Potassium channel modulators and schizophrenia: an overview of investigational drugs

ABSTRACT

Introduction

Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest.

Areas covered

This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer’s website.

Expert opinion

Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.

KEYWORDS:

• Schizophrenia
• psychopharmacology
• potassium channel modulators
• AUT00206
• gamma oscillations
• NMDA receptor
• glutamate

Article highlights

• Existing pharmacologic options for schizophrenia have limited efficacy in treating cognitive and negative symptoms.

• Potassium channels are found throughout the brain and help to modulate and regulate neurotransmitter release, including dopamine and glutamate.

• Potassium Kv3 channels are located on parvalbumin-positive (PV+) interneurons which generate gamma oscillations and are dysregulated in schizophrenia.

• AUT00206 is an investigational drug which modulates Kv3.1 and 3.2 ion channels and is hypothesized to normalize potassium channel functioning.

• In preliminary studies, AUT00206 decreased resting gamma power in patients with schizophrenia, and in a subset of patients with schizophrenia, also decreased dopamine synthesis capacity.

• AUT00206 did not improve performance on the monetary incentive delay (MID) task but did result in activation of the left associative striatum and a trend toward significance in the right associative striatum.

Declaration of interest

Justin Faden – Consultant BioXcel therapeutics, Noven pharmaceuticals. Meghan Musselman, Eric Lee, Eric Huynh, Rachana Kelshikar, Mohammed Malik have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.