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Negative findings on oxytocin in schizophrenia spur some to ‘move on’


 

EXPERT ANALYSIS AT THE ECNP CONGRESS

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AMSTERDAM – 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.”

Dr. Mark Weiser

Dr. Mark Weiser

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.

Dr. Inga Neumann

Dr. Inga Neumann

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.”

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