Robert H. Yolken, MD

 an additional $98 million as part of the National Institutes of Health budget resolution in December 2019, which brings the NIMH budget to just under $2 billion and represents a 35% increase since 2015, one of the largest increases in the history of the NIMH. Yet, during the 5 years from 2015 through 2019, NIMH funded a total of 2 new drug treatment trials for schizophrenia and bipolar disorder, according to 

. This contrasts with the 5-year period from 2006 through 2010 when NIMH funded 48 such trials. NIMH has thus almost entirely given up its role of evaluating drugs for the treatment of 2 disorders.

Schizophrenia and bipolar disorder are among the most serious psychiatric disorders and play a disproportionate role among individuals who end up homeless, incarcerated, and who commit suicide. The cost of schizophrenia alone in the US was estimated to be $155.7 billion, based on a 2013 

 Traditionally, the pharmaceutical industry and NIMH have been the main developers of new psychiatric drugs. In recent years, the former has reduced its efforts to develop such drugs, at least in part because of the failure of genetic research to identify new targets for new drug development. Given the semi-withdrawal of the pharmaceutical industry, it would seem reasonable to expect the NIMH to increase, rather than decrease, its efforts.

A big part of the problem is the NIMH policy of requiring the identification of specific biological targets in the brain for treatment trials. This has been widely interpreted to mean that the NIMH is not really interested in supporting clinical trials at this time. Indeed, the NIMH has been widely criticized for focusing exclusively on basic brain research rather than clinical research that could help people currently affected by diseases such as schizophrenia and bipolar disorder. For example, in 2016, 20 current and former members of the NIMH National Advisory Mental Health Council published an editorial in the British Journal of Psychiatry criticizing the NIMH’s overemphasis on basic research.

 Joshua Gordon, MD, PhD, the current NIMH director, has “

that neither genetic research nor the study of complex circuits was likely to produce new treatments anytime soon.”

In fact, genetic findings relating to the immune system have been among the strongest genetic findings to date, and there is substantial genetic overlap between serious psychiatric disorders and a range of autoimmune diseases.

from small studies indicating that immune modulatory drugs have promise for the treatment of schizophrenia and bipolar disorder should be followed with larger scale studies.

 In addition, there are neuro-hormones such as estrogen that are promising as well as probiotics and other agents to modulate the microbiome and gut-brain axis.

 Given the fact that the last new psychiatric drug for psychosis was 

, which was approved 30 years ago, the time is long past due when the NIMH should undertake an aggressive search for better drugs. And now it has $2 billion in taxpayer funds to do so.

The opinions expressed here are those of the authors and do not necessarily reflect the opinions of 

 and Associate Director for Research at the Stanley Medical Research Institute; 

 is Theodore and Vada Stanley Distinguished Professor of Neurovirology in Pediatrics, Johns Hopkins University Medical School, Baltimore, MD.

1. Cloutier M, Aigbogun MS, Guerin A, et al. The economic burden of schizophrenia in the United States in 2013. 

2. Lewis-FernÃ¡ndez R, Rotheram-Borus Mj, Betts vt, et al. Rethinking funding priorities in mental health research. 

3. Heimer H. ICOSR 2017: The Prospects for New Drugs to Treat Schizophrenia. 

https://forum.schizophrenia.com/t/icosr-2017-the-prospects-for-new-drugs-to-treat-schizophrenia/78131

4. Hoeffding LK, Rosengren A, Thygesen JH, et al. Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies. 

5. Severance EG, Dickerson F, Yolken RH. Autoimmune phenotypes in schizophrenia reveal novel treatment targets. 

6. Mueller N. Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. 

7. Kulkarni J, Gavrilidis E, Wang W, et al. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of childbearing age. 

8. Dickerson F, Adamos M, Katsafanas E, et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: a randomized controlled trial. 

Articles

Schizophrenia and bipolar disorder are among the most serious psychiatric disorders and play a disproportionate role among individuals who end up homeless, incarcerated, and who die by suicide. Why the lack of research?

Riches Abound, So Where Are the Trials for Schizophrenia and Bipolar Disorder?

The idea that schizophrenia and bipolar disorder might be caused by infection is not new. This was a prominent hypothesis in the early years of the last century. For example, an article entitled, Is insanity due to a microbe? was published in 

 as early as 1896. Research to test this hypothesis by identifying causative viruses was already being conducted by the 1930s, when data were reported from experiments in which cerebrospinal fluid (CSF) from patients with schizophrenia was injected into rabbit brains.

New research in the field continues, aided increasingly by impressive technologic advances in microbiology and virology. As recently as the past decade, reports documented the presence of influenza virus, rubella virus, bovine disease virus, and other infectious agents in patients with schizophrenia and bipolar disorder, as well as the presence of other infectious agents in childhood pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and obsessive-compulsive disorder.

In this article, we briefly highlight the background of such research; discuss our own research on 

, herpes simplex virus (HSV), Cytomegalovirus (CMV), and endogenous retroviruses; and consider the future implications of such research for psychiatric clinicians.

Why should we look for infectious agents in schizophrenia and bipolar disorder? Such a hypothesis is consistent with the known genetic contributions to these disorders. Indeed, a genetic predisposition is well established for most chronic infectious diseases, including tuberculosis, malaria, polio, AIDS, and peptic ulcers caused by 

 The hypothesis is consistent with the role of neurotransmitter abnormalities in schizophrenia and bipolar disorder, because specific infectious agents have been shown to alter dopamine, serotonin, glutamate, γ-aminobutyric acid, and acetylcholine in animal models. The hypothesis is also consistent with neurodevelopmental models of schizophrenia and bipolar disorder. Pearce

 and others developed animal models that show how exposure to specific infectious agents during neurodevelopment correlates with later behavioral alterations in animals.

An additional important reason to look for infectious agents in schizophrenia and bipolar disorder is that CNS infection by specific pathogens frequently mimics the clinical symptoms of primary psychiatric diseases. For example, Caroff and colleagues

 reviewed 108 cases of psychiatric disorders resulting from suspected or confirmed CNS viral infections; in 62 cases, a specific virus was implicated, including HIV, HSV-1, HSV-2, Epstein-Barr, and CMV; and measles, mumps, coxsackie, and influenza viruses. Among bacteria, the fact that the spirochete of syphilis can cause the symptoms of schizophrenia was well known to psychiatric clinicians of an earlier era. More recently, infection with the spirochetal organism 

 has also been associated with schizophrenia-like symptoms in some persons.

Another reason to look for infectious agents in schizophrenia and bipolar disorder is the well-established association between the risk of these disorders and winter-spring seasonal birth.

 There have been more than 200 studies of this phenomenon, and it remains one of the most highly replicated findings of these diseases. Because many infectious diseases occur seasonally, with a peak in the winter or spring, it is reasonable to postulate that fetal or newborn infection could contribute to subsequent mental illness.

At the present time, we are focusing our research on 4 infectious agents as possible causes of schizophrenia and bipolar disorder. These are 

,  HSV-1 and HSV-2, CMV, and endogenous retroviruses.

 is a protozoan parasite whose definitive host is the cat family. Humans become infected by ingesting oocysts shed in the feces of infected cats or by eating undercooked meat from an animal that came into contact with infected cat feces. 

 is one of the most widespread human parasites; 10% to 20% of Americans test seropositive by adulthood. Exposure to 

 during early pregnancy can cause severe fetal CNS abnormalities. Exposure during late pregnancy was never considered a problem until recently, when animal data showed that late exposure to the organism causes behavioral changes, neurologic symptoms, and stillbirths.

Since 1956, more than 20 studies have compared antibodies to 

 in adults with and without schizophrenia.

 An overall analysis of the studies indicates that serologic evidence of Toxoplasma infection is almost 3 times more common in persons with schizophrenia than in controls living in the same geographic region.Two additional studies reported an increased level of 

 antibodies in the late-pregnancy serum of women giving birth to infants in whom schizophrenia later developed. 

 Other studies have reported greater childhood exposure to cats among persons with schizophrenia than among controls.

 Our research is focusing on the timing of 

 infections in relation to development, as well as on possible differences in 

 strains and human genetic susceptibility.

, HSV-1 and HSV-2 are common causes of infection in humans. HSV-1 may be spread by either sexual or nonsexual contact with infected persons, while HSV-2 is primarily spread through sexual contact. Both of these viruses are known to cause encephalitis and to be highly neurotropic. Traditionally, however, these viruses have been regarded as relatively benign in the majority of asymptomatic patients who carry them. Recent data suggest that this may not be true. One study evaluated the mothers of patients in whom schizophrenia or bipolar disorder developed. These women had increased levels of HSV-2 serum antibodies just before parturition.

Comparison studies of persons with and without schizophrenia or bipolar disorder show that HSV-1 infection significantly increases cognitive dysfunction-especially recent memory deficits-in persons with schizophrenia or bipolar disorder.

 This did not occur in persons infected with other viruses in the herpes family and also did not occur in persons without schizophrenia or bipolar disorder who were infected with HSV-1.

In a follow-up study, Dickerson and associates

 showed that a polymorphism on the COMT gene (COMT Val 158 Met polymorphism) also increases cognitive dysfunction; this suggests a synergistic effect between HSV infection and the gene. This kind of interaction may be a model for future research that integrates multiple factors in the development of schizophrenia and bipolar disorder.

CMV is another member of the herpes family of viruses. Infection is widespread and is known to occasionally cause encephalitis, primarily in patients with immunosuppression.

In contrast to older studies, recent studies report significantly more CMV antibodies in persons with schizophrenia than in controls. In a study by Leweke and colleagues,

 for example, 36 treatment-naive schizophrenic patients had significantly more antibodies in their sera (

 P 20 Another recent study reports that serum antibodies to CMV are particularly high in schizophrenic persons who have predominantly negative symptoms (the so-called deficit syndrome).

Finally, a recent treatment trial showed significant symptomatic improvement in schizophrenic patients who were treated with valacyclovir, an antiviral agent effective against herpes viruses.

Endogenous retroviruses are DNA elements that have become part of the human genome through infection and integration into germ line cells of humans and nonhuman primate progenitors. Retroviruses lie dormant most of the time. When activated, however, they can influence the transcription of genes above or below the site of their chromosomal integration. Genetic polymorphisms of endogenous retroviruses have been linked with an alteration in immune response and increased susceptibility to autoimmune disorders.

Endogenous retroviruses share properties of both genes and infectious agents, and are thus potential links between the two.

 Of particular interest is the fact that endogenous retroviruses may be activated by infections with herpesviruses or protozoan organisms such as 

, providing a potential link between infectious agents and genetic elements as causative factors in human psychiatric diseases. Increased retroviral transcription in the CSF and blood of persons with recentonset psychosis supports a possible role for human endogenous retrovirus in the development of schizophrenia.

Proving a causative role for infectious agents in schizophrenia and bipolar disorder would open the door to new treatments and disease prevention strategies. With the support of The Stanley Medical Research Institute, we are conducting several double-blind treatment trials that involve the use of adjunctive antibiotics and antiviral medications in persons with schizophrenia and bipolar illness. To date, these medications show some promise in patients with recent-onset disease. The results are less remarkable in persons with long-standing illness. In the future, it might even be possible to develop a vaccine to protect children against possible infections that contribute to these 2 mental illnesses.

Even with what is known today, in clinical settings, some patients who present initially with symptoms suggestive of schizophrenia or bipolar disorder could instead be in the initial stages of viral encephalitis. Some physicians would argue that patients with first-admission psychosis should have a lumbar puncture and CSF analysis, adding other studies as appropriate if indicated by an increase in CSF protein or lymphocytes. A small sample of the CSF could be frozen and stored for future analysis. With further advances in research at the interface between psychiatry and infectious disease, these samples may eventually provide the key to proving the connection between infection and mental disturbance, and pave the way for pharmacologic treatment specifically targeted to that causative infectious organism.

Dr Yolken is director of the Stanley Division of Developmental Neurovirology and professor, department of pediatrics, The Johns Hopkins University School of Medicine, Baltimore. Dr Torrey is associate director for laboratory research, The Stanley Medical Research Institute, and professor of psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md.

 Goodall E. The exciting cause of certain states of disease, at present classified under ‘schizophrenia’ by psychiatrists, may be infection. J Ment Sci. 1932;78:746-755. 


 Yolken RH, Torrey EF. Hypothesis of a viral etiology in bipolar disorder. In: Soares JC, Gershon S, eds. Bipolar Disorders: Basic Mechanisms and Therapeutic Implications.New York: Marcel Dekker; 2000:305-315. 


 Pearce BD. Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol Psychiatry. 2001;6:634-646. 


 Caroff S, Mann SC, Gliatto MF, et al. Psychiatric manifestations of acute viral encephalitis. Psychiatr Ann. 2001;31:193-204. 


 Hess A, Buchmann J, Zettl UK, et al. Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder. Biol Psychiatry. 1999;45:795. 


 Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res.;28:1-38. 


 Jones-Brando L, Torrey EF, Yolken R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res. 2003;62:237-244. 


 Webster JP. Rats, cats, people and parasites: the impact of latent toxoplasmosis on behaviour. Microbes Infect. 2001;3:1037-1045. 


 Remington JS, McLeod R, Thulliez P, et al. Toxoplasmosis. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia: WB Saunders; 2001:224, 227. 


 Torrey EF, Yolken RH. Toxoplasma gondii and schizophrenia. Emerg Infect Dis. 2003;9:1375-1380. 


 Brown AS, Cohen P, Greenwald S, Susser E. Nonaffective psychosis after prenatal exposure to rubella. Am J Psychiatry. 2000;157:438-443. 


 Mortensen PB, Yolken RH, Lindum B, et al. Toxoplasmosis and other early infections in relation to schizophrenia risk [abstract]. Schizophr Bull. 2005;31:232. Abstract. 


 Torrey EF, Yolken RH. Could schizophrenia be a viral zoonosis transmitted from house cats? Schizophr Bull. 1995;21:167-171. 


 Torrey EF, Rawlings R, Yolken RH. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000;46:17-23. 


 Buka SL, Tsuang MT, Torrey EF, et al. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001;58:1032-1037. 


 Dickerson FB, Boronow JJ, Stallings CR, et al. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60:466-472. 


 Dickerson FB, Boronow JJ, Stallings C, et al. Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol Psychiatry. 2004;55:588-593. 


 Dickerson FB, Boronow JJ, Stallings C, et al. The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. Bipolar Disorders. 2006;8:124-132. 


 Leweke FM, Gerth CW, Koethe D, et al. Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatr Clin Neurosci. 2004;254:4-8. 


 Albrecht P, Torrey EF, Boone E, et al. Raised cytomegalovirus- antibody level in cerebrospinal fluid of schizophrenic patients. Lancet. 1980;2:769-772. 


 Dickerson F, Kirkpatrick B, Boronow J, et al. Deficit schizophrenia: association with serum antibodies to cytomegalovirus. Schizophr Bull. 2006;32:396-400. 


 Dickerson FB, Boronow JJ, Stallings CR, et al. Reduction of symptoms by valacyclovir in cytomegalovirus- seropositive individuals with schizophrenia. Am J Psychiatry. 2003;160:2234-2236. 


 Marguerat S, Wang WY, Todd JA, Conrad B. Association of human endogenous retrovirus K-18 polymorphisms with type 1 diabetes. Diabetes. 2004; 53:852-854. 


 Yolken RH, Karlsson H, Yee F, et al. Endogenous retroviruses and schizophrenia. Brain Res Rev. 2000; 31:193-199. 


 Karlsson H, Bachmann S, Schroder J, et al. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci U S A. 2001;98:4634-4639. 


 Karlsson H, Schroder J, Bachmann S, et al. HERVW-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry. 2004;9:12-13.

The idea that schizophrenia and bipolar disorder might be caused by infection is not new. New research on infectious agents in patients with schizophrenia and bipolar disorder has implications for psychiatric clinicians.

Robert H. Yolken, MD

Articles

Riches Abound, So Where Are the Trials for Schizophrenia and Bipolar Disorder?

Infectious Agents in Schizophrenia and Bipolar Disorder