29 March 2011. During the second day of talks at the NYAS meeting on Advancing Drug Discovery in Schizophrenia on 11 March 2011, researchers knuckled down to assess targets for treatment. Jeffrey Lieberman of Columbia University set the stage with an overview of current approaches, which include manipulations of neurotransmitter receptor function or intracellular signaling pathways. There would be no "magic bullet" that would treat all three symptom domains of schizophrenia, he said. Instead, he proposed that research should find adjunctive therapies to treat negative and cognitive symptoms, which likely stem from problems different from those underlying positive symptoms. Because antipsychotics already treat positive symptoms with some success, the challenge will be to find adjunctive therapies that won't undermine the benefits of other drugs.
Lieberman also noted that outcomes are better when psychosis is treated early with antipsychotics, and that early treatment may prevent brain changes that are associated with the worsening of symptoms and cognitive deterioration (Lieberman, 2006). He proposed that brain changes may precede changes in behavior, and that they may make good targets for treatment. In support of this idea, he cited a study that found abnormal fMRI signals in the hippocampus in individuals at risk for schizophrenia that predicted progression to psychosis (see SRF related news story).
Jeffrey Conn of Vanderbilt University described his work looking for ways to boost metabotropic glutamate receptor (mGluR) function—particularly that of mGluR5. Tightly associated with and spurring activity in NMDA receptors, mGluR5 provides a backdoor to normalizing NMDA function, which is hypothesized to be underactive in schizophrenia (see SRF hypothesis). Going after selective agonists for the mGluR5 receptor has been stymied by a highly conserved binding site across all metabotropic receptors. As an alternative, Conn has been developing positive allosteric modulators (PAMs) for mGluR5, which bind a different site than the agonist but still promote mGluR5 responses to endogenous glutamate. He described one in detail, a potent and selective mGluR5 PAM that nearly doubles activity of the receptor when it is bound by an agonist. The compound had antipsychotic-like effects in mice, reversing their amphetamine-induced hyperlocomotion and disruption in prepulse inhibition, and improved performance of mice in the Morris water maze, a test of spatial learning (Ayala et al., 2009). Before moving cousins of this particular PAM into the clinic, Conn emphasized the need to fully characterize them, because subtle changes to their structure can alter their mode of action.
Shifting from receptors to intracellular signaling pathways, Stephen Haggarty of Harvard University and the Broad Institute discussed inhibition of glycogen synthase kinase β (GSK3β) as a strategy for treating psychiatric illness. At a nexus of molecular pathways implicated in schizophrenia and bipolar disorder, GSK3β is an enzyme whose numerous interactions suggest it plays multiple roles in development and in the adult nervous system. It has come to the fore in schizophrenia research through studies that find it is suppressed by the mood stabilizer, lithium (see SRF related news story), by antipsychotics (see SRF related news story), and most recently, by DISC1 (see SZGene entry and Mao et al., 2009). Taking a cue from this theme of GSK3β inhibition, Haggarty described a novel compound that is a selective inhibitor of GSK3β in brain, and also had antimanic and antidepressant-like effects in mice (Pan et al., 2011).
Using small molecule microarray screens to probe the ability of 12,000 compounds to bind to DISC1 variants, Haggarty reaped 383 hits which either activated or attenuated GSK3β activity through DISC1. Stressing the need to characterize these compounds in human neurons to more accurately model how they act in the brain, he described his success in deriving neurons from induced pluripotent stem cells (iPSCs) developed from human skin cells, saying, "We can grow buckets of these." Applying a GSKβ inhibitor to these neurons increased activity in signaling molecules downstream from GSK3β, consistent with suppression of GSK3β.
…to clinical trials
Amanda Law of the National Institute of Mental Health covered a different part of the GSK3β signaling network: the PI3K/AKT pathway. Aberrations in this pathway are suspected in schizophrenia because genetic studies have pointed to variants in the neuregulin gene (see SZGene entry) and its receptor ErbB4 (see SZGene entry), which act upon the PI3K/AKT pathway. AKT, in turn, inhibits GSK3β. To probe the integrity of this pathway in disease, Law used human lymphoblastoid cell lines from controls and people with schizophrenia, saying, "They give you the genetic architecture of a real person."
She reported abnormal upregulation of an isoform of ErbB4, called CYT-1, and an isoform of PI3K called PI3KCD, in schizophrenia and in people homozygous for the risk allele for ErbB4. These upregulations are also found in postmortem brains from people with schizophrenia. Elevated levels of PI3KCD suppress AKT activity, which disinhibits GSK3β and ultimately attenuates neuregulin signaling. This means selective PI3KCD inhibitors may normalize activity in this pathway, and cancer research—which is interested in GSK3β because of its role in cell proliferation—has already come up with some. One that has been tested prevents amphetamine-induced hyperlocomotion in mice, without effects on cognition. PI3KCD inhibitors are in clinical trials already, and these results may establish a place for PI3KCD in the network of schizophrenia-related molecules.
Returning to the idea that underactive NMDA receptors may be at the heart of schizophrenia, Brian Campbell of Pfizer presented a way to suppress kynurenic acid levels in the brain, which are elevated in the CSF in schizophrenia. Kynurenic acid antagonizes NMDA receptors, and abnormally high levels may contribute to cognitive deficits found in schizophrenia. Campbell targeted the key enzyme that makes kynurenic acid in the brain, called kynurenine aminotransferase II (KAT II), with a compound that potently and selectively inhibits KAT II. This KAT II inhibitor reduced kynurenic acid levels by as much as 80 percent in rats and improved performance of rats and nonhuman primates in tasks measuring attention and working memory. It also rapidly reversed anhedonia, as measured by a decrease in sucrose consumption, that resulted from subjecting rats to chronic, mild stress. However, this KAT II inhibitor did not affect the usual models of psychosis-like behavior, like prepulse inhibition or amphetamine-induced hyperlocomotion. This suggests that KAT II inhibitors could work as an adjunctive to antipsychotics to treat cognitive and negative symptoms. Campbell said that the KAT II inhibitor did not interfere with the antipsychotic's ability to normalize psychosis-related measures, but that it was still unclear whether an antipsychotic would undermine the KAT II inhibitor's effect on cognitive measures.—Michele Solis.