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Letters to the Editor
Response to “Toward Personalized Sexual Medicine: Where is the Evidence?” DOI: 10.1111/jsm.12644
The authors of the letter “Toward Personalized Sexual Medicine: Where is the Evidence?” raise several concerns regarding the validity of the theoretical claims and findings described in our three “Toward Personalized Sexual Medicine” articles discussing two potential on-demand drug combinations for hypoactive sexual desire disorder (HSDD) ( J Sex Med 2013;10:791–809, 810–23, 824–37). It goes without saying that we appreciate critical review of our articles, but we believe that we can easily address the authors’ questions to the reader’s satisfaction. Empirical science consists of theoretical assumptions concerning cause-and-effect relationships, which are not directly observable. In other words, science is engaged with abstractions of the world. Based on such assumptions, predictions with observable consequences are made, which are tested against the empirical reality. If the results are consistent with what has been predicted, they can be regarded as (provisional) confirmation of the underlying theoretical assumptions (it is very unlikely that we will ever directly “see” the real truth). If the prediction does not come about (i.e., the empirical reality is recalcitrant), then doubts can be raised about the theoretical background (but this need not always be true). In the empirical sciences, we see scientists reporting correlations they have observed between variables. Such reports are descriptions of what the scientists have seen, not explanations in terms of the underlying mechanisms linking cause with effect. Such explanations are, strictly speaking, not part of science (although they can serve a hypothesis-forming function and, in this way, provide a gateway to the wonderful world of science).
Subgroup Analysis and Dual Control The authors of “Where is the Evidence?” claim that in our research, inhibition is defined as lack of sexual activation. According to them, this would be in conflict with the basic tenets of the dual-control model, which assumes the inhibitory and excitatory components are relatively independent systems regulating sexual behavior. The authors are unclear on which basic tenet of the dual-control model is violated, but we assume that they believe that inhibition means decreased sexual response (compared with baseline). However, the dual-control model states that the sexual excitation and inhibition systems are separate but interacting systems. The opposing sexual excitation and inhibition systems determine behavior depending on the presence of external stimuli and on internal state, including outcome expectations (of reward and of negative consequences). For example, sexual stimuli (e.g., erotic video clips) might trigger the sexual excitation system but do not necessarily induce a sexual response. This is dependent upon the relative strength of the erotic stimulus, the internal state (e.g., satiated or nonsatiated), and other internal or external stimuli signaling the advantageousness or disadvantageousness of a sexual response. If a sexual stimulus is potent enough to activate the sexual excitation system and the consequences of responding sexually are not perceived as negative, either consciously or subconsciously, it may induce a sexual response. If, on the other hand, the same sexual stimulus is presented in a setting in which responding sexually is disadvantageous or inappropriate, it may activate the sexual inhibition system, preventing a sexual response. The dualcontrol model does not assume that activation of the inhibition system results in a “negative” or inverse sexual response. Rather,
Statistical Analysis Strategy 30
Our trilogy was originally a single article. The complex theory and the large amount of data prompted us to rewrite it as three articles. As a result of this rewrite, the description of the statistical interaction effect in the Stroop data in the second part of the trilogy was accidentally placed after the second sentence on page 817, instead of in the first sentence, where it belongs. We thank the authors for pointing out to us this unfortunate mistake, but the analysis is not inaccurate as they suggest. Thus, the degrees of freedom given on page 817 refer to the interaction between placebo vs. testosterone plus phosphodiesterase type 5 inhibitor (T + PDE5i) and the two groups (low- vs. highsensitive); this interaction effect is indeed F(1,54) = 13.27 (P < 0.001). In figure 3, only the results for the low-sensitive group are represented, although the t-value should have been reported as well: t(1,28) = −3.93 (P = 0.001). The results of the high-sensitive group were not reported because the hypothesis was that only the low-sensitive group would show an increase in attention and would respond to the combination of T + PDE5i (which was the subject of the article); therefore, reporting the Stroop results for the high-sensitive group had no relevance for the article. For the reader’s information, these results were the following: t(1,26) = 1.69, P = 0.104. See also Figure 1.
Preconscious aenonal bias for eroc cues (ms)
Stroop Subgroup Analysis
low-sensive high-sensive
20 10
P = 0.104
0 Placebo –10
P = 0.001
T + PDE5i
–20 –30
Figure 1 Preconscious attentional bias for sexual cues in lowsensitive women and high-sensitive women after placebo and T + PDE5i intake.
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2360 sexual inhibition can block activation of excitatory sexual mechanisms, as we postulated for our “inhibitory” subgroup. Furthermore, the functional magnetic resonance imaging studies described in the first part of the trilogy clearly illustrate the dualcontrol model’s notion that activation of inhibitory mechanisms is important in certain subgroups or certain situations and that this is accompanied by a lack of response and not necessarily a decrease in response. We exposed women to all kinds of manipulations (erotic film clips, drugs theorized to increase sexual excitation, instructions) meant to induce activation of sexual excitation. These manipulations resulted in our finding a subdivision of women who indeed showed an increase in sexual response. This occurred, as predicted, in the low-sensitive women. We hypothesized beforehand that a subdivision of women would not respond to our manipulations because of activation of inhibitory mechanisms (a phasic increase in serotonergic activity in the dorsolateral prefrontal cortex, provoked by sexual stimulation). Based on this hypothetical inhibitory mechanism, we subsequently hypothesized that this group would respond to treatment with the combination of T and a serotonin (5HT1A) receptor agonist. This hypothesis was also corroborated by the results of our experiments. Furthermore, we expected that the noninhibitor group would not respond to this treatment because they would not have a phasic increase in activity of serotonin in the prefrontal cortex. The results of treatment of this group with T + 5HT1A receptor agonist were in agreement with this expectation as well. Because the results were in concurrence with our hypotheses, we assume—for the time being—that the hypothesized underlying mechanisms are actually present.
Substantiation of Subgroup Differentiation We tried to substantiate our claims as much as possible. Neurophysiological data were not available for the subjects in the studies under discussion. However, neurophysiological data from other studies from our lab substantiating our claims were presented in part 1 of the series. This article presented the basics of the theories tested in parts 2 and 3 and contributed to a greater understanding of the different regulating mechanisms involved in sexual behavior. In other words, the results of our previous experiments were the basis for the formulation of the hypothesis of subgroup differentiation. As suggested by the authors of “Where is the Evidence?” we looked at baseline clinical and anamnesic data and presented them in the manuscripts. The only related variables were number of children and relationship duration. The authors of “Where is the Evidence?” emphasize that these variables are known to be related to a decline in sexual desire and to reduced quality of marital sex (as also discussed by us). However, they then suggest that this may be an alternative explanation for the lack of response to PDE5i. We assume they mean to refer to a lack of response to T + PDE5i, because we did not measure response to PDE5i separately in the experiment under discussion. Although the authors of “Where is the Evidence?” do recognize here that our subdivision into responders and nonresponders to treatment with T + PDE5i is valid, we still fail to see how this is more than a statement about a correlation between these two measures. Any suggestions about possible mechanisms underlying nonresponse to treatment with T + PDE5i are sadly lacking in their comment. After all, an attempt toward an explanation (i.e., model) should at least hypothesize why these women do not respond, that is, what the biological or psychological mechanisms are that underlie their nonresponse. It is particularly striking, then, that this subgroup of women does in fact respond to treatment with T + 5HT1A receptor agonist. In addition, in light of their recognition of the subdivision of nonresponders and their proposed alternative explanation, they should also explain why these women in particular (and not the other subdivision of women!) show a positive response to treatment with the combination of T + 5HT1A
J Sex Med 2014;11:2357–2363
Letters to the Editor receptor agonist. To mention a correlation without attempting to understand the phenomenon by taking into account the network of causal mechanisms is not an explanation at all. There are no validated questionnaires assessing our definition of low sensitivity vs. high inhibition. The Kinsey Institute’s Sexual Inhibition and Sexual Excitation Scales are validated scales that spring to mind. However, their approach to the distinction between inhibition and excitation differs from ours. In our case, for example, we believe that the operation of these mechanisms occurs to a large extent outside of consciousness. That is why we used a subliminal version of the Emotional Stroop Task and, in our later experiments, genetic markers and intra-endocrinological processes to measure sensitivity and insensitivity of the brain to sexual cues. Consequently, we do not believe (and have never found evidence) that the division we propose can be captured by a questionnaire, in the same way that sensitivity to certain types of breast cancer therapy is also not measurable by just a questionnaire (see our ideas on the involvement of biological foundations in the causation of HSDD in the first part of the trilogy). According to the authors of “Where is the Evidence?” the meaning of negative sexual experience in the high-inhibition group is unclear. As stated in the literature on the dual-control model, but also in the first part of our trilogy and in two of our earlier articles ( J Sex Med 2009;6:429–39, 777–90), inhibition is activated when there is a perceived threat of a (potential) negative consequence of sexual response/behavior. Our thesis is that all kinds of experiences and situations can trigger activation of an inhibition of sexual response. Some experiences or situations can also lead—consciously or subconsciously—to a learned negative association with sexual stimuli (internal or external). It is possible that a sexual stimulus may automatically evoke activation of sexual inhibitory mechanisms. In our view, negative sexual experiences (among other types of experience) leading to negative associations with sex might be more likely candidates to induce sexual inhibition compared with the factors proposed by the authors of “Where is the Evidence?” Because these processes can occur subconsciously, questionnaires are inadequate in determining to which of the proposed subdivisions a woman might belong. These negative consequences may be scripted by standard social conventions, but they may also be scripted by implicit memories thereof, or direct memories related to situations in which a negative association could be formed.
Baseline Sexual Desire of the Two Subgroups The authors of “Where is the Evidence?” are correct in observing that the low-sensitive women have the same response to placebo with regard to sexual desire and genital arousal as high-inhibitory women. They ask what dysfunction is being treated. The answer is that both groups have the same DSM-IV diagnosis, namely HSDD with or without female sexual arousal disorder. Apparently, the authors of “Where is the Evidence?” assume that our subdivision implies different levels of baseline sexual functioning. In fact, we have stated the contrary: the two HSDD subgroups may exhibit similar complaints, but these complaints may have very different underlying mechanisms. We regret that this basic underpinning of our research, discussed at length in our articles, has apparently gone unnoticed. Moreover, the authors of “Where is the Evidence” remark that it is also unknown to what extent such negative experiences may have led to posttraumatic stress, by which they concur that such experiences could have a disastrous impact on the psychological and sexual functioning of the victims. During the psychological interviews in our studies, different questions were asked regarding factors that could influence sexual functioning; one of them was negative sexual experiences. As these negative sexual experiences were not the topic of this study and were solely taken into account
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Letters to the Editor in order to establish the DSM-IV diagnosis of HSDD, further research is warranted. It is known that negative sexual experiences can lead to posttraumatic stress; however, these experiences were thoroughly discussed in the psychological interview, which was supervised by Prof. Dr. Walter Everaerd, and if the psychologist was of the opinion that these experiences could influence the validity of the diagnosis or study results, the women who mentioned them were excluded from the study.
Efficacy of Both Drugs in Both Populations The authors of “Where is the Evidence?” wonder why overall group data of both drugs were not reported. They ask whether they were not reported because no drug effects were found. Again, as extensively described in the present trilogy under “Debate” and in our earlier articles ( J Sex Med 2009;6:429–39, 777–90), a fundamental assumption of our research is that the two different subdivisions of women with HSDD would benefit from different drug treatments (T + PDE5i or T + 5HT1A receptor agonist). It was therefore never expected that either one of the drugs would have a beneficial effect on all subjects. So the assumption made by the authors of “Where is the Evidence?” is correct. The basis of a personalized medicine approach is that different treatments apply to different individuals; giving the wrong treatment to the wrong person may result in its not working or even having counterproductive effects. Imagine that a drug being trialed produces a positive response of 1 in half of the subjects and a negative response of −1 in the other half of the subjects. It should be clear what the mean response would be for the whole group. Still, the authors of “Where is the Evidence?” not only ask why these data are lacking, they even doubt the integrity of our research group, based on poor understanding of our a priori hypotheses and the literature they refer to. That is, Sun and colleagues (BMJ 2010;340:c117) show that reporting a subgroup analysis when overall analysis fails to show efficacy is more likely when a pharmaceutical company sponsors the trial. This citation is irrelevant in our studies, as we stated a priori that our subgroups would be expected to respond mainly to only one of our two drug combinations. This expectation was already formulated in former publications of our group in 2009 ( J Sex Med 2009;6:429–39, 777–90), as well as the research proposals on which the experiments under discussion were based. The authors of “Where is the Evidence?” state that such a distinction should be made prior to randomization. In agreement with our theoretical framework, we formulated the hypothesis that T + PDE5i would produce a positive sexual response in lowsensitive women (identified as such by the Emotional Stroop Task) and that treatment with T + a 5HT1A receptor agonist would work for women who did not respond to T + PDE5i. The proof-of-concept articles in our trilogy described the situation at the time the study was conducted. In response to the call for a distinction prior to randomization, we recently developed a demarcation formula based on biological and psychological variables (see the first part of our trilogy) to enable this. This formula has been used in our two Phase 2b studies in the United States, which we are currently finalizing. We find it regrettable that the authors of “Where is the Evidence?” did not understand the first part of our series (which was clearly defined as the first part of the series) and that they accuse us of ad hoc “cherry picking.”
Intention to Treat A final point of statistical concern raised by the authors of “Where is the Evidence?” deals with the fact that we did not analyze according to the intention-to-treat (ITT) principle. The internationally accepted guidelines they cite to support their position are the CONSORT guidelines. These guidelines do not advocate
analysis according to ITT per se. What they do advocate is that one should be transparent with regard to which subjects were included in analyses and, more importantly, which subjects were not analyzed, how many, and why. This is the function of the CONSORT diagram. We ask the reader to refer to our CONSORT diagram in the second part of our series. ITT analyses are recommended for Phase 3 trials, and even then, per protocol analyses are allowed and often used to demonstrate effect in a “perfect” (per protocol) group. Any differences between them can then be the subject of explicit discussion and interpretation (see FDA and EMA guidelines on Statistical Principles for Clinical Trials). We did not deviate from legislation or guidelines by excluding women from analyses, and we clearly reported that we did this and the completely understandable reasons why we did this.
Clinical Significance The authors of “Where is the Evidence?” question the clinical significance of the patient-related outcomes. We would first like to thank them for observing an omission in our report. However, they frequently erred in interpreting the data. The Subjective Evaluation of Gain (SEG) questionnaire is a two-item questionnaire with response options of no (1) and yes (2), which results in a response range of 1–2, not 0–2 (as reasoned by the authors of “Where is the Evidence?”). Increases relative to placebo within subgroups varied from 0.3 to approximately 0.5, not 0.2–0.4, indicating that 30–50% benefitted from the medication in the 3 weeks that they could use it in this study. Patient-reported sexual improvement was measured on a 1–3 scale (1 = no improvement, 2 = improvement in only desire or only arousal, 3 = improvement in desire and arousal). Explanation of this scale was accidentally omitted from the manuscript, which is regrettable. The authors of “Where is the Evidence?” state that this improvement was less than 1.5 in both studies in which it was used (parts 2 and 3). In both studies, it was approximately 2, as can be read in the results sections and as can be seen in figures 7 (part 2) and 5 (part 3). This means that overall, a significant improvement was in fact reported, contrary to what the authors of “Where is the Evidence?” believe. The authors of “Where is the Evidence?” state that effect sizes for SEG and Subjective Evaluation of Improvement were large, which only confirms that is the effect is likely meaningful. Finding a significant increase on a scale designed to measure clinical relevance, especially if there is a large effect size, would by definition be indicative of clinical relevance. Therefore, the rationale behind the questions raised in this section by the authors of “Where is the Evidence” is not entirely clear to us.
Placebo Control Our previous research ( J Sex Med 2009;6:429–39, 777–90) clearly demonstrated that when the two active components T and PDE5i were combined, a synergistic effect occurred. Separate administration of T and PDE5i was ineffective for both subgroups (irrespective of adverse event profile). In these studies, the combination also showed superiority not only over placebo but also over separate administration. Note that sildenafil alone has been repeatedly shown to be inactive by other researchers. In spite of these earlier findings, the authors of “Where is the Evidence?” state that theoretically, with combination therapy, women may be using an inactive ingredient, which is undesirable. Practically—and the authors of “Where is the Evidence?” should have known this—using a PDE5I alone can be regarded—in the context of the aim of this study—as using an inactive ingredient, which is undesirable.
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2362 Buspirone alone was hypothesized to be inactive. Regarding the buspirone component in the combination therapy, the hypothesis is that a phasic increase of serotonin activity in the dorsolateral prefrontal cortex is an important mechanism through which sexual inhibition occurs. Buspirone is a substance that, when administered acutely, will transiently decrease serotonin output in the prefrontal cortex and was therefore chosen as a possible treatment option in our trials (in combination with T). There are no other known studies in which buspirone appears to be effective in HSDD women; however, no such study has ever administered buspirone acutely, and therefore we cannot base our conclusions on the research of others. To reiterate, our assumption is that the combinations of components are effective and that the components are effective only in combinations. Moreover, introducing components separately in a study would certainly expose women to known ineffective treatments in the case of a PDE5i and probably in the case of buspirone also, something the authors of “Where is the Evidence?” believe to be undesirable, as do we. According to the authors of “Where is the Evidence?” the active treatments may have had physiological side effects that would allow women to determine whether they had received active treatment or placebo. They mention that facial flushing and nasal congestion are well known side effects of PDE5i. They therefore recommend the use of “active” placebos in drug development programs in which PDE5i are used. This suggestion is inspired by the assumption that negative side effects, such as nasal congestion, might influence the expectations of the women in the trial in such a way that they might report greater sexual arousal than is actually enabled by the drugs. To substantiate this suggestion, the authors of “Where is the Evidence?” refer to a study in which the effects of a PDE5i and placebo were studied in men. However, with respect to the use of PDE5i and placebos, the situation in men and that in women are totally incomparable. The physical effects in men—both the positive main effect on genital response and the negative side effects—are widely known. This knowledge may have an effect on responses to active treatment vs. placebo. The research and treatment goal in men is an increase in genital response; our research program is mainly focused on subjective factors (sexual motivation, sexual desire, etc.). In women with HSDD, no positive effect of PDE5i on physiological or subjective sexual response has ever been demonstrated. By the reasoning used by the authors of “Where is the Evidence?” negative side effects could also have hampered sexual response during active treatment. The expectation that PDE5i will have no effect in women and the presence of possible negative side effects (information that the women read in the patient information document and consent forms) could have affected the efficacy of our treatments. Lastly, there exists an adage about effective drugs: “no main effect without side effects.” This means, if we take the suggestion of the “Where is the Evidence?” authors seriously, that all drug development programs should make use of “active” placebos. We are impressed by their ambition but believe that this will prove to be an unattainable enterprise. We are aware that the combinations of T with PDE5i and T with 5HT1A receptor agonist will have to show superiority over their respective monotherapies as well as over placebo (also known as the combination drug rule, a regulatory requirement). In our Phase 2b trials, we have investigated the effects of the combination therapies compared with placebo and monotherapies, and these results will be available soon. We expect that these results will satisfy the authors of “Where is the Evidence?” As for the intake of the placebo treatment vs. the intake of the combination treatments, the mean intake of the placebo (mean of 3 weeks of treatment) was 3.56 units (solution and capsule), that of T + PDE5i was 3.84 units, and that of T + 5HT1A receptor 3.80 units. Thus, there were no significant differences in the intake of the treatments between treatment arms.
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Letters to the Editor Conflicts of Interest Lorraine Dennerstein was acting editor-in-chief for these articles and thus made the final decision to publish. The authors of “Where is the Evidence?” ask for the names of the reviewers. In assessing manuscripts for scientific journals, a basic rule is that reviewers are anonymous. We received many questions and comments on our manuscripts from the anonymous reviewers. Like all authors of scientific articles that undergo review, we are often curious as to which scientists are actually giving these constructive comments. However, we believe it is a good principle that reviewers remain anonymous, in the same way as we have to reply to the authors of “Where is the Evidence?” without knowing who they are. Asking for the names of anonymous reviewers is obviously not in agreement with basic principles and conventions in the scientific world. The authors of “Where is the Evidence?” point out that we, the writers of the ”Toward Personalized Sexual Medicine” articles, also have interests in the company that sponsored the research. We indicated this in conflict of interest statements according to the JSM publishing guidelines, as most other journals also require. These guidelines exist so that readers can make up their own mind with respect to conflicts of interest. It is beyond the scope of a journal’s editorial board to determine how conflicts of interest could affect the presentation of results. On a personal note, Emotional Brain is a small research company in which the employees are involved in scientifically driven research, and we are all passionate about what we do. One of our interests is that we really want to know the mechanisms responsible for sexual dysfunctions. When a company is involved in drug development, and the intention is to gain marketing approval for these drugs, the company and the studies it conducts are bound by strict rules and regulations. If a company does not adhere to these rules and regulations (which the authors of “Where is the Evidence?” seem to imply of us), it will only hurt its case. Every facet of such a study is regulated and has to be thoroughly checked and verified by independent experts. The drug allocation and unblinding are performed by another group of independent experts after the database is sealed by the first group. During the process of drug development, each step and process will be subjected to extensive due diligences and audits by organizations and institutions independent of the company. At the end of the process, the regulatory agencies will go over the study one more time with a fine-toothed comb. In their final conclusion, the authors of “Where is the Evidence?” refer to their comment as an “editorial.” In general, an editorial is a leading article and reflects an opinion written by the senior editorial staff or publisher of a newspaper, magazine, or scientific journal. Editorials may be assumed to reflect the opinion of the periodical. However, the authors of “Where is the Evidence?” raise the question of whether these articles should have been published in their current form. During peer review, we answered the questions and constructive critical comments of the reviewers. Given the sophistication of their comments, it was clear for us that the original article reviewers had read our manuscripts thoroughly and really understood the conceptual framework of our approach and studies, indicating their expertise in this complex domain of research. We surmise that the editors of JSM based their judgment on the intelligent and knowledgeable comments of the experienced reviewers.
Conclusion The concerns raised by the authors of “Where is the Evidence?” are mostly based on misunderstandings and unfortunately convey an underlying tone of distrust toward scientists working for a pharmaceutical company. Moreover, we believe that our three
Letters to the Editor published articles, in which we have been as transparent as possible regarding the data, leave the possibility open for critical reviewers to identify potential limitations of the studies and address them in future research, so—not surprisingly, perhaps—we do not subscribe to the arguments put forth in “Where is the Evidence?” Conflict of Interest: Funding for this study was provided by Emotional Brain B.V. AT is CEO and shareholder of EB. JB, KvR, SP, JG and DvH are employees of EB. LdL and WE are advisors to EB.
2363 Adriaan Tuiten, PhD,*† Jos Bloemers, MSc,*† Kim van Rooij, MD,*† Saskia Poels, MD,*† Jeroen Gerritsen, MSc,*† Diana van Ham, MSc,*† Leo de Leede, PhD,‡ and Walter Everaerd, PhD§ *Emotional Brain B.V., Almere, The Netherlands; †Utrecht Institute for Pharmaceutical Sciences, Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands; ‡Exelion Bio-Pharmaceutical Consultancy B.V., Waddinxveen, The Netherlands; §Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands
J Sex Med 2014;11:2357–2363
Letters to the Editor
Response to “Toward Personalized Sexual Medicine: Where is the Evidence?” DOI: 10.1111/jsm.12644
The authors of the letter “Toward Personalized Sexual Medicine: Where is the Evidence?” raise several concerns regarding the validity of the theoretical claims and findings described in our three “Toward Personalized Sexual Medicine” articles discussing two potential on-demand drug combinations for hypoactive sexual desire disorder (HSDD) ( J Sex Med 2013;10:791–809, 810–23, 824–37). It goes without saying that we appreciate critical review of our articles, but we believe that we can easily address the authors’ questions to the reader’s satisfaction. Empirical science consists of theoretical assumptions concerning cause-and-effect relationships, which are not directly observable. In other words, science is engaged with abstractions of the world. Based on such assumptions, predictions with observable consequences are made, which are tested against the empirical reality. If the results are consistent with what has been predicted, they can be regarded as (provisional) confirmation of the underlying theoretical assumptions (it is very unlikely that we will ever directly “see” the real truth). If the prediction does not come about (i.e., the empirical reality is recalcitrant), then doubts can be raised about the theoretical background (but this need not always be true). In the empirical sciences, we see scientists reporting correlations they have observed between variables. Such reports are descriptions of what the scientists have seen, not explanations in terms of the underlying mechanisms linking cause with effect. Such explanations are, strictly speaking, not part of science (although they can serve a hypothesis-forming function and, in this way, provide a gateway to the wonderful world of science).
Subgroup Analysis and Dual Control The authors of “Where is the Evidence?” claim that in our research, inhibition is defined as lack of sexual activation. According to them, this would be in conflict with the basic tenets of the dual-control model, which assumes the inhibitory and excitatory components are relatively independent systems regulating sexual behavior. The authors are unclear on which basic tenet of the dual-control model is violated, but we assume that they believe that inhibition means decreased sexual response (compared with baseline). However, the dual-control model states that the sexual excitation and inhibition systems are separate but interacting systems. The opposing sexual excitation and inhibition systems determine behavior depending on the presence of external stimuli and on internal state, including outcome expectations (of reward and of negative consequences). For example, sexual stimuli (e.g., erotic video clips) might trigger the sexual excitation system but do not necessarily induce a sexual response. This is dependent upon the relative strength of the erotic stimulus, the internal state (e.g., satiated or nonsatiated), and other internal or external stimuli signaling the advantageousness or disadvantageousness of a sexual response. If a sexual stimulus is potent enough to activate the sexual excitation system and the consequences of responding sexually are not perceived as negative, either consciously or subconsciously, it may induce a sexual response. If, on the other hand, the same sexual stimulus is presented in a setting in which responding sexually is disadvantageous or inappropriate, it may activate the sexual inhibition system, preventing a sexual response. The dualcontrol model does not assume that activation of the inhibition system results in a “negative” or inverse sexual response. Rather,
Statistical Analysis Strategy 30
Our trilogy was originally a single article. The complex theory and the large amount of data prompted us to rewrite it as three articles. As a result of this rewrite, the description of the statistical interaction effect in the Stroop data in the second part of the trilogy was accidentally placed after the second sentence on page 817, instead of in the first sentence, where it belongs. We thank the authors for pointing out to us this unfortunate mistake, but the analysis is not inaccurate as they suggest. Thus, the degrees of freedom given on page 817 refer to the interaction between placebo vs. testosterone plus phosphodiesterase type 5 inhibitor (T + PDE5i) and the two groups (low- vs. highsensitive); this interaction effect is indeed F(1,54) = 13.27 (P < 0.001). In figure 3, only the results for the low-sensitive group are represented, although the t-value should have been reported as well: t(1,28) = −3.93 (P = 0.001). The results of the high-sensitive group were not reported because the hypothesis was that only the low-sensitive group would show an increase in attention and would respond to the combination of T + PDE5i (which was the subject of the article); therefore, reporting the Stroop results for the high-sensitive group had no relevance for the article. For the reader’s information, these results were the following: t(1,26) = 1.69, P = 0.104. See also Figure 1.
Preconscious aenonal bias for eroc cues (ms)
Stroop Subgroup Analysis
low-sensive high-sensive
20 10
P = 0.104
0 Placebo –10
P = 0.001
T + PDE5i
–20 –30
Figure 1 Preconscious attentional bias for sexual cues in lowsensitive women and high-sensitive women after placebo and T + PDE5i intake.
J Sex Med 2014;11:2357–2363
2360 sexual inhibition can block activation of excitatory sexual mechanisms, as we postulated for our “inhibitory” subgroup. Furthermore, the functional magnetic resonance imaging studies described in the first part of the trilogy clearly illustrate the dualcontrol model’s notion that activation of inhibitory mechanisms is important in certain subgroups or certain situations and that this is accompanied by a lack of response and not necessarily a decrease in response. We exposed women to all kinds of manipulations (erotic film clips, drugs theorized to increase sexual excitation, instructions) meant to induce activation of sexual excitation. These manipulations resulted in our finding a subdivision of women who indeed showed an increase in sexual response. This occurred, as predicted, in the low-sensitive women. We hypothesized beforehand that a subdivision of women would not respond to our manipulations because of activation of inhibitory mechanisms (a phasic increase in serotonergic activity in the dorsolateral prefrontal cortex, provoked by sexual stimulation). Based on this hypothetical inhibitory mechanism, we subsequently hypothesized that this group would respond to treatment with the combination of T and a serotonin (5HT1A) receptor agonist. This hypothesis was also corroborated by the results of our experiments. Furthermore, we expected that the noninhibitor group would not respond to this treatment because they would not have a phasic increase in activity of serotonin in the prefrontal cortex. The results of treatment of this group with T + 5HT1A receptor agonist were in agreement with this expectation as well. Because the results were in concurrence with our hypotheses, we assume—for the time being—that the hypothesized underlying mechanisms are actually present.
Substantiation of Subgroup Differentiation We tried to substantiate our claims as much as possible. Neurophysiological data were not available for the subjects in the studies under discussion. However, neurophysiological data from other studies from our lab substantiating our claims were presented in part 1 of the series. This article presented the basics of the theories tested in parts 2 and 3 and contributed to a greater understanding of the different regulating mechanisms involved in sexual behavior. In other words, the results of our previous experiments were the basis for the formulation of the hypothesis of subgroup differentiation. As suggested by the authors of “Where is the Evidence?” we looked at baseline clinical and anamnesic data and presented them in the manuscripts. The only related variables were number of children and relationship duration. The authors of “Where is the Evidence?” emphasize that these variables are known to be related to a decline in sexual desire and to reduced quality of marital sex (as also discussed by us). However, they then suggest that this may be an alternative explanation for the lack of response to PDE5i. We assume they mean to refer to a lack of response to T + PDE5i, because we did not measure response to PDE5i separately in the experiment under discussion. Although the authors of “Where is the Evidence?” do recognize here that our subdivision into responders and nonresponders to treatment with T + PDE5i is valid, we still fail to see how this is more than a statement about a correlation between these two measures. Any suggestions about possible mechanisms underlying nonresponse to treatment with T + PDE5i are sadly lacking in their comment. After all, an attempt toward an explanation (i.e., model) should at least hypothesize why these women do not respond, that is, what the biological or psychological mechanisms are that underlie their nonresponse. It is particularly striking, then, that this subgroup of women does in fact respond to treatment with T + 5HT1A receptor agonist. In addition, in light of their recognition of the subdivision of nonresponders and their proposed alternative explanation, they should also explain why these women in particular (and not the other subdivision of women!) show a positive response to treatment with the combination of T + 5HT1A
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Letters to the Editor receptor agonist. To mention a correlation without attempting to understand the phenomenon by taking into account the network of causal mechanisms is not an explanation at all. There are no validated questionnaires assessing our definition of low sensitivity vs. high inhibition. The Kinsey Institute’s Sexual Inhibition and Sexual Excitation Scales are validated scales that spring to mind. However, their approach to the distinction between inhibition and excitation differs from ours. In our case, for example, we believe that the operation of these mechanisms occurs to a large extent outside of consciousness. That is why we used a subliminal version of the Emotional Stroop Task and, in our later experiments, genetic markers and intra-endocrinological processes to measure sensitivity and insensitivity of the brain to sexual cues. Consequently, we do not believe (and have never found evidence) that the division we propose can be captured by a questionnaire, in the same way that sensitivity to certain types of breast cancer therapy is also not measurable by just a questionnaire (see our ideas on the involvement of biological foundations in the causation of HSDD in the first part of the trilogy). According to the authors of “Where is the Evidence?” the meaning of negative sexual experience in the high-inhibition group is unclear. As stated in the literature on the dual-control model, but also in the first part of our trilogy and in two of our earlier articles ( J Sex Med 2009;6:429–39, 777–90), inhibition is activated when there is a perceived threat of a (potential) negative consequence of sexual response/behavior. Our thesis is that all kinds of experiences and situations can trigger activation of an inhibition of sexual response. Some experiences or situations can also lead—consciously or subconsciously—to a learned negative association with sexual stimuli (internal or external). It is possible that a sexual stimulus may automatically evoke activation of sexual inhibitory mechanisms. In our view, negative sexual experiences (among other types of experience) leading to negative associations with sex might be more likely candidates to induce sexual inhibition compared with the factors proposed by the authors of “Where is the Evidence?” Because these processes can occur subconsciously, questionnaires are inadequate in determining to which of the proposed subdivisions a woman might belong. These negative consequences may be scripted by standard social conventions, but they may also be scripted by implicit memories thereof, or direct memories related to situations in which a negative association could be formed.
Baseline Sexual Desire of the Two Subgroups The authors of “Where is the Evidence?” are correct in observing that the low-sensitive women have the same response to placebo with regard to sexual desire and genital arousal as high-inhibitory women. They ask what dysfunction is being treated. The answer is that both groups have the same DSM-IV diagnosis, namely HSDD with or without female sexual arousal disorder. Apparently, the authors of “Where is the Evidence?” assume that our subdivision implies different levels of baseline sexual functioning. In fact, we have stated the contrary: the two HSDD subgroups may exhibit similar complaints, but these complaints may have very different underlying mechanisms. We regret that this basic underpinning of our research, discussed at length in our articles, has apparently gone unnoticed. Moreover, the authors of “Where is the Evidence” remark that it is also unknown to what extent such negative experiences may have led to posttraumatic stress, by which they concur that such experiences could have a disastrous impact on the psychological and sexual functioning of the victims. During the psychological interviews in our studies, different questions were asked regarding factors that could influence sexual functioning; one of them was negative sexual experiences. As these negative sexual experiences were not the topic of this study and were solely taken into account
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Letters to the Editor in order to establish the DSM-IV diagnosis of HSDD, further research is warranted. It is known that negative sexual experiences can lead to posttraumatic stress; however, these experiences were thoroughly discussed in the psychological interview, which was supervised by Prof. Dr. Walter Everaerd, and if the psychologist was of the opinion that these experiences could influence the validity of the diagnosis or study results, the women who mentioned them were excluded from the study.
Efficacy of Both Drugs in Both Populations The authors of “Where is the Evidence?” wonder why overall group data of both drugs were not reported. They ask whether they were not reported because no drug effects were found. Again, as extensively described in the present trilogy under “Debate” and in our earlier articles ( J Sex Med 2009;6:429–39, 777–90), a fundamental assumption of our research is that the two different subdivisions of women with HSDD would benefit from different drug treatments (T + PDE5i or T + 5HT1A receptor agonist). It was therefore never expected that either one of the drugs would have a beneficial effect on all subjects. So the assumption made by the authors of “Where is the Evidence?” is correct. The basis of a personalized medicine approach is that different treatments apply to different individuals; giving the wrong treatment to the wrong person may result in its not working or even having counterproductive effects. Imagine that a drug being trialed produces a positive response of 1 in half of the subjects and a negative response of −1 in the other half of the subjects. It should be clear what the mean response would be for the whole group. Still, the authors of “Where is the Evidence?” not only ask why these data are lacking, they even doubt the integrity of our research group, based on poor understanding of our a priori hypotheses and the literature they refer to. That is, Sun and colleagues (BMJ 2010;340:c117) show that reporting a subgroup analysis when overall analysis fails to show efficacy is more likely when a pharmaceutical company sponsors the trial. This citation is irrelevant in our studies, as we stated a priori that our subgroups would be expected to respond mainly to only one of our two drug combinations. This expectation was already formulated in former publications of our group in 2009 ( J Sex Med 2009;6:429–39, 777–90), as well as the research proposals on which the experiments under discussion were based. The authors of “Where is the Evidence?” state that such a distinction should be made prior to randomization. In agreement with our theoretical framework, we formulated the hypothesis that T + PDE5i would produce a positive sexual response in lowsensitive women (identified as such by the Emotional Stroop Task) and that treatment with T + a 5HT1A receptor agonist would work for women who did not respond to T + PDE5i. The proof-of-concept articles in our trilogy described the situation at the time the study was conducted. In response to the call for a distinction prior to randomization, we recently developed a demarcation formula based on biological and psychological variables (see the first part of our trilogy) to enable this. This formula has been used in our two Phase 2b studies in the United States, which we are currently finalizing. We find it regrettable that the authors of “Where is the Evidence?” did not understand the first part of our series (which was clearly defined as the first part of the series) and that they accuse us of ad hoc “cherry picking.”
Intention to Treat A final point of statistical concern raised by the authors of “Where is the Evidence?” deals with the fact that we did not analyze according to the intention-to-treat (ITT) principle. The internationally accepted guidelines they cite to support their position are the CONSORT guidelines. These guidelines do not advocate
analysis according to ITT per se. What they do advocate is that one should be transparent with regard to which subjects were included in analyses and, more importantly, which subjects were not analyzed, how many, and why. This is the function of the CONSORT diagram. We ask the reader to refer to our CONSORT diagram in the second part of our series. ITT analyses are recommended for Phase 3 trials, and even then, per protocol analyses are allowed and often used to demonstrate effect in a “perfect” (per protocol) group. Any differences between them can then be the subject of explicit discussion and interpretation (see FDA and EMA guidelines on Statistical Principles for Clinical Trials). We did not deviate from legislation or guidelines by excluding women from analyses, and we clearly reported that we did this and the completely understandable reasons why we did this.
Clinical Significance The authors of “Where is the Evidence?” question the clinical significance of the patient-related outcomes. We would first like to thank them for observing an omission in our report. However, they frequently erred in interpreting the data. The Subjective Evaluation of Gain (SEG) questionnaire is a two-item questionnaire with response options of no (1) and yes (2), which results in a response range of 1–2, not 0–2 (as reasoned by the authors of “Where is the Evidence?”). Increases relative to placebo within subgroups varied from 0.3 to approximately 0.5, not 0.2–0.4, indicating that 30–50% benefitted from the medication in the 3 weeks that they could use it in this study. Patient-reported sexual improvement was measured on a 1–3 scale (1 = no improvement, 2 = improvement in only desire or only arousal, 3 = improvement in desire and arousal). Explanation of this scale was accidentally omitted from the manuscript, which is regrettable. The authors of “Where is the Evidence?” state that this improvement was less than 1.5 in both studies in which it was used (parts 2 and 3). In both studies, it was approximately 2, as can be read in the results sections and as can be seen in figures 7 (part 2) and 5 (part 3). This means that overall, a significant improvement was in fact reported, contrary to what the authors of “Where is the Evidence?” believe. The authors of “Where is the Evidence?” state that effect sizes for SEG and Subjective Evaluation of Improvement were large, which only confirms that is the effect is likely meaningful. Finding a significant increase on a scale designed to measure clinical relevance, especially if there is a large effect size, would by definition be indicative of clinical relevance. Therefore, the rationale behind the questions raised in this section by the authors of “Where is the Evidence” is not entirely clear to us.
Placebo Control Our previous research ( J Sex Med 2009;6:429–39, 777–90) clearly demonstrated that when the two active components T and PDE5i were combined, a synergistic effect occurred. Separate administration of T and PDE5i was ineffective for both subgroups (irrespective of adverse event profile). In these studies, the combination also showed superiority not only over placebo but also over separate administration. Note that sildenafil alone has been repeatedly shown to be inactive by other researchers. In spite of these earlier findings, the authors of “Where is the Evidence?” state that theoretically, with combination therapy, women may be using an inactive ingredient, which is undesirable. Practically—and the authors of “Where is the Evidence?” should have known this—using a PDE5I alone can be regarded—in the context of the aim of this study—as using an inactive ingredient, which is undesirable.
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2362 Buspirone alone was hypothesized to be inactive. Regarding the buspirone component in the combination therapy, the hypothesis is that a phasic increase of serotonin activity in the dorsolateral prefrontal cortex is an important mechanism through which sexual inhibition occurs. Buspirone is a substance that, when administered acutely, will transiently decrease serotonin output in the prefrontal cortex and was therefore chosen as a possible treatment option in our trials (in combination with T). There are no other known studies in which buspirone appears to be effective in HSDD women; however, no such study has ever administered buspirone acutely, and therefore we cannot base our conclusions on the research of others. To reiterate, our assumption is that the combinations of components are effective and that the components are effective only in combinations. Moreover, introducing components separately in a study would certainly expose women to known ineffective treatments in the case of a PDE5i and probably in the case of buspirone also, something the authors of “Where is the Evidence?” believe to be undesirable, as do we. According to the authors of “Where is the Evidence?” the active treatments may have had physiological side effects that would allow women to determine whether they had received active treatment or placebo. They mention that facial flushing and nasal congestion are well known side effects of PDE5i. They therefore recommend the use of “active” placebos in drug development programs in which PDE5i are used. This suggestion is inspired by the assumption that negative side effects, such as nasal congestion, might influence the expectations of the women in the trial in such a way that they might report greater sexual arousal than is actually enabled by the drugs. To substantiate this suggestion, the authors of “Where is the Evidence?” refer to a study in which the effects of a PDE5i and placebo were studied in men. However, with respect to the use of PDE5i and placebos, the situation in men and that in women are totally incomparable. The physical effects in men—both the positive main effect on genital response and the negative side effects—are widely known. This knowledge may have an effect on responses to active treatment vs. placebo. The research and treatment goal in men is an increase in genital response; our research program is mainly focused on subjective factors (sexual motivation, sexual desire, etc.). In women with HSDD, no positive effect of PDE5i on physiological or subjective sexual response has ever been demonstrated. By the reasoning used by the authors of “Where is the Evidence?” negative side effects could also have hampered sexual response during active treatment. The expectation that PDE5i will have no effect in women and the presence of possible negative side effects (information that the women read in the patient information document and consent forms) could have affected the efficacy of our treatments. Lastly, there exists an adage about effective drugs: “no main effect without side effects.” This means, if we take the suggestion of the “Where is the Evidence?” authors seriously, that all drug development programs should make use of “active” placebos. We are impressed by their ambition but believe that this will prove to be an unattainable enterprise. We are aware that the combinations of T with PDE5i and T with 5HT1A receptor agonist will have to show superiority over their respective monotherapies as well as over placebo (also known as the combination drug rule, a regulatory requirement). In our Phase 2b trials, we have investigated the effects of the combination therapies compared with placebo and monotherapies, and these results will be available soon. We expect that these results will satisfy the authors of “Where is the Evidence?” As for the intake of the placebo treatment vs. the intake of the combination treatments, the mean intake of the placebo (mean of 3 weeks of treatment) was 3.56 units (solution and capsule), that of T + PDE5i was 3.84 units, and that of T + 5HT1A receptor 3.80 units. Thus, there were no significant differences in the intake of the treatments between treatment arms.
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Letters to the Editor Conflicts of Interest Lorraine Dennerstein was acting editor-in-chief for these articles and thus made the final decision to publish. The authors of “Where is the Evidence?” ask for the names of the reviewers. In assessing manuscripts for scientific journals, a basic rule is that reviewers are anonymous. We received many questions and comments on our manuscripts from the anonymous reviewers. Like all authors of scientific articles that undergo review, we are often curious as to which scientists are actually giving these constructive comments. However, we believe it is a good principle that reviewers remain anonymous, in the same way as we have to reply to the authors of “Where is the Evidence?” without knowing who they are. Asking for the names of anonymous reviewers is obviously not in agreement with basic principles and conventions in the scientific world. The authors of “Where is the Evidence?” point out that we, the writers of the ”Toward Personalized Sexual Medicine” articles, also have interests in the company that sponsored the research. We indicated this in conflict of interest statements according to the JSM publishing guidelines, as most other journals also require. These guidelines exist so that readers can make up their own mind with respect to conflicts of interest. It is beyond the scope of a journal’s editorial board to determine how conflicts of interest could affect the presentation of results. On a personal note, Emotional Brain is a small research company in which the employees are involved in scientifically driven research, and we are all passionate about what we do. One of our interests is that we really want to know the mechanisms responsible for sexual dysfunctions. When a company is involved in drug development, and the intention is to gain marketing approval for these drugs, the company and the studies it conducts are bound by strict rules and regulations. If a company does not adhere to these rules and regulations (which the authors of “Where is the Evidence?” seem to imply of us), it will only hurt its case. Every facet of such a study is regulated and has to be thoroughly checked and verified by independent experts. The drug allocation and unblinding are performed by another group of independent experts after the database is sealed by the first group. During the process of drug development, each step and process will be subjected to extensive due diligences and audits by organizations and institutions independent of the company. At the end of the process, the regulatory agencies will go over the study one more time with a fine-toothed comb. In their final conclusion, the authors of “Where is the Evidence?” refer to their comment as an “editorial.” In general, an editorial is a leading article and reflects an opinion written by the senior editorial staff or publisher of a newspaper, magazine, or scientific journal. Editorials may be assumed to reflect the opinion of the periodical. However, the authors of “Where is the Evidence?” raise the question of whether these articles should have been published in their current form. During peer review, we answered the questions and constructive critical comments of the reviewers. Given the sophistication of their comments, it was clear for us that the original article reviewers had read our manuscripts thoroughly and really understood the conceptual framework of our approach and studies, indicating their expertise in this complex domain of research. We surmise that the editors of JSM based their judgment on the intelligent and knowledgeable comments of the experienced reviewers.
Conclusion The concerns raised by the authors of “Where is the Evidence?” are mostly based on misunderstandings and unfortunately convey an underlying tone of distrust toward scientists working for a pharmaceutical company. Moreover, we believe that our three
Letters to the Editor published articles, in which we have been as transparent as possible regarding the data, leave the possibility open for critical reviewers to identify potential limitations of the studies and address them in future research, so—not surprisingly, perhaps—we do not subscribe to the arguments put forth in “Where is the Evidence?” Conflict of Interest: Funding for this study was provided by Emotional Brain B.V. AT is CEO and shareholder of EB. JB, KvR, SP, JG and DvH are employees of EB. LdL and WE are advisors to EB.
2363 Adriaan Tuiten, PhD,*† Jos Bloemers, MSc,*† Kim van Rooij, MD,*† Saskia Poels, MD,*† Jeroen Gerritsen, MSc,*† Diana van Ham, MSc,*† Leo de Leede, PhD,‡ and Walter Everaerd, PhD§ *Emotional Brain B.V., Almere, The Netherlands; †Utrecht Institute for Pharmaceutical Sciences, Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands; ‡Exelion Bio-Pharmaceutical Consultancy B.V., Waddinxveen, The Netherlands; §Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands
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