Theta Burst Stimulation for Male Sexual Dysfunction in Bipolar Depression—A Case Series

Bipolar disorder (BD) is a chronic, recurrent often disabling mood disorder affecting approximately 1% to 3% of the population. ¹ In BD, depression has predominant polarity and is associated with marked impairment in (social and occupational) functioning and increased risk of suicide. Sexual dysfunction, specifically decreased libido, is an important symptom domain of bipolar depression.^2,3 It has been noted that 20% to 30% of adult men, among general population, have at least 1 manifest sexual dysfunction. ⁴ Compared to other medical patients (~20%), greater number of male psychiatric patients (~50%), specifically 55% of those with BD, have been shown to have sexual dysfunctions. ⁵ Management of BD involves the use of mood stabilizers, antipsychotics, antidepressants, and benzodiazepines, depending on the phase of the illness. ⁶ Apart from the role of illness characteristics, psychotropic medications used in the treatment of bipolar depression are implicated to have an adverse effect of the sexual function too. ⁷ Greater sexual dysfunction involves high personal distress and negative impact on treatment compliance and prognosis. ⁸ Unfortunately, nonpharmacological treatment options including psychotherapeutic interventions are relatively limited, apart from with the very fact that sexual dysfunction in the context of depression is underreported by the patients as well as underestimated by clinicians. ⁹ These facts have led to the investigation of other possible interventions, such as noninvasive brain stimulation in this regard.

A new noninvasive and potentially quite promising form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), applies short bursts (typically 3 pulses) at 50 Hz (within the gamma range of endogenous brain oscillations). These short bursts occur every 200 ms, or at 5 Hz, which is within the theta oscillation range. ⁸ TBS is more potent when compared with conventional repetitive TMS. While continuous TBS (cTBS) has inhibitory effects, intermittent TBS (iTBS) has been shown to have excitatory effects. ¹⁰

The literature pertaining to use of rTMS/TBS is very limited and specific mechanisms underlying the effect of rTMS in treating the domains of sexual dysfunctions, more specifically in the context of psychiatric disorders, have not yet been explored systematically. However, there are anecdotal reports of low frequency (inhibitory) rTMS delivered to supplementary motor area and deep TMS targeting the anterior cingulate cortex for the treatment of compulsive/hypersexual behaviors.^11,12 Prause et al ¹³ investigated the influence of both cTBS and iTBS on sexual behaviors. They found that both iTBS and cTBS, delivered to the left dorsolateral prefrontal cortex (lDLPFC), modulate the sensitivity to rewards that predict sexual behaviors. More recently, Schecklmann et al ¹⁴ found that stimulation of right dorsolateral prefrontal cortex (rDLPFC) using a single session of high-frequency rTMS, which leads to cortical excitation similar to iTBS, significantly reduced subjective sexual arousal; stimulation delivered to the lDLPFC had no effect. Therefore, on the premise of this background literature, we aimed at delivering inhibitory stimulation (ie, cTBS) to target the rDLPFC for improving the predominantly hypoactive sexual dysfunctions.

This case series included 3 male patients with bipolar affective disorder, current episode depression (moderate to severe) complaining of sexual difficulties—reduced sexual desire, erectile dysfunction, and delayed ejaculation, and received an adjunctive cTBS treatment. The diagnosis was made according to the diagnostic criteria for research (DCR) of International Classification of Diseases-tenth edition (ICD-10). ¹⁵ Subjects were evaluated, pre and post the stimulation sessions, on the Hamilton Depression Rating Scale (HAM-D) ¹⁶ and the 14-item-Changes in Sexual Functioning Questionnaire (CSFQ-14). ¹⁷ The male version of the CSFQ-14 was used. It measures sexual dysfunction in 5 domains (subscales), that is, Pleasure (item—1); Desire/Frequency (items—2 and 3); Desire/Interest (items—4, 5, and 6); Arousal/Excitement (items—7, 8, and 9); and Orgasm/Completion (items—11, 12, and 13). Write about cut-offs here. The values of responses for all 14 items are added up to calculate the total CSFQ score and the subscale scores are calculated by adding up values for only the items that correspond to a particular subscale. Scores “at or below” 47 for total CSFQ score; and 4, 8, 11, 12, and 11 for subscales—Pleasure, Desire/Frequency, Desire/Interest), Arousal/Excitement, and Orgasm/Completion, were considered cut-off points indicative of sexual dysfunction for males (note: scores received on items 10 and 14 are not counted in the calculation of subscale scores). The rTMS-Side-Effects Checklist ¹⁸ was used to assess the side-effects of rTMS after each session.

Informed consent to undergo cTBS as well as to report their case was taken from all the 3 patients. All the 3 patients were delivered 15 cTBS sessions (3 sessions per day each spaced half an hour apart 5 days in a week, intensive protocol) targeting the rDLPFC (right dorsolateral prefrontal cortex). cTBS protocol consisted of a burst of 3 pulses delivered at 50 Hz, which was repeated every 200 ms (at 5 Hz) for a total of 600 pulses and lasted the 40s. A total of 1,800 pulses was delivered per day. Treatment, that is, dosage of medications remained unchanged throughout the course of 15 days from the start of cTBS (see Table 1 for treatment details).

Table 1.

Clinical Characteristics

Patient	Age	Gender	Total Duration of Illness in Years	Number of Depressive Episodes	Duration of Current Episode	Duration of Sexual Dysfunction in Months	Medications the Patients Received (Dose, Duration) During the Current Episode	Scores on the Hamilton Depression Rating Scale
								Preintervention	Postintervention
P1	28 years	M	5 years	3	4 months	4 months	_	18	10
P2	22 years	M	2 years	2	5 months	5 months	•  Bupropion (150 mg, 3 months) •  Levosulpiride (40 mg, 3 months)	25	21
P3	28 years	M	2 years	2	3 months	24 months	•  Lithium (800 mg, 6 months) •  Lamotrigine (50 mg, 6 months) •  Propranolol (10 mg, 6 months)	31	13

A MagVenture-MagPro-R30 device with Theta Burst booster and B65 coils (figure-of-8 shaped coil) was utilized in the delivery of items. The standard 10-20 international electroencephalogram (EEG) system was used for positioning the TMS coil as it accounts for variability in participant skull size and is consistently used in clinical TMS applications. The coil was centered over the rDLPFC (F4, 10-20 international system). All 3 patients reported improvement in sexual dysfunction after cTBS treatment. The CSFQ scores increased from baseline to posttreatment indicating improvement. None of the patients reported any side-effects and they tolerated the sessions well.

Subject 1, a 28-year-old, unmarried male presented to us with 5 years history of BD and 4 months of a current depressive episode. Since the beginning of this episode, he complained of less desire to engage in sexual activity and inability to achieve or maintain an erection. He also reveals that even reading erotic literature to get engaged in sexual fantasies doesn’t work. In addition, the patient reported not having the same level of pleasure or enjoyment from sexual arousal and orgasm as experienced since the onset of BD. He was drug free for >1 year, that is, since the remission of the previous episode. At baseline, the total CSFQ-14 score of 45 was lower than the cut-off point. The scores obtained in each subscale were: Pleasure (3); Desire-Frequency (6); Desire-Interest (9); Excitement (12); and Completion (10). The values for all scales lower than the cut-off points indicated overall sexual dysfunction. Postintervention, he showed enhanced performance on all subscales of CSFQ-14 including Pleasure; Desire-Frequency; Desire-Interest; Excitement; and Completion (see Table 1). After 15 days of treatment, his total CSFQ-14 score of 54 was higher than cut-off point suggesting the absence of overall sexual dysfunction (Table 2). Although all subscale scores were improved, he reports a mild increase in his sexual drive and improvement in penile erection but is not fully satisfied, complaint of not being able to reach the levels of sexual arousal and enjoyment that he experienced before the treatment of disease persist.

Table 2.

Scores on the Changes in Sexual Functioning Questionnaire (CSFQ-14)

Patient	Time Point	Total	Pleasure	Desire/Frequency	Desire/Interest	Excitement	Completion
P1	Pre	45	3	6	9	12	10
	Post	54	4	8	11	12	11
P2	Pre	57	4	9	15	11	9
	Post	65	4	9	15	13	14
P3	Pre	32	1	2	5	5	9
	Post	51	3	4	9	13	12

Subject 2 is a 22-year-old unmarried male patient with 2 years history of BD and 3 months of a current depressive episode. He also reports that despite having a strong desire to engage in sexual activity, he could not ejaculate when he wants to, decreased quantity of ejaculate, and poor quality of orgasm for last 5 months. He was receiving Bupropion 150 mg and Levosulpiride 40 mg daily for 3 months. On assessing the frequency and severity of sexual problems on the CSFQ-14, he scored a total of 57, at baseline, which was higher than the cut-off value. Although his total score and score on Pleasure (4), Desire-Frequency (9), and Desire-Interest (15) reached cut-off points and indicated the absence of sexual dysfunction, the scores obtained in the Excitement (11) and Completion (9) subscale were lower than cut-off points. Postintervention, he showed increased performance on all subscales, including Pleasure; Frequency; Desire; Excitement; and Completion. After 15 days of treatment, his total CSFQ-14 score of 65, which was again higher than the reference value or cut-off point, suggesting the absence of overall sexual dysfunction (Table 2). These results indicate that the patient made progress considering the recovery of most sexual functions after receiving cTBS treatment.

The third subject was a 28-year-old married patient with 2 years history of BD and 3 months of a current depressive episode. For the last 2 years, he complained of a complete loss of sexual interest and inability to achieve or maintain an erection causing significant problems in marital life. The patient was receiving Lithium 800 mg, Lamotrigine 50 mg, and propranolol 10 mg. At baseline, the total CSFQ-14 score was 32, which was lower than the reference value. The scores obtained in each subscale were: Pleasure (1); Frequency(2); Desire/Interest(5); Excitement (5); and Completion(9). The values for all scales were lower than the cut-off points and indicated overall sexual dysfunction in all phases of sexual functioning. Postintervention, all subscale scores improved. However, only the scores for Excitement (13) and Completion (12) crossed the cut-off points. After 15 days of treatment, his total CSFQ-14 score was 51, which was higher than the reference value or cut-off point, suggesting the absence of overall sexual dysfunction (Table 2).

Our study is the first to use TBS, targeted to the DLPFC, with stimulation intensity moderated by patient tolerability and with sexual dysfunction as a primary outcome. We showed changes in sexual function in patients with BD with cTBS. Although this case series includes only 3 subjects, it was encouraging that all 3 showed increase in CSFQ score with cTBS. The TBS treatment might have produced positive results because among benefits on mood patients reported to be more confident during sexual activity and participated more in the relationship.

The present study provides evidence of feasibility in using cTBS in patients with bipolar depression, and given the demonstration of the possibility of TBS in affecting sexual dysfunction, suggests that a larger clinical trial might be fruitful. Future endeavors, controlling for state-dependent effects and studying the effects of varying stimulation parameters, would also require TMS/electroencephalogram monitoring as well as online TMS/functional magnetic resonance imaging-based approaches to examine the effect of cTBS on functional connectivity between DLPFC and other brain regions. We consider our study to be a pilot for research leading in this direction.