Paroxetine is metabolized by CYP2D6 and is also a CYP2D6 inhibitor. Thus, paroxetine inhibits its own metabolism. As a result, withdrawal symptoms are more likely to occur and are typically more severe compared to discontinuation syndrome caused by other SSRIs. Symptoms of withdrawal from paroxetine can include dizziness, lethargy, nausea and vomiting, headache, vivid dreams, electric shock-like sensation, dyskinesia, irritability, and depersonalization (Shrestha et al., 2021). Geriatric patients are at higher risk for side effects with paroxetine and should be started on a 10-mg dose in most cases. It’s recommended to use a maximum dose of 40 mg in this population. No dose adjustment is required for mild to moderate renal or hepatic impairment. For creatinine clearance below 30 mL/min,
or in the setting of severe hepatic impairment, the maximum recommended dose is 40 mg (50 mg for the delayed-release formulation). Sertraline (Zoloft) Sertraline is FDA-approved to treat panic disorder and social anxiety disorder. It’s also used off-label for treating generalized anxiety disorder (Singh & Saadabadi, 2022). Sertraline is given once daily, either in the morning or evening. Somnolence is a possible adverse effect which can be addressed by administering the dose in the evening. For treating anxiety disorders, the recommended starting dose is 25 mg once daily, and may be increased by 50-mg in weekly intervals up to a maximum dose of 200 mg. See Table 2.
Table 2: FDA-approved and Off-Label Use of SSRIs for Treating Anxiety Disorders Medication FDA-approved Anxiety Disorders Off-label uses
Therapeutic Dose Range
Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox)
None GAD
GAD, PD, SAD , AG
20-40 mg/day 10-20 mg/day 20-60 mg/day 100-300 mg/day 20-60 mg/day 27-75 mg/day
PD, SAD, AG
PD
GAD, SAD
None
GAD, PD, SAD
Paroxetine (Paxil)
GAD, PD, SAD
AG
Paroxetine extended- release (Paxil CR)
PD, SAD
GAD
Sertraline (Zoloft)
PD, SAD
GAD, AG
50-200 mg/day
SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)
Serotonin and norepinephrine reuptake inhibitors (SNRIs) block reuptake of both serotonin and norepinephrine in synapses. Individual SNRIs vary in their affinity for serotonin and norepinephrine transporters. Class adverse effects include sexual dysfunction, dry mouth, dizziness, sleep disturbances diaphoresis, headache, bone resorption, and hypertension (Sheffler & Abdijadid, 2021). Like SSRIs, SNRIs can produce SIADH and serotonin syndrome as Duloxetine is FDA-approved for treating GAD and may also be used off-label to treat panic disorder or SAD (Garakani et al., 2020). In addition to inhibiting reuptake of serotonin and norepinephrine, duloxetine also increases dopamine in the prefrontal cortex (Dhaliwal et al., 2021). A meta-analysis by Curtiss et al. analyzing efficacy of pharmacotherapy for SAD found duloxetine to have the largest effect size among SNRIs (Curtiss et al., 2017). serious adverse effects. Duloxetine (Cymbalta) Duloxetine comes in capsules, which may be opened and sprinkled on applesauce or apple juice, remaining stable in this mixture for up to 2 hours (Dhaliwal et al., 2021). For treating GAD, the recommended starting dose is 30 to 60 mg once daily. Studies have shown no additional benefit to raising the dose above 60 mg per day, but some clinicians have reported benefit in patients treated with higher doses (Dhaliwal et al., 2021). Venlafaxine XR (Effexor XR) Venlafaxine XR is FDA-approved to treat GAD, PD, and SAD. (The immediate-release formulation is only indicated for treatment of major depressive disorder). Venlafaxine XR is available as extended-release capsules. At a 75-mg dose, the drug primarily functions as a serotonin reuptake inhibitor. As doses increase (such as to 225 mg), its effects on norepinephrine transporters become more pronounced, without loss of serotonin reuptake inhibition (Singh & Saadabadi, 2021). Typical starting dose for venlafaxine XR is 75 mg once daily. This may be titrated in 75-mg increments every four days, up to the maximum dose of 225 mg daily. Doses should be administered with food and may be given in the morning or evening. If
the patient experiences insomnia with evening doses, move administration to the morning (Singh & Saadabadi, 2021). See Table 3. Table 3: FDA-Approved and Off-Label Use of SNRIs for Treating Anxiety Disorders Medication FDA- approved Anxiety Disorders Off-Label Uses Therapeutic Dose Range
Desvenlafaxine (Pristiq)
None
GAD, PD, SAD
50-100 mg/day
Duloxetine (Cymbalta)
GAD PD, SAD 30-60 mg/day
Venlafaxine XR (Effexor XR)
GAD, PD, SAD
AG
75-225 mg/day
Buspirone Buspirone was originally developed as an antipsychotic but turned out to be ineffective for treating psychosis. However, the medication has found use as an anxiolytic (Wilson & Tripp, 2021). It is FDA-approved for the management of anxiety disorders, as well as for short-term relief of anxiety symptoms. In practice, buspirone is commonly prescribed as a second-line treatment in patients who do not respond or who have intolerable side effects with SSRIs. Buspirone may also be prescribed as an augmentation agent and may be useful to decrease SSRI- induced sexual dysfunction (Wilson & Tripp, 2021). Buspirone is as effective as benzodiazepines for treating GAD. Unlike benzodiazepines, buspirone carries no risk for abuse, misuse, physical dependence, or withdrawal symptoms; the drug has no effect on GABA receptors. However, buspirone has little to no efficacy for acute anxiety relief. It typically takes two to four weeks for the drug’s clinical effects to take hold (Wilson & Tripp, 2021). In general, buspirone has a more tolerable side effect profile compared to other pharmacological treatments for anxiety.
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