The Unusual Side Effect of Excessive Sexual Desire with Paroxetine Use
Primary Psychiatry. 2006;13(3):40-42
Dr. Samuel is president and medical director at the Boca Raton Psychiatric Group in Florida.
Disclosure: Dr. Samuel is on the speaker’s bureau of Pfizer.
Please direct all correspondence to: Roger Z. Samuel, MD, President and Medical Director, Boca Raton Psychiatric Group, 7284 W. Palmetto Park Rd, Suite 201S, Boca Raton, FL 33433; Tel: 561-368-8998; Fax: 561-392-9170; E-mail: email@example.com.
Increased arousal and sexual desire in patients on antidepressants do not always signify the presence of mania or hypomania. While serotonin reuptake inhibitors have frequently been associated with decreased sexual function (eg, decreased libido or arousal; erectile and orgasmic dysfunction), and while paroxetine is notorious for being the worst offender, there are rare occurrences of hypersexuality associated with antidepressant treatment. The following case report examines a female patient who developed increased sexual arousal with the use of paroxetine for depressive symptoms. The presence of other manic symptoms was ruled out and the implications of drug-supplement interactions were examined.
This case report discusses the incidence of sexual dysfunction with antidepressant therapy, and examines the causes and postulated mechanisms by which it occurs. Possible forms of sexual dysfunction, including the rare side effect of hyperarousal in connection with paroxetine use, are discussed. Other reported cases of hypersexuality and drugs associated with them are reviewed. The importance of a careful evaluation of treatment-emergent symptoms and the need to keep an open mind to a broad differential diagnosis will be emphasized. This case report also highlights the necessity of keeping track of over-the-counter remedies and watching out for their side effects and interactions with prescription drugs.
A 56-year-old white female was referred to the Boca Raton Psychiatric Group by her psychotherapist out of concern that the sudden appearance of hypersexuality might be due to new-onset mania. The patient’s 5-month history of depressed mood associated with worthlessness, insomnia, fatigue, impaired concentration, anhedonia, and anxiety, was consistent with a major depressive episode (MDE).
Her past psychiatric history was significant, as follows. Zolpidem twice per week was initiated in 1997 by her gynecologist for the treatment of middle insomnia. Her gynecologist then prescribed nefazodone 100 mg QD from 1996–1998 for perimenopausal symptoms. The patient engaged in purging throughout her 40s. She became depressed after stock market losses in 2002, and experienced interrupted sleep and diminished energy and activity levels; however, there were no other MDE symptoms. Without seeing a psychiatrist, she took paroxetine 20 mg QD, which she obtained from a friend. After improving, she stopped the paroxetine in autumn 2004, which preceded her current episode by 9 months. Careful questioning revealed no history of manic or hypomanic episodes in the past.
The patient put herself back on paroxetine 10 mg QD 10 days prior to her referral. She developed new-onset sexual arousal 3 days later, which persisted after she increased the paroxetine to 20 mg QD. She was otherwise anhedonic. She did not have spontaneous orgasms or clitoral changes, and refrained from engaging in sexual activity. A detailed inquiry revealed no evidence of mania or hypomania. There was no reduction in sleep nor increase in energy, activities, spending, rate of speech, or thoughts. Her affect, psychomotor activity, and mood were consistent with depression. There were no manic symptoms in the preceding months nor was there a family history of mania or bipolar disorder. The absence of other manic/hypomanic symptoms was corroborated by her therapist.
The patient’s medications consisted of paroxetine 20 mg QD, zolpidem 10 mg 2/3 tab HS PRN, and supplements (red yeast rice, milk thistle, flax seed oil, and vitamin C). She was drinking one half to two thirds a bottle of wine daily; her alcohol consumption had increased over the last decade.
She was diagnosed with major depressive disorder and alcohol abuse. Thyroid-stimulating hormone was normal. She was tapered off paroxetine over the course of 3 days, and abstinence was advised. Clorazepate 3.75 mg prn and 7.5 mg HS was prescribed.
At 1-week follow-up the patient was off the paroxetine for 3 days and using clorazepate occasionally in the day and QHS. She had markedly reduced her alcohol consumption. Her libido/sexual arousal had returned to its normal level and her mood had improved such that she chose to avoid antidepressant use. No manic or hypomanic symptoms ever occurred.
One month later, due to anxiety over a new breast lump and persisting depression, the patient agreed to a trial of citalopram, starting at 10 mg QD for 4 days, and then 20 mg QD. At 2-week follow-up, her mood had improved but she had the side effect of heightened libido, albeit less than with paroxetine. Two weeks later, her libido had returned to normal while still on citalopram 20 mg QD. She did not display manic or hypomanic symptoms at any time.
Serotonin reuptake inhibitors (SRIs), such as paroxetine and citalopram, are known to cause sexual side effects. However, these are usually diminution of sexual function such as hyposexuality, erectile dysfunction, and orgasmic difficulty. SRIs are known to have a deleterious effect on sexual function through increased serotonin effects as well as increased prolactin, opioid, and cortisol effects.
SRIs were initially reported to have lower rates of sexual side effects than are currently believed to be accurate, due to study and surveillance reporting defects1 (eg, fluoxetine was listed as having a 2% rate of sexual side effects). More recent reports suggest sexual side-effect rates of 22% to 43% for all antidepressants (with paroxetine having the highest rate of 43%),2 and paroxetine has been reported to cause diminished sexual desire at a 9% rate.3
A review of the literature revealed a report of yawning, clitoral engorgement, and orgasm associated with fluoxetine,4 as well as of yawning associated with clomipramine.5 There is also a report of sexual stimulation in three women treated with the SRIs fluoxetine, paroxetine, and fluvoxamine. Two of the women experienced undesirable sexual arousal, and the third had increased sexual desire, arousal, and hypersexuality. The woman on paroxetine was also prescribed methylphenidate.6 Anecdoctal reports (in lay media, the Internet) of hypersexuality related to SRIs do occur, some of which refer to this phenomenon as a SRI-discontinuation symptom. A persistent sexual arousal syndrome7 as well as premenstrual hypersexuality have been reported,8 but these are unrelated to SRI use.
Among other things, sexual function is affected by dopamine-serotonin balance,9 ie, dopamine being excitatory and serotonin being inhibitory in nature. Dopamine mechanisms are important in libido function. Stimulation of serotonin 2A receptors in mesocortical centers by SRIs may reduce libido by diminishing dopamine activity.10 Nitric oxide and acetylcholine are important in arousal.10 The arousal pathway travels from the brain to the spinal cord, and then to nerve fibers of the peripheral autonomic system and the sexual tissue. By reducing nitric oxide synthesis, SRIs cause sexual dysfunction (ie, arousal dysfunction). Drugs with anticholinergic activity can also inhibit sexual functioning.10
There is conflicting data about whether the effect of serotonin on sexual response is primarily inhibitory, excitatory, or mixed, depending on the receptor subtype stimulated.4 Serotonin agonism occurs with acute administration of SRIs and hypersexual responses have been reported secondary to acute increases in central serotonergic neural activity.4 The spontaneous sexual response and yawning associated with clomipramine use was attributed to corticotropin-releasing factor (CRF)-activated neural circuits resulting from clomipramine’s effect on serotonin reuptake, which causes increased brain serotonin levels and releases hypothalamic CRF.11
Animal studies implicate an association between altered norepinephrine transmission and the hormonal changes associated with female sexual behavior. Systemic treatment with α- and β-receptor agonists and antagonists modulate such behavior.12 Studies have shown that stimulation of α1 receptors in certain parts of the brain plays a role in hormonal facilitation of female animal sexual behavior, whereas stimulation of β-receptors seems to inhibit this behavior.
Paroxetine is a potent SRI with some norepinephrine reuptake inhibition at higher doses as well as muscarinic cholinergic antagonism.10-13 Citalopram, on the other hand, has been called a “true selective serotonin reuptake inhibitor” because it functions as a “selective” SRI without other significant activity.
The sequence of hypersexuality onset with initiation of paroxetine, combined with resolution with discontinuation and later re-emergence with initiation of citalopram, suggests a side effect of SRI use. No other causes explain this phenomenon. A review of the supplements red yeast rice, milk thistle, and flax seed oil14 revealed no evidence for instigating hypersexuality, except that flaxseed is reported to have weak antiestrogenic, estrogenic, and steroid-like activity. However, as the patient had been on these supplements for months prior to and after the 10 days of hypersexuality, this symptom was deemed unrelated to the supplement use.
It can be postulated that this patient’s hypersexuality was connected in some complex but unclear way to paroxetine’s norepinephrine effects; however, the occurrence of a similar reaction with citalopram and the reports of hypersexuality with fluoxetine, paroxetine, and fluvoxamine4,6 argue against it. Rather, it might make more sense to suggest that initial serotonin agonism caused by SRI administration in a subgroup of susceptible females can provoke hypersexuality due to increased central serotonergic activity. It is also possible that there was an interaction between flaxseed oil and SRI effects. PP
1. Goldstein B, Goodnick P. Selective serotonin reuptake inhibitors in the treatment of affective disorders—III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol. 1998;12(3 suppl B):S55-S87.
2. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.
3. Agren H, Aberg-Wistedt A, Akerblad AC. Sertraline vs paroxetine in major depression—a multicenter, double-blind, 24 week comparison. Poster presented at: 151st Annual Meeting of the American Psychiatric Association; May 30-June 4, 1998; Toronto, Ontario, Canada.
4. Modell JG. Repeated observations of yawning, clitoral engorgement, and orgasm associated with fluoxetine administration. J Clin Psychopharmacol. 1989;9(1):63-65.
5. McLean JD, Forsythe RG, Kapkin IA. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry. 1983;28(7):569-570.
6. Elmore JL, Quattlebaum JT. Female sexual stimulation during antidepressant treatment. Pharmacotherapy. 1997;17(3):612-616.
7. Leiblum SR. Sexual problems and dysfunction: epidemiology, classification, and risk factors. J Gend Specif Med. 1999;2(5):41-45.
8. Riley A. Premenstrual hypersexuality. J Sex Mar Ther. 1994;9(1):87-93.
9. Crenshaw TL, Goldberg JP. Sexual Pharmacology: Drugs That Affect Sexual Functioning. New York, NY: Norton; 1996.
10. Stahl S. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press; 2000.
11. Harrison W, Stewart J, McGrath PJ, Quitkin F. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry. 1984;29(6):546.
12. Bloom FE, Kupfer DJ. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995.
13. Frazer A. Norepinephrine involvement in antidepressant action. J Clin Psychiatry. 2000;61(suppl 10):25-30.
14. Fetrow CW, Avila JR. Professional’s Handbook of Complementary & Alternative Medicines. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.