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Divide and Conquer: Isolating Negative Symptoms in Schizophrenia

20 March 2013. The debilitating negative symptoms of schizophrenia garner the spotlight in two new studies published online March 6 in JAMA Psychiatry. The first, led by Donald Goff of the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, finds that 16 weeks of taking folate and vitamin B12 supplements can selectively improve negative symptoms, but only among a subset of people with a particular genotypic variant related to folate absorption. The second report, a brain imaging study led by Aristotle Voineskos of the University of Toronto in Canada, finds that people with deficit syndrome, a subtype of schizophrenia characterized by profound negative symptoms, have distinct axon pathway structure that differentiates them from the non-deficit form of schizophrenia.

Focus on the negative
The findings offer hope for understanding the causes of and finding ways to treat negative symptoms, which include social withdrawal, apathy, and reduced emotional expression. Once considered less dire than the hallucinations and delusions of positive symptoms, negative symptoms are now recognized as key barriers to work and independent living. This has renewed interest for finding therapies that can deal with negative symptoms, which are not touched by antipsychotic medication.

“We are just desperate for novel therapies to test,” says William Carpenter of the University of Maryland in Baltimore, who was not involved in either study.

The studies also validate an approach that considers subsets of schizophrenia’s varied symptoms in isolation. Focusing on such subsets could identify subtypes of the disorder, and get cleaner answers to the causes and treatment of schizophrenia than studies that do not take into account this variability. “You really have to deconstruct schizophrenia into its component parts,” Carpenter told SRF.

Carpenter and colleagues originally suggested that negative symptoms were one of these components, and in 2001, Carpenter and colleague Brian Kirkpatrick took this further by proposing that people with high levels of negative symptoms constituted a subtype of schizophrenia, which they termed “deficit syndrome” (Kirkpatrick et al., 2001). People with the deficit subtype of schizophrenia also suffer from hallucinations and delusions, but their negative symptoms are more pronounced than those with non-deficit schizophrenia. Deficit syndrome is estimated to include 15-25 percent of cases of schizophrenia.

As the measurement of negative symptoms becomes more refined (see SRF related news story on a new clinical scale), tracking how negative symptoms interact with the other symptoms could also bring some clarity to drug trials. For example, social withdrawal due to paranoia is quite a different thing than social withdrawal due to a sincere lack of interest in other people. In the first case, the social withdrawal could be ameliorated with antipsychotic drugs, but not in the second case. “These are tangibly different pathologic phenomena,” Carpenter says.

Carpenter’s group has tried to differentiate between negative symptoms that are primary to schizophrenia and those that are secondary to other aspects of schizophrenia (Kirkpatrick et al., 2006). Keeping track of this is crucial to meaningful drug trials, which could conclude whether a drug improved negative symptoms in their own right, or if the improvements were just along for the ride.

Why folate?
Folate is a vitamin that humans need to get from their diet, and it has many brain-related functions, including neural tube formation, neurotransmitter synthesis, DNA replication, and DNA methylation, by which it influences gene expression. Epidemiology has linked famine, and presumably low folate levels in pregnant mothers, to increased risk for schizophrenia in their offspring (see SRF related news story). Adults with schizophrenia exhibit low folate levels in their blood, too, which worsens with negative symptom severity (Goff et al., 2004)—something that suggests adding back folate as a treatment strategy. Though grains have been fortified with folate in the United States since 1998, inefficiencies in how folate is absorbed and used in the body by a cadre of enzymes could leave someone effectively folate deficient. Consistent with this, Goff and colleagues previously found that folate could improve negative symptoms in people with schizophrenia, but only in those carrying a genotype affecting an enzyme involved in folate metabolism, called methylenetetrahydrofolate reductase (MTHFR) (Hill et al., 2011; see SRF related news story and accompanying Q&A with Roffman on folate metabolism and schizophrenia).

In the new study, first author Joshua Roffman and colleagues explored folate’s effects in a larger sample, and considered variants within genes encoding multiple folate-related enzymes: folate hydrolase 1 (FOLH1), methionine synthase (MTR), catechol O-methyltransferase (COMT), and MTHFR. Using a randomized, double-blind, placebo-controlled design, the study tested the effects of daily intake of 2 mg of folic acid and 400 μg of vitamin B12, which enhances folate’s actions. Of the 140 people with schizophrenia enrolled in the trial, 94 were assigned to folate plus vitamin B12 and 46 to placebo; 121 completed the trial.

Sixteen weeks later, negative symptoms had not improved significantly in the folate group as a whole, but there was a significant finding when genotype was taken into account. Among those carrying two copies of the 484T allele in FOLH1, folate reduced negative symptoms compared to placebo by an average of 0.59 points per week on the Scale for the Assessment of Negative Symptoms (SANS). In contrast, no significant difference was found between folate and placebo among 484C allele carriers. For the MTHFR genotype highlighted in their previous study, the difference between folate and placebo missed statistical significance (p = 0.17). The improvements stemmed largely from reductions in alogia, a poverty of speech.

No changes to positive symptoms were detected, which argues that the negative symptom improvement here was not just a byproduct of reducing psychosis. This suggests that modulating the folate pathway may be an inroad to treating negative symptoms themselves—at least in those whose folate metabolism is somehow compromised, or whose diet lacks folate.

Delineating deficit syndrome
The second study addresses negative symptoms through the lens of deficit syndrome, a subtype of schizophrenia marked by profound and stable social withdrawal, apathy, and blunted emotion. Beyond the different symptom profile of deficit syndrome compared to the rest of “non-deficit” schizophrenia, neurodevelopmental, epidemiological, and brain imaging studies have also reported differences (Kirkpatrick et al., 2001).

First author Voineskos and colleagues looked for brain signatures of deficit syndrome with the latest brain imaging techniques, including measurements of cortical thickness and diffusion tensor imaging (DTI) of the axon-containing white matter tracts. The researchers scanned 77 people with schizophrenia, 18 of whom met the deficit criteria, and 79 healthy controls. In one analysis—a careful comparison of regions previously implicated in schizophrenia—18 deficit cases were individually matched with 18 non-deficit cases for medication history, age of onset, illness duration, and age. The deficit cases had disrupted white matter structures in three fiber tracts that connect brain regions involved in emotional and social function: the right inferior longitudinal fasciculus, the right arcuate fasciculus, and the left uncinate fasciculus.

This disruption emerged in the larger, unmatched sample, too, with the same tract abnormalities detected in the 18 deficit cases versus the 59 non-deficit cases and 79 healthy controls. Positive symptom scores did not differ between the deficit and non-deficit groups, which suggests that the tract irregularities were linked specifically to negative symptoms. In contrast, the researchers found a similar pattern of reduced cortical thickness in deficit and non-deficit cases relative to controls. This casts cortical thinning as a generic feature of schizophrenia (see SRF overview story on cortical thinning).

The differences found in the brains of people with deficit syndrome bolster the idea that deficit syndrome is a distinct subtype of schizophrenia, and suggest that future studies would do well to keep track of the symptom profiles of study participants. Not only might it help clarify results, but it may also eventually help target brain regions that are crucial for real-world function.—Michele Solis.

Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, Goff DC. Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA Psychiatry. 2013 Mar 6:1-9. Abstract

Voineskos AN, Foussias G, Lerch J, Felsky D, Remington G, Rajji TK, Lobaugh N, Pollock BG, Mulsant BH. Neuroimaging Evidence for the Deficit Subtype of Schizophrenia. JAMA Psychiatry. 2013 Mar 6:1-9. Abstract

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