Can a Diuretic Quell Refractory Hallucinations in Schizophrenia?

By David Levine

NEW YORK—Bumetanide, a strong diuretic, might reduce treatment-resistant hallucinations in patients with schizophrenia, although it does not appear to have other effects on the disease, two small trials from Iran suggest.

"Our results showed that two months of bumetanide treatment strikingly reduced hallucination score of schizophrenic patients," write Reza Rahmanzadeh, a medical student at Iran University of Medical Sciences in Tehran, and colleagues in a letter to the editor published online December 9 in Schizophrenia Research.

But why would anyone use a diuretic to treat schizophrenia? According to the Iranian researchers, hallucinations have been linked to subcortical dopaminergic dysregulation, which, in turn, may be triggered by hippocampal overactivity.

There is some evidence that the level of cortical chloride transporters in the hippocampus may be altered in schizophrenia, which could increase neural activity by switching GABAergic function from inhibitory to excitatory, the team speculates. Bumetanide, a selective inhibitor of Na-K-Cl cotransporter 1, has been shown to restore inhibitory GABAergic function in disorders like epilepsy and autism. Possibly, it could dampen an overactive hippocampus, and thus hallucinations, in people with schizophrenia, the researchers hypothesize.

At first, they were disappointed. In a randomized, placebo-controlled study of 26 schizophrenia patients, bumetanide 1 mg twice daily had no effect on the Positive and Negative Syndrome Scale (PANSS) total score or subscores. Nor did it improve the Brief Psychiatric Rating Scale total score, as Rahmanzadeh and his colleagues noted in a letter to the editor of Psychiatry and Clinical Neurosciences, published online December 21.

But a case report from France (https://bit.ly/2jA9QIc) had hinted that long-term bumetanide therapy had curbed hallucinations in an adolescent with schizophrenia.

Because half the patients in the negative trial from Iran had not been suffering from hallucinations, the team decided to do another study, explained Dr. Mohammad Taghi Joghataei of Iran University of Medical Sciences, the senior author of both letters. This time they focused only on the P3 score of PANSS (hallucinatory behavior, ranging from 1=absent to 7=extreme), he told Reuters Health by email.

They enrolled 24 schizophrenia patients, each with a history of antipsychotic resistance and with auditory hallucinations rated 4 or higher on item P3. Again, half the group was randomly assigned to treatment with bumetanide 1 mg twice daily for two months, and the rest to placebo.

There was no effect at one month, but after two months the severity of hallucinations was significantly lower in the treatment group (p<0.001). The difference persisted after the one-month washout period.

"Interestingly, although all ten patients of bumetanide group had a P3 score higher than four at baseline, indicating at least a moderate hallucination, following a two-month treatment eight patients had a P3 score of 3 or lower (indicating a mild or less severe hallucination)," the researchers write in Schizophrenia Research. (This study was published before the negative study, although it was done a year later, Dr. Joghataei explained. He also noted that his team used the same trial registration number for the two studies.)

The editor-in-chief of Schizophrenia Research, Dr. Matcheri Keshavan, said he did not find the two studies to be at odds.

"I am of the view that schizophrenia being such a heterogeneous entity, it is not at all surprising that a drug that may have no effect on global measures in the general population of schizophrenia, could have different effects on a treatment-resistant population, and may have distinct effects of different symptoms," said Dr. Keshavan, also a professor of psychiatry at Harvard Medical School in Boston.

"Indeed, there is some evidence recently that treatment-responsive vs. treatment-resistant schizophrenia may have different pathophysiological mechanisms," he told Reuters Health by email.

The U.S. Food and Drug Administration requires a boxed warning for bumetanide products, noting that "careful medical supervision" and an individually adjusted dosage schedule are necessary because the drug is a potent diuretic that can lead to "profound diuresis with water and electrolyte depletion" when used in excess. The agency also warns that toxic epidermal necrolysis has been reported in association with bumetanide use.

In one of their letters, the Iranian researchers say they found "no serious side-effects," while in the other they report "no considerable adverse effects."

Dr. David J. Greenblatt, professor of integrative physiology and pathobiology at the Sackler School of Graduate Biomedical Sciences at Tufts University in Boston, told Reuters Health he had never heard of anyone being treated with a diuretic for schizophrenia.

He expressed concern about bumetanide's powerful diuretic effects, and stressed that the studies "were published as letters to the editor, which are not subject to the peer-review standard of a published journal article."

So should doctors try bumetanide if antipsychotics fail to control their patients' hallucinations? Dr. Joghataei, who also chairs the Iranian Neuroscience Society, said it may be too soon to recommend this use in routine clinical practice.

"Actually, we still need more confirmation from larger trials," he said, adding that his team had already begun one such study and expects to publish the results next year.

SOURCE: https://bit.ly/2hQRxAb

Schizophr Res 2016.

https://bit.ly/2iRWipO

Psychiatry Clin Neurosci 2016.

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