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SIRS 2014—Epidemiology Digs Deeper Into the Infection-Psychosis Link

May 13, 2014. The immune system is again gaining attention in the etiology of schizophrenia and other psychotic disorders (see SRF related news report; SRF news report), and has featured prominently in many recent scientific meetings. The 2014 meeting of the Schizophrenia International Research Society in Florence, Italy, was no exception. An April 7 session chaired by Christina Dalman of the Karolinska Institutet in Stockholm, Sweden, described recent epidemiological studies investigating the link between psychosis and different types of infections.

Viral pathogens
Seropositivity for the Epstein-Barr virus (EBV), a member of the herpes virus family, has recently been linked to psychotic experiences during adolescence. In the first talk of the session, Golam Khandaker, University of Cambridge, UK, presented data on the first longitudinal study to examine this association. Khandaker and colleagues used data from a subset of the Avon Longitudinal Study of Parents and Children (ALSPAC), a general population birth cohort of more than 14,000 people born in the UK in the 1990s. Antibodies to EBV were measured at age four, which revealed seropositivity in 25 percent of the sample. Khandaker reported that those with exposure to the virus were five times more likely to have had psychotic events (PEs) (17 percent of sample) at age 13 than those who were not seropositive (11 percent).

Exposure to herpes simplex virus 1 (HSV1), another member of the herpes virus family, has been linked to cognitive dysfunction in both control subjects and people with schizophrenia (Dickerson et al., 2003), so Khandaker and colleagues reasoned that IQ may mediate the effect of EBV exposure on later PEs. However, although EBV-exposed children did have lower IQs at age nine than controls, this effect was not significant when accounting for confounding factors and did not explain the increased risk for later PEs.

In a follow-up from the 2012 SIRS meeting (see SRF related conference report), Alan Brown, Columbia University, New York, discussed his recently published data on the influence of maternal influenza exposure on bipolar disorder in the Child Health and Development Study population-based birth cohort (Canetta et al., 2014). A strong link between a mother's influenza exposure and a greater risk of schizophrenia in her offspring has been found (see SRF related news report), but the diagnostic specificity of this finding has not been conclusively assessed, Brown said.

Although Brown and colleagues did not find an association between serologically documented maternal influenza and bipolar disorder as a whole in the offspring, a mother's infection did raise the risk of bipolar disorder with psychotic features fivefold, consistent with an earlier study in the same birth cohort. Combined with the schizophrenia data, the results suggest that prenatal influenza infection may raise the risk for psychosis more generally, though Brown noted that the inability to distinguish influenza infection during pregnancy from that which occurred prior to conception is a limitation of the study.

Hakan Karlsson, of the Karolinska Institutet described a large Swedish study that examined the effect of chronic maternal infections on the newborn immune system (Gardner et al., 2013). He reported that babies born to mothers with a Toxoplasma gondii infection have higher levels of acute proteins (an important component of the innate immune system) shortly after birth, demonstrating an immune reaction to her infection. In contrast, babies who later develop non-affective psychosis do not show this same elevation, suggesting that they don't mount a proper immune response. Karlsson and colleagues observed a similar effect when looking at babies of mothers with cytomegalovirus, but not with herpes simplex virus 1 or 2.

Beyond specific pathogens
Asa Blomstrom, also from the Karolinska Institutet, provided an update on data she had presented at the 2012 SIRS meeting (see SRF related conference report). In the current study, she investigated the link between infections (more generally) and psychosis by examining hospital admissions for infections in children born in Sweden from 1973 to 1997. After correcting for multiple confounding factors, she observed a small but significant association between hospital admissions for any infection up to age 13 and a subsequent diagnosis of non-affective psychosis (including schizophrenia) (Blomstrom et al., 2013). Bacterial infection had the strongest effect on risk for subsequent psychosis. Similar results were obtained when schizophrenia patients alone were examined.

An audience member presented an alternative take on the general hypothesis that infections themselves increase risk for psychosis, instead speculating that perhaps the elevated risk for non-affective psychosis was due to alterations in the microbiome resulting from the antibiotics used to treat the infections.

Urs Meyer, Swiss Federal Institute of Technology in Zurich, presented an overview of the use of animal models of immune activation, focusing on prenatal immune activation. He emphasized the role of animal studies in providing "experimental support" for human epidemiological studies. The elevated risk of schizophrenia conveyed by maternal infection does not seem to be pathogen specific, Meyer added, and highlighted four animal models of general maternal immune activation during pregnancy: influenza, polyinosinic/polycytidylic acid, lipopolysaccharide, and turpentine. "We should also think beyond the brain," said Meyer, reviewing data on metabolic changes resulting from maternal immune activation. All of these animal models are neurodevelopmental in nature and thus may be useful in a number of psychiatric illnesses thought to have a developmental origin, he added.

Discussant Robert Yolken, Johns Hopkins University, Baltimore, Maryland, concluded the session with an overview of the field of immune activation in psychosis. He highlighted the need for an improvement in the measurement of immune and inflammation molecules, pointing to mass spectroscopy as a potentially useful tool. In terms of risk factors for psychosis, Yolken emphasized low birth weight as one that needs to be further explored (see SRF related news report). It will be important to "get the message out that some aspects of these diseases are preventable," he said. Several strategies such as the monitoring and treatment of infections during pregnancy, immunizations, and safe sexual practices should be communicated to both doctors and patients, Yolken added.—Allison A. Curley.

Comments on Related News


Related News: Gestation Matters: Preterm Birth Raises Risk for Psychiatric Illness

Comment by:  Marit S Indredavik
Submitted 6 July 2012
Posted 6 July 2012

This study provides important and partly new information on long-term psychiatric outcomes after preterm birth. It is a historical, population-based cohort study using data from Swedish national registers, showing increased risk for severe psychiatric disorders—nonaffective psychosis, depressive, bipolar, and even eating disorders—in the very preterm population. The risk was also increased, although to a lesser degree, for the moderately preterm group (except for eating disorders). Maternal psychiatric history, socioeconomic or perinatal factors could not explain the findings. Interestingly, being small for gestational age increased the risk for drug and alcohol dependency.

This expands present knowledge, and supplements the emerging evidence of increased risk for adult psychiatric disorders in low-birth-weight populations (Moster et al., 2008; Walshe et al., 2008; Hack, 2009; and Lund et al., 2011). The study takes care of several aspects that usually limit other studies: a large sample size, inclusion of the moderately preterm group, maternal psychiatric morbidity, and a range of prenatal and perinatal factors. As such, this well-performed study deserves credit. The results underline the concern that psychiatric morbidity is one of the major health issues after preterm birth.

The authors suggest impaired neurodevelopment as a plausible biological basis for psychiatric disorders associated with preterm birth. They propose that similar etiologies may lead to a variety of different outcomes, although non-optimal fetal growth may represent other or additional risk factors. Future studies combining advanced cerebral MRI techniques, and clinical, genetic/epigenetic, and environmental data, may provide new knowledge on the etiology. A better understanding of the mechanisms involved may point to improved prevention and intervention aiming to reduce the psychiatric morbidity for low-birth-weight individuals.

References:

Hack M. Adult outcomes of preterm children. J Dev Behav Pediatr 2009;30(5):460-70. Abstract

Lund LK, Vik T, Skranes J, Brubakk AM, Indredavik MS. Psychiatric morbidity in two low birth weight groups assessed by diagnostic interview in young adulthood. Acta Paediatr 2011;100:598-604. Abstract

Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262-273. Abstract

Walshe M, Rifkin L, Rooney M, Healy E, Nosarti C, Wyatt J, Stahl D, Murray RM, Allin M. Psychiatric disorder in young adults born very preterm: Role of family history. European Psychiatry 2008;23:527-531. Abstract

View all comments by Marit S Indredavik

Related News: SIRS 2014—Refining Schizophrenia Clinical Drug Trials

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 4 June 2014
Posted 4 June 2014

This was an important symposium, but I am concerned about the impression that these findings suggest a problem with translating data from animal models to the clinic. In order to translate effectively, one must use an animal model that recapitulates as much of the disease state as possible, and acute pharmacological challenges are inadequate for this. Developmental models should be a more effective screen. But perhaps more important, there is a very big difference between animal models and clinical trials: In animal models, the first therapeutic drug that the animal sees is the novel target compound. In contrast, clinical trials comprise patients that have been treated for antipsychotic drugs for decades, then withdrawn for only a single week before the test compound is evaluated.

It has been known for quite some time that repeated D2 antagonists change the brain in substantial ways. In our recent paper (Gill et al., 2014), we found that a GABAA alpha 5 compound that was highly effective in reversing dopamine neuron hyper-responsivity and amphetamine hyperlocomotion in MAM model rats was completely ineffective if the MAM rats were given just three weeks of haloperidol and withdrawn from the drug for one week. Therefore, once maintained on a D2 antipsychotic drug, we posit that the system changes from a hippocampal overdriven dopamine system to a postsynaptic dopamine receptor supersensitivity psychosis, such that only another D2 antagonist can now effectively replace the drug that had been withdrawn. We need to rethink clinical trial design if we are to effectively evaluate drugs with novel targets, or we may never get away from D2 antagonist therapy.

References:

Gill KM, Cook JM, Poe MM, Grace AA. Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr Bull. 2014 Mar ;40(2):341-50. Abstract

View all comments by Anthony Grace

Related News: Evidence Mounts for the Maternal Inflammation Hypothesis of Schizophrenia

Comment by:  Stephen Marder, SRF Advisor
Submitted 10 July 2014
Posted 11 July 2014

Accumulating evidence indicates that activation of the maternal immune system—from infectious and non-infectious sources—increases the risk of schizophrenia. This interesting study using data from the Finnish Prenatal Study of Schizophrenia measured C-reactive protein, a general marker of inflammation, in maternal serum from 777 schizophrenia subjects and an equal number of controls. The importance of this study derives from the size of the sample and the strength of the relationship between immune activation and schizophrenia risk.

View all comments by Stephen Marder

Related News: Evidence Mounts for the Maternal Inflammation Hypothesis of Schizophrenia

Comment by:  Chris Carter
Submitted 16 July 2014
Posted 16 July 2014
  I recommend the Primary Papers

If the development of schizophrenia depends upon maternal infection, perhaps a large number of susceptibility genes (possibly related to infection susceptibility and the immune system) would be concentrated in maternal alleles, with other maternal/paternal genes contributing later in life, and in different ways, for the offspring.

Have there been , or are there programmed, any genome-wide association studies on non-schizophrenic mothers of schizophrenic patients? A comparison of maternal/paternal genetic donation might perhaps be a useful means of dissecting out the various pathways leading to disease.

View all comments by Chris Carter

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  David GoldmanColin Hodgkinson
Submitted 20 July 2014
Posted 21 July 2014

The fact that schizophrenia is moderately to highly heritable is yesterday’s news; however, this genetic study, because of its large magnitude and with >100 genome-wide significant loci, is a watershed event in the discovery of the genetic variation that must be responsible for this inheritance. There are limitations. The principal limitation is that not one of the findings reported in this paper meets the standard demanded in medical genetics. As reviewed by Flint and Munafo, and following the emphasis of the paper, the focus is on the statistical findings rather than the identification and validation of any one of the >100 genome-wide significant loci at the level of the functional nucleotide difference and how that translates into behavior.

In fact, the principle finding of this study is that no common coding sequence variant accounts for any large fraction of the genetic liability to schizophrenia. It is interesting to speculate on the nature of the genetic variation that causes schizophrenia based on the loci discovered here, which are responsible for an important but still small part of that genetic liability. However, the conclusion that the variants are regulatory in nature will have to await a more complete accounting of the genes and loci involved, and the actual identification of the loci responsible. This is different than pointing to significant associations to SNPs outside of coding regions and to lack of associations to SNPs within coding regions.

Despite the cold water thrown on the eight hundred candidate genes previously implicated in schizophrenia, all of which Flint and Munafo label as “of dubious value,” it is actually critically important that more than a few were among the genome-wide significant loci. Otherwise, and for example if genetic variation at no dopamine or glutamate gene was found to be important, one might doubt the validity of this study. We shouldn’t aggregate or characterize the other association results as if we really understand them or know why they did not generate signals in this genome-wide association study. Clearly some are false positives. Some involve VNTR loci that are not even captured by SNP arrays. Some may be valid in particular populations but not others where the functional variant is absent. Some may depend on the study of particular phenotypes that are not the schizophrenia diagnosis itself but are associated with the disease (for example COMT and cognitive phenotypes) or that can be conflated with schizophrenia (for example DISC1 and schizoaffective disorder).

This genome-wide association study is a starting point for studies on more than 100 genes to elucidate their roles in schizophrenia but it is also a challenge to all of us interested in the biology of schizophrenia. It is best to keep an open mind about the genes involved in schizophrenia and the types of alleles at these genes until some of those functional alleles have been verified.

View all comments by David Goldman
View all comments by Colin Hodgkinson

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Francis McMahon, SRF Advisor
Submitted 22 July 2014
Posted 22 July 2014

Those of us who attended the annual meeting of the International Society of Psychiatric Genetics in Boston last October were electrified by the striking findings of the Psychiatric Genomics Consortium, reporting over a hundred genome-wide significant genetic marker associations in the largest ever genome-wide association study of schizophrenia. After what seemed like a long wait, this landmark work has now appeared in the journal Nature.

The results further demonstrate the highly polygenic nature of schizophrenia risk. The implicated genes represent a large range of biological functions and converge on a few well-known pathways, chiefly FMRP. The most significant individual finding remains the HLA region, adding to the now widely-held idea that immunity plays an important role in the etiology of schizophrenia.

What now? The mapping of functional alleles in individual genes is the logical next step, but will be a major challenge. Some critics will express skepticism that we have learned much more than we knew after the last large GWAS. Clearly the GWAS method works for schizophrenia – but will we now want to study even larger samples? Skeptics might reasonably ask what we will learn from the next 100 markers that we have not already learned from the first 100.

As a field, we should challenge ourselves to run at least one of these findings to ground, establishing the functional risk alleles and using this information to formulate bold new hypotheses about the causes and treatment of schizophrenia. Even one new effective medication that comes out of these findings will make the entire effort worthwhile.

View all comments by Francis McMahon

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Bryan Roth, SRF Advisor
Submitted 22 July 2014
Posted 22 July 2014

This is indeed a "landmark paper" and one eagerly awaited by the field of psychiatry, and likely medicine in general.

One thing to emphasize (which was nicely stated in Tom Insel's blog) is that in no case was an actual gene identified. As these are all rather large loci which contain both open reading frames (ORFs) as well as non-coding regions (introns and probably other yet to be identified non-coding RNAs), the real work will be to identify the precise mutation(s) associated with the loci.

Additionally, it will be critically important to determine the directionality of the mutation(s) identified for each locus. Thus, before embarking on a drug discovery expedition, it is important to know if the particular mutations augment or inhibit the activity of the particular molecular entity imputed.

If we take DRD2 (D2-dopamine receptor) as an example, it is important to know if the mutations reside in the coding region and, if so, whether they alter expression, signaling, signaling bias, neuronal targeting, and so on. If the mutation(s) are in non-coding regions (introns, promoter regions, non-coding 3'-region), it will be important to understand how this might alter the expression/function of DRD2. For essentially all of the targets imputed to drive a drug discovery program forward, it is essential to know this information.

Thus, for the calcium channels implicated (CACNA1C, CACNB2, and CACNA1I, which encode voltage-gated calcium channel subunits), we need to know how (and if) the mutations ultimately identified affect channel function, as the design of drugs at these targets will depend upon whether we need to augment or inhibit activity.

Finally, as each of these risk alleles has only a minute effect on the overall risk for schizophrenia, it is unknown whether creating a drug which modulates the activity of a single target could ever lead to a population-wide effect on disease progression/outcome.

Nonetheless, these findings are foundational for the field and provide proof for the power of this approach.

View all comments by Bryan Roth

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Philip Seeman (Disclosure)
Submitted 22 July 2014
Posted 22 July 2014

Of the many DNA regions found to be associated with schizophrenia in this study (Ripke et al., 2014), the only region that is associated with current treatment is the dopamine D2 receptor. The study shows that this DNA region is 50,000 bases away from the D2 gene and is in the DNA promoter region that controls the expression of the D2 gene. Let’s hope that other DNA regions may lead to improved treatment.

These current results support Van Rossum’s long-standing hyper-dopamine transmission theory of schizophrenia. While there are many causes for schizophrenia, it appears that a final common path for clinical signs and symptoms goes through dopamine D2 receptors.

References:

Ripke S. et al. Nature, July 21, 2014. doi 10.1038.nature13595.

View all comments by Philip Seeman

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Zoran Vukadinovic
Submitted 23 July 2014
Posted 31 July 2014

My brief comment will focus on one of the findings which is replicated in this study. Namely, this is the second GWAS which has reported that the gene encoding the CaV3.3 subtype of T-type calcium channel (CACNA1L/I) is involved in the pathophysiology of schizophrenia. The reference for the first study can be found below (Strange et al., 2012).

This is an important finding, as CaV3.3 is expressed in the thalamic reticular nucleus (TRN) and has a role in the generation of sleep spindles (Astori et al., 2011), which are markedly reduced in schizophrenia (Ferrarelli and Tononi, 2011). Thus, the finding reported in this GWAS has an important potential pathophysiologic correlate. Sleep spindle reductions in some individuals with schizophrenia may be related to abnormalities of the CaV3.3 subtype the of T-type calcium channel. How this could lead to other deficits in this illness remains to be determined (see Vukadinovic, 2011).

Epidemiologic evidence suggests that cannabis use may be the strongest environmental risk factor for the development of schizophrenia. It is interesting and potentially important that exogenous cannabinoids were found to directly, and independently of, cannabinoid receptors, block T-type calcium channels (including the CaV3.3 subtype) in both cell cultures and neuronal tissues (Ross et al., 2008). This effect may be related to the psychotogenic potential of exogenous cannabinoids (Vukadinovic et al., 2013).

Thus, the now replicated finding that the CACNA1L/I gene may be a susceptibility gene for the development of schizophrenia fits with pathophysiologic evidence of sleep spindle reductions (and possibly TRN deficits) and may, moreover, intersect with a major environmental risk factor (i.e., cannabis use). These three issues may help elucidate the etiology of schizophrenia in at least some patients and should be investigated further.

References:

Strange A., Riley B.P., Spencer C.C.A., Morris D.W., Pirinen M., O’Dushlaine C.T., et al., 2012. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry . 2012 Oct 15 ; 72(8):620-8. Abstract

Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, Lüthi A. The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc Natl Acad Sci U S A . 2011 Aug 16 ; 108(33):13823-8. Abstract

Ferrarelli F, Tononi G. The thalamic reticular nucleus and schizophrenia. Schizophr Bull . 2011 Mar ; 37(2):306-15. Abstract

Vukadinovic Z. Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness. Eur J Neurosci . 2011 Oct ; 34(7):1031-9. Abstract

Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem . 2008 Jun 6 ; 283(23):16124-34. Abstract

Vukadinovic Z, Herman MS, Rosenzweig I. Cannabis, psychosis and the thalamus: a theoretical review. Neurosci Biobehav Rev . 2013 May ; 37(4):658-67. Abstract

View all comments by Zoran Vukadinovic

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Hugo Geerts
Submitted 4 August 2014
Posted 6 August 2014

While this might be a blockbuster breakthrough study from an academic point of view, I would caution that there is still a very long way to go before this could be turned into potential drug targets and discovery programs. Many of the SNPs are contributing very little to the schizophrenia phenotype, suggesting that there might be many different ways to arrive at the same phenotype.

One could say that, for schizophrenia, we are now at a situation in the Alzheimer’s field some 22 years ago when ApoE (major risk factor with an OR of about 4) in sporadic patients and APP in familial patients were identified. Yet no drug program focused on ApoE has entered a Phase 2 POC study, and the (many and expensive) APP clinical programs all have failed to live up to expectations in the clinic so far. It suggests that the one gene-one phenotype hypothesis likely is much too simple. Also, the SNPs listed do not include currently pursued clinical targets such as PDE10 or α7 nAChR.

Under the leadership of Dr. Zaven Khachaturian and the Alzheimer's Association, we have set up a workgroup on how to go from Big (-omics) Data to Smart Data; i.e., how could we generate actionable knowledge (in a drug discovery sense) from all the databases that identify "correlations" or "associations" with certain clinical phenotypes in Alzheimer’s disease? I was wondering if the time would be right to start a similar pre-competitive workgroup initiative in schizophrenia so as to incentivize the pharmaceutical industry by providing it with useful, actionable knowledge about what possible targets are worth pursuing for a large number of patients and how to best affect these targets (i.e., agonism or antagonism).

View all comments by Hugo Geerts