Oxytocin Enhancement of the Placebo Effect May Be a Novel Therapy for Working Memory Impairments

Zhao, Weihua; Becker, Benjamin; Yao, Shuntian; Ma, Xiaole; Kou, Juan; Kendrick, Keith M.

doi:10.1159/000495260

Cited by 22 publications

(27 citation statements)

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“…Intranasal oxytocin (OT) has been proposed as a potential therapy for social dysfunction in psychiatric disorders in relation to autism spectrum disorder, schizophrenia and social anxiety [1][2][3] as well as in the context of fear-extinction [4] and as an adjunct to the placebo effect for working memory deficits [5]. To date the functional effects of intranasal OT administration have been based primarily on a single dose and there is evidence that a 24IU dose may be optimal [6].…”

Section: Introductionmentioning

confidence: 99%

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Kou

Zhang

Zhou

et al. 2018

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23Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy 24 for social dysfunction but some clinical trials have reported small or no beneficial 25 96 promising key neural mechanisms: attenuated amygdala fear responses and increased 97 resting state functional connectivity between the amygdala and medial prefrontal 98 cortex (Kendrick et al., 2017; Spengler et al., 2017). Both neural markers have been 99 primarily associated with attenuated anxiety in terms of reduced responses to social 100 threat and enhanced top-down control of emotion (Zhao et al., 2019), although OT 101 effects on the amygdala may also mediate its actions on a range of social cognition 102 6 domains (Kendrick et al., 2017; Meyer-Lindenberg et al., 2011; Spengler et al., 2017; 103 Young and Barrett, 2015). 104In order to determine optimal treatment protocols for chronic intranasal OT 105 administration the current pre-registered double-blind, randomized between subject 106 placebo (PLC)-controlled pharmacological neuroimaging trial (see Fig. 1) in 138 107 adult male subjects therefore aimed at determining the effects of acute (single dose) 108 and repeated doses (daily or every other day for 5 days) of 24IU OT versus PLC on 109 amygdala-centered neural and behavioral (valence, arousal and intensity ratings of 110 fear faces) mechanisms of OT. To identify individuals with the most promising 111 treatment sensitivity we additionally assessed the influence of OXTR rs53576 and 112 rs2254298 polymorphisms on acute and repeated dose OT effects. 113 Results 114 Acute effects of OT on neural responses to emotional faces 115 In accordance with the primary outcome measure of the trial analyses focused on the 116 neural responses to fearful faces, however no significant effects of OT were found for 117 happy or angry faces. Comparison of single-dose OT-(combined OT3 and OT5 groups) 118 and PLC-treated subjects (1 st day) revealed significantly decreased right amygdala 119 reactivity towards fearful faces on the whole brain level (k = 78, pFWE = 0.043, x=27, 120 y=-4, z=-13) (Fig.2A). Cytoarchitectonic probabilistic localization (Anatomy toolbox 121 V1.8 (Eickhoff et al., 2005)) mapped the peak coordinate with >80% probability to 122 the basolateral amygdala sub-region. In addition, OT also decreased fear-reactivity in 123 7 the right superior frontal gyrus and bilateral primary visual cortex (see SI and Table 124 S1). There were no significant differences between the OT3 and OT5 groups on the 1 st 125 day. 126 Primary outcome measures: effects of repeated doses on OT-evoked 127 changes 128 Mixed ANOVAs with treatment (PLC, OT3, OT5) and time point (1 st day, acute 129 effects; 5 th day, chronic effects) as factors and right amygdala fear reactivity as 130 dependent variable revealed a significant main effect of treatment (F2, 135 = 7.85, p = 131 0.001, η 2 p = 0.104) and a treatment x time point interaction (F2, 135 = 5.74, p = 0.004, 132 η 2 p =0.078). Post-hoc Bonferroni corrected comparisons between group...

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Section: Introductionmentioning

confidence: 99%

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Kou

Zhang

Zhou

et al. 2018

Preprint

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“…Both placebo and nocebo have a huge impact on clinical outcomes in a broad variety of medical conditions [1]. The potential for clinicians to use oxytocin to influence responses to medicines and psychological interventions is highly tempting [10]. However, our findings indicate a lack of evidence for the effect of oxytocin on placebo analgesia and nocebo hyperalgesia.…”

Section: Karger@kargercommentioning

confidence: 73%

Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia

Liu

Huang

Chen

et al. 2019

Psychother Psychosom

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cues associated with either a high or low electrical pain for 20 times each. In the testing stage, the high cue, low cue, and a new cue were all paired with identical moderate pain for 20 times each. In study 2, a verbal suggestion plus conditioning paradigm was used. Three identical inert ointments were applied to 3 sites on each participant's forearm, with the sites randomized across participants. A female experimenter described ointments as creams that increase pain (nocebo), reduce pain (placebo), and have no effect on pain (control), respectively. After 10 min, the 3 sites were stimulated for 10 times with high, moderate, and low shocks, corresponding to their instructed functions, to strengthen the effect of verbal suggestions. In the subsequent testing stage, all 3 sites were paired with moderate shocks for 20 times each.Participants rated how much pain they felt after each shock, using the same 9-point numeric rating scale. The placebo and nocebo effects were assessed as participants rated the low-cue (study 1) or placebo site (study 2)-associated shock as less painful and high-cue/nocebo site-associated shock as more painful compared to the new-cue/control site-associated shock during the test stage.Data from 12 participants were excluded because of poor pain discrimination during calibration or doubt of ointments' effects, leaving 306 participants for analysis (age, 18-26 years). A 2 (group: oxytocin/saline) × 2 (dosage: 24/40 IU) factorial ANOVA on placebo effect revealed no main effects and interaction effect in both studies (study 1: group, F(1, 156) = 0.16, p = 0.692; dosage, F(1, 156) = 0.06, p = 0.814; group × dosage, F(1, 156) = 0.30, p = 0.588; study 2: group, F(1, 142) = 0.17, p = 0.682; dosage, F(1, 142) = 0.03, p = 0.860; group × dosage, F(1, 142) = 0.09, p = 0.764). A similar ANOVA on nocebo effect also revealed no main effects and interaction effect (study 1: group, F(1, 156) = 0.29, p = 0.589; dosage, F(1, 156) = 0.65, p = 0.420; group × dosage, F(1, 156) = 1.12, p = 0.292; study 2: group, F(1, 142) < 0.001, p = 0.99; dosage, F(1, 142) = 0.57, p = 0.452; group × dosage, F(1, 142) = 0.98, p = 0.324).To further examine whether sex modulates the effect of oxytocin on placebo and nocebo effects, we conducted a 2 (group: oxytocin/ saline) × 2 (dosage: 24/40 IU) × 2 (sex: female/male) factorial ANOVA on placebo and nocebo responses, respectively. Results showed no sex-related effects (p values > 0.1), possibly due to the small number of participants in each subgroup for each gender. In addition, we examined pain ratings in the conditioning stage and found no significant differences across 4 arms in both studies (p values > 0.1), suggesting that the strength of conditioning was well-balanced across groups.In summary, using a randomized, double-blind design, we found no evidence for oxytocin effects on placebo and nocebo across paradigms and dosages in a large sample. Our findings challenge previous findings that placebo responses can be enhanced by the application of intranasal oxytocin and furth...

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“…Interestingly, in a clinical context, patients who report greater similarities with and trust in their clinician tend to report greater reduction in pain after treatment [11]. Further studies therefore need to assess the extent to which trust in an expert may influence the ability of oxytocin to facilitate placebo effects.An important difference between the placebo analgesia studies and that reporting altered performance following oxytocin combined with verbal suggestion in working memory tasks is that in the latter, there was no placebo effect in the absence of oxytocin [5]. This raises the possibility that oxytocin may be more effective in enhancing the power of verbal suggestion in influencing complex cognitive behaviors that do not show pronounced placebo effects and are based on objective task performance rather than subjective ratings.During the last decade, the placebo effect has gained considerable attention in clinical and basic research.…”

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confidence: 98%

“…An important difference between the placebo analgesia studies and that reporting altered performance following oxytocin combined with verbal suggestion in working memory tasks is that in the latter, there was no placebo effect in the absence of oxytocin [5]. This raises the possibility that oxytocin may be more effective in enhancing the power of verbal suggestion in influencing complex cognitive behaviors that do not show pronounced placebo effects and are based on objective task performance rather than subjective ratings.…”

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confidence: 98%

“…A number of studies have considered whether the neuropeptide oxytocin, which increases attention to social cues and conformity to the opinions of trusted individuals [3], might enhance placebo effects. Some studies have reported that intranasal oxytocin can enhance placebo analgesia [4] and even generate both placebo and nocebo effects in working memory performance [5] in men. However, several other recent studies on men [6] and women [7,8] found no evidence for effects of oxytocin.…”

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Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

Becker

Zhao

Kendrick

2020

Psychother Psychosom

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in the placebo analgesia paradigms experimenters are involved in causing actual physical pain to subjects, this may even have contributed to a reduced trust in them. Interestingly, in a clinical context, patients who report greater similarities with and trust in their clinician tend to report greater reduction in pain after treatment [11]. Further studies therefore need to assess the extent to which trust in an expert may influence the ability of oxytocin to facilitate placebo effects.An important difference between the placebo analgesia studies and that reporting altered performance following oxytocin combined with verbal suggestion in working memory tasks is that in the latter, there was no placebo effect in the absence of oxytocin [5]. This raises the possibility that oxytocin may be more effective in enhancing the power of verbal suggestion in influencing complex cognitive behaviors that do not show pronounced placebo effects and are based on objective task performance rather than subjective ratings.During the last decade, the placebo effect has gained considerable attention in clinical and basic research. Although traditionally considered an unspecific confounder in treatment evaluation trials requiring strictly controlled designs [1], more recently potential enhancement of the placebo effect as a strategy to facilitate treatment responses in clinical samples has been considered [2]. A number of studies have considered whether the neuropeptide oxytocin, which increases attention to social cues and conformity to the opinions of trusted individuals [3], might enhance placebo effects. Some studies have reported that intranasal oxytocin can enhance placebo analgesia [4] and even generate both placebo and nocebo effects in working memory performance [5] in men. However, several other recent studies on men [6] and women [7,8] found no evidence for effects of oxytocin. In an attempt to resolve these conflicting results Liu et al. [9] have systematically re-evaluated the effects of intranasal oxytocin on placebo analgesia across sexes, dosages, and placebo effect induction paradigms in a large sample of subjects. They report no evidence for oxytocin enhancing either placebo or nocebo effects on analgesia.The study by Liu et al. [9] and other previous studies were powered sufficiently to detect effects of oxytocin on placebo analgesia, and while there are methodological differences between them, a parsimonious conclusion at this point is that oxytocin has no influence. However, an important consideration in this respect is that oxytocin rather than simply increasing trust in others may instead act to increase conformity to the opinions of only the most trusted experts [3,10]. Unfortunately, none of the studies conducted so far has quantified levels of trust by subjects in the experimenter(s), although interestingly in both studies reporting positive effects of oxytocin, experimenters in white coats identified as physicians/ medical experts gave the verbal suggestions. Thus, while subjects across the different analge...

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Oxytocin Enhancement of the Placebo Effect May Be a Novel Therapy for Working Memory Impairments

Cited by 22 publications

References 10 publications

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia

Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

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