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IPRN 2011: Putting Roadblocks on the Road to Psychosis

10 May 2011. Just before the opening reception for the 13th International Congress on Schizophrenia Research, the International Prodromal Research Network held a symposium to advance research on ways to help people at risk of developing psychosis. Tyrone Cannon, University of California, Los Angeles, quipped that the prodromal satellite meeting might be considered the prodrome to the big meeting, although the ensuing discussion certainly seemed healthy. Clearly, the network had come far since 2002, when Barbara Cornblatt, Zucker Hillside Hospital, Long Island, New York, gathered 30 people to talk about methodological issues in prodromal research. This year’s meeting, organized by IPRN co-directors Cornblatt and Cannon, attracted 130 participants.

The symposium began with talks on strategies for delaying the transition to psychosis, relieving symptoms, and improving functioning in at-risk people. After lunch, the focus turned to biological, clinical, and cognitive markers of psychosis risk and progression. With a nod of appreciation to IPRN co-directors Cornblatt and Cannon for their gracious welcome, SRF reports on the morning session here. Our coverage of the afternoon session will follow.

A pill for the prodrome
The first speaker, Stephen Marder, University of California, Los Angeles, discussed pharmacological ways to enhance and preserve cognition in prodromal patients. Since most clinical trials of drugs to improve cognition in schizophrenia have focused on patients with established disease, he had to extrapolate from trials in recent-onset patients. He said the results have been mixed, but studies of α7 nicotinic-receptor agonists and drugs that affect glutamate transmission, including glycine-reuptake inhibitors and D-serine, have produced some encouraging results (see SRF conference story).

Marder noted that cognitive losses occur during the prodrome, sometimes as early as first grade, and at least three research groups have found progressive brain changes that start prodromally and continue into the early years of illness. This hints that protecting the nervous system from harm in prodromal and early schizophrenia might lead to better cognition later on. In this regard, he and others in the TURNS (Treatment Units for Research on Neurocognition and Schizophrenia) consortium have studied the peptide AL-108 (davunetide, NAPVSIPQ, or NAP), which he said strengthens neural tubules.

In a randomized, double-blind trial, Marder and colleagues at seven sites explored the effects of a nasal spray containing AL-108 in patients with schizophrenia. For 12 weeks, subjects received either a placebo or one of two dosages of the peptide, in addition to their regular antipsychotic medication. The researchers found that neither the 5- nor the 30-milligram dose of AL-108 significantly enhanced performance on the MATRICS Consensus Cognitive Battery. The low dose did improve scores on the UCSD Performance-based Skills Assessment at six weeks, but at week 12, the results were no longer statistically significant.

The study included no prodromal subjects, but Marder said evidence that neuroprotective medication might work during the prodrome comes from a recent trial in which omega-3 fatty acids prevented conversions to psychosis during the study period. Noting that the typical subject in schizophrenia clinical trials has been ill for 20 years, Marder asked, “Are we studying the wrong people?” He reasoned that early deficits in prodromal patients might be more amenable to treatment than those that have persisted for decades.

What patients want
Despite the hunt for drugs to prevent psychosis, the next speaker, Jean Addington, had previously found that few patients at clinical high risk for psychosis want medication. In contrast, 90 to 95 percent are willing to accept psychological treatment. Addington, of the University of Calgary in Alberta, Canada, spoke about cognitive and other psychosocial interventions for clinical high-risk youth. She said that about 15 to 35 percent of these young people eventually develop psychosis; even before then, many experience impaired social functioning, comorbid mental illness, and, of course, cognitive deficits.

Most studies of psychosocial interventions in prodromal patients have focused on cognitive-behavioral therapy. CBT, which dovetails with the stress-vulnerability model of psychosis, teaches strategies for coping with environmental stressors. It helps patients understand their atypical perceptual experiences and addresses the social isolation of many of these patients. According to Addington, research shows that CBT curbs psychotic symptoms, related distress, and mood disorders. Earlier studies hint that it delays conversion to psychosis.

Addington presented recently published findings from the ADAPT (Access, Detection, and Psychological Treatments) study (Addington et al., 2011). This randomized, controlled trial tested whether CBT can quash budding psychosis or lessen presenting concerns in a clinical high-risk population. The 51 subjects, 15 to 30 years old, received up to 20 sessions of either CBT or supportive therapy for six months. The supportive therapy combined interactions with an empathic therapist and advice on how to manage crises.

By the end of treatment, three subjects in the supportive therapy group and none in the CBT group had developed psychosis, a statistically insignificant difference. Those who had received CBT gained faster relief from positive symptoms, but the other subjects caught up with them. Neither treatment improved negative symptoms or social functioning.

As for the disappointing results, Addington wondered whether they resulted from inadequate statistical power, too little CBT, or insufficient targeting of the therapy to patients’ needs. She concluded that the issue of which psychosocial interventions work best for which people during the prodrome has yet to be resolved.

Pluripotent clinical stages
The next presenter, Patrick McGorry, University of Melbourne, Parkville, Australia, talked about delivering the right interventions at the right time and in the right order. He noted that many people who develop “something resembling the clinical phenotype of psychosis” do not need care, while others seek help for sub-threshold psychotic symptoms, distress, and functional decline. McGorry said that those in the first group should be protected from intervention and possible iatrogenic harm, while those in the latter group should be able to obtain services when needed and not have to wait until they reach an arbitrary threshold. He advocated a stepped-care model that starts with simple, relatively benign interventions for early help-seekers.

To determine what might help vulnerable youngsters, McGorry presented new one-year follow-up data from a Melbourne study of ultra-high-risk individuals. This double-blind controlled trial evaluated whether certain interventions could prevent transition to psychosis, reduce symptoms, and improve functioning. It randomly assigned 115 young people at ultra-high risk of psychosis to risperidone plus CBT, placebo plus CBT, or placebo plus supportive therapy.

Even at baseline, subjects showed high levels of symptoms, mood disorders, other Axis I conditions, and functional impairment. None of the treatments outshone the others in reducing the likelihood of psychosis. Although symptoms and functioning improved over time, they did so similarly across groups. Since all the treatments performed about the same, he said, the results do not support using antipsychotic drugs, which carry risks, as the first treatment for this population.

Having found considerable comorbidity in at-risk patients, McGorry spoke of “pluripotent clinical stages,” characterized by increased risk not just for schizophrenia but other psychiatric disorders as well. He agrees with Ron Kessler’s emphasis on “primary prevention of secondary disorders,” an idea put into practice at Headspace. This enhanced primary-care program provides mental health services for young people in a non-stigmatizing environment, and McGorry’s founding of it contributed to him being named 2010 Australian of the Year.

Discussant David Miklowitz, University of California, Los Angeles, echoed McGorry’s admonition to think ”outside of our schizophrenia silo.” Having seen the bipolar field struggle with many of the same questions about early treatment, he cautioned, “We may be missing the boat by not looking at both populations at the same time.” In addition, he said that positive and negative symptoms may require different interventions.

Miklowitz stressed the need to remember that even psychosocial interventions might trigger adverse events, especially in vulnerable people. For instance, some conflicts may be better left underground, he warned. The morning ended with a lively discussion of the complexities and challenges faced by psychosis-prevention researchers.—Victoria L. Wilcox.

Comments on Related News


Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover