Phobic Disorders Medication

Pharmacotherapy of phobic disorders includes antidepressant agents (selective serotonin reuptake inhibitors [SSRIs], selective serotonin/norepinephrine reuptake inhibitors [SNRIs]), benzodiazepines, serotonin (5HT) 1 agonists, antihypertensive agents, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

The evidence for medication recommendations for simple phobias is scant. However, there is good evidence for medication recommendations for social anxiety disorder (SAD). Accordingly, for SAD, first-line recommendations include SSRIs and the SNRI venlafaxine, while second-line agents include benzodiazepines, TCAs, and MAOIs.^{[41, 42]} MAOIs, both reversible (eg, moclobemide) and irreversible (eg, phenelzine), and TCAs are not commonly used. While effective, due to the risk for drug-to-drug and dietary interaction (for the MAOIs) and tolerability issues (for TCAs), these agents should be considered as second- and third-line choices.

Antihypertensive beta-blockers can be used as augmentation strategies. Selected anticonvulsants (eg, gabapentin, pregabalin, valproic acid, topiramate, tiagabine) have been shown to be effective for SAD in mostly open-label, noncontrolled clinical trials.^[42] The evidence regarding the 5HT-1 agonist buspirone for SAD is conflicting.^[42] A few other medications, including second-generation antipsychotics levetiracetam and D-cycloserine, do not have sufficient evidence at this time for clear recommendations.^{[41, 42]}

Class Summary

Selective serotonin reuptake inhibitors (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 through their inhibition of cytochrome P450 enzymes and by displacement of other drugs from protein-binding sites.

SSRIs are greatly preferred over other classes of antidepressants for the treatment of anxiety disorders, and all appear similarly efficacious. The choice of SSRI depends on adverse effects, drug interactions, and history of previous response.

The relatively benign adverse effect profile of SSRIs is less prominent (including minimal anticholinergic effects) and helps compliance. Common adverse effects include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating, fatigue, somnolence, and sexual dysfunction. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants (TCAs).

Pediatric, adolescent, and young adult suicidality

Suicide risk must always be considered, particularly when treating a child or adolescent with a mood disorder.

Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric and geriatric populations.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed, because suicidality occurred in both treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

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 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, 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),^{[43, 44]} panic disorder, and obsessive-compulsive disorder (OCD).^[43] Escitalopram is not approved for use in children younger than 12 years.

Citalopram hydrobromide (Celexa)

Citalopram enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. This agent is not FDA approved for treatment of anxiety disorders but randomized controlled trial data support its use for agoraphobia.

Paroxetine hydrochloride (Paxil, Paxil CR)

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 also is a low-potency dopamine and norepinephrine reuptake inhibitor.

Sertraline 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)

Fluoxetine selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine. Sexual dysfunction is common, 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 due to 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.

Fluvoxamine is FDA approved for use in OCD in children (8-17 y) and adults. It is also approved for the treatment of social anxiety disorder. Fluvoxamine may be helpful for other anxiety disorders.

Class Summary

Selective serotonin/norepinephrine reuptake inhibitors can help prevent panic attacks and alleviate symptoms of anxiety and depression.

Venlafaxine hydrochloride (Effexor, Effexor XR)

Venlafaxine is a reuptake inhibitor of both serotonin and norepinephrine. This agent is approved by the US Food and Drug Administration (FDA) for use (in the extended-release capsule only) in the treatment of social phobia, panic disorder with or without agoraphobia, and generalized anxiety disorder.

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)

Alprazolam is the best-studied benzodiazepine agent. This drug has a rapid (20 min) onset and short half-life, which can contribute to increased dependency during tapering attempts.

Alprazolam is approved by the FDA for use in panic disorder, with or without agoraphobia, as well as anxiety disorders (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 approved by the FDA for use in anxiety disorders.

When a patient needs to be sedated for longer than 24 hours, lorazepam is an excellent choice. This drug is not significantly metabolized by the liver, and it can be prescribed for intravenous (IV) or intramuscular (IM) administration.

Clonazepam (Klonopin, Klonopin Wafer)

Clonazepam is a long-acting benzodiazepine that increases the presynaptic GABA inhibition and reduces the 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, Valium)

Diazepam modulates the postsynaptic effects of GABA-A transmission, resulting in 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 rapidly distributes to other body fat stores. Individualize the dosage and increase cautiously to avoid adverse effects, as the serum concentration level of diazepam drops to 20% of Cmax 20 minutes after the initial IV infusion.

Class Summary

Serotonin (5-HT) 1 agonist drugs such as buspirone may be used to treat anxiety.

Buspirone

Buspirone is an antianxiety agent not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. Rather, this drug is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the central nervous system (CNS). Buspirone has an anxiolytic effect but may take up to 2-3 weeks for full efficacy.

Class Summary

Antihypertensive agents are useful for the circumscribed treatment of situational/performance anxiety on an as-needed basis.

Atenolol (Tenormin)

Atenolol is used to treat hypertension and acts by selectively blocking beta1-receptors with little or no effect on beta2 type receptors. Beta-adrenergic blocking agents affect blood pressure via multiple mechanisms, and their actions include 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. This agent is 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 the left ventricle (LV), decrease diastolic dysfunction, and increase LV compliance, thereby reducing the pressure gradient across the LV outflow tract. By decreasing myocardial oxygen consumption, myocardial ischemia potential is thereby reduced, and by decreasing heart rate, myocardial oxygen consumption and myocardial ischemia potential are reduced.

During IV administration, carefully monitor the patient's blood pressure, heart rate, and electrocardiogram (ECG).

Propranolol (Inderal LA, InnoPran XL)

Propranolol is recommended for situational social anxiety (stage fright) on an as-needed basis. The dosing regimen is an oral (PO) dose of 10-20 mg as needed, with a maximum total daily dose of up to 40-80 mg PO in divided doses.

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 family of TCAs. This agent acts by inhibiting the membrane pump mechanism responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Clomipramine affects serotonin uptake; it also affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. It is believed that these actions are responsible for preventing panic disorders.

Clomipramine acts as an antagonist at muscarinic acetylcholine receptors and is also an antagonist at histamine H1 receptors.

This agent is approved by the US Food and Drug Administration (FDA) for use in the treatment of obsessive-compulsive disorder (OCD) (adult and pediatric, age 10 y and older).

Imipramine hydrochloride (Tofranil)

Imipramine hydrochloride inhibits reuptake of norepinephrine or serotonin (5-HT) at the presynaptic neuron. This agent is an antagonist at histamine H1 and alpha-1-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.

Class Summary

Monoamine oxidase inhibitors (MAOIs) are most commonly prescribed for patients with social phobia. Advantages of these agents are a low risk of dependence and less anticholinergic effect than tricyclic antidepressant agents (TCAs). The disadvantages of MAOIs are 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. Over-the-counter medications should be used with great caution.

Phenelzine (Nardil)

Phenelzine is the most commonly used MAOI for anxiety disorders. (Tranylcypromine administered at 30-60 mg/d doses is also effective.) Phenelzine is usually reserved for patients who do not tolerate or have a response to the TCA or selective serotonin reuptake inhibitor (SSRI) antidepressants.

Class Summary

Selected anticonvulsants have been shown to be effective for social anxiety disorders in mostly open label, non-controlled clinical trials and may also be useful in the treatment of phobic disorders.

Gabapentin (Neurontin)

Gabapentin is a membrane stabilizer and a structural analogue of the inhibitory neurotransmitter GABA, which, paradoxically, is thought not to exert effects on GABA receptors. It appears to exert action via the alpha2delta1 and alpha2delta2 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 alpha2delta site (a calcium channel subunit). In vitro, it reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function.

Valproic acid (Depakote, Depakote ER, Depakene)

The mechanism of action of valproic acid is not established and 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 have a direct membrane-stabilizing effect.