Sex, Drugs & Dual Control: a personalized sexual medicine drug development program based on the dual control model of sexual response

Abstract

Low sexual desire, with or without sexual arousal problems, is the most common sex-related complaint reported by women. As a result, many women suffer from sexual dissatisfaction, which often negatively interferes with their psychological wellbeing. Unfortunately, the therapeutic arsenal for these complaints is limited. Sex, Drugs & Dual Control describes a research program which was directed at finding pharmacotherapeutic interventions for desire and arousal problems in women, which to date is still an unmet medical need. A personalized sexual medicine approach was taken, seeking for altered function in different underlying mechanisms within one and the same indication, and designing and testing different pharmacotherapies that target the specific dysfunctional system. The research program is based on the dual control model of sexual response. The main premise of this model is that Hypoactive Sexual Desire Disorder (HSDD) (Female Sexual Interest/Arousal Disorder (FSIAD) in DSM5) is caused and sustained by dysfunction in one of two separate but interacting systems, the sexual excitation and the sexual inhibition system. The dual control model postulates that individuals who have low propensity for sexual excitation or a high propensity for sexual inhibition are more likely to experience problems of impaired sexual response or reduced sexual interest. HSDD/FSIAD may therefore be caused by dysfunction in either one of these two distinct mechanisms, which means that at least two subgroups within HSDD/FSIAD may exist, depending on which system is out of balance. Knowledge of how these systems operate, and where they fail, should guide the development of potential drugs for HSDD/FSIAD. The drug development program described investigated underlying neurobiological mechanisms for dysfunctional sexual excitation and dysfunctional sexual inhibition, which led to two subgroups: HSDD/FSIAD as the result of low sensitivity for sexual cues, or HSDD/FSIAD as the result of dysfunctional over-activation of sexual inhibitory mechanisms. This led to the inception of two on-demand drug therapies: combined administration of testosterone (0.5 mg) and a phosphodiesterase 5 inhibitor (sildenafil, 50 mg) for the former group and combined administration of testosterone (0.5 mg) and a serotonin 1A receptor agonist (buspirone, 10 mg) for the latter group. Sex, Drugs & Dual Control describes cognitive, psychophysiological, subjective, neuroanatomical and pharmacological evidence, that these two subgroups in HSDD/FSIAD do indeed exist. This has major consequences for the field. To date, pharmacotherapeutic treatments in development adhere to the assumption that HSDD/FSIAD is a homogenous disorder. If this disorder should indeed be divided into two or more subgroups, pharmacotherapeutic treatments which treat HSDD/FSIAD as a homologous disorder will be (largely) ineffective in one of the two proposed subgroups. Consequently, they will fail to show efficacy because of the substantial size of the non-responder groups in clinical trials. Acknowledging the existence of different HSDD/ FSIAD subgroups generates two therapeutic targets. Selective pharmacotherapeutic- and/or psychological therapies can be designed to tackle each underlying cause of these HSDD/FSIAD subtypes, instead of a “one size fits all” approach.