A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. (2015)

A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. (2015)

Schizophrenia is associated with significant impairments in both higher and lower order social cognitive performance and these impairments contribute to poor social functioning. People with schizophrenia report poor social functioning to be one of their greatest unmet treatment needs. Recent studies have suggested the potential of oxytocin as such a treatment, but mixed results render it uncertain what aspects of social cognition are improved by oxytocin and, subsequently, how oxytocin might best be applied as a therapeutic. The aim of this study was to determine whether a single dose of oxytocin improved higher-order and lower-order social cognition performance for patients with schizophrenia across a well-established battery of social cognition tests. Twenty-one male patients received both a single dose of oxytocin nasal spray (24IU) and a placebo, two weeks apart in a randomized within-subjects placebo controlled design. Following each administration, participants completed the social cognition tasks, as well as a test of general neurocognition. Results revealed that oxytocin particularly enhanced performance on higher order social cognition tasks, with no effects on general neurocognition. Results for individual tasks showed most improvement on tests measuring appreciation of indirect hints and recognition of social faux pas. These results suggest that oxytocin, if combined to enhance social cognition learning, may be beneficial when targeted at higher order social cognition domains. This study also suggests that these higher order tasks, which assess social cognitive processing in a social communication context, may provide useful markers of response to oxytocin in schizophrenia

“…it would be useful to identify reliable markers of response to oxytocin in different clinical populations, to be able to predict who is receiving adequate dosing and likely to respond to treatment. Currently, there is little understanding as to what constitutes a reliable response to oxytocin, although some social cognitive tests, such as emotion recognition, have shown promise as potential markers in healthy populations.

Thus, the aim of this study was to further explore the different domains of social cognition in patients with schizophrenia following intranasal administration of oxytocin. We utilized well-known and established tests of higher order and lower order social cognition to further test recent claims that oxytocin has specific effects on higher order in comparison to lower order social cognition tasks.”

“Participants received either 24 international units (IU) of oxytocin or placebo (4 IU per spray, 3 sprays per nostril) at each administration (Phases A and B). Nasal sprays were labeled with sequential numbers and Phase A or Phase B; blocking was in sets of 6 (3 active and 3 placebo sprays) in a randomly generated order. All research staff members conducting assessments and participants were blind to treatment allocation and unaware of randomization.”

“The results of this study showed that when conducting overall analysis, a single dose of oxytocin nasal spray improves performance overall on higher order social cognition. This effect was significant on two individual higher order social cognition tests, the hinting task and the non-faux condition of the Faux Pas Recognition Task. In contrast, we found improvement on only one lower order social cognition test, accuracy for detecting vocal intonations of affect, and no effect on general neurocognition. There was no effect on general neurocognition. Oxytocin was well tolerated and patients seemed unable to detect the active dose in this cross-over design.”

“Our finding that oxytocin improves higher order social cognition is consistent with previous research that suggests oxytocin effects may be particularly powerful for these higher order processes in schizophrenia that require more complex social cognitive processing. It is of note that the individual tasks that showed most benefit of oxytocin, the Faux Pas Recognition Task and the Hinting Task, involve appreciation of the social nuances in communicative exchanges. Further research is now needed to link changes in brain function during higher order social cognition tasks of this type to further understand the neurobiological basis of the impact of oxytocin on social cognition in schizophrenia. This research also suggests that oxytocin may have particular potential to provide adjunctive therapeutic benefit for patients when combined specifically with higher-order social cognition training treatment approaches.”

“As information about symptomatology was only assessed at the initial assessment, in accord with common practice using the SAPS and SANS to assess symptom severity over a month, we were unable to assess whether oxytocin had any significant impact on symptoms at the time of drug administration. Although oxytocin has been shown to exhibit therapeutic effects on positive and negative symptoms, this was observed after a two-week treatment with oxytocin (Pedersen et al., 2011), and psychotic symptoms are unlikely to shift with a single dose. We have also previously reported on the current limitations of oxytocin nasal spray administration (Guastella et al., 2013) in single dose and longitudinal studies. Future research should endeavor to improve current delivery methods of oxytocin to central and peripheral sites of action (Quintana et al., 2015). We did not assess a range of individual difference factors that have been proposed to moderate response to oxytocin (Bartz et al., 2011). These include polydipsia in schizophrenia (Goldman et al., 2011). We also acknowledge that our findings can only be generalized to a male schizophrenia population, and that the effects of oxytocin on other social cognitive abilities (e.g. social perception, attributional style etc.) have yet to be explored. Finally, we note the small sample size and the appearance of trends on other measures of social cognition could suggest that with more power oxytocin may influence other measures of social cognition (e.g., Reading the Mind in the Eyes Test).

In conclusion, the overall results of this study confirm the use of oxytocin nasal spray to enhance higher order social cognition performance in schizophrenia. Future studies are now needed to link these performance changes to neurobiological mechanisms (e.g., imaging, Aoki et al., 2015; physiological, Quintana et al., 2013) markers, and to link these changes to more functional measures of social behavior. Results of this study would also support further evaluation of the impact of combining oxytocin with social cognition training procedures (e.g., Cacciotti-Saija et al., 2015) but with a greater focus on learning programs that might enhance specifically higher-order social cognitive processes.”

Another study is also interesting:

Differential Effects of Oxytocin on Agency and Communion for Anxiously and Avoidantly Attached Individuals

Oxytocin promotes prosocial behavior, especially in those individuals who are low in affiliation (e.g., avoidantly attached individuals), but can exacerbate interpersonal insecurities in those preoccupied with closeness (e.g., anxiously attached individuals). One explanation for these opposing observations is that oxytocin induces a communal, other-orientation. Becoming more other oriented should help those people who focus on the self to the exclusion of others, but could be detrimental to those who are other focused but have little sense of an agentic self. Using a within-subjects design, we administered intranasal oxytocin and placebo to 40 males and measured their agency (self-orientation) and communion (other-orientation). Oxytocin produced a slight increase in communion for the average participant; however, as predicted, avoidantly attached individuals were especially likely to perceive themselves as more communal (“kind,” “warm,” “gentle,” etc.) after receiving oxytocin than after receiving the placebo. There was no main effect of oxytocin on agency for the average participant; however, anxiously attached individuals showed a selective decrease in agency (“independent,” “self-confident,” etc.) following administration of oxytocin. These data help explain the complex social effects of oxytocin.

I’ve tried both buccal (200IU) and intranasal oxytocin at various doses (exceeding 24IU) and for periods of up to a couple of weeks in the past without noticing anything subjectively. I was more focused on improving negative affect, most particularly relating to loneliness and didn’t specifically try to evaluate improvements in social cognition. My social skills are pretty crappy and I have an autism spectrum condition which adds to my social impairments, so this is an area of research I hope to see evolving as fast as possible.

See also:

Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice. (2015)

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)


Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review


Sex differences in incidence, onset and course of schizophrenia suggest sex hormones play a protective role in the pathophysiology. Such a role is also proposed for oxytocin, another important regulator of reproduction function. Evidence on the efficacy of sex hormones and oxytocin in the treatment of schizophrenia is summarized.


Double-blind, placebo-controlled, randomized studies were included, examining augmentation with estrogens, selective estrogen receptor modulators (SERMs), testosterone, dehydroepiandrosterone (DHEA), pregnenolone, and oxytocin. Outcome measures were total symptom severity, positive and negative symptom subscores, and cognition. In meta-analyses, combined weighted effect sizes (Hedges’ g) per hormone were calculated.


Twenty-four studies were included, examining 1149 patients. Significant effects were found for estrogen action (k = 10), regarding total symptoms (Hedges’ g = 0.63, p = 0.001), positive (Hedges’ g = 0.42, p < 0.001), and negative symptoms (Hedges’ g = 0.35, p = 0.001). Subgroup analyses yielded significant results for estrogens in premenopausal women (k = 6) for total, positive, and negative symptoms, and for the SERM raloxifene in postmenopausal women (k = 3) for total and negative, but not positive symptoms. Testosterone augmentation in males (k = 1) was beneficial only for negative symptoms (Hedges’ g = 0.82, p = 0.027). No overall effects were found for DHEA (k = 4), pregnenolone (k = 4), and oxytocin (k = 6). Results for cognition (k = 12) were too diverse for meta-analyses, and inspection of these data showed no consistent benefit.


Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account. Future trials are needed to study long-term effects and effects on cognition.

Meta-analysis of estrogen action augmentation on total symptom severity. Studies above the red line used estrogens (in premenopausal women, and in one study in men), and studies below the red line used raloxifene (in postmenopausal women).

Meta-analysis of dehydroepiandrosterone (DHEA) augmentation on total symptom severity

Meta-analysis of pregnenolone augmentation on total symptom severity.

Meta-analysis of oxytocin augmentation on total symptom severity.

“Cognitive results were available for studies on estrogens, DHEA, pregnenolone, and oxytocin, with most studies describing several cognitive domains. Raw data per domain or composite scores were sparse, therefore meta-analyses could not be performed. Memory was most frequently tested (ten studies), significant effects were observed in three studies: raloxifene improved verbal learning more than placebo (Huerta-Ramos et al., 2014), pregnenolone improved visual memory (Ritsner et al., 2010), and verbal memory was higher in the oxytocin versus placebo group (Feifel et al., 2012). Executive function, attention, and processing speed were each examined in seven studies. Significant improvements relative to placebo were found in executive functioning after pregnenolone (Kreinin et al., 2014), in visual attention after DHEA (Ritsner et al., 2010) and pregnenolone (Kreinin et al., 2014), and in processing speed after pregnenolone (Ritsner et al., 2010). Five studies examined visuospatial, constructional, and movement skills; significant effects were found only for DHEA (Ritsner et al., 2006a and Ritsner et al., 2006b). One study examined verbal fluency and found a significant effect of raloxifene on phonemic fluency (Huerta-Ramos et al., 2014). Social cognition was examined in five studies; two studies on oxytocin found significant effects for second order false belief identification (Pedersen et al., 2011) and fear recognition and perspective taking (Gibson et al., 2014).”

“In conclusion, hormonal augmentation strategies are an interesting direction in the development of new treatment methods for schizophrenia. Especially estrogen augmentation in women warrants further investigation, as beneficial effects on total, positive and negative symptom severity were found. However, risks of side effects of estrogens, partially associated with longer duration use, should be taken into account. For this reason, SERMs may serve as a favorable alternative for estrogens that is also appropriate for use in men. Testosterone could be effective in reducing negative symptom severity in men, but this finding needs replication. The precursors DHEA and pregnenolone do not seem to be of therapeutic value for schizophrenia, neither does oxytocin. Regarding cognition, some promising results were found for each of the studied hormones. Future research is needed to carefully examine the therapeutic effects of hormone augmentation, especially in the long term and effects on cognition, as new treatment strategies could emerge from which patients with schizophrenia may benefit.”

See also:

Neurosteroids as therapeutics

Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice. (2015)

An interesting article on designing an oxytocin analogue with improved properties:

Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice. (2015)

Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson’s disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

On  intranasal administration of oxytocin itself, the following are interesting articles:

Accumulating evidence demonstrates the important role of oxytocin (OT) in the modulation of social cognition and behavior. This has led many to suggest that the intranasal administration of OT may benefit psychiatric disorders characterized by social dysfunction, such as autism spectrum disorders and schizophrenia. Here, we review nasal anatomy and OT pathways to central and peripheral destinations, along with the impact of OT delivery to these destinations on social behavior and cognition. The primary goal of this review is to describe how these identified pathways may contribute to mechanisms of OT action on social cognition and behavior (that is, modulation of social information processing, anxiolytic effects, increases in approach-behaviors). We propose a two-level model involving three pathways to account for responses observed in both social cognition and behavior after intranasal OT administration and suggest avenues for future research to advance this research field.

Oxytocin improves mentalizing – Pronounced effects for individuals with attenuated ability to empathize. (2015)

The ability to predict the behavior of others based on their mental states is crucial for social functioning. Previous studies have provided evidence for the role of Oxytocin (OXT) in enhancing the ability to mentalize. It has also been demonstrated that the effect of OXT seems to strongly depend on socio-cognitive skills with more pronounced effects in individuals with lower socio-cognitive skills. Although recent studies indicate that mentalizing is related to empathy, no study has yet examined whether the effects of OXT on mentalizing depend on the ability to empathize. 71 male participants participated in a double-blind, between-subjects, placebo-controlled experiment. The Reading the Mind in the Eye Test (RMET) was used to investigate mentalizing abilities. We analyzed the effect of OXT on easy and difficult items of the RMET depending on differential empathy scores of the participants as assessed with the Empathy Quotient (EQ). Our results showed that OXT improves mentalizing for difficult but not for easy items. We generally observed increased mentalizing accuracy in participants with higher empathy scores. Importantly, however, whereas the performance in participants with higher empathy scores was comparable in both OXT and placebo condition, OXT specifically enhanced mentalizing accuracy in participants with lower empathy scores. Our findings suggest that OXT enhances mentalizing abilities. However, we also demonstrate that not all participants benefited from OXT application. It seems that the effects of OXT strongly depend on baseline social-cognitive skills such as empathy.

See also:

Oxytocin selectively facilitates learning with social feedback and increases activity and functional connectivity in emotional memory and reward processing regions.