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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


Issue 33, December 2014: Guest Commentator - Diana O. Perkins, M.D., MPH, Professor of Psychiatry, University of North Carolina School of Medicine


Biological insights from 108 schizophrenia-associated genetic loci.
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Nature. 2014 Jul 24;511(7510):421-7. doi: 10.1038/nature13595. Epub 2014 Jul 22.


This study aimed to identify regions of the genome that contained common schizophrenia risk genes. 



DNA is made of nucleotide bases (Adenine, Thymine, Cytosine, Guanine). DNA is double-stranded, with A pairing with T, and G pairing with C. Every ~300 bases there is a common variation, called a single nucleotide polymorphism (SNP).  For common variants, about 5-50% of people with have one of the pairs and about 50-95% of people will have the other pair at that genomic location.

A genome-wide association array study (GWAS) compared the frequency of 9.5 million common SNP variants in 36,989 persons with schizophrenia and 113,075 unaffected persons. Because so many comparisons are being made, the investigators required that the differences in frequencies between schizophrenia and unaffected persons have a probability less than 1x10-6 of being a chance finding.

Linkage refers to the fact that SNPs that are in close proximity are inherited as a unit, called a “haplotype”.  The actual size of the haplotype varies with ancestry. In this study care was taken to ensure that the analysis was not biased by ancestry or other population stratification.

To understand the functional importance the investigators identified SNPs that could possibly impact the protein structure, and also used a method called “expression quantitative trait loci” (eQTL) analysis that examined if the SNPs associated with schizophrenia actually impacted gene expression.



There were 108 genomic regions with significantly different proportions of SNP variants in schizophrenia compared to unaffected persons. 

The differences between groups was relatively small, with the almost all of the SNP variants between 6%-10% different in frequency between groups. 

The highest risk genes were combined to form a “polygenic risk score”, and although persons with schizophrenia had significantly higher scores, the polygenic risk score was not very useful in predicting schizophrenia risk. 

Functional analysis of the genes in these genomic regions indicated involvement of the immune system, glutamate and dopamine receptors (including calcium channels), and brain development. 


Common variations in the genome contribute to schizophrenia risk. Likely there is some combination of these variants (as yet unknown) that lead to vulnerability. The 108 genomic regions identified in this study likely represent “the tip of the iceberg”.


Clinical Commentary:
Most of the data for this landmark study is openly available to other researchers, and there will likely be many more papers analyzing these results to better understand schizophrenia vulnerability. The finding that the immune system may be involved in schizophrenia risk is supported by many other studies, suggesting completely novel pathways for schizophrenia treatment development.  The results also suggest that it may be difficult to use genetic data to predict schizophrenia risk.


Genetic predisposition to schizophrenia associated with increased use of cannabis
RA Power, et al.
Molecular Psychiatry(2014) 19, 1201-1204; doi:10.1038/mp2014.51


This study aimed to determine whether there was a shared genetic vulnerability between schizophrenia and marijuana use.



There were 2082 study subjects taken from a larger population study of young adults, who had both genotype data and marijuana use data. 

A second cohort of 990 twin pairs (608 dizygotic and 382 monozygotic) served to confirm the results from the general population subjects.

Marijuana use was defined as ever-use versus never-use, and as a quantitative variable.

A “polygenic risk score” was calculated from the results of large scale genome-wide association studies. 

Polygenic risk score values were compared in marijuana users versus never-users. 



About half of the subjects had used marijuana, with average age of first use at 19 years. 

The polygenic risk score was significantly higher in persons who had ever used marijuana compared to persons who had never used marijuana, in both the general population and the twin groups. 

There was a correlation between polygenic risk score and amount of use in the marijuana users. However, the variance in marijuana use explained by the polygenic risk score was small, indicating that the shared risk genes likely play a minor role.


Schizophrenia is associated with marijuana use, with well-replicated findings that persons with schizophrenia are more likely to use marijuana than the general population, and heavy and early marijuana use prior to schizophrenia is more common in persons who develop schizophrenia than the general population.  The results of this study suggest that part of this association is that a shared set of genes may contribute to both conditions.   


Clinical Commentary:
Cannabis use is common, with concern about the medical consequences of use. This study highlights the potential complexity of genetic and environmental vulnerability.  There is evidence that endogenous cannabidiol system may be disrupted in persons with schizophrenia, lending further plausibility to the idea that cannabis use and schizophrenia may have a common genetic basis. 


The STRIDE weight loss and lifestyle intervention for individual taking antipsychotic medications: A Randomized Trial
Green, CA et al.
Am J Psychiatry. 2014 Sep 15. doi: 10.1176/appi.ajp.2014.14020173. [Epub ahead of print]


The purpose of this study was to determine if a tailored lifestyle intervention could reduce weight and diabetes risk in persons who were prescribed antipsychotics and who were overweight (body mass index > 27).



The lifestyle modification program included monitoring diet and physical activity, creating a personalized diet (based on the DASH diet, emphasizing portion size and calories) and physical activity plan. 

There were 200 participants, with 96 randomly assigned to usual care group and 104 to the intervention group. The average age was 47, thus this was a middle-aged cohort.

The raters measuring outcomes did not know group assignment.



Most subjects completed the study, with subjects participating in an average of 14 of the 24 intervention sessions.  

Persons in the STRIDE intervention group lost 7 kg, compared to a 2 kg weight loss in the usual care group; this difference was statistically significant.

Fasting glucose levels significantly decreased in the STRIDE participants, but increased in the usual care subjects. 

STRIDE participants were significantly less likely to be hospitalized for a medical condition during the study (6.7% of intervention versus 18.8% of usual care).


Persons with serious mental illnesses taking antipsychotics who are over-weight or obese benefit from a tailored lifestyle intervention with weight loss and reduced fasting glucose. 


Clinical Commentary:
The difference in medical hospitalization is striking, and it would have been interesting to have seen a cost analysis, as it is possible that the cost savings from medical hospitalization might well have exceeded the cost of the intervention.  One limitation is that 40% of persons randomized to the intervention did not actually participate. Not all persons who are overweight were ready to engage in a lifestyle change intervention, thus it may be that use of motivational interviewing or other strategies prior to lifestyle change could increase program participation. 



Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.
Cabungcal et al.
Neuron. 2014 Sep 3;83(5):1073-84. doi: 10.1016/j.neuron.2014.07.028. Epub 2014 Aug 14.


Schizophrenia risk may be related to oxidative stress, either through impaired oxidative stress defenses or elevated production of oxidants. In a rat developmental model of schizophrenia the investigators determined whether elevating glutathione, an important cellular antioxidant, could prevent the cellular and behavioral disturbances from emerging in adulthood.



An established developmental rat model of schizophrenia involves lesion of the neonatal ventral hippocampus; this results in cellular changes to the prefrontal cortex, as well as electrophysiological and behavior deficits thought to be analogous to human schizophrenia, that emerge only when the rats reach adulthood. 

The investigators propose that a mechanism by which neonatal ventral hippocampal lesions cause adult deficits is via oxidative stress. 

An important endogenous antioxidant is glutathione, a small protein made from the amino acids glycine, glutamate, and cysteine. Cysteine concentration controls the amount of glutathione. Oral consumption of n-acetyl cysteine (NAC) will increase glutathione levels, and thus increase cellular antioxidant defense capacity.

One group of pregnant rats received NAC, the other did not. The pups’ hippocampus was lesioned at birth. After birth the pups in the treated group continued to receive NAC.



Cellular results: Similar to findings in schizophrenia, the untreated lesioned rats had a reduction of parvalbumin (PV) interneuron activity in the prefrontal cortex, with NAC treated rats have normal activity.

Free radical damage results: Free radicals damage DNA, measured by levels of 8-oxo-dG, and proteins, measured by 3-NT levels. Untreated lesioned rats had highly elevated levels of 8-oxo-dG and 3-NT in adolescence and adulthood in prefrontal cortical pyramidal neurons and PV-interneurons, however NAC treated rats did not have these elevations.

Cellular electrophysiological results: Similar to findings in schizophrenia, untreated lesioned rats had prefrontal cortical pyramidal neurons with reduced response to dopamine, however NAC treated rats showed normal pyramidal neuron response to dopamine. 

Mismatch negativity: When listening to repeated tones, healthy persons will have an increased response as measured by EEG when a novel tone is played (called “mismatch negativity), persons with schizophrenia show a blunting of this response. Similar to schizophrenia, untreated lesioned rats had blunted mismatched negativity, however NAC treated rats showed normal mismatch negativity.

Sensorimotor integration:  If a weak warning sound is given first, healthy persons will show a reduced startle response to a loud sound, persons with schizophrenia do not show reduced startle. Similar to schizophrenia, untreated lesioned rats did not have attenuated startle, while NAC treated rats showed attenuated startle when given a warning.

In a second experiment NAC treatment in lesioned rats was delayed until early adolescence. In adulthood NAC treated rats had normalized startle response.


In rats, impaired hippocampal input to the prefrontal cortex results in elevated oxidative stress during adolescence and adulthood, leading to multiple deficits that are analogous to deficits found in schizophrenia, and can be prevented by NAC administration. 


Clinical Commentary:
It is unknown whether animal models of schizophrenia actually reflect human pathology, thus the relevance of animal models to schizophrenia pathology is uncertain. With that said, these results suggest that elevated prefrontal cortical oxidative stress is a consequence of reduced hippocampal inputs, and can cause neuropathology similar to that seen in schizophrenia.  NAC is an over-the-counter supplement, and relevant to this study, there are two double-blind placebo controlled studies showing that NAC improves residual negative symptoms in persons with schizophrenia1,2. 


Effect of the Affordable Care Act’s Young Adult Insurance Expansions on Hospital-Based Mental Health Care
Goldberstein et al.
Am J Psychiatry. 2014 Sep 29. doi: 10.1176/appi.ajp.2014.14030375. [Epub ahead of print]


In 2010 the Affordable Care Act (ACA) required insurers to allow dependents to remain on their parent’s insurance up until age 26. This study aimed to evaluate the impact of the ACA on young adults’ use of hospital services for psychiatric disorders in California. 



Data sources were from 2005 to 2011, and included the National Inpatient Samples, a random sample of 20% of US community hospitals (excluding specialty mental health or substance use facilities), California’s State Inpatient Database (that includes specialty mental health and substance use), and the California’s State Emergency Department Databases

Trends for persons ages 19-25 were compared to persons ages 26-29 (not affected by the ACA) before and after the initiation of the ACA.

Primary outcome measures included rates of psychiatric inpatient admissions, emergency room visits, and the expected primary payer for these visits.



Psychiatric diagnoses for non-childbirth-related inpatient admissions to community hospitals are common, representing 16% of national admissions, and for 19-25 year olds in California 20% of admissions.

Use of inpatient psychiatric care in non-specialty hospitals increased slightly (1.4 per 10,000 admissions) for 19-25 year olds relative to 26-29 year olds. 

Use of ERs for psychiatric emergency visits declined slightly (4.5 per 10,000 ER visits) for 19-25 year olds relative to 26-29 year olds.  

After the ACA, inpatient admissions and ER visits for psychiatric diagnoses were less likely to be uninsured after the ACA, and the likelihood that insurance coverage was through private payers increased. 


The ACA led to a small increase in psychiatric hospitalization and a somewhat larger, but still small decrease in psychiatric ER visits for young adults ages 19-25, with more of these young adults covered by health care insurance. The authors speculate that increased insurance may have led to greater access to outpatient treatment and thus the identification of mental illness requiring hospitalization.


Clinical Commentary:
Concerns that the ACA would lead to accelerated growth in costs of mental health treatment for young adults ages 19-26, who began eligible to remain on their parent’s health care insurance, appears not to have been realized. The impact is modest, and in the direction of avoiding ER-based interventions for mental illness.




1 Berk, M. et al. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biological psychiatry 64, 361-368, doi:10.1016/j.biopsych.2008.03.004S0006-3223(08)00270-9 [pii] (2008).

2 Farokhnia, M. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clinical neuropharmacology 36, 185-192, doi:10.1097/WNF.0000000000000001 (2013).



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