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SIRS 2016—Of Vitamin D, Critical Periods, and Clinical Trials

13 Apr 2016

April 14, 2016. In the first plenary talk on Tuesday, April 5, at the Schizophrenia International Research Society meeting in Florence, Italy, John McGrath of Queensland Brain Institute in Brisbane, Australia, deftly bridged the gap between epidemiology and neuroscience. McGrath first identified vitamin D as a risk factor for schizophrenia (McGrath et al., 2010), and he showed that the relationship between low levels of vitamin D at birth and risk for schizophrenia could be replicated in a larger sample. Delving into the actions of vitamin D, a steroid, he showed that it could induce a calcium signal in some but not all neurons. McGrath suggested that calcium signaling, which has also been highlighted by genetics studies, could shape brain development, and a dearth of vitamin D might delay brain maturation. This might be remedied in public health campaigns that screen babies for low vitamin D and then supplement as necessary.

Takao Hensch of Harvard University in Cambridge, Massachusetts, filled his plenary talk with the molecular mediators of critical periods—the time windows during which the brain is particularly open to being changed by experience. Using the visual cortex and its malleability by visual experience as the venue, Hensch described the central role that inhibitory neurons play in critical period timing, which he suggested is disrupted in the run-up to mental disorders. On the flipside, neuronal stability provides a way to consolidate changes wrought during critical periods. Therapeutically, finding ways to reopen critical periods may be helpful for brain injuries, or to boost effects of training.

Clinical trials update
An evening session devoted to some of the latest clinical trials of drugs for schizophrenia offered a smattering of good news. Though current antipsychotic drugs attenuate the hallucinations and delusions of psychosis, researchers have been stymied in finding something to treat the paralyzing lack of motivation and expression comprising schizophrenia's so-called negative symptoms. Wolfgang Fleischhacker of the Medical University of Innsbruck in Austria described a Phase 3 trial of cariprazine in people with predominantly negative symptoms. Cariprazine is unusual in its preferential but not selective activation of D3 dopamine receptors. The randomized, controlled study found that six months of cariprazine treatment decreased negative symptoms and increased social performance more so than risperidone did; importantly, positive symptoms did not worsen.

Patrick McGorry of Orygen Youth Health and the University of Melbourne in Australia presented results from the Neuro-ProE study, a 10-site, randomized, controlled study designed to replicate an earlier trial suggesting that omega-3 fatty acids (in fish oil capsules) could prevent transition to psychosis among young people deemed at high risk (Amminger et al., 2010). After six months of treatment with either fish oil or placebo, McGorry reported no difference in transition rates between the two in nearly 1,000 people, either at six or 12 months. This lack of replication is complicated by the fact that those on fish oil did not reliably take their capsules. Transition rates were also lower than in earlier studies (11 percent vs. 25 percent), suggesting that it may be necessary to follow participants for a longer time; this follow-up is currently underway.

Clinicians will often keep a patient on an antipsychotic for a month or two before deciding whether it is effective or not. According to a study presented by Stephen Heres of the Technical University of Munich in Germany, clinicians can make the call much earlier, in just two weeks. In a randomized, double-blind study, called the SWITCH trial, patients were given olanzapine or amisulpride for two weeks. If at two weeks they had gained a 25 percent improvement in their total PANNS score, they were maintained on that drug. If they didn't reach this level, they were either switched to the other drug or maintained on the same drug. Six weeks later, the switchers had reached the same rates of remission as the initial responders had; the non-switchers, however, only achieved a little over half that rate.

Kimberly Vanover of Intra-Cellular Therapies presented another round of positive results from a Phase 3 trial for its drug called ITI-007. The drug has multiple targets, including serotonin, dopamine, and glutamate systems, which are engaged in a step-like fashion as the dose is increased. Following a positive Phase 2 trial (Lieberman et al., 2015), the new in-patient study found that a daily 60-mg dose of ITI-007 induced a significant decrease in PANSS total score at day 28 compared to placebo, with good control of symptoms in as quickly as one week. They also documented improvements in illness severity, and personal and social performance. The drug was as safe and tolerable as placebo. Side effects included mild sedation and fatigue, which Vanover suggested might be mitigated by taking the drug at bedtime.

In the search for treatments for negative symptoms, repetitive transcranial magnetic stimulation (rTMS) has offered some hope, with meta-analyses finding moderate effects that exceed those of antipsychotic drugs. Alkomiet Hasan of Ludwig-Maximilians-Universitat in Munich, Germany, shared recently published work from a multicenter trial of rTMS over the dorsolateral prefrontal cortex (DLPFC) for negative symptoms (Wobrock et al., 2015). Taking eight years in all to complete, the trial randomly assigned 175 patients with predominately negative symptoms either into rTMS or sham stimulation groups. After three weeks of treatment sessions each workday, Hasan reported no difference between the rTMS and sham groups. He did, however, hold out a new thread of hope: Brain scanning revealed that when rTMS resulted in volume changes of hippocampal regions, the extent of this change correlated with negative symptom reductions. This suggests that measures of how well rTMS engages the relevant brain circuitry will be important in evaluating rTMS as a treatment.

Philip McGuire of King's College London rounded out the session with a trial of cannabidiol (CBD), the second-most abundant compound in cannabis. Animal and human studies have suggested CBD has some antipsychotic effects not mediated by D2 receptor blockade (Leweke et al., 2012), making it a possible add-on therapy to usual antipsychotics. The trial randomized 88 patients who responded to antipsychotic drugs but who remained symptomatic to take either placebo or CBD in addition to their usual antipsychotic. Six weeks later, the CBD group had greater improvements in their positive symptoms than those with placebo, and had twice as many subjects with at least a 20 percent change in total PANSS score. Because patients who use cannabis run a greater risk of relapse, McGuire suggested that replacing cannabis with CBD might avoid the psychosis-inducing effects of the predominant cannabinoid, tetrahydrocannabinol (THC).—Michele Solis.