Schizophrenia is a severe mental illness that causes major functional impairment. Current pharmacologic treatments are inadequate, particularly for addressing negative and cognitive symptoms of the disorder. Oxytocin, a neuropeptide known to moderate social behaviors, has been investigated as a potential therapeutic for schizophrenia in recent years. Results have been decidedly mixed, leading to controversy regarding oxytocin's utility. In this review, we outline several considerations for interpreting the extant literature and propose a focused agenda for future work that builds on the most compelling findings regarding oxytocin effects in schizophrenia to date. Specifically, we examine underlying causes of heterogeneity in randomized clinical trials (RCTs) conducted thus far and highlight the complexity of the human oxytocin system. We then review evidence of oxytocin's effects on specific deficits in schizophrenia, arguing for further study using objective, precise outcome measures in order to determine whether oxytocin has the potential to improve functional impairment in schizophrenia.

Introduction

Mentalizing, the ability to infer other people's intentions and emotions, is commonly impaired in schizophrenia and may represent an endophenotype. The hypothalamic neuropeptide oxytocin has been shown to improve mentalizing in men with schizophrenia, but its effects in women remain unclear. Given sex differences in the clinical manifestations of schizophrenia and oxytocin system function, this is an important gap to address.

Methods

We tested the effects of a single-dose oxytocin challenge (40 IU) on mentalizing task performance among 26 women with schizophrenia and 38 healthy control women using a randomized, placebo-controlled, double-blind, crossover design. We aimed to replicate our prior study of oxytocin effects on mentalizing in men with schizophrenia, using the same oxytocin administration procedures and performance-based assessments. We used mixed-effects models and equivalence testing as well as Bayesian hierarchical models to examine oxytocin effects.

Results

In contrast to our previous finding in a male sample, oxytocin did not improve mentalizing in this sample of women with schizophrenia. Exploratory analyses showed that higher anti-dopaminergic medication dosage was associated with a decreased response to oxytocin, consistent with previous findings in men.

Conclusion

These findings provide preliminary evidence that exogenous oxytocin administration may have sex-specific effects on mentalizing in schizophrenia. Inclusion of women in future clinical studies with larger samples is critical, as oxytocin effects observed in men may not extend to women with the disorder.

Abnormal eye gaze is common in schizophrenia and linked to functional impairment. The hypothalamic neuropeptide oxytocin modulates visual attention to social stimuli, but its effects on eye gaze in schizophrenia are unknown. We examined visual scanning of faces in men with schizophrenia and neurotypical controls to quantify oxytocin effects on eye gaze. In a randomized, double-blind, crossover study, 33 men with schizophrenia and 39 matched controls received one dose of intranasal oxytocin (40 IU) and placebo on separate testing days. Participants viewed 20 color photographs of faces while their gaze patterns were recorded. We tested for differences in fixation time on the eyes between patients and controls as well as oxytocin effects using linear mixed-effects models. We also tested whether attachment style, symptom severity, and anti-dopaminergic medication dosage moderated oxytocin effects. In the placebo condition, patients showed reduced fixation time on the eyes compared to controls. Oxytocin was associated with an increase in fixation time among patients, but a decrease among controls. Higher attachment anxiety and greater symptom severity predicted increased fixation time on the eyes on oxytocin versus placebo. Anti-dopaminergic medication dosage and attachment avoidance did not impact response to oxytocin. Consistent with findings that oxytocin optimizes processing of social stimuli, intranasal oxytocin enhanced eye gaze in men with schizophrenia. Further work is needed to determine whether changes in eye gaze impact social cognition and functional outcomes. Both attachment anxiety and symptom severity predicted oxytocin response, highlighting the importance of examining potential moderators of oxytocin effects in future studies.

Growing evidence suggests that psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve symptoms of depression, leading to recent breakthrough status designation by the FDA and legalization for mental health treatment in some jurisdictions. Depression in bipolar disorder is associated with significant morbidity and has few effective treatments. However, there is little available scientific data on the risk of psilocybin use in people with bipolar disorder. Individuals with bipolar disorder have been excluded from modern clinical trials, out of understandable concerns of activating mania or worsening the illness course. As psilocybin becomes more available, people with these disorders will likely seek psilocybin treatment for depression and have likely already been doing so in unregulated settings. Our goal here is to summarize the known risks of psilocybin use (and similar substances) in bipolar disorder and to systematically evaluate examples of published case history data, in order to critically evaluate the relative risk of psilocybin as a treatment for bipolar depression. We found 17 cases suggesting that there is potential risk for activating a manic episode, thereby warranting caution. Nonetheless, the relative lack of systematic data or common case examples indicating risk appears to show that a cautious trial, using modern trial methods focusing on appropriate ‘set’ and ‘setting’, targeted at those lowest at risk for mania in the bipolar spectrum (e.g., bipolar 2 disorder), is very much needed, especially given the degree to which depression impacts this population.

Rationale

Treatments with the serotonergic psychedelic psilocybin are being investigated for multiple neuropsychiatric disorders. Because many patients with these disorders use selective serotonin reuptake inhibitors (SSRIs), understanding interactions between psilocybin and SSRIs is critical for evaluating the safety, efficacy, and scalability of psilocybin-based treatments. Current knowledge about these interactions is limited, as most clinical psilocybin research has prohibited concomittant SSRI use.

Objectives

We aimed to explore potential interactions between psilocybin and SSRIs by characterizing peoples' real-world experiences using psilocybin mushrooms and SSRIs together.

Methods

We conducted a systematic search of Reddit for posts describing psilocybin mushroom and SSRI coadministration. We identified 443 eligible posts and applied qualitative content analysis to each.

Results

8% of posts reported negative physical or psychological effects resulting from coadministration. These included 13 reports that may reflect serotonin toxicity, and 1 concerning for a psychotic/manic episode. 54% of posts described reduced intensity of the acute psilocybin experience, but 39% reported unchanged intensity with SSRI coadministration.

Conclusions

Psilocybin's interactions with SSRIs are likely complex and may depend on multiple factors. Prospective studies are needed to evaluate whether psilocybin treatments are reliably safe and effective in the setting of SSRI use.