DosingInteractionsContraindicationsPrecautionsCarbamazepine and disulfiram decrease effects; toxicity increases with cimetidine, lithium, contraceptives, and CNS depressants (including alcohol)

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; severe respiratory depression, narrow angle glaucoma, preexisting hypotension

DosingInteractionsContraindicationsPrecautionsPregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Withdrawal symptoms, including seizures, may occur upon abrupt discontinuation of drug



Buspirone (BuSpar)
Antianxiety agent not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. A 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in CNS. Has anxiolytic effect but may take up to 2-3 wk for full efficacy.

DosingInteractionsContraindicationsPrecautionsAdult
15 mg/d PO divided tid initially; may increase by 5 mg/d q2-4d; not to exceed 60 mg/d



Pediatric
<18 years: Not approved; not established; suggested dose based on limited data

Children: 2.5 mg/d PO; may increase by 2.5 mg q3-4d, adding doses to achieve tid dosing with a total daily dose of 20 mg/d

Adolescents: Titrate as for children with eventual adult dose

Note that younger individuals and those who are developmentally delayed may respond to lower doses than adults; thus, conservative advancing is prudent

DosingInteractionsContraindicationsPrecautionsToxicity is increased with MAOIs, phenothiazines, and CNS depressants; increases toxicity of digoxin and haloperidol

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Caution in hepatic or renal impairment

Anticonvulsants
Drug of choice in this category is the gamma-aminobutyric acid derivative pregabalin. Be careful when prescribing (prescribe the smallest amount with fewest refills) as it is a Schedule V medication due to the possibility of drug diversion and drug dependance as it has a "street value" to drug addicts.



Pregabalin (Lyrica)
Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2 -delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

DosingInteractionsContraindicationsPrecautionsAdult
50 mg PO tid initially; if needed, may increase to 100 mg tid within 1 wk; increase as tolerated until desired effect or 600 mg/d maximum achieved

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMay cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min); angioedema has been reported during postmarketing surveillance

Antipsychotic agents
Atypical and typical neuroleptic medications are used. Mechanisms of action generally include a combination of neuroreceptor blockade (generally dopaminergic blockade) as well as up- and downregulation of receptor sensitivity.

All drugs in this class may increase risk of life-threatening neuroleptic malignant syndrome, acute dystonias, tardive dyskinesia, weight gain, metabolic syndrome, and potential to cause diabetic ketoacidosis as well as stroke, hypertension, hypotension, or sudden death from cardiac conduction or cardiac electrophysiological abnormalities. Quetiapine has a pending application for approval by the FDA for use in generalized anxiety disorder as well as in major depressive disorder for patients whose symptoms do not remit with other treatments as it seems that low doses (50-300 mg range) of quetiapine may not be associated with the risk of hyperglycemia and metabolic syndrome that potentially can occur in higher dosage ranges or with other antipsychotic medications. Antipsychotic medications are generally used more as augmentation strategies and are second line treatment options in generalized anxiety disorder.32



Risperidone (Risperdal)
Binds to dopamine D2 receptor with a 20-times lower affinity than for the 5-HT2 receptor. Improves negative symptoms of psychoses and reduces incidence of extrapyramidal adverse effects.

Response to antipsychotics is less dramatic than in true psychotic Axis I disorders, but symptoms such as anxiety, hostility, and sensitivity to rejection may be reduced. Antipsychotics are typically used for a short time while the symptoms are active.


DosingInteractionsContraindicationsPrecautionsAdult
0.25-6 mg/d PO


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsCoadministration with carbamazepine may decrease effects; risperidone may inhibit effects of levodopa; clozapine may increase risperidone levels; oral solution not compatible with cola or tea

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May cause extrapyramidal reactions, hypotension, tachycardia, and arrhythmias; hyperglycemia may occur and in some cases be extreme, resulting in ketoacidosis, hyperosmolar coma, or death; do not split or chew oral disintegrating tablets; lower dose and slower titration may be required in elderly or debilitated patients, those with severe renal or hepatic impairment, or individuals predisposed to hypotension; elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs have increased risk of death compared with placebo



Aripiprazole (Abilify)
Improves positive and negative schizophrenic symptoms. The mechanism of action is unknown but is hypothesized to work differently than other antipsychotics. Aripiprazole is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist and antagonize serotonin (5HT2A). Additionally, no QTc interval prolongation was noted in clinical trials. Available as tab, orally disintegrating tab, or oral solution.

DosingInteractionsContraindicationsPrecautionsAdult
10-30 mg PO qd; if needed, may increase dose gradually q2wk; usually effective dosage is 15 mg; not to exceed 30 mg/d


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsCYP450 3A4 and 2D6 isoenzyme substrate; thus, inhibitors (ie, ketoconazole, quinidine, fluoxetine, paroxetine) or inducers (ie, carbamazepine) may increase or decrease serum levels respectively

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Common adverse effects include headache, anxiety, somnolence, or insomnia; rare reports of tardive dyskinesia and neuroleptic malignant syndrome; may cause orthostatic hypotension, seizure, dysphagia, or suicidal ideation; hyperglycemia may occur and in some cases be extreme, resulting in ketoacidosis, hyperosmolar coma, or death



Quetiapine (Seroquel)
May act by antagonizing dopamine and serotonin effects.

Newer antipsychotic used for long-term management. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive dyskinesia. Immediate- and extended-release formulations available.

DosingInteractionsContraindicationsPrecautionsAdult
IR: Start with 25 mg PO bid/tid and increase by 25-50 mg bid/tid on second or third d to achieve range by fourth d of 300-400 mg divided bid/tid; adjust as needed at intervals of at least 2 d with adjustments of 25-50 mg bid
Maintenance: 150-750 mg/d PO; not to exceed 800 mg/d
XR: 300 mg PO qhs initially; may increase as frequently as 1-day intervals up to 300 mg/d; effective dosage range is 400-800 mg/d

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMay antagonize levodopa and dopamine agonists; phenytoin, thioridazine and other liver enzyme inducers may reduce quetiapine levels; CYP450 3A inhibitors (eg, ketoconazole, fluconazole, erythromycin) increase quetiapine serum concentration

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May induce orthostatic hypotension associated with dizziness, tachycardia, and syncope; the neuroleptic malignant syndrome and tardive dyskinesia has been associated with this treatment; hyperglycemia may occur and in some cases be extreme, resulting in ketoacidosis, hyperosmolar coma, or death; caution in hepatic impairment (decrease dose); swallow XR tab whole (do not chew, crush, or split)



Haloperidol (Haldol)
DOC for patients with acute psychosis when no contraindications exist. Haloperidol and droperidol (below) are of butyrophenone class, and are noted for high potency and low potential for causing orthostasis. However, the potential for EPS/dystonia is high.
Parenteral dosage form may be admixed in same syringe with 2-mg lorazepam for better anxiolytic effects.

DosingInteractionsContraindicationsPrecautionsAdult
0.5-40 mg PO divided bid/tid

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMay increase tricyclic antidepressant serum-concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects of haloperidol; haloperidol coadministration with anticholinergics may increase intraocular pressure; encephalopathy-like syndrome associated with concurrent administration of lithium and haloperidol

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; narrow angle glaucoma, bone marrow suppression, severe cardiac or liver disease, severe hypotension

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Severe neurotoxicity manifesting as rigidity or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; if IV/IM, watch for hypotension; caution in diagnosed CNS depression, subcortical brain damage, or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if occurs)



Molindone (Moban)
Dihydroindolone antipsychotic with pharmacologic profile in laboratory animals that predominantly resembles that of major tranquilizers causing reduction of spontaneous locomotion and aggressiveness, suppression of a conditioned response and antagonism of the bizarre stereotyped behavior and hyperactivity induced by amphetamines.

DosingInteractionsContraindicationsPrecautionsAdult
5-10 mg PO tid/qid

Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsMay worsen effect of anticholinergic agents; calcium ions from excipient of drug calcium sulfate may interfere with absorption of preparations containing phenytoin sodium and tetracyclines

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; severe CNS depression (alcohol, barbiturates, narcotics, etc) or comatose states

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May cause tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, and anticholinergic effects; caution in Parkinson disease

Antihypertensive agents
Agents in this class may have a positive effect on the physiological symptoms of anxiety.



Clonidine (Catapres)
Investigational agent. Central alpha-adrenergic agonist that stimulates alpha2-adrenoreceptors in brain stem and activates an inhibitory neuron, resulting in a decrease in vasomotor tone and heart rate. Available in tab or transdermal skin patches. Frequently given to children. Affects alpha1-, alpha2-, and alpha3-adrenergic receptors.


DosingInteractionsContraindicationsPrecautionsAdult
0.05 mg/d PO initially; may increase by 0.05 mg q3-4d until dose reaches 0.1-0.3 mg/d PO divided tid



Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsTricyclic antidepressants inhibit hypotensive effects of clonidine; coadministration of clonidine with beta-blockers may potentiate bradycardia; tricyclic antidepressants may enhance hypertensive response associated with abrupt clonidine withdrawal; hypotensive effects of clonidine are enhanced by narcotic analgesics

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairment



Propranolol (Inderal, Betachron E-R, InnoPran XL)
Investigational agent. Blocks the physiological symptoms of anxiety and may be helpful for decreasing the severity of the somatic symptoms of anxiety. May cause unpleasant cardiovascular and GI adverse effects and is not the DOC especially as hypotension and/or cardiac block can occur. Initiation of therapy should be performed with close monitoring of blood pressure to prevent hypotensive crisis. Do not discontinue abruptly as this may precipitate hypertensive crisis. Available as tablets, sustained release, and liquid preparations.


DosingInteractionsContraindicationsPrecautionsAdult
10-80 mg PO divided bid


Pediatric
Not established

DosingInteractionsContraindicationsPrecautionsCoadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol

DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; uncompensated congestive heart failure; bradycardia, cardiogenic shock; A-V conduction abnormalities

DosingInteractionsContraindicationsPrecautionsPregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely

Generalized Anxiety Disorder: Follow-up
Author: Bettina E Bernstein, DO, Assistant Professor, Department of Psychiatry, Philadelphia College of Osteopathic Medicine; Private Practice at the Wynnewood House; Consultant, Child Guidance Resource Centers, Early Elementary Education Program, Clinical Affiliate, Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Dec 2, 2009

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Overview
Differential Diagnoses & Workup
Treatment & Medication
Follow-up
References
Keywords
Further Reading

Information from Industry
Are your patients with moderate to severe chronic pain taking other medications? These patients may be at risk for drug-drug interactions.
Learn more Follow-up
Further Inpatient Care
Inpatient care is generally not needed except in the case of complications such as major depression with vegetative signs and/or suicidal/homicidal ideation or adverse reactions to medications.

Further Outpatient Care
Outpatient treatment usually consists of weekly therapy sessions for at least 12 weeks. Often, booster sessions are needed to maintain treatment goals. A therapist should be experienced in CBT, which may be more easily accessible in a teaching hospital or university setting. Adjunctive modalities such as relaxation training, assertiveness training, play therapy, or creative arts therapies can be helpful.27



Inpatient & Outpatient Medications
Monitoring with a psychiatrist (child psychiatrist if patient is a child or adolescent) is optimal to prevent medication-related complications and to determine appropriate duration and intensity of treatment. When antidepressants are prescribed, abrupt discontinuation should be avoided and close monitoring should occur when dosage is adjusted, especially due to potential suicidal risk.

Deterrence/Prevention
Psychoeducation to improve coping skills for normal stressors
Decrease exposure to traumatic events or psychosocial stressors
Regular exercise and adaptive leisure pursuits
Supportive relationships
Minimize unnecessary medical testing or procedures and especially avoid invasive procedures3
Complications
Addiction to anxiolytics
Suicidality or parasuicidal behaviors related to SSRIs, SNRIs, or antidepressants
Comorbid depression or panic disorder
Impairment of relationships
Substance abuse or dependance (generally alcohol) as self medication of anxiety, with concomitant complications that can be life threatening, such as alcoholic gastritis/bleeding, hepatic cancer or fatty liver or liver failure (caused by alcoholism), delirium tremors with uncontrolled seizure disorder (due to unmonitored substance withdrawal from benzodiazepines or alcohol)
Prognosis
Prognosis is generally fair to excellent depending on response to treatment. A significant risk of suicide exists in untreated individuals usually related to alcohol-related complications and depression (unremitting anxiety can likely cause hopelessness or depression).

Patient Education
Psychoeducation should focus on decreasing additional stressors including decreasing negative emotional expressivity within the family, if possible.
A healthy lifestyle should be actively attempted (no excessive alcohol, caffeine, or calorie and fat intake, and regular exercise).
Studies show that a good fit between the patient and the therapist is helpful. See Medscape’s Patient-Provider Relations in Psychiatry & Mental Health.
Web sites with patient education information:
MayoClinic, Generalized anxiety disorder
National Institute of Mental Health, Generalized Anxiety Disorder (GAD)
Anxiety Disorders Association of America, Generalized Anxiety Disorder (GAD)
WebMD, Generalized Anxiety Disorder
Miscellaneous
Medicolegal Pitfalls
Failure to diagnose generalized anxiety disorder and subsequent development of significant comorbid depression, panic attacks, and suicide or related alcohol abuse or dependance
Patients who are encouraged to decrease alcohol intake should be closely monitored for withdrawal syndromes and nutritional deficiency syndromes (eg, Wernicke-Korsakoff).
Comorbid undiagnosed learning disorders that lead to later development of underachievement
Later development of substance abuse or dependance due to lack of appropriate treatment of generalized anxiety disorder
Incomplete history taken, failing to discern the presence of treatable medical conditions contributing to generalized anxiety disorder33