Pam Harrison

September 02, 2015

AMSTERDAM — Two small studies failed to detect any functional improvement from the use of intranasal oxytocin (multiple brands) in patients with schizophrenia, even when coupled with social skills training, research presented here indicates.

"The hypothesis was that oxytocin would increase understanding of emotions, empathy, and facial expression and that the combination of oxytocin and social skills training would bring the highest level of improvement," Mark Weiser, MD, chairman of psychiatry, Tel Aviv University, Israel, told delegates.

"But the bottom line was in our hands ― in these patients, oxytocin was not efficacious in improving social function in schizophrenia."

"We had rigorous inclusion criteria around enduring primary negative symptoms," said Deanna Kelly, PharmD, professor of psychiatry, University of Maryland School of Medicine, in Baltimore, "and we saw no effect of oxytocin on negative symptoms from baseline to study end point 6 weeks later either."

Both studies were presented here during the 28th European College of Neuropsychopharmacology (ECNP) Congress.

Intranasal Oxytocin

The Israeli study was carried out in 48 patients with schizophrenia in a 2-by-2 factorial study design.

Half of the patients received intransal oxytocin, at a dose of 24 international units (IU) three times a day, or placebo. Patients were separated into two groups: those who received social skills training, and those who received supportive psychotherapy (controls).

At enrollment, patients were not acutely psychotic; their mean Positive and Negative Syndrome Scale (PANSS) total score was approximately 70.

The mean baseline PANSS positive score was approximately 13 for both groups; the mean baseline PANSS negative score was approximately 21 for both groups.

All patients had significant impairment in social abilities, Dr Weiser pointed out.

The primary outcome measure was a structured assessment of videotaped interviews with blinded raters who assessed interactions, focusing on patients' gaze, vocalization, affect, body tone, and other nonverbal signals.

"None of the measures came through as significant, controlling for baseline values," Dr Weiser reported.

There was also no significant improvement from baseline to study end point in any of the PANSS scales that were assessed or in any of a number of different emotional battery tasks.

In a post hoc analysis in which investigators looked at the effect of oxytocin on individual items used to rate the patient-rated video interaction, they did see an effect size of 0.54 on negative affect.

"While not statistically significant," Dr Weiser observed, "an effect size of 0.54 is actually quite large."

They also saw a smaller effect size of 0.44 on decreased tension in patients treated with intranasal oxytocin compared with control patients.

However, a comparison of patients who received nine sessions of social skills training vs those who received supportive psychotherapy revealed no significant differences in PANSS scores at study end point.

"Oxytocin helps social behaviors in autism, which is similar to schizophrenia in that it has severe social deficits, and some investigators have found positive results with oxytocin on certain symptom domains in schizophrenia, so it was a good idea to test oxytocin in this patient population," Dr Weiser said.

"But since, overall, this was a negative study, we suggest meta-analyzing the data available from randomized controlled trials before performing new studies of oxytocin in schizophrenia."

Significant Unmet Need

Dr Kelly pointed out that negative symptoms and cognitive impairment represent significant unmet needs in patients with schizophrenia, and these symptoms often run together.

"Both of them are related to functional outcomes, even moreso than positive symptoms," she added. "But we don't know if they represent distinct underlying pathways, so it's important to see if we can separate out these pathways."

To this end, Dr Kelly and colleagues tested the effect of intranasal oxytocin, at a dose of 24 IU twice a day, on social affiliation and negative symptoms and the effect of galantamin (Razadyne, Janssen Pharmaceuticals Inc) 12 mg twice a day on cognitive impairment in a 6-week double-blind placebo-controlled trial.

The primary negative symptom outcome was the Scale for the Assessment of Negative Symptoms (SANS) total score at 0, 2, 4, and 6 weeks.

For cognition, investigators used the MATRICS Consensus Cognitive Battery (MCCB) composite score, looking specifically at the effect of galantamine vs placebo on attention and memory.

A total of 20 patients with primary persistent negative symptoms were assigned to receive galantamine, another 16 received oxytocin, and 20 received placebo and served control participants.

"We had a lot of negative findings as well," Dr Kelly said.

With an SANS total score at baseline of 35, the SANS total score at study end point ranged from 31 to 35 in the three treatment groups, "so there was no effect of oxytocin on negative symptoms," Dr Kelly confirmed.

Neither was there any significant difference between the patients who received galantamine and the patients who received placebo on the MCCB composite score, she added.

Other clinical assessments included the Brief Psychiatric Rating Scale (BPRS) positive symptom item score and Calgary Depression Rating Scale total score.

"Patients assigned to galantamine tended to have larger reductions in the BPRS total score from baseline than participants assigned to placebo (effect size, 0.41; P = .014)," Dr Kelly noted.

"But after adjusting for baseline scores, neither the galantamine-placebo difference (effect size, 0.09) nor the oxytocin-placebo difference (effect size, 0.15) was significant."

Signals for Efficacy?

Asked by Medscape Medical News whether these two studies signal an end to oxytocin research into schizophrenia, Dr Kelly did not feel that they would because there have been other studies that did show some efficacy of oxytocin in schizophrenia.

"We need to do a better job at identifying patients we need to treat and what doses we need to use and make sure we are getting the drug into the brain, and then we have to use oxytocin in combination with some kind of psychosocial intervention to optimize its effect," Dr Kelly said.

Dr Kelly also felt that the dose both she and Dr Weiser used in their studies — 24 IU, either twice or three times a day — may be inadequate, and dosing studies are needed to establish whether higher doses might be more effective. The Food and Drug Administration has only approved the use of 24 IU intranasal oxytocin, which is why the researchers had to use that particular dose.

Currently, a joint study is under way at the University of Maryland and at universities in California in which oxytocin is being used in combination with cognitive-behavioral therapy and social skills training. In that study, patients will be treated for a much longer period.

"In the next few years, we will see findings come out of long-term studies that include social skills learning," Dr Kelly predicted.

"And if oxytocin doesn't work in these trials, then I'd have to say it's dead in the water, but certainly if patients could improve their social skills, they might have better functioning."

Not an End to Research

Commenting on the two studies, Filippo Drago, MD, PhD, University of Catania Medical School, in Italy, told Medscape Medical News that he agrees with Dr Kelly that these two studies should not bring research into the use of oxytocin in schizophrenia to an end.

"There are a number of possible explanations for these disappointing data," Dr Drago said.

First, both studies may have been too short in duration to detect any difference oxytocin might have made with longer-term use. "I think they could possibly increase the dose of oxytocin and improve the effectiveness of the treatment as well," Dr Drago added.

He also felt that the videotaped, rater-reviewed interviews that were used as an assessment tool in the Israeli study may not have been the right way to assess outcomes.

"I strongly believe that oxytocin can work in patients with schizophrenia because it works in other conditions where there is lack of empathy and social withdrawal to improve social interaction," Dr Drago reaffirmed.

"So I think this is something that still needs to be assessed in schizophrenia, but in a better way, and I am quite convinced that some other study in the future will show a different type of result."

Dr Weiser, Dr Kelly, and Dr Drago have disclosed no relevant financial relationships.

28th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts S13.03 and S.13.04. Presented August 31, 2015.

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