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Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

11 January 2012. Elevated dopamine synthesis in the striatum predates the onset of psychosis, according to a study published in December in the American Journal of Psychiatry. Led by Oliver Howes of Kings College London, U.K., the study finds that, among individuals identified as at-risk for a mental disorder, those who later go on to develop psychosis had higher dopamine synthesis capacity in the striatum, as measured by positron emission tomography (PET), compared to those who did not.

The results support the idea that an overactive dopamine system precedes illness, as well as being associated with psychosis itself (see SRF Hypothesis). An inkling of this came from a previous study finding elevated dopamine synthesis in the at-risk group compared to healthy controls (see SRF related news story). The new study looks at these same data again, but with follow-up information in hand about who did and who did not transition to psychosis.

A biomarker that can predict whether someone with "attenuated" psychotic symptoms will develop schizophrenia is much sought after, as only about one-third of individuals with these sub-threshold symptoms develop a psychotic illness within two years (see SRF Live Discussion). One study, published online November 10 in the Schizophrenia Bulletin, proposes a combination of brain measures obtained from structural magnetic resonance imaging (MRI) that may discriminate between at-risk individuals who later go on to develop psychosis and those who do not. The other study, published online December 20 in Molecular Psychiatry, highlights decreased nervonic acid levels from blood samples as a possible predictor of future psychosis.

Dopamine in overdrive
In Howes’ study, the participants were 30 individuals identified as at ultra-high risk of psychosis and 29 matched controls. The researchers used PET scanning with [18F]6-fluoro-L-DOPA as a detectable substrate for the dopamine-making enzyme. This allowed them to measure the dopamine synthesis capacity in the striatum, a recipient of dopaminergic terminals that has shown dopamine dysregulation in psychosis. At least three years later, the researchers found that nine of the ultra-high-risk participants had developed psychosis and 15 had not; the remaining six who had developed schizotypal personality disorder were excluded from the main analysis.

Going back to the pre-psychosis PET scans, the researchers found that the psychosis transition group had a greater dopamine synthesis capacity in the striatum compared to healthy controls. Specifically, the mean uptake value for [18F]DOPA in the striatum was greater in the whole striatum (effect size = 1.18, as measured by Cohen’s d), and in the associative striatum (effect size = 1.24) in the psychosis transition group compared to controls. The associative striatum comprises much of the caudate nucleus and receives inputs from the dorsal lateral prefrontal cortex, a region also implicated in the at-risk state (Fusar-Poli et al., 2010).

The individual PET signals correlated with an individual’s prodromal symptoms in the group developing psychosis later. Greater dopamine synthesis capacity in the whole striatum was associated with more severe symptoms as assessed by the Comprehensive Assessment of At-Risk Mental States (r = 0.67, p = 0.049) and by the Positive and Negative Syndrome Scale (r = 0.71, p = 0.032).

The PET scans also revealed a difference between at-risk individuals, depending on whether they developed psychosis later. Though there was no difference in clinical symptoms at the time of scanning between these two groups, the psychosis transition group had elevated dopamine synthesis capacity in the striatum compared to the ones who did not. Comparison between the non-transition group and the controls did not reveal any differences.

Brain and blood
Could a snapshot of the brain foretell future development of psychosis? Nikolaos Koutsouleris of Ludwig-Maximilian-University in Munich, Germany, and colleagues are trying to do this by analyzing neuroanatomical features seen in structural MRI brain scans with a pattern classifier algorithm. Finding some success in a previous study (Koutsouleris et al., 2009), the researchers tested their classifier out on a second, independent population, drawn from the prospective FePsy study on predicting psychosis in at-risk individuals (Riecher-Rössler et al., 2007). Their algorithm discriminated between MRI scans from those who later developed psychosis and those from healthy controls, correctly identifying 93.8 percent of at-risk individuals who later developed psychosis and 90.9 percent of healthy controls. Among those at risk, the pattern classifier correctly identified 81.0 percent of those who later developed psychosis and 87.5 percent of those who did not.

Others are aiming for the ease of a blood test to predict psychosis. A new study from G. Paul Amminger of the University of Melbourne in Australia and colleagues reports decreased blood levels of nervonic acid in people clinically identified as at-risk for psychosis who subsequently developed psychosis within one year. Nervonic acid is an omega-9 fatty acid important for myelin-making. Abnormal levels of polyunsaturated fatty acids have been implicated in schizophrenia (Assies et al., 2001), and restoring them with dietary supplements may have some benefit (see SRF related news story). The new study examined the fatty acid composition in blood cell membranes—used here as a proxy for the state of neuronal membranes—and found a decreased nervonic acid level in the 11 individuals who converted to psychosis compared to the 30 who didn’t, with an effect size of 0.79 (Cohen’s d).

Whether or not the goal of predicting individual fates is reached, mining the prodromal period for clues may help unravel the processes underlying illness onset and build a more mechanistic understanding of schizophrenia.—Michele Solis.

References:
Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

 
Comments on News and Primary Papers
Primary Papers: Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.

Comment by:  Anissa Abi-Dargham
Submitted 9 January 2012 Posted 9 January 2012

The elegant studies of Oliver Howes and colleagues (Howes et al., 2011; Howes et al., 2009; Howes et al., 2011) have contributed valuable information regarding the high-risk state and dopamine (DA). Because of these studies, it is now clear that striatal dopamine dysregulation precedes onset of psychosis, relates to symptoms, and affects the associative striatum most predominantly, at least initially, extending into the sensorimotor subregion with time (Howes et al., 2011), while the ventral striatum remains relatively spared. These are difficult studies in terms of recruitment, characterization, and retention of subjects for longitudinal follow-up, and represent a great contribution to our field.

The paper discussed here (  Read more


View all comments by Anissa Abi-Dargham

Primary Papers: Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 11 January 2012 Posted 11 January 2012

Howes et al. make an important contribution in reporting increased striatal dopamine synthesis in a patient/subject cohort at ultra high risk for psychosis. Most interesting is the correlation between dopamine synthesis and transition to psychosis. An important milestone in the dopamine hypothesis of schizophrenia came with in-vivo neuroimaging evidence of increased dopamine release in persons with schizophrenia reported by Breier and colleagues (Breier et al., 1997) and by Laruelle and colleagues (Laruelle et al., 1996). This was the first direct evidence for the dopamine hypothesis. Howes et a. cite recent reviews by Abi-Dargham and others, and a meta-analysis is now available with advance access in the Schizophrenia Bulletin (Fusar-Poli and Meyer-Lindenberg, 2011) for the interested reader.

This report is timely for several reasons:

  • A rapidly growing and now large literature reporting empirical evidence for the validity of a disorder/syndrome referred to as "at risk...  Read more

View all comments by William Carpenter

Comment by:  Thomas McGlashan
Submitted 21 January 2012 Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified...  Read more


View all comments by Thomas McGlashan
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