Clinicians Use SSRIs Off- Label in Many Conditions

When selective serotonin reuptake inhibitors (SSRIs) were first introduced, researchers hailed them as the first rationally designed psychotropic drug because they were developed with a specific target in mind: selective inhibition of 5-hydroxytryptamine reuptake.1 Since the FDA approved fluoxetine (Prozac; Eli Lilly) in 1987, SSRIs have dominated the treatment of depression in the United States.²

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FDA approved for bulimia nervosa, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder, SSRIs are dispensed often in pharmacies. Three SSRIs (fluoxetine, paroxetine, and sertraline) are FDA approved for premenstrual syndrome and premenstrual dysphoric disorder.^2-4

SSRIs selectively block serotonin (5-hydroxytryptamine) transporters, increasing their levels at the neuron’s somatodendritic and presynaptic ends.⁵ Targeting this site reduced the number of adverse effects and improved the safety profile over other classes of antidepressants in clinical trials.^6,7 As the data about SSRIs’ safety and efficacy profile accumulated, so, too, did the propensity for clinicians to use these medications off-label.

BODY DYSMORPHIC DISORDER (BDD)

BDD manifests as debilitating obsessions on single or multiple body parts (eg, ears, face, hair, nose) and is often associated with compulsive counter behaviors that affect quality of life.^8,9 Because the SSRIs address obsessive pathology, researchers have proposed they could be effective in BDD. Although serotoninergic signaling seems to be somewhat impaired in BDD, only a few small studies demonstrate SSRIs’ utility. Four open-label studies found that escitalopram (Lexapro; AbbVie), citalopram (Celexa; Allergan), and fluvoxamine (Luvox; Jazz Pharmaceuticals) improved BDD in more than half of participants when given with cognitive behavioral therapy (CBT).^10-13

IMPULSE CONTROL DISORDER (ICD)

Impulsivity (the tendency to act abruptly without reflection or forethought) often manifests as kleptomania, pyromania, intermittent explosive disorder, and pathological gambling.⁹ Serotonin might modulate impulsive behaviors in the prefrontal cortex.¹⁴ The most common SSRI employed in ICD is fluoxetine 20 mg/d to 60 mg/d, but some clinicians have used citalopram 20 mg/d to 60 mg/d. Large, well-structured studies addressing specific types of impulsivity are lacking, and more work is needed to establish efficacy.¹⁵

IRRITABLE BOWEL SYNDROME (IBS)

IBS—a functional disorder that includes diarrhea, constipation, bloating, and abdominal pain—emanates from multiple etiologies, but psychological factors contribute.¹⁶ When antidepressants are used, tricyclic antidepressants have proven the most effective of the antidepressants, but some results with SSRIs have been encouraging. A review and metaanalysis including trials of SSRIs compared with placebo found that half of participants in active treatment groups reported significantly reduced IBS symptoms.¹⁷ Clinical trials employing paroxetine 5 mg/d to 20 mg/d reported significant improvements in patient-reported gastrointestinal symptoms and clinical evaluations.¹⁸

MIGRAINE

Theoretically, reduced serotonin levels may be instrumental in migraine’s pathogenesis, as researchers have identified low serotonin levels and brief upregulation during attacks.^19,20 Typical off-label SSRI use in migraine is for prophylaxis. Regardless, compared with other antidepressants like tricyclic antidepressants, SSRIs tend to be less effective, possibly because they do not cause sedation.²¹ Fluoxetine has been studied most at doses between 20 mg/d and 40 mg/d.^21,22 The American Academy of Neurology and American Headache Society guidelines bestow a rating of U (inadequate or conflicting data) for fluoxetine and fluvoxamine in migraine.²³ One consideration of concern is that headache is a common adverse effect associated with SSRIs.²⁴

PARAPHILIAS AND HYPERSEXUALITY

Some clinicians have used SSRIs for paraphilic disorders (recurrent, intense, sexually arousing fantasies, sexual urges, or behaviors) and hypersexuality (compulsive sexual behavior). Evidence suggests enhancing serotonin levels can suppress sexual drive, and SSRIs may address the compulsive element of these diagnoses.^25,26 For these reasons, the World Federation of Societies of Biological Psychiatry recommends trying SSRIs in mild paraphilic disorders with obsessive features unresponsive to CBT.²⁵ However, few studies are available to provide firm evidence of SSRIs’ benefit.

PREMATURE EJACULATION

Up to 40% of men experience premature ejaculation. Serotonin contributes to regulation of ejaculatory reflex, and SSRIs may delay ejaculation. A meta-analysis evaluating long-acting and short-acting SSRIs found that paroxetine was associated with the best results.²⁸ Some prescribers use once-daily, chronic dosing, but on-demand regimens have also been used.²

CONCLUSION

Whenever patients take SSRIs, counseling is in order. The Table^2,3 lists key counseling points. When patients use SSRIs for off-label indications, they may have questions or concerns. Pharmacists are well positioned to help address these concerns and guide both patients and health care professionals in selecting the most appropriate treatment regimen.

About the Author

Jeannette Y. Wick, RPH, MBA, FASCP, is the director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

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