SSRI-Induced Hypersexuality

Mr. M is a 42-year-old married Caucasian male with a history of papillary thyroid carcinoma, who underwent a total thyroidectomy and left modified radical neck dissection, followed by a full course of radioactive iodine treatment. He presented to the psychiatry clinic for assessment and treatment of inattention and fatigue that began with the cancer treatment and had persisted for 1 year after treatment completion.

During the initial psychiatric interview, Mr. M further characterized his symptoms as fatigue despite good sleep and increased anxiety and irritability. A screening measure indicated a moderate level of depression. The most troublesome symptoms to him were cognitive issues, which included forgetfulness, inattention, and difficulties with retaining and organizing new information. His symptoms impaired his occupational functioning and family relationships. Neuropsychological testing confirmed that his cognitive symptoms were of new onset and not developmental in nature. He denied any history of depression, anxiety, bipolar disorder, psychotic disorder, OCD, trauma, or substance use disorder. He had no past inpatient psychiatric hospitalizations. Psychiatric review of systems was negative for mania-hypomania, psychosis, OCD, posttraumatic stress disorder (PTSD), eating disorder, suicidality, and homicidality. The patient did not report any family history of severe mental illnesses or intolerance of psychotropic medications. His medications on presentation included levothyroxine 0.224 mg daily and omeprazole 20 mg twice a day. His thyroid-stimulating hormone (TSH) was monitored monthly by endocrinology following the surgery, with a goal of 0.1 mIU/L to 0.5 mIU/L. TSH had been consistently within this range until 1 month prior to his psychiatric presentation, when it was elevated to 12.4 mIU/L. His levothyroxine dose was adjusted by his endocrinologist, and TSH returned to normal range in the subsequent months. According to the patient's report, his psychiatric symptoms predated this aberration in TSH and persisted despite normalization of thyroid function. Other lab tests, including vitamin B12 level, were within normal limits. No brain imaging was performed.

The patient started bupropion XL 150 mg once daily 1 month after the initial psychiatric evaluation to address persistent symptoms despite stabilized thyroid function. However, the medication was discontinued 1 week after initiation because of a significant increase in irritability. Sertraline was then started at 50 mg once daily, and the patient subsequently reported a dramatic improvement in cognitive symptoms, mood, anxiety, energy, fatigue, and self-esteem, stating that he felt "like myself again." Nonetheless, he also developed adverse effects, including hypersexuality (increased sex drive, constant sexual thoughts, and compulsive masturbating throughout the day, including strong urges to do so at work), as well as hyposexuality (delayed ejaculation). He described both these side effects as debilitating and shameful, and he noted that the hypersexuality in particular was negatively affecting his marriage and career, although not as severely as his presenting symptoms had. There were no signs of mania or hypomania.

Sertraline was switched to duloxetine 30 mg once daily because of these side effects. The sexual side effects were attenuated but persistent, and the patient complained that the duloxetine was not effective in controlling the cognitive and mood symptoms on 2-month follow-up. Escitalopram was trialed for 2 months subsequently, but it elicited no positive treatment effects, even though no further sexual side effects were reported. After consideration of other treatment options, the patient elected to restart on sertraline, because he felt the benefits had outweighed the side effects. Sertraline was started at 50 mg daily. With this trial, he experienced no symptoms of hypersexuality, and delayed ejaculation was subjectively less severe than with the prior trial. The daily dose was subsequently increased to 100 mg; side effects were unchanged. He described a complete resolution in his cognitive, mood, and energy symptoms on 2-month follow-up.

Sexual side effects are highly prevalent but underreported in patients receiving treatment with SSRIs. The rate of patients self-reporting sexual side effects is around 14%, whereas the likelihood of endorsement of such side effects when asked directly by a physician is reported to be 58% (2). Although limited to case reports, a growing body of evidence has suggested that hypersexuality is part of the side-effect profile of SSRIs and other serotonin-enhancing medications, including duloxetine (3) and venlafaxine (4). Das et al. (5) reported a similar case of sertraline-induced hypersexuality, characterized by heightened sexual desire resulting in marital discord, without signs of mania or hypomania in a 55-year-old male with history of PTSD and major depressive disorder. In their report, a confounding factor was that the patient was taking bupropion when sertraline was added. However, the temporal relationship between the initiation of sertraline and the onset of hypersexuality convinced those authors that sertraline was at least partially involved in the development of this side effect. Drug-drug interaction should also be considered in that case, given that sertraline can inhibit the metabolism of bupropion (6), potentially by inhibiting CYP2B6 (7).

Our case was different in that bupropion preceded sertraline, with no overlap between the two medications throughout the treatment course. This further supported the conclusion that sertraline caused the hypersexual side effects. A series of cases have been reported on hypersexual side effects from fluoxetine, paroxetine, fluvoxamine, citalopram, and escitalopram (8–17) (Table 1). Some described a similar clinical profile with enhanced sexual desire and excessive masturbation (5, 9, 14), as noted in our case. However, most reported a unique cluster of symptoms (8, 10–14), and except for one case of exercise-induced orgasm (8), these symptoms included brief and automatic episodes of sexual excitement or an orgasm-like feeling, lasting 10 to 60 seconds, with a frequency ranging from one to four or more times per day. The episodes might be associated with tingling feelings in the genital area but not always with penile or clitoral engorgement. These episodes were not necessarily unpleasant, but they could be ego-dystonic and could trigger shame and anxiety, especially when they occurred without sexual stimulation in public scenarios.

Other potential clinical features of SSRI-induced hypersexuality have been noted. Episodes may occur as early as 2 weeks into treatment, and in cases where there is a quick and prominent antidepressant response that could occur sooner than 4 weeks after initiation of SSRI medication (8, 14). There are no other signs of mania or hypomania could explain the hypersexuality (4, 5, 14). In some cases, the propensity for such episodes occurred in those with preexisting neurologic conditions, including stroke, or in those that had undergone radiation therapy (3, 10, 13). In other cases, the hypersexuality episodes were accompanied by yawning (9, 11, 12). Intriguingly, citalopram and escitalopram have not been independently associated with heightened sexual desire or arousal or with automatic orgasm, but only with clitoral priapism (15) and spontaneous erection (16) and ejaculation (16, 17). Yanik (4) reported a case of spontaneous orgasms initiated by venlafaxine, which persisted after the venlafaxine was switched to citalopram. It is worth noting that in Yanik's report, the patient eventually ceased drug treatment because of the side effects and started electroconvulsive therapy, after which she recovered from both hypersexuality and depression.

The mechanism of SSRI-induced hypersexuality is unclear. Up-regulation (which can be induced by brain injuries or neurologic conditions) of serotonin receptors (5-HTR) has been suggested as having the main role in enhanced sexual stimulation (13). This may explain only a portion of the cases with preexisting brain organicity, e.g., stroke (3, 13). The co-occurrence of yawning and spontaneous orgasms, which can occur in opioid withdrawal, raised the hypothesis that endogenous opiates may decrease with fluoxetine, explaining the sexual side effects (12, 18). Overall, it has been suggested that abnormal increases in central serotonergic neuronal activity may underlie the hypersexual side effects caused by SSRIs (10). Further studies are required to understand the pathophysiology.

It appears that SSRI-induced hypersexuality may be a distinct entity, with characteristic clinical features. It is important for clinicians to identify this unique side effect, be aware of the range of the SSRI sexual side-effect spectrum, and differentiate it from an antidepressant-induced mood switch. Management of hypersexuality induced by SSRIs should involve psychoeducation, to reassure and destigmatize this phenomenon by informing patients of the existence of this side effect in order to alleviate possible anxiety and guilt. Second, in most cases, the hypersexuality diminished when the SSRI doses were decreased or the medication was discontinued; some of the patients also benefited from switching medication (14, 16, 17) or substituting other treatment modalities, e.g., ECT (4). For patients whose hypersexuality continues despite a switch to other antidepressants, it may be worthwhile to rechallenge with the original SSRI that elicited significant treatment response (as reported in our case), because the sexual side effects may not recur.

The authors thank Alice-Lee Vestner, M.D., Assistant Professor of Psychiatry, and Dr. Lawrence H. Price, M.D., Professor of Psychiatry in the Department of Human Behavior and Psychiatry at Brown University for their invaluable guidance. The authors also thank the patient for his trust and enlightenment.

Dr. Yuan's effort is supported by NIMH (grant R25MH101076).

The authors confirm that details of the case have been disguised to protect patient privacy.