EXPERT ANALYSIS AT THE ECNP CONGRESS

AMSTERDAM (FRONTLINE MEDICAL NEWS) – For decades, researchers have studied whether oxytocin has the potential to have a therapeutic effect in schizophrenia. Recently, however, the lack of consistently positive findings has caused some to wonder whether the hormone’s value as a schizophrenia treatment is at a dead end.

“There are plenty of good reasons to study this,” said Dr. Mark Weiser , chair of the psychiatry department at Tel Aviv University, in an interview conducted at the annual congress of the European College of Neuropsychopharmacology. “It looks really promising from the nonclinical data.”

One recent study found that patients with schizophrenia tend to have lower plasma levels of the hormone but more positive symptoms of the disease than do controls. People on the autism spectrum who have resulting social deficits, similar to those in schizophrenia, also have been shown to have lower plasma levels of oxytocin ( Biol Psychiatry. 2007 Feb 15;61:498-503 ); ( Proc Natl Acad Sci U S A. 2010 Mar 2;107[9]:4389-94. ); and ( Biol Psychiatry. 2010 Apr 1;67[7]:692-4. ).

A study published earlier this year showed that while oxytocin pathway genes were not implicated in a person’s susceptibility to psychotic disorders, variations in the genes “might play a role in the development of impaired social behavior” ( Front Hum Neurosci. 2015 Jan 23;9:9 ). Still, the absence of replicable positive studies and the increasing number of investigations with negative results, such as the randomized, controlled trial conducted by Dr. Weiser and his colleagues, has led Dr. Weiser to conclude that despite intimations of promise over the years, it’s time to just move on.

“There is a reasonable amount of clinical data raising questions about whether it’s worth spending time and effort on doing further clinical trials [on oxytocin in schizophrenia],” Dr. Weiser said. “Even when you look at the so-called positive findings and go into the data, they don’t really come out to be positive.”

He cited a recent meta-analysis that concluded oxytocin’s effect on cognition was “too diverse for meta-analyses, and inspection of these data showed no consistent benefit” ( Schizophr Res. 2015 Apr 23. pii: S0920-9964[15]00174-7. ).

Dr. Weiser began his own inquiry under the premise that the “feel-good” hormone implicated in a person’s experience of love and intimacy would help those with schizophrenia better read and understand the emotional cues of others, fostering better social functioning as a result.

Previous studies have shown that oxytocin in people with schizophrenia mitigate their positive and negative symptoms, and the hormone has been associated with increased levels of trust ( Depress Anxiety. 2012 Nov;29[11]: 924-30 ); ( Physiol Behav. 2011 Feb 1;102[2]:221-4. ).

But in Dr. Weiser’s study, only nonsignificant differences were found in social functioning between those given placebo, and either supportive therapy or social skills training and those given intranasal oxytocin and one of the two talk therapies.

“My data do not support developing this,” Dr. Weiser said in the interview. There is “perhaps” promise, he said for those who’d like to spend the time and effort conducting meta-analyses of individual patient data from a range of studies and doing comparative analyses. But the time necessary to do so, plus the theoretical issues to clarify, such as whether it would be better to separate patients with well-established schizophrenia from those with first-episode or to evaluate them together, or what the primary outcome measures should be, make it unlikely such an analysis will take place. “It’s what should be done,” but, he said, “Given the negative findings, no one is going to fund it.”

Yet some experts – such as Inga D. Neumann, Ph.D. , chair of behavioral and molecular neurobiology at the University of Regensburg (Germany) – argue that the therapeutic promise of oxytocin in schizophrenia is there. But they say the studies to date have not been well designed.

According to Dr. Neumann, the duration of treatment and the levels of synthetic oxytocin used in human studies interfere with the endogenous oxytocin system. In an interview at the ECNP meeting, Dr. Neumann said the typical human study uses more oxytocin “than the body’s entire pituitary content and is supplied in a single shot twice daily over 5 or 6 weeks.” Animal studies have shown that such intense and chronic treatment leads to the decrease of oxytocin receptors in the brain and overall impairment of the oxytocin system. “The down-regulation of the receptors is important to consider” but often isn’t, she said.

The level of damage to the endogenous system incurred, and whether it is permanent in these bench studies remain unknown. But levels of oxytocin receptors in the limbic regions of the brain are still suppressed at least 3 weeks after oxytocin treatments are stopped. “These are only in animal studies,” Dr. Neumann said. “What we could do in humans is to test their oxytocin systems right before treatment, right after it, and then, say, half a year later to see if there are changes in the system.”

Dr. Neumann believes clinical studies also should first determine what a high level of oxytocin looks like in healthy people whose oxytocin systems have been stimulated vs. what constitutes a high level in those whose systems are impaired, such in those with schizophrenia. In her work with animals, Dr. Neumann said she has found that different kinds of stimulation, whether it be exercise, sex, or stress, lead to different levels of oxytocin released into the blood stream. These kinds of data from humans would help determine the right amount of the hormone necessary to establish a positive treatment effect. “This should be done more in laboratories, not just the taking of basal levels. Basal levels mean nothing.”

Deanna L. Kelly, Pharm.D. , professor of psychiatry and the director of the treatment research program at the University of Maryland, Baltimore, also wonders about trial designs, albeit her more pressing concerns are how the study drug is administered and in what setting.

“I think it’s important for us as a field to make sure we’re delivering [oxytocin] appropriately,” Dr. Kelly said during a presentation at the meeting. She noted her theory that, of the single-dose challenge studies in schizophrenia that have shown an effect on social cognition, most were likely conducted under tight supervision to ensure the medication was “delivered properly.”

Dr. Kelly presented her own negative data from a study of 56 people, mostly men in their mid- to late 40s with schizophrenia or schizoaffective disorder, selected for their enduring negative symptoms. Participants were treated either in an in- or outpatient setting based on their normal treatment regimen and were randomly assigned to receive either placebo, oxytocin, or the acetylcholinesterase inhibitor galantamine.

Oxytocin, which was administered intranasally at 24 IU twice daily, was chosen for its effect on negative symptoms in schizophrenia. Galantamine – often used to treat impaired cognition in Alzheimer’s disease – was dosed orally at 12 mg twice daily and was intended to address cognitive deficits. After a 4-week lead-in phase and 6 weeks of double-blind treatment, neither of the study drugs was found superior to placebo when it came to improving either negative symptoms or cognitive processes.

Some differences were found between those in the in- and outpatient settings, although they were not significant. However, in a previous study, Dr. Kelly conducted with her colleagues, patients treated with intranasal oxytocin in the inpatient setting showed significant improvement vs. controls treated in the inpatient setting. However, they did not find an overall negative symptom effect, and no difference was found among those treated as outpatients ( Schizophr Res. 2013 Apr;145[0]:110-5 ).

“It could be that these patients are more closely watched by the nursing staff, and they’re getting the six sprays twice daily into the nose, whereas the outpatients might not be spraying it correctly … [so that] it gets into the brain,” Dr. Kelly said.

For his part, Dr. Weiser said his study might have been too short in duration with too few subjects who already were too far into their disease state. The 48 people in his 3-week study were typically male, 37 years old, and with an average age of disease onset of about 23 years. Positive and Negative Syndrome Scale (PANSS) scores were about 69 for the study group and 66 for the placebo group.

“Perhaps patients with more severe PANSS scores might show more improvement,” Dr. Weiser said in his presentation.

Regardless, unless a genetic breakthrough occurs that helps identify subgroups of people in whom oxytocin treatments would have a positive effect, Dr. Weiser thinks interest in oxytocin for schizophrenia should end.

“The field is thirsty for something that works for schizophrenia,” said Dr. Weiser in the interview. “But regardless of wonderful preclinical [findings] on oxytocin, if the bottom line is that when you give it to patients they don’t get better, then we need to figure out a different intervention to try.”

Not so fast, Dr. Neumann says. “We have to look more carefully. We can’t just take any patients, treat them with a huge, superficial dose and then think, ‘Oh, this will do something.’ We have to do better homework.”

Dr. Weiser’s and Dr. Kelly’s respective research is funded by the Stanley Medical Research Institute. Dr. Kelly is an adviser to Lundbeck and XOMA.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

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