Nature Looks Back, and Ahead, at Schizophrenia

23 November 2010. Schizophrenia goes into the scanner in the November 11 issue of Nature. A series of thought pieces and news articles cover a large part of the terrain that is the schizophrenia universe, from genomics to stigma. The tone of the series alternates between cautious and hopeful. The caution comes from the reality that, "We don’t even understand schizophrenia at the biological level," as Thomas Laughren, the FDA’s director of psychiatric drugs, notes in a news feature by Nature writer Alison Abbott. The article also points out that the recent history of clinical schizophrenia research is, in the end result, not much different from that of the previous century: much hope for new ideas that have not panned out (see SRF related news story; SRF news story). One difference, however, is that the newer research is built on a greater understanding of how the brain works, and this, along with some new data, methods, and collaboratives in schizophrenia research, is what lies behind the optimism evident in some of the pieces.

News and commentary
The issue leads with features from Nature writers David Dobbs and Alison Abbott. Dobbs discusses how the disorder seems to strike during adolescence, but also explores the work of David Lewis, who has taken a rigorous approach to a circumscribed topic—the basic neurobiology of cortical microcircuits and evidence that it is perturbed in schizophrenia. Abbott traces the history of drug development in schizophrenia, and notes that the current state is not a promising one, with several companies recently pulling out of psychiatric research altogether. The one hopeful ember in the ashes is an effort put together by the pharmaceutical company H Lundbeck and the Institute of Psychiatry in London, which will pool previously proprietary data from different drug makers and allow industry and academic scientists to comb them for something that could spark new research.

In the commentary section, researcher Norman Sartorius, now president of the Association for the Improvement of Mental Health Programmes, Geneva, Switzerland, describes the continuing stigma associated with schizophrenia. He cites research showing that three-quarters of people with schizophrenia conceal their diagnosis, and argues that the biggest problem with anti-stigma campaigns is that they tend to be too short: if they last less than a year, he writes, they tend not to have a sustained effect, and thus they leave those who did the work feeling let down at the end.

Noting the recent evidence for the effectiveness of cognitive behavioral therapy for schizophrenia, Til Wykes of the Institute of Psychiatry, London, contrasts this with the miniscule amount of research funding the method receives. The remedy for this, she suggests, is for researchers in the area to buttress the experimental evidence. "It is time to develop models of how the training works, analyze how basic cognitive improvements help patients, and discover how best to implement the therapy and to whom it should be offered. DSM diagnoses are discrete entities." Wykes writes.

In the books section, Roy Richard Grinker, an anthropologist at George Washington University, Washington, DC, takes a historical look at the Diagnostic and Statistical Manual (DSM), particularly its treatment of schizophrenia. He notes that there is a trend toward returning to the earliest formulation of the manual—begun as a project by the U.S. Surgeon General to diagnose World War II veterans—wherein there was more emphasis on identifying individual symptoms, many of which are shared by different disorders, than on providing a false sense that diagnoses discrete entities.

Perspectives
In the first of three longer Perspectives articles, Tom Insel, director of the U.S. National Institute of Mental Health, Bethesda, Maryland, gives a synopsis of just about everything we know about schizophrenia, and then focuses on the hypothesis of neurodevelopmental origins. Viewing schizophrenia through a neurodevelopmental prism, Insel describes the interventions that one can imagine someday making at each stage of life, though he notes that lack of diagnostic specificity of early symptoms will likely complicate any attempts at early treatment. He does venture to predict that 20 years from now, some avenues of prevention might lead to lower rates of schizophrenia. He also has hopes for strategies to address cognitive deficits and for better, more integrated care of patients. Finally, he predicts that increased knowledge of the genetic and biological bases of the "schizophrenias" might allow us to lay that term, and its attendant stigma, to rest.

Andreas Meyer-Lindenberg of the University of Heidelberg at Mannheim, Germany, picks up where Insel leaves off, expanding on what we know from structural and functional imaging of schizophrenia, both of the apparent structural pathology and connectivity disturbances between brain regions, as well as insights into acute psychosis. He goes into detail on the promise of looking for disease-associated genetic variation on brain function during various cognitive tasks. Meyer-Lindenberg also discusses the possible synaptic, local cortical circuit, and long-range axonal connections that might underlie the observed functional imaging alterations in schizophrenia.

Jim van Os and colleagues at Maastricht University Medical Centre, the Netherlands, and at the Institute of Psychiatry in London, review the varying levels of evidence for environmental factors asserted to raise the risk for schizophrenia, and also explore the questions of what cognitive processes and biological systems might channel these exposures into the psychopathology that is deemed schizophrenia. Finally, they enter the more complicated territory of gene-environment interactions.—Hakon Heimer.

References:
Abbott A. Schizophrenia: The drug deadlock. Nature. 2010 Nov 11;468(7321):158-9. Abstract

Dobbs D. Schizophrenia: The making of a troubled mind. Nature. 2010 Nov 11;468(7321):154-6. Abstract

Grinker RR. Nature. In retrospect: The five lives of the psychiatry manual. 2010 Nov 11;468(7321):168-70. Abstract

Insel TR. Rethinking schizophrenia. Nature. 2010 Nov 11;468(7321):187-93. Abstract

Meyer-Lindenberg A. From maps to mechanisms through neuroimaging of schizophrenia.Nature. 2010 Nov 11;468(7321):194-202. Abstract

van Os J, Kenis G, Rutten BP. The environment and schizophrenia. Nature. 2010 Nov 11;468(7321):203-12. Abstract

Sartorius N. Short-lived campaigns are not enough. Nature. 2010 Nov 11;468(7321):163-5. No abstract available. Abstract

Wykes T. Cognitive remediation therapy needs funding. Nature. 2010 Nov 11;468(7321):165-6. Abstract

This paper is further evidence of an important and laudable new trend in schizophrenia psychopharmacology: namely the development and test of compounds on the basis of their relationship to circuit abnormalities, evidence derived from postmortem, genetic, and animal model studies. The authors based their choice of MK-0777 for test in schizophrenia on evidence for decreased cortical GABA neurotransmission onto pyramidal neurons at receptors having the α2 subunit, and other evidence pointing to the GABA-pyramidal neuron interaction as important in cognition and in generation of γ band oscillations. In this add-on, double-blind placebo study, the Ns were underpowered and more subjects need to be studied to be certain about clinical effects. However, one test, the Preparing to Overcome Prepotency Test (POP), had significant improvements in response latency and showed concomitant improvement in increased frontal γ band activity induced during the task, although not meeting the criterion for statistical significance. POP requires subjects either to “go with the flow” (indicated by a green light) and respond in the same direction as an arrow, or when cued by a red light to “go upstream” and point in the opposite direction, a test previously used in the Cho et al. 2006 PNAS paper and found to be accompanied by increased induced γ band oscillations.

γ band activity has justifiably attracted considerable attention, since there is mounting evidence of its relevance to human cognition as well as to basic neuroscience studies of neuronal assembly communication. Its important basis in the GABA cortical neuronal interaction with pyramidal cells makes it especially fascinating in schizophrenia. However, an important caution light was recently flashed by Yuval-Greenberg et al. in an article in Neuron (2008) in which they presented strong evidence that apparent increases or decreases in the “induced γ band oscillations” (those not temporally linked to a response or stimulus) could be the result of the eye muscle activation associated with small saccadic eye movements, “a saccadic spike potential” that could be confused with γ band oscillations. The Yuval-Greenberg article appeared too late for the authors to discuss in the present paper, but its implications for future work using induced γ are important. For studies of induced γ, we all will have to begin using eye movement measures sensitive to mini-saccades. Those of us who measure γ phase-locked to measureable events, such as sensory stimuli or responses, appear to be off the hook since we condition on known events, unlike conditions where induced γ is measured.

References:

Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83. Abstract

Yuval-Greenberg S, Tomer O, Keren AS, Nelken I, Deouell LY. Transient induced gamma-band response in EEG as a manifestation of miniature saccades. Neuron. 2008 May 8;58(3):429-41. Abstract

View all comments by Robert McCarley

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Paul Shepard
Submitted 23 April 2009
Posted 26 April 2009

When the 17 sites with high placebo responders were removed from the analysis, were only participants randomized to placebo removed or were all subjects who were recruited at these sites removed?

View all comments by Paul Shepard

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  C. Anthony Altar
Submitted 28 April 2009
Posted 2 May 2009

Reply to P. Shepard
At ICOSR, Dr. Kinon presented the effects on PANSS positive values over 4 weeks for the placebo group, the groups receiving various LY2140023 doses, and those receiving olanzepine, but "without the 17 sites." I am reasonably sure, but not 100% positive, that this excluded all data from those sites, not just the placebo responders. Anything less would have introduced an unacceptable bias, even for a post-hoc analysis.

View all comments by C. Anthony Altar

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Ralph Hoffman
Submitted 19 May 2009
Posted 20 May 2009

These placebo results are certainly irksome, but may be important in positive ways. I am thinking of two hypotheses to account for these results. First, perhaps second-generation antipsychotic drugs (that are now more widely in use than ever) have more sustained therapeutic effects after discontinuation, so when patients are taken off their prescribed drugs to participate in these trials, their vulnerability to symptomatic worsening is less.

Of course, this would not explain the greater improvements in placebo groups. But perhaps with growing expectations regarding patient safety and support during randomized clinical trials overall, participants are getting more contact with research staff, which may have non-specific positive effects. We have, for instance, solid data indicating that significant social isolation is a trigger for psychotic symptoms independent of neuropsychological impairment in vulnerable individuals (unpublished data). The combination of reduced social isolation, increased staff support, plus (perhaps) sustained protective effects of second-generation drugs might account for emergence of greater positive placebo response.

View all comments by Ralph Hoffman

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