Medication Summary
First-line pharmacologic therapies for panic disorder include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). [55] These 3 classes of agents are preferred over benzodiazepines as monotherapies for patients with co-occurring depression or substance use disorders.
The FDA issued a Drug Safety Communication in August 2011 stating that the SSRI, citalopram (Celexa), should not be used at doses greater than 40 mg per day, owing to the potential for dangerous abnormalities in cardiac electrical activity. [57] Citalopram 20 mg per day is the maximum recommended dose in patients with hepatic impairment, who are older than 60 years, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (Tagamet) or another CYP 2C19 inhibitor. Such individuals can have higher blood levels of citalopram, leading to an increased risk of prolonged QT interval and torsade de pointes. [57]
Additional warnings as of March 2012 discourage the use of citalopram at any dose in patients with certain conditions (congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure) due to potentially dangerous prolongation of the QT interval. [57]
For patients requiring rapid symptom control, benzodiazepines can be used as adjuncts with antidepressant agents to treat residual anxiety symptoms, and they may be preferred (as monotherapies or in combination with antidepressants). [55] Clinicians must carefully assess the benefit of more rapid response against the potential complications of benzodiazepine therapy.
The American Psychiatric Association (APA) recommends avoiding TCAs for patients with panic disorder who also have acute narrow-angle glaucoma or clinically significant prostatic hypertrophy. [55] TCAs may increase the risk of falls and fractures, particularly in elderly patients. In addition, owing to the potential for significant or fatal arrhythmia in patients with preexisting cardiac conduction abnormalities, it is important to obtain an electrocardiogram (ECG) in these individuals before starting TCA treatment. Use TCAs with caution in suicidal patients as overdoses with these drugs can cause cardiac toxicity and death. [55]
Anxiolytics, Benzodiazepines
Class Summary
By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters. These agents are effective on standing-dose and as-needed (prn) schedules
Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a short onset of effects and a relatively intermediate half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic and reticular formations.
Clonazepam (Klonopin)
Clonazepam is a sedative hypnotic that is a long-acting benzodiazepine with a half-life of approximately 36 hours and an intermediate onset of action. This agent facilitates inhibitory GABA neurotransmission and other inhibitory transmitters.
Alprazolam (Xanax, Xanax XR)
Alprazolam is used for the management of anxiety attacks. It is a short-acting anxiolytic with an intermediate onset of effects. This agent binds to receptors at several sites within the CNS, including the limbic system and the reticular formations. The effects of alprazolam may be mediated through the GABA receptor system. Alprazolam has been widely reviewed in the literature, although its use is currently discouraged because of its higher potential to elicit dependency.
Diazepam (Valium, Diastat, Diazepam Intensol)
Diazepam is an anxiolytic benzodiazepine and has a rapid onset of effects. This medication depresses all levels of the CNS (eg, the limbic and reticular formations), possibly by increasing the activity of GABA.
Antidepressants, SSRIs
Class Summary
Selective serotonin reuptake inhibitors (SSRIs) are first-line agents for the long-term management of anxiety disorders. Control is gradually achieved over a 2- to 4-week course, depending on the required dosage increases.
All commonly used SSRIs appear to have a role in the treatment of panic disorder. Fluoxetine is covered here, because it has a very long half-life; this makes 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.
Fluoxetine (Prozac)
Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on reuptake of norepinephrine or dopamine. It has a long half-life and therefore a lower risk of withdrawal symptoms. However, fluoxetine does require slower titration and has CNS stimulating effects.
Paroxetine (Paxil, Paxil CR, Pexeva)
Paroxetine is the least stimulating SSRI. This agent is a potent selective inhibitor of neuronal serotonin reuptake. Paroxetine also has a very weak effect on norepinephrine and dopamine neuronal reuptake. It does not significantly bind to muscarinic, alpha-adrenergic, or histamine receptors and therefore has fewer adverse effects than do tricyclic antidepressants (TCAs).
Sertraline (Zoloft)
Sertraline selectively inhibits presynaptic serotonin reuptake. It also has a very weak inhibitory effect on norepinephrine and dopamine neuronal reuptake.
Fluvoxamine (Luvox, Luvox CR)
Fluvoxamine is a potent selective inhibitor of neuronal serotonin reuptake. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and therefore has fewer adverse effects than do tricyclic antidepressants.
Citalopram (Celexa)
Citalopram enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. SSRIs are the antidepressants of choice due to minimal anticholinergic effects.
Escitalopram (Lexapro)
Escitalopram is an SSRI and an S-enantiomer of citalopram. Its mechanism of action is thought to be potentiation of serotonergic activity in the CNS resulting from the inhibition of CNS neuronal reuptake of serotonin.
Antidepressants, TCA
Class Summary
Tricyclic antidepressants (TCAs) have the advantages of once-daily dosing, low risk of dependence, and no dietary restrictions. However, these drugs are discontinued in 35% of patients because of adverse effects, such as blurred vision, dry mouth, dizziness, weight gain, gastrointestinal disturbance, agitation, insomnia, headache, and decreased libido or ability to orgasm.
TCAs must be started in low doses to avoid amphetamine-like stimulation and can require up to 8-12 weeks for treatment response.
Imipramine (Tofranil, Tofranil-PM)
The mechanism of action of imipramine is not fully known. However, the clinical effect is hypothesized as being due to the inhibition of the reuptake of norepinephrine and serotonin (5-hydroxytryptamine [5-HT]) at presynaptic neurons.
Desipramine (Norpramin)
Desipramine may increase the synaptic concentration of norepinephrine in the CNS by inhibiting the reuptake by the presynaptic neuronal membrane. It may have effects in the desensitization of adenyl cyclase, downregulation of beta-adrenergic receptors, and downregulation of serotonin receptors.
Clomipramine (Anafranil)
Clomipramine affects serotonin uptake. This agent also affects norepinephrine uptake when converted into its metabolite, desmethylclomipramine.
Antidepressants, MAO Inhibitors
Class Summary
Monoamine oxidase inhibitors (MAOIs) are effective in patients with social phobia and refractory anxiety disorders, including panic disorder. Advantages of MAOIs include a low risk of dependence and less anticholinergic effect than tricyclic antidepressants (TCAs). Disadvantages include the higher number of adverse effects, including sexual difficulty, hypotension, weight gain, dry mouth, tachycardia, insomnia, drowsiness, headache, weakness, and constipation.
Phenelzine (Nardil)
Nardil is the MAOI that is most commonly used for managing panic disorder. It has demonstrated clear superiority over placebo in double-blind trials for treating specific symptoms of panic disorder. This drug is usually reserved for patients who do not tolerate or whose condition does not have a response to traditional cyclic or second-generation antidepressants.
Tranylcypromine (Parnate)
Tranylcypromine is also effective against panic disorder. It binds irreversibly to MAO, thereby reducing monoamine breakdown and enhancing synaptic availability.
Antidepressants, SNRI’s
Class Summary
Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants inhibit serotonin reuptake receptors and, unlike the pure selective serotonin reuptake inhibitors (SSRIs), inhibit the reuptake of norepinephrine as well.
Venlafaxine (Effexor, Effexor XR)
Venlafaxine is a serotonin/norepinephrine reuptake inhibitor. It may treat depression by inhibiting neuronal serotonin and norepinephrine reuptake. In addition, it causes beta-receptor down-regulation.
Antidepressants, Others
Class Summary
Other antidepressants are those that are unique and not categorized into the classification of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SSNIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).
Trazodone (Desyrel, Desyrel Dividose, Oleptro)
Trazodone is useful in the treatment of panic disorder and agoraphobia with panic attacks. It is an antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Trazodone also has a negligible affinity for cholinergic and histaminergic receptors.
In animals, this drug selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan.
Mirtazapine (Remeron, Remeron SolTab)
Mirtazapine is an alpha-2 adrenergic antagonist that increases synaptic norepinephrine and serotonin, while also blocking some postsynaptic serotonergic receptors that conceptually mediate excessive anxiety when stimulated with serotonin. This agent causes significant sedation which generally reduces its potential to aggravate initial anxiety and may cause residual morning sedation that often improves with continued therapy.
Sedating antidepressants such as mirtazapine are usually prescribed for use only at night before bed to help improve sleep, but they should include a warning for patients not to operate a motor vehicle or machinery if they are feeling sedated or directly after the dose.
Mirtazapine may also cause an increase in appetite or weight gain.
