A Novel Target in Schizophrenia?

AUT00206, a novel compound that targets potassium channels in brain interneurons, not only improves gamma oscillations in patients with schizophrenia, it also improves their symptoms, new randomized trial data suggest.

In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206 compared with placebo increased the power of gamma oscillations, which were in turn associated with positive symptom scores.

The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.

In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told Medscape Medical News that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.

Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Large said.

The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.

“Opportunity to Intervene”

Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades “and the pathology of that stage is then different.”

For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Large.

In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power — and reduced power and “phase locking” to cyclical stimuli — the researchers note.

Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.

Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.

To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18 to 50 years.

Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.

At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.

Positive Associations

Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli, but not in phase locking.

There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).

Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).

While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.

They add that a larger study is now needed to confirm their findings and to “explore efficacy vs clinical symptoms.”

However, Large noted that participants in their next study will have fragile X syndrome.

He added the reason for this is “not because we’ve given up on schizophrenia — we feel that schizophrenia is a massive opportunity.”

Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Large said.

In contrast, fragile X is “genetically homogeneous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”

Preliminary goal Worth Pursuing?

Commenting on the study for Medscape Medical News, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, Massachusetts, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”

Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said McNally, who was not involved with the research.

He added that the “idea of ​​targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”

The study was funded by Autifony Therapeutics, of which Large is an employee.

SIRS 2022. Abstract T168. Presented April 7, 2022.

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