Medication Summary
Pharmacotherapy for phobic disorders (ie, social anxiety disorder, specific phobia, and agoraphobia) includes antidepressant agents (eg, selective serotonin reuptake inhibitors [SSRIs] and selective serotonin/norepinephrine reuptake inhibitors [SNRIs]), benzodiazepines, serotonin (5HT) 1 agonists, antihypertensive agents, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).
Antidepressants, SSRIs
Class Summary
SSRIs can help prevent panic attacks and alleviate symptoms of anxiety and depression. These drugs may require 2-6 weeks of daily use to become effective, usually with side effects appearing first. SSRIs have been shown to be effective in controlled clinical trials, and as a class, these medications tend to have the fewest adverse effects. However, the SSRIs can produce drug-drug interactions by inhibiting cytochrome P450 enzymes and by displacing other drugs from protein-binding sites.
SSRIs are greatly preferred to other classes of antidepressants for the treatment of anxiety disorders, and they all appear to be similarly efficacious. The choice of an SSRI depends on adverse effects, drug interactions, and history of previous response.
The relatively benign adverse effect profile of SSRIs (including minimal anticholinergic effects) facilitates compliance. Common adverse effects include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating, fatigue, somnolence, and sexual dysfunction. SSRIs do not carry the cardiac arrhythmia risk associated with TCAs.
Citalopram hydrobromide (Celexa)
Citalopram enhances serotonin activity through selective reuptake inhibition at the neuronal membrane. This agent is not approved by the US Food and Drug Administration (FDA) for treatment of anxiety disorders, but data from randomized, controlled trials support its use for treatment of agoraphobia.
Escitalopram oxalate (Lexapro)
Escitalopram is an S-enantiomer of citalopram. The onset of depression relief may be obtained after 1-2 weeks, which is sooner than relief can be obtained with other antidepressants, suggesting that escitalopram may work faster than similar drugs.
Although this agent is not approved by the FDA for treatment of phobic disorders, its class membership and good tolerability make it an attractive option for long-term treatment. Off-label use of escitalopram for anxiety disorders includes social anxiety disorder (social phobia), panic disorder, and obsessive-compulsive disorder (OCD). Escitalopram is not approved for use in children younger than 12 years.
Paroxetine hydrochloride (Paxil, Paxil CR, Pexeva)
Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake, but it has a weak effect on norepinephrine and dopamine neuronal reuptake. This agent is a low-affinity antagonist at some subtypes of muscarinic acetylcholine receptors and is a nitric oxide synthase inhibitor. The anticholinergic effects of paroxetine may result in sedation or cardiovascular effects.
Paroxetine is FDA-approved for use in social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder, OCD, major depressive disorder (MDD), premenstrual dysphoric disorder (PMDD), and posttraumatic stress disorder (PTSD).
Sertraline hydrochloride (Zoloft)
Sertraline selectively inhibits presynaptic serotonin reuptake and is a low-potency dopamine and norepinephrine reuptake inhibitor. It is-FDA approved for use in social anxiety disorder; panic disorder; major depressive disorder; OCD in adults, children, and adolescents; PMDD; and PTSD.
Fluoxetine (Prozac, Prozac Weekly)
Fluoxetine selectively inhibits presynaptic serotonin reuptake but has minimal or no effect on reuptake of norepinephrine or dopamine. A common side effect is sexual dysfunction, which may impact long-term compliance. Fluoxetine is FDA-approved for use in panic disorder (with and without agoraphobia) and OCD, as well as other disorders.
Fluvoxamine (Luvox CR)
Fluvoxamine enhances serotonin activity through selective reuptake inhibition at the neuronal membrane. Because this drug does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors, it has fewer side effects than TCAs do. Fluvoxamine is FDA-approved for treating OCD in children (8-17 years) and adults; it is also approved for treating social anxiety disorder. Fluvoxamine may be helpful for other anxiety disorders as well.
Antidepressants, SNRIs
Class Summary
SNRIs can help prevent panic attacks and alleviate symptoms of anxiety and depression.
Venlafaxine hydrochloride (Effexor XR)
Venlafaxine is a reuptake inhibitor of both serotonin and norepinephrine. It is FDA-approved (in the extended-release capsule only) for the treatment of social phobia, panic disorder with or without agoraphobia, and generalized anxiety disorder.
Benzodiazepines
Class Summary
In general, this category of medication should not be prescribed to patients with a history of alcohol/drug abuse or emotional dependence. Some psychiatrists feel that the longer-acting benzodiazepines (eg, diazepam, clonazepam) have advantages such as less frequent dosing and more consistent levels throughout the day. Slowly taper benzodiazepines (usually after 6 mo) to avoid withdrawal and to avoid precipitating panic.
Alprazolam (Xanax, Xanax XR, Niravam)
Alprazolam is the best-studied benzodiazepine. It has a rapid onset (20 minutes) and a short half-life, which can contribute to increased dependency during tapering attempts. Alprazolam is FDA approved for use in panic disorder, with or without agoraphobia, generalized anxiety disorder, and anxiety disorders (in the immediate-release tablet).
Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a short onset of effects and a relatively long half-life. By increasing the action of gamma aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the central nervous system (CNS), including the limbic and reticular formation. This agent is FDA-approved for use in anxiety disorders.
When a patient must be sedated for longer than 24 hours, lorazepam is an excellent choice. It is not significantly metabolized by the liver, and it can be administered either intravenously (IV) or intramuscularly (IM).
Clonazepam (Klonopin)
Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. This drug also suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Clonazepam reaches peak plasma concentration at 2-4 hours after oral or rectal administration.
Clonazepam has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). This agent is FDA-approved for use in anxiety disorders.
Diazepam (Diastat AcuDial, Diastat Pediatric, Valium)
Diazepam modulates the postsynaptic effects of GABA-A transmission, thereby bringing about an increase in presynaptic inhibition. This agent appears to act on part of the limbic system, the thalamus, and hypothalamus to induce a calming effect and has also been found to be an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders. This agent is FDA-approved for use in anxiety disorders.
Diazepam is rapidly distributed to other body fat stores. To avoid adverse effects, the diazepam dosage should be individualized and increased cautiously; the serum concentration of the drug drops to 20% of its peak value 20 minutes after the initial IV infusion.
Antianxiety Agents
Class Summary
Serotonin agonists such as buspirone may be used to treat anxiety.
Buspirone
Buspirone is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. Rather, it is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. Buspirone has an anxiolytic effect but may take up to 2-3 weeks to reach its full efficacy. Buspirone is approved for the treatment of anxiety disorders or short-term relief of the symptoms of anxiety.
Antihypertensive Agents
Class Summary
Antihypertensive agents are useful for the circumscribed treatment of situational/performance anxiety on an as-needed basis.
Beta-adrenergic blockers reduce the inotropic state of the left ventricle (LV), decrease diastolic dysfunction, and increase LV compliance, thereby reducing the pressure gradient across the LV outflow tract. Decreasing myocardial oxygen consumption reduces myocardial ischemia potential, and lowering the heart rate reduces myocardial oxygen consumption and myocardial ischemia potential.
Atenolol (Tenormin)
Atenolol acts by selectively blocking beta1 receptors, with little or no effect on beta2 receptors. Beta-blockers affect blood pressure via multiple mechanisms, including a negative chronotropic effect that decreases heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys.
Atenolol is used to improve and preserve hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure. During IV administration, the patient's blood pressure, heart rate, and electrocardiogram (ECG) must be carefully monitored.
Propranolol (Inderal LA, InnoPran XL)
Propranolol is recommended for situational social anxiety (stage fright) on an as-needed basis. An oral (PO) dose of 10-20 mg is given
Antidepressants, TCAs
Class Summary
The tricyclic antidepressants (TCAs) clomipramine and imipramine have demonstrated efficacy for the treatment of panic disorder with and without agoraphobia. These are also relatively inexpensive medications. However, due to their broad spectrum of action and their inhibition of multiple neurotransmitter systems, the TCAs have more side effects, such as anticholinergic and cardiovascular side effects, and therefore, these agents present problems for long-term treatment. The treatment response of TCAs occurs on the same order as the Selective serotonin reuptake inhibitors (SSRIs), within 2-6 weeks.
TCAs have a black box warning that states that patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications.
Clomipramine hydrochloride (Anafranil)
Clomipramine is a dibenzazepine compound that belongs to the TCA family. It acts by inhibiting the membrane pump mechanism responsible for norepinephrine and serotonin uptake in adrenergic and serotonergic neurons. Clomipramine affects serotonin uptake; it also affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. Clomipramine acts as an antagonist at muscarinic acetylcholine receptors and is also an antagonist at histamine H1 receptors.
Clomipramine is approved by the FDA for use in the treatment of OCD (adult and pediatric, age ≥10 years).
Imipramine hydrochloride (Tofranil, Tofranil-PM)
Imipramine hydrochloride inhibits reuptake of norepinephrine or serotonin at the presynaptic neuron. This agent is an antagonist at histamine H1 and alpha1 adrenoceptors, as well as at M2 muscarinic acetylcholine receptors. Parenteral administration can be used for starting therapy only in patients unable or unwilling to use oral medication.
Antidepressants, MAO Inhibitors
Class Summary
MAOIs are most commonly prescribed for patients with social anxiety disorder (social phobia). Their main advantages are a low risk of dependence and a lesser anticholinergic effect than is seen with TCAs. Their main disadvantage is the higher number of adverse effects, including sexual difficulty, hypotension, and weight gain. A diet low in tyramine must be followed to avoid a hypertensive crisis. Use concomitant medications, including over-the-counter medications, with great caution. Because of the high risk for serotonin syndrome or hypertensive crisis, MAOIs are contraindicated in patients taking selective serotonin reuptake inhibitors; dual serotonin and norepinephrine reuptake inhibitors; tricyclic antidepressants; bupropion (Wellbutrin); mirtazapine (Remeron); buspirone (Buspar); and certain analgesics, vasoconstrictors, sympathomimetics, and anticonvulsants.
Phenelzine (Nardil)
Phenelzine is the most commonly used MAOI for anxiety disorders. (Tranylcypromine 30-60 mg/day is also effective.) Phenelzine is usually reserved for patients who cannot tolerate or do not respond to TCAs or SSRIs.
Selegiline (Emsam)
Selegiline is a selective MAO-B inhibitor at lower therapeutic doses. As such, at the target dose of 6 mg per 24 hours, special dietary restrictions are not needed. In addition, the selegiline transdermal patch has the advantage of avoiding the first pass effect, which decreases the impact of CYP high/low-metabolizer status in terms of medication effects and tolerability.
Anticonvulsants
Class Summary
Selected anticonvulsants have been shown to be effective for social anxiety disorder in mostly open-label, uncontrolled clinical trials and may also be useful in the treatment of other phobic disorders.
Gabapentin (Neurontin, Gralise)
Gabapentin is a membrane stabilizer and a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which, paradoxically, is thought not to exert effects on GABA receptors. It appears to exert action via the alpha-2-delta1 and alpha-2-delta2 auxiliary subunits of voltage-gated calcium channels and has apparent anxiolytic properties.
Pregabalin (Lyrica)
Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. It binds with high affinity to alpha-2-delta calcium channel subunits. In vitro, it reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function.
Valproic acid (Depakote, Depakote ER, Depakene, Stavzor)
The mechanism of action of valproic acid is not established; its activity may be related to increased brain levels of GABA or enhanced GABA action. Valproic acid may also potentiate postsynaptic GABA responses, affect the potassium channel, or exert a direct membrane-stabilizing effect.
