Sexual dysfunctions are associated with multiple medical and psychiatric disorders, as well as pharmacotherapies used to treat these disorders.Reference McCabe, Sharlip, Lewis, Atalla, Balon and Fisher1, Reference Montejo, Montejo and Baldwin2 Although sexual dysfunctions negatively affect both quality of life (QoL) and treatment adherence, patients infrequently volunteer these symptoms and clinicians often do not pose directed questions to determine their presence or severity.Reference Montejo, Montejo and Baldwin2–Reference Mitchell and Selmes5 Further, patients may not share their nonadherence, resulting in both symptomatic regression and potentially inappropriate medical and/or psychiatric care. This issue is especially important in psychiatric patients, for whom most common psychotropics may cause sexual dysfunctions (antidepressants, antipsychotics, anxiolytics and mood-stabilising agents).Reference La Torre, Giupponi, Duffy and Conca6–Reference La Torre, Giupponi, Duffy, Pompili, Grözinger and Kapfhammer8
Sexual dysfunction adverse effects, including delayed orgasmic activity, have been reported with different benzodiazepines with varying frequency and selectivity.Reference La Torre, Giupponi, Duffy, Pompili, Grözinger and Kapfhammer8–Reference Lydiard, Howell, Laraia and Ballenger11 The limited literature addressing alprazolam and these adverse effects, anorgasmia in particular, is inconsistent, which may be secondary to methodology and sample size. The Lydiard study was an open, uncontrolled small survey (N = 32) without a standardised scale that reported 50% of patients with decreased orgasmic activity.Reference Lydiard, Howell, Laraia and Ballenger11 The O'Sullivan study, presenting safety and side-effect data associated with a randomised placebo-controlled efficacy trial of alprazolam (mean total daily dose 5 mg) in the treatment of panic disorder with agoraphobia, reported that 25% of patients in the alprazolam treatment arm (N = 77) noted sexual dysfunction (‘decreased libido and delay in or failure to reach orgasm’).Reference O'Sullivan, Noshirvani, Başoğlu, Marks, Swinson and Kuch12 The recent Márquez study, comparing the efficacy of alprazolam in two different formulations in the treatment of acute phase panic disorders (N = 190), utilised the standardised Arizona Sexual Experience Scale (ASEX) and noted that the 60-day treatment ASEX scores were non-significantly lower than baseline, concluding that alprazolam ‘did not affect the patients in their sexual sphere’.Reference Márquez, Arenoso and Caruso13, Reference McGahuey, Gelenberg, Laukes, Moreno, Delgado and McKnight14
To better appreciate the importance of anorgasmia with alprazolam, its role in treatment nonadherence and patient-oriented dosing strategies, this case report describes alprazolam-induced dose-dependent anorgasmia.
Method
Case analysis with PubMed literature review.
Results
A 30-year-old male psychiatric patient presented with new-onset anorgasmia in the context of asymptomatic generalised anxiety disorder, social anxiety, panic disorder with agoraphobia, obsessive–compulsive disorder, major depression in remission, and attention-deficit hyperactivity disorder treated with escitalopram 10 mg q.a.m., gabapentin 1000 mg total daily dose, lisdexamfetamine dimesylate 70 mg q.a.m., nortriptyline 60 mg q.h.s. and alprazolam extended release (ER) 2.5 mg total daily dose (1 mg–0.5 mg−1 mg). Medical conditions included elevated transaminases, obesity (body mass index 31.86 kg/m2), dyslipidaemia and gastroesophageal reflux disorder (GERD). All standard blood chemistries (comprehensive metabolic panel, complete blood count, thyroid stimulating hormone and lipid panel) were normal, excluding elevated transaminases (aspartate aminotransferase (AST) 43 U/L and alanine aminotransferase (ALT) 87 U/L), elevated triglycerides (202 mg/dL) and decreased high-density lipoprotein (35 mg/dL). His nortriptyline blood level was 68 mcg/mL. A right upper quadrant abdominal ultrasound revealed fatty liver changes. His medical conditions were stable during the time period of alprazolam titrations.
All psychotropic doses had been constant for >6 months, excluding alprazolam ER, which was titrated from 1 mg to 2.5 mg total daily dose for recently increased anxiety that resolved on the higher daily dose. The patient denied any sexual dysfunction with alprazolam ER at 1 mg q.d. and 1 mg b.i.d.. Within 1 week of increasing alprazolam ER to 2.5 mg total daily dose, the patient reported anorgasmia. Anorgasmia was alprazolam dose-dependent, as anorgasmia resolved with reduced weekend dosing (1 mg b.i.d. Saturday; 1.5 mg total daily dose Sunday). During a 10-week period, the patient had repetitively reduced weekend alprazolam, creating an on/off/on/off dose-dependent adverse effect response pattern. He reviewed all aspects of sexual functioning and recognised that at alprazolam ER 1.5 mg total daily dose (Sundays) there was no sexual dysfunction, at 1 mg b.i.d. there was limited delayed orgasmic activity (Saturdays), and at 2.5 mg total daily dose (weekdays) there was anorgasmia. Further, following the 10-week period described, the patient experimented with taking weekday alprazolam ER 2–2.5 mg q.a.m. only and noted significantly improved orgasmic activity in the evening, suggesting that beyond being dose dependent, this adverse effect is concentration dependent.
Discussion
This unique case presents important steps in determining the aetiology of this patient's sexual dysfunction (decreased orgasmic activity and subsequent anorgasmia) in the context of multiple psychiatric diagnoses, medical comorbidities and psychotropic interventions.Reference Kaufman, Coluccio, Sivaraaman and Campeas3 By addressing each step with the addition of a timeline describing the development and/or improvement in the sexual dysfunction, the probability of alprazolam-induced anorgasmia could be scored as doubtful, possible, probable or definite by the Naranjo Scale for adverse drug effects.Reference Naranjo, Shear and Lanctôt15
First, each of the patient's psychiatric diagnoses were associated with sexual dysfunctions – major depressive disorder, obsessive–compulsive disorder, generalised anxiety disorder, social anxiety, panic disorder and attention-deficit hyperactivity disorder.Reference McCabe, Sharlip, Lewis, Atalla, Balon and Fisher1, Reference Kendurkar and Kaur16–Reference Bijlenga, Vroege, Stammen, Breuk, Boonstra and van der Rhee20 Of note, reported findings may have been influenced by concurrent treatment with pharmacotherapies and/or associated comorbidities. Second, both GERD and obesity are associated with increased sexual dysfunction.Reference McCabe, Sharlip, Lewis, Atalla, Balon and Fisher1, Reference Iovino, Pascariello, Limongelli, Tremolaterra, Consalvo and Sabbatini21, Reference Katz22 Third, escitalopram, gabapentin, nortriptyline and alprazolam have each been associated with increased sexual dysfunction.Reference La Torre, Giupponi, Duffy and Conca6, Reference La Torre, Giupponi, Duffy, Pompili, Grözinger and Kapfhammer8, Reference Lydiard, Howell, Laraia and Ballenger11, Reference O'Sullivan, Noshirvani, Başoğlu, Marks, Swinson and Kuch12, Reference Serretti and Chiesa23–Reference Kaufman and Struck25 Thus, multiple factors (psychiatric/medical comorbidities and various psychotropics), individually and/or in various combinations, may be the aetiological basis for one or more sexual dysfunctions. Fourth, the patient described normal sexual function with stable medical and psychiatric diagnoses and baseline psychotropics. Fifth, when considering the onset of decreased orgasmic activity and anorgasmia, only two events had occurred – increased anxiety that had necessitated, and was responsive to, increased alprazolam. Sixth, the patient's relative weekend alprazolam nonadherence resulted in an on/off/on/off design compared with the standard weekday regimen, with sexual dysfunction (delayed orgasmic activity or anorgasmia) mirroring the alprazolam total daily dose which was repeated over a 10-week time period. Seventh, the patient's further experimentation with morning weekday dosing only, as opposed to morning/midday/evening dosing, with diminished effect on the presumptive alprazolam-induced sexual dysfunction, suggested a concentration effect.Reference Wright26, Reference Glue, Fang, Gandelman and Klee27 Based on this stepwise analysis, alprazolam-induced anorgasmia was scored as probable by the Naranjo Scale.Reference Naranjo, Shear and Lanctôt15
Alprazolam-induced anorgasmia has no well-defined mechanism of action in humans. Potential indirect and direct aetiologies include, but are not limited to, drug–drug pharmacokinetic interactions, pharmacodynamic synergism of prescribed medications/psychotropics on sexual dysfunctions, and effects of alprazolam on neurotransmitters. In the first instance, alprazolam is a substrate of cytochrome P450 3A4 (CYP3A4) and is not an inhibitor/inducer of other cytochrome isoenzymes; as such, the presence of alprazolam in different dosages would not be expected to change the concentrations of other prescribed medications that might also cause sexual dysfunctions. In this case, only escitalopram was a (weak) CYP3A inhibitor; it has been suggested that at therapeutic dosage there should be no clinically significant effect on alprazolam.Reference Hall, Naranjo, Sproule and Herrmann28 In the second instance, pharmacodynamic synergism could be considered a possible factor in the current and similar presentations – but determination of such would require medication withdrawal, which in this case was clinically neither feasible nor warranted in light of the dose-dependent alprazolam-induced anorgasmia which resolved with dose reduction. In the third instance, alprazolam, similar to other benzodiazepines, is a positive allosteric modulator of the gamma-amino butyric acid (GABA)-A receptor.Reference Goodchild29, Reference Griffin, Kaye, Bueno and Kaye30 GABA is the primary central nervous system inhibitory neurotransmitter, with high concentrations in the cortex and limbic system.Reference Griffin, Kaye, Bueno and Kaye30 Animal studies with GABA agonists, metabolic inhibitors, antagonists and synthesis inhibitors confirm the importance of GABA in sexual functioning – increased GABA activity is associated with decreased sexual behaviours, whereas decreased GABA activity is associated with increased sexual functioning.Reference Fernández-Guasti, Larsson and Beyer31, Reference Rodríguez-Manzo and Canseco-Alba32 Hypothetically, anorgasmia could be secondary to GABA inhibition of dopamine, with resultant increased prolactin levels.Reference Lee and Pan33, Reference Hollander, Pastuszak, Hsieh, Johnson, Scovell and Mai34
Key strengths in this case report include that: (a) the patient's relative alprazolam nonadherence with an on/off/on/off design revealed a direct correlation between total daily dose of alprazolam and anorgasmia; (b) excluding the recent increase in anxiety and associated increased alprazolam, the patient had been stable for >6 months with no other documented changes in psychotropics; (c) although patients are frequently reluctant to reveal sexual dysfunction symptoms, this patient immediately identified anorgasmia as an important treatment problem, as it negatively affected his QoL; and (d) the clinician included both sexual dysfunction questions and a review of psychotropic adverse effects including sexual dysfunction in each session.
Limitations in this case report include that: (a) as a single case report (N = 1), the findings cannot be generalised; (b) as no alprazolam blood levels were obtained, the concentration-dependent effects of alprazolam could not be reported; (c) the patient's increased anxiety could be a confounding factor, as anxiety is associated with decreased sexual functioning; however, no rating scales (e.g. the Hospital Anxiety and Depression Scale (HADS) or the Hamilton Anxiety Rating Scale (HAM-A)) were used that might help elucidate this issue; (d) no pill counts were obtained, which might have suggested any additional psychotropic noncompliance that could affect the reported sexual dysfunction; (e) no psychometric sexual functioning scale (e.g. ASEX) was used; and (f) no hormone levels were obtained. Finally, for ethical reasons, the patient could not be requested to repeat the relative nonadherence with further testing to verify the current findings.
The potential clinical implications of this report can best be appreciated in the context of anxiety disorder prevalence and alprazolam prescription patterns. Specifically, the National Comorbidity Survey Replication (NCS-R) study,Reference Kessler, Berglund, Demler, Jin, Merikangas and Walters35 using retrospective ascertainment, reported that anxiety disorders have a 28.8% lifetime prevalence, while the Dunedin study,Reference Moffitt, Caspi, Taylor, Kokaua, Milne and Polanczyk36 using prospective ascertainment as opposed to retrospective ascertainment in the NCS-R study, noted a lifetime anxiety disorder prevalence of 49.5% by age 32. Alprazolam is the most frequently prescribed benzodiazepine and the third most frequently prescribed psychotropic in the USA (5.29 million individuals and approximately 25.7 million prescriptions in 2013).Reference Moore and Mattison37 Since sexual dysfunctions are frequently not volunteered by patients nor queried by physicians, alprazolam-induced sexual dysfunction may be a very significant problem affecting QoL that remains underappreciated and inadequately addressed by healthcare professionals. To address this problem, large-scale studies are required, as are routine sexual histories, and further education for clinicians and patients.
Conclusion
Sexual dysfunction is an important psychosocial comorbidity affecting QoL and treatment adherence. This case described dose-dependent alprazolam-induced anorgasmia in the context of multiple psychotropics, psychiatric diagnoses, and medical diagnoses. Routine sexual histories are necessary to ascertain the presence of sexual dysfunctions, avoid medicine nonadherence, and to maximise treatment outcomes. Further education regarding alprazolam-induced sexual dysfunction is indicated for both clinicians and patients.
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