Medication Summary
Antidepressant agents are the drugs of choice in the treatment of anxiety disorders, particularly the newer agents that have a safer adverse effect profile and higher ease of use than the older tricyclic antidepressants (TCAs), such as selective serotonin reuptake inhibitors (SSRIs). Antidepressants that are not FDA-approved for the treatment of a given anxiety disorder, such as nefazodone and mirtazapine still may be beneficial. Older antidepressants, such as TCAs and monoamine oxidase inhibitors (MAOIs), also are effective in the treatment of some anxiety disorders.
A Cochrane review of second-generation antipsychotic drugs found that quetiapine and risperidone were effective when combined with antidepressants; however, adverse side effects were also reported. [73]
Selective Serotonin Reuptake Inhibitors
Class Summary
The SSRIs include paroxetine (Paxil), escitalopram (Lexapro), sertraline (Zoloft), fluoxetine (Prozac), fluvoxamine (Luvox), and citalopram (Celexa). SSRIs are first-line agents for long-term management of anxiety disorders, with control gradually achieved over a 2- to 4-wk course, depending on required dosage increases.
SSRIs are helpful for generalized anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), and social phobia. All SSRIs may be equal in the treatment of anxiety disorders; however, higher doses may be necessary in the treatment of OCD.
All commonly used SSRIs appear to have a role in the treatment of panic disorder. However, patients with panic disorder may be more sensitive to treatment with antidepressants and frequently need lower initial doses and slower titration to accomplish successful therapy.
Fluoxetine has a very long half-life, making it well suited for patients who have difficulty remembering to take all of their medications each day. The longer half-life also minimizes the risk and severity of SSRI withdrawal that can occur when patients exhaust or abruptly discontinue their SSRI.
Paroxetine (Paxil)
Alternative sedating SSRI. Potent selective inhibitor of neuronal serotonin reuptake. Also has weak effect on norepinephrine and dopamine neuronal reuptake. For maintenance dosing, make dosage adjustments to maintain patient on lowest effective dosage, and periodically reassess patient to determine need for continued treatment.
Escitalopram (Lexapro)
The FDA has approved escitalopram for generalized anxiety disorder in patients aged 7 years and older. Escitalopram is the S-enantiomer of racemic citalopram. It inhibits the reuptake of serotonin, with little or no effect on norepinephrine or dopamine reuptake.
Sertraline (Zoloft)
FDA-approved for panic disorder, PTSD, social phobia, and OCD. May be helpful for other anxiety disorders.
Fluoxetine (Prozac)
FDA-approved for OCD and panic disorder. May be helpful for other anxiety disorders.
Fluvoxamine (Luvox)
FDA approved for OCD in children (8-17 y) and adults. May be helpful for other anxiety disorders.
Citalopram (Celexa)
Enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. Citalopram is a 50:50 racemate of r- and s-citalopram. Reports of dose-dependent QT interval limit dose escalation and coadministration with CYP2C19 inhibitors.
Serotonin and Norepinephrine Reuptake Inhibitors
Class Summary
Pharmacologic agents with reuptake inhibition of serotonin and norepinephrine such as venlafaxine (Effexor and Effexor XR) and duloxetine (Cymbalta) may be helpful in a variety of mood and anxiety disorders.
Venlafaxine (Effexor XR)
FDA-approved for generalized anxiety disorder, panic disorder and social anxiety disorder in adults. May be helpful for other anxiety disorders.
Duloxetine (Cymbalta)
Potent inhibitor of neuronal serotonin and norepinephrine reuptake. It is indicated for generalized anxiety disorder in patients aged 7 years and older.
Atypical Antidepressants
Class Summary
Antidepressants that are not FDA-approved for the treatment of a given anxiety disorder, such as nefazodone and mirtazapine still may be beneficial for the treatment of anxiety disorders. Mirtazapine has a much more sedating effect, generally reducing its potential to aggravate initial anxiety. Mirtazapine acts distinctly as an alpha-2 antagonist, consequently increasing synaptic norepinephrine and serotonin, while also blocking some postsynaptic serotonergic receptors that conceptually mediate excessive anxiety when stimulated with serotonin.
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.
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.
Mirtazapine (Remeron)
Increases availability of serotonin and norepinephrine.
Tricyclic Antidepressants
Class Summary
The tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They include imipramine (Tofranil) and clomipramine (Anafranil). Caution is warranted in the use of TCAs because of their higher toxicity and potential lethality in overdose. Their use should be limited to cases in which SSRIs are ineffective or cannot be afforded. Clomipramine has an FDA indication in the treatment of OCD and is the only TCA effective in the treatment of this condition. Indeed, it can be effective in cases refractory to treatment with SSRI agents.
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.
Amitriptyline (Elavil)
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.
Clomipramine (Anafranil)
Dibenzazepine compound belonging to family of tricyclic antidepressants. Inhibits membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Clomipramine affects serotonin uptake while it affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. Believed that these actions are responsible for its antidepressant activity.
Nortriptyline (Pamelor)
Has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the central nervous system. Pharmacodynamic effects such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.
Protriptyline (Vivactil)
Increases synaptic concentration of serotonin and/or norepinephrine in CNS by inhibiting their reuptake by the presynaptic neuronal membrane.
Doxepin (Sinequan)
Increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. These effects are associated with a decrease in symptoms of depression.
Amoxapine
Inhibits reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neuron. Metabolite (7-hydroxyamoxapine) has significant dopamine receptor blocking activity similar to haloperidol. Elicits strong anticholinergic effects.
Trimipramine (Surmontil)
Inhibits reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neuron. Elicits strong anticholinergic effects.
Benzodiazepines
Class Summary
Benzodiazepines often are used with antidepressants as adjunct treatment. They are especially useful in the management of acute situational anxiety disorder and adjustment disorder where the duration of pharmacotherapy is anticipated to be 6 weeks or less and for the rapid control of panic attacks. They include lorazepam (Ativan) and clonazepam (Klonopin).
If long-term use of benzodiazepines seems necessary, obtaining a confirmatory opinion from a second clinician may be helpful because chronic benzodiazepine use may be associated with tolerance, withdrawal, and treatment-emergent anxiety. The risk of addiction with benzodiazepines should be carefully considered before use in the anxiety disorders. Avoid use in patients with a prior history of alcohol or other drug abuse. Closely monitor for evidence of unauthorized dose escalation or obtaining benzodiazepine prescriptions from multiple sources.
Alprazolam (Xanax)
For management of anxiety attacks. Binds receptors at several sites within the central nervous system, including the limbic system and reticular formation. Effects may be mediated through GABA receptor system.
Lorazepam (Ativan)
Sedative hypnotic in the benzodiazepine class that has a short onset of effect and a relatively long half-life. By increasing action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of the CNS, including limbic and reticular formation. Available for PO, IV, or IM use.
Clonazepam (Klonopin)
Long-acting benzodiazepine that increases the presynaptic GABA inhibition and reduces the monosynaptic and polysynaptic reflexes. Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). Reaches peak plasma concentration at 2-4 h after oral or rectal administration.
Diazepam (Valium)
Modulates postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. Appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect. Also has been found to be an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders.
Rapidly distributes to other body fat stores. Twenty minutes after initial IV infusion, serum concentration drops to 20% of Cmax.
Individualize dosage and increase cautiously to avoid adverse effects.
Chlordiazepoxide (Librium)
Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing gamma-aminobutyric acid (GABA) activity, a major inhibitory neurotransmitter. Provides rapid onset and efficacy in sedating aggressive patients.
Oxazepam (Serax)
Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Antianxiety Agents
Class Summary
Buspirone is a nonsedating antipsychotic drug unrelated to benzodiazepines, barbiturates, and other sedative-hypnotics. It has been found to be comparable with benzodiazepines in reducing symptoms of anxiety in double-blind placebo-controlled clinical trials and has fewer sedative or withdrawal adverse effects than benzodiazepines. Buspirone also has fewer cognitive and psychomotor adverse effects, which makes its use preferable in elderly patients. Major limitations include lack of antipanic activity and reduced anxiolytic effects in patients recently withdrawn from benzodiazepines. Also has a longer onset of action and, thus, is of fairly limited use as a sole agent in the treatment of acute anxiety in the ED.
Buspirone is a novel antianxiety agent with no other members in its class.
Buspirone (BuSpar)
5-HT1A agonist affecting serotonergic neurotransmission in CNS. Has some dopaminergic activity as well. In addition, has demonstrated anxiolytic effect but can take up to 2-3 wk for full efficacy. Also has a low abuse potential and does not mitigate panic attacks. Not useful in benzodiazepine withdrawal but has a low adverse-effect profile.
Anticonvulsant
Class Summary
The drug of choice in this category is the gamma-aminobutyric acid derivative pregabalin (Lyrica).However, caution is necessary 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 dependence and has a “street value” to drug addicts. Some anticonvulsant medications, such as divalproex (Depakote) and gabapentin (Neurontin), may have a role in the treatment of anxiety disorders, especially in patients with high potential for abusing benzodiazepines.
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.
Gabapentin (Neurontin)
Membrane stabilizer, a structural analogue of inhibitory neurotransmitter gamma-amino butyric acid (GABA), which paradoxically is thought not to exert effect on GABA receptors. Appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels
Has apparent anxiolytic properties.
Divalproex (Depakote, Depakote ER)
Has proven effectiveness in treating and preventing mania. Classified as a mood stabilizer and can be used alone or in combination with lithium. Useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination of valproic acid and valproate has been effective in treating persons in manic phase, with a success rate of 49%.
Antihypertensive Agent
Class Summary
Agents in this class may have a positive effect on the physiological symptoms of anxiety. Beta-blockers such as atenolol, nadolol, or propranolol may be useful for the circumscribed treatment of situational/performance anxiety on an as-needed basis. A pilot study revealed propranolol is effective in decreasing physiological signs of hyperarousal for up to 1 week when used shortly after patients with PTSD re-experience their traumatic event. [17]
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.
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.
Nadolol (Corgard)
Competitively blocks beta1 and beta2-receptors. Does not exhibit membrane stabilizing activity or intrinsic sympathomimetic activity.
Atenolol (Tenormin)
Used to treat hypertension. Selectively blocks beta1-receptors with little or no affect on beta2 types. Beta-adrenergic blocking agents affect blood pressure via multiple mechanisms. Actions include negative chronotropic effect that decreases heart rate at rest and after exercise, negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys. Used to improve and preserve hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure.
Beta-adrenergic blockers reduce inotropic state of left ventricle, decrease diastolic dysfunction, and increase LV compliance, thereby reducing pressure gradient across LV outflow tract. Decreases myocardial oxygen consumption, thereby reducing myocardial ischemia potential. Decreases heart rate, thus reducing myocardial oxygen consumption and reducing myocardial ischemia potential. During IV administration, carefully monitor blood pressure, heart rate, and ECG
Monoamine Oxidase Inhibitor (MAOI)
Class Summary
MAOIs are most commonly prescribed for patients with social phobia. They include the agents phenelzine (Nardil), selegiline (Emsam), tranylcypromine (Parnate), and isocarboxazid (Marplan).
Advantages of MAOIs are low risk of dependence and less anticholinergic effect than TCAs. Disadvantages are the higher number of adverse effects, including sexual difficulty, hypotension, and weight gain, and potential lethality in overdose. A diet low in tyramine must be followed to avoid a hypertensive crisis. Over-the-counter medications should be used with great caution.
The use of MAOIs should be limited to cases in which SSRIs are ineffective or cannot be afforded. MAOIs may be especially indicated in treatment-refractory panic disorder and social anxiety disorder. MAOIs also may have a role in the treatment of certain subtypes of OCD refractory to conventional treatment, such as patients with symmetry obsessions or associated panic attacks.
Phenelzine (Nardil)
In one double-blind placebo-controlled trial, was more efficient in reducing intrusion symptoms. 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.
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.
Tranylcypromine (Parnate)
Treats major depression. Binds irreversibly to MAO, thereby reducing monoamine breakdown and enhancing synaptic availability.
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.
Antipsychotic Agent
Class Summary
Atypical and typical antipsychotic medications are generally used more as augmentation strategies and are second-line treatment options in generalized anxiety disorder. [74] 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.
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.
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.
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.
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.
Clozapine (Clozaril)
Demonstrates weak D2-receptor and D1-receptor blocking activity, but noradrenolytic, anticholinergic, antihistaminic, and arousal reaction inhibiting effects are significant. Also possesses antiserotonergic (5-HT1c, 5-HT2, 5-HT3) properties. Affinity for mesolimbic D4 dopamine receptor accounts for striking effects in control of behavioral and psychiatric symptoms with low incidence of extrapyramidal symptoms. Histamine receptor blockade accounts for increased incidence of sleep disturbances. Associated with a risk of agranulocytosis when used at doses required for treatment of patients with schizophrenia whose symptoms are refractory to standard neuroleptics. In US, weekly dosing and weekly CBCs are required for clozapine to be dispensed; discontinuing therapy at first sign of leukopenia decreases but does not eliminate risk of agranulocytosis; whether agranulocytosis is associated with low doses in treating elderly patients and those with dementia is not clear.
Olanzapine (Zyprexa)
May inhibit serotonin, muscarinic, and dopamine 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.
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Anxiety. Chart showing the female-to-male sex ratio for anxiety disorders. Adapted from Kessler et al, 1994.
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Anxiety. Age of onset for anxiety disorders based on specific anxiety disorder type.
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Brain structures involved in dealing with fear and stress.
