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A phase 2 trial of an adjunctive treatment for schizophrenia has stopped after failing to meet its primary and secondary endpoints. The treatment, CTP-692, developed by Concert Pharmaceuticals Inc, was a deuterated form of D-serine.

“The body of evidence in the field supporting D-serine as an adjunctive treatment for schizophrenia was compelling and led us to advance CTP-692 into a Phase 2 proof of concept study,” Roger Tung, PhD, president and chief executive officer of Concert Pharmaceuticals 

. “Unfortunately, we didn’t see the results we hoped for to support continuation of this program.”

CTP-692 was designed to improve on the efficacy and safety profile of existing schizophrenia treatments. Current research suggests that D-serine can improve outcomes for patients with schizophrenia, but it is accompanied by significant 

 Patients with schizophrenia also experience from cognitive impairments, and it was hoped that D-serine, which has shown positive effects on cognition in other contexts, would improve patient cognition without the renal risks.

The phase 2 trial was a double-blind, placebo-controlled study. It included 325 patients on antipsychotic medication. These participants were randomly selected to receive 1, 2, or 4-gram doses of CTP-692 once-daily, or a placebo. The trial took place over a 12-week period.

At the end of the 12-week period, the patients showed no improvement on the Positive and Negative Syndrome Scale (PANSS) compared to baseline scores, and the trial was discontinued. The company has also decided to discontinue study of this compound.

1. Concert Pharmaceuticals announces results from CTP-692 phase 2 trail in patients with schizophrenia. News release. Concert Pharmaceuticals Inc. February 1, 2021. Accessed February 17, 2021. 

https://ir.concertpharma.com/news-releases/news-release-details/concert-pharmaceuticals-announces-results-ctp-692-phase-2-trial

2. Concert Pharmaceuticals discontinues schizophrenia drug after trial failure. GlobalData Healthcare. February 3, 2021. February 17, 2021. 

https://www.clinicaltrialsarena.com/comment/concert-pharmaceuticals-schizophrenia-failure/

Is this phase 2 trial the end of the road for a potential new treatment?

A Potential Schizophrenia Treatment Trial Falls Short 

Elyn R. Saks is a lawyer and a professor at the University of Southern California Gould School of Law. In a book aptly titled 

 she tells how she managed to achieve this goal in spite of a chronic mental illness that was diagnosed, at different times, as paranoid schizophrenia and schizoaffective disorder, depressive type.

Elyn grew up in Miami, Florida, graduated from Vanderbilt, received a B Phil from Oxford, and a law degree from Yale-all with the highest distinction. This in spite of her struggle with a hydra-headed psychosis that came and went but never went away, and a “center” that disintegrated again and again, after being temporarily restored with the help of therapy, friendship, work, and psychotropic medication.

The first indications that Elyn might be heading for a difficult psychological life came while she was an undergraduate at Vanderbilt.

Her anxiety was constant, although less while doing academic work, from which she drew most of her identity.

Away from home, faced with new challenges and new expectations, Elyn began to “unravel.” She describes herself as “frantic during the day, sleepless during the night,”

 and she found it hard to concentrate and to think clearly. This daughter of fastidious professional parents let her hygiene slip, even as she realized that her body “stank.”

“My best guess,” she writes of that time, “is that my illness was beginning to poke through the shell (for lack of a better word) that helped me, indeed helps all of us, maintain a separation between what is real and what is not. For the next few years, that’s where things would precariously balance-me unwittingly trying to keep the shell strong, and my illness trying equally hard to break through.”

 In this psychic tug of war, substance abuse was not a contributing factor. Unlike many patients who begin to show signs of a major mental illness at her age, Elyn did not abuse drugs or alcohol.

In spite of a psyche that was increasingly blurring the boundaries between fantasy and reality, Elyn graduated from Vanderbilt with a perfect academic record, was named class valedictorian and won a Marshall scholarship to study ancient philosophy at Oxford-where her life really began to fall apart. There were trips to the emergency room, stays in psychiatric hospitals, psychiatrists and psychoanalysts, and psychotropic medications.

At Oxford, Elyn continued to excel academically even as reality became a tougher slog, and she retreated further into her fantasy world. She did not feel herself to be real, live, and continuous as R. D. Laing characterized the grounding of the ontologically secure person in 

 Nor did she experience others as real, live, and continuous. It was as if she lived behind a wall of glass-Silvia Plath’s bell jar comes to mind-cutting her off from what was going on around her. Elyn became frustrated and angry in her isolation and turned that anger against others, seeing ulterior motives where there were none. In fact, she had a coterie of loyal friends, teachers, and colleagues.

In her dreams, Elyn killed these friends, teachers, and colleagues because she was able to trick herself into believing that they wanted to kill her. This “killing” was how she feigned control when in fact she had ceded control to her illness, or her illness had taken it from her (most likely, it worked both ways). Elyn was self-deceived, depressed, paranoid, and psychotic much of the time:

Psychosis is like an insidious infection that nevertheless leaves some of your faculties intact; in a psychiatric hospital, for example, even the most debilitated schizophrenic patients show up on time for meals, and they evacuate the ward when the fire alarm goes off. So it was for me. Completely delusional, I still understood essential aspects of how the world worked. For example, I was getting my schoolwork done, and I vaguely understood the rule that in a social setting, even with the people I most trusted, I could not ramble on about my psychotic thoughts. To talk about killing children, burning whole worlds, or being able to destroy cities with my mind was not part of polite conversation. 

At times, though, I was so psychotic that I could barely contain myself. The delusions expanded into full-blown hallucinations, in which I could clearly hear people whispering. I could hear my name being called when no one was physically around-in a corner of the library, or late at night, in my bedroom where I slept alone.

While at Oxford, Elyn became the patient of a Kleinian psychoanalyst-Mrs Jones-with whom she formed a strong therapeutic alliance, and whom Elyn credits with being the “glue” that held her together, if precariously: “I was falling apart, flying apart, exploding-and she gathered my pieces and held them for me.”

 After 3 years of intense psychoanalytic work, and finishing her B Phil, again with high distinction, Elyn considered staying in England to continue therapy. But Mrs Jones encouraged her to return home. As expected with someone of Elyn’s psychic fragility, the prospect of losing this alliance induced great anxiety and led to a regression:

I go to my session. I threaten Mrs Jones with a knife. I am very psychotic and out of control. Mrs Jones is kind and gentle. She asks me for the knife and I give it to her. I start screaming. I throw myself against the wall. Mrs Jones and her husband restrain me. The ambulance arrives and takes me to the hospital. I become out of control again and am subdued. I am crying and sobbing that I will be leaving Mrs Jones . . . . Mrs. Jones had been the glue that held me together. With that glue soon to be gone, would I not shatter into a thousand pieces? The anxiety was overwhelming, and our sessions became more intense and hallucinatory.

You can’t leave. I won’t let you. Plupenitenary issues must be addressed. That’s a dress. Come home with me, please?

 I think, you see, that you make yourself confused because you want to avoid the pain of separation. It’s upsetting to think I have a life of my own, apart from you. You are trying to live inside me.

Elyn has fused with Mrs Jones by obliterating the person-to-person boundaries that nonpsychotic persons observe. She has crossed a line in her attempt to 

 the person who has provided the “glue” that allowed her to have a fledgling, brittle center of self. Note the neologism plupenitenary and the clang association addressed/dress, which are indications of formal thought disorder-an upshot of the psychotic mind’s need to create different words and different links between words.

While psychotic, Elyn was mostly lost to the world of reality, and had no insight. During a stable interval, she looked back on what that was like for her: “With psychosis, the wall that separates fantasy from reality dissolves; inside my head, the fantasies were real, and everything was actually happening. The images I saw, the actions I took, were all real, and it made me frantic.”

After graduation, Elyn left Oxford and Mrs Jones, returned to Miami and stayed with her parents until fall when she moved to New Haven to begin law school at Yale-where she continued her pattern of academic excellence and periodic ontic collapse. Her psychotic episodes became more severe and bizarre, requiring physical restraint and, eventually, her first antipsychotic medication, which she strenuously resisted verbally and physically. During the next few years, this drug (unnamed in the book), was replaced in turn by perphenazine, thiothixene, olanzapine, and clozapine, as eventual inefficacy and adverse effects demanded a change.

No drug completely erased Elyn’s psychotic symptoms, but each, for a time, lessened these symptoms and their impact, allowing her to finish law school, though not without taking a year off to deal with her illness. After Yale and several short-term jobs, Elyn was hired to teach at the University of Southern California Gould School of Law, where she was promoted to professor and given tenure. She married her longtime boyfriend, Will, who was as dedicated to serving her needs as any man possibly could be.

As Elyn lived with and against her illness, she became increasingly analytical and insightful as we can see in this cri de coeur: “I needed to understand what lay behind my terrible thoughts and feelings and how my psychosis served to protect me.”

 We might ask, How did she come to have these “terrible thoughts and feelings” in the first place? Whom or what did she need to be protected 

Elyn gives little space in her book to her parents, but what she does say about them seems probative. Both parents were emotionally distant from their daughter: “[T]here was a wall of appropriateness between us at all times; in fact, we’d spent years carefully constructing it, I on one side with my particular set of tools, they on theirs, with the tools they’d chosen.”

Had Elyn’s mother been “good enough,” in the Winnicott sense? And her father? At all stages of Elyn’s life, they seem to have been such vague presences, as if they were there, but not there for her. A family therapist noted that the parents had “made light of [her] illness and didn’t seem willing to accept its seriousness.”

 Elyn admits to being complicit in this cover-up: “I always did everything I could to 

 its seriousness: I cracked jokes, and laughed, and was gratified when they did the same. It was our way of handling it. It was our habit-and every family has its habits. The levity and irreverence made it possible for us to be together without everyone falling completely apart.”

 Laing might have said that Elyn and her parents had denied their being to save their being-

It eventually occurred to Elyn that a double trickery had ruled her life:

The illness-the entity-is always just off to the side, just barely out of my sight. But I know it’s there. And it tries to trick me into believing this isn’t the real Will, and this isn’t the real Steve [Elyn is describing Capgras syndrome, a delusion where she came to believe that her husband and closest friend were imposters], that reality isn’t reality, that I can kill thousands of people with my thoughts, or that I’m profoundly evil and unworthy. 

At the same time, I’m trying to trick the people around me. I’m OK. I’m functional, I’m fine. And maybe, sometimes, this determined effort to trick them tricks the illness itself. It’s like one big con. Steve says he’s never seen anyone who fights as I do. I don’t consider myself a fighter (and I certainly don’t come across as ferocious). But if he’s right, then perhaps in my childhood, and in this push-pull with my parents, one can see not only the beginnings of my illness, but the seeds of my health and strength as well. If I’m a fighter, perhaps it’s because that’s who they taught me to be

Without directly saying that her parents had a role in the development of her psychosis, Elyn, perhaps influenced by Laing and Bateson,

 considers that possibility. The “push-pull” with her parents sounds like the kind of mixed discourse, comprised of 2 incompatible and emotionally conflicting signals that Bateson characterized as a double bind. Bateson believed that such a conflict, 

, can, through a “twisting” of the psyche, lead the child to fragment reality and create the kind of psychotic thought, behavior, and discourse that Elyn lapsed into.

One can imagine Elyn as a child being in what Laing calls a state of ontological insecurity-profound anxiety about who she was and how she was to live-putting on a false self-“I’m fine, I’m strong; I don’t need you”-and the parents, caught up in their own self-absorption and blindness, wanting to believe her pose, responding with the same emotional coldness that they appear to have shown throughout Elyn’s life. This nonresponse to Elyn’s needs may have deprived her of the nurture necessary to trust the world sufficiently to take on the challenges of each new developmental milestone, leaving her mind and brain primed for developing a chronic mental illness.

Elyn knew that she would most likely never be entirely free of her illness. However, during a hospitalization at the Yale Psychiatric Institute, when she was initially floridly psychotic (“People are controlling me, putting thoughts into my head”

), and on a high dose of antipsychotic medication, she began to see that she could do something significant to help herself. After weeks of miserable and contentious confinement, her psychosis began to lift, and Elyn had an epiphany:

And then something threw a switch in my head, and I got it. I got it. The only barrier between me and the door out was me. I simply had to stop it. Stop voicing the hallucinations and delusions, even when they were there. Stop babbling incoherently, even if those were the only words that came to my lips; no, no, it was better to be quiet. Stop resisting; just behave. 

Being in a psychiatric hospital is nonsense, I thought. I am a law student, not a mental patient. I want my life back, damn it! And if I have to bite my tongue until it bleeds, I’m going to get it back.

By being “quiet” Elyn meant not just putting on an act but making an effort to at least mute her psychotic constructions, until she could face the world more realistically without them: “Maybe I couldn’t keep the thoughts from coming into my head, but I could organize them, and keep them from getting out. 

 For the first time, it seems, Elyn was asserting herself as an active agent against the illness itself, realizing that she had some complicity in the condition she found herself in, and some capacity to overcome that condition as well.

Near the end of the book, Elyn gives credit to Dr Freed, a psychoanalyst, who, she says, “helps me to understand how I sometimes use my psychotic thoughts to avoid the ordinary bad feelings that everyone experiences-sadness, rage, garden-variety disappointment . . . he tries to understand my psychotic thoughts as unconsciously motivated and meaningful (which of course they are).”

As she brings her story to an end, Elyn is still taking clozapine and is told by her psychopharmacologist that she will most likely have to take some antipsychotic medication for the rest of her life. She credits both psychoanalysis and psychopharmacology for the progress she has made. “While medication had kept me alive,” she acknowledges, “it had been psychoanalysis that had helped me find a life worth living.”

 For someone so long and so tightly in the grip of a psychotically transformed world as Elyn has been, the challenge of breaking that defensive structure is probably in some ways akin to breaking an addiction to a chemical substance.

Elyn’s descriptions of her psychotic (and normal) experiences are taken here to be primary data, in the way that numbers, and the statistical elaboration of these numbers, are considered data in the empirical approach to studying psychopathology. Hermeneutic analysis of what Elyn tells us about her fall into psychosis and her efforts to have a career and a life-her 

 of the phenotypes of the heterogeneous illness we call schizophrenia. Her narrative draws us into the interior world of the psychotic person, territory that few clinicians attempt to access or assess.

The Center Cannot Hold: My Journey Through Madness

. New York: Hyperion;  2007.
2. Laing RD. 

The Divided Self: An Existential Study in Sanity and Madness

. Baltimore: Penguin  Books; 1965.
3. Bateson G, Jackson DD, Haley J, Weakland J. Toward  a theory of schizophrenia. 

In spite of a chronic mental illness (schizophrenia)and a psyche that increasingly blurred the boundaries between fantasy and reality, this lawyer and professor graduated from Vanderbilt with a perfect academic record.

Eliciting the Phenomenon of Schizophrenia From an Autobiographical Narrative

In 2004, the news that Americans had committed abuse and mistreatment in Abu Ghraib and Guantanamo was shocking. Even more alarming were the revelations that physicians, psychiatrists, and other mental health professionals had assisted with interrogations that bordered on torture.

In the span of just 2 generations, the United States had drifted from condemning Nazi physicians at the Nuremberg Trials for their collusion with torture, in­human experimentation, and cruel mistreatment to justifying waterboarding in the pursuit of better intelligence.

As a retired brigadier general and Army psychiatrist, committed to a strong military and national defense, I find these scandals to be most disturbing. The complicity of psychiatrists and other physicians clearly deviated from the fundamental ethical principles of the medical profession and military medicine. My generation of soldiers, who had served during the Vietnam War, vowed not to repeat the misdeeds of the My Lai massacre and rampant indiscipline we witnessed.

But after the attack on the World Trade Towers, fear and anger dominated the country’s emotional climate and the principles of our profession were hijacked. The incessant drumbeat of political rhetoric that “the war on terror is a war like no other” and that “we must take all measures possible to stop the enemy” made it somehow easier for psychiatrists to apply their skills and training to exploit the vulnerabilities of prisoners. To this day, former government officials justify cruel and inhuman treatment of detainees at Bagram and Guantanamo with unsubstantiated assertions that their confessions led to the trail of Osama bin Laden.

The public supported such conduct, and the television show 

 gained wide popularity as viewers were captivated by threats of violence and new gimmicks for bringing the bad guys down. Even the presidential candidates in 2008 were ambushed by questions that judged their fitness to be Commander in Chief by their willingness to torture a suspect who planted a “ticking bomb.” But there is no evidence to confirm the assertions that torture of prisoners has helped the war effort at all.

The plain fact is that nothing that has been claimed in the name of defending our country can justify cruel, inhuman, and degrading treatment of another man or woman. Torture, in any form-light or heavy-is not a tool of interrogation or useful for gathering good intelligence. It is a propaganda tool, and it degrades the perpetrator as well as the victim. This is not just the rhetoric of bleeding heart progressives. It is the opinion of more than 50 retired admirals, generals, and senior government officials convened by Human Rights First to discuss this issue, and our conclusions can be stated simply:

General George Washington laid down the directive that American soldiers will treat the enemy humanely and conform to high moral and ethical principles on the battlefield.

Experienced interrogators acknowledge that information extracted by the use of torture is unreliable.

Veteran FBI and military interrogators have spoken out publicly against the use of physical pressure in interrogation.

 “. . . a person who is tortured is damaged, but so are the torturer, the nation, and the military.”

Torture has long been associated with political repression and with regimes without any semblance of an independent judiciary or media. The Soviet Union’s imprisonment of dissenters and forced use of psychotropic medication on them, the Khmer Rouge’s torture of thousands of people in Cambodia, and the Augusto Pinochet regime’s brutality against prisoners in Chile all bear witness to the association between totalitar­ian or authoritarian regimes and their use of torture.

The human rights lawyer Leonard Rubenstein and I wrote in March 2010

The medical staff at the CIA and the Pentagon played a critical role in developing and carrying out torture procedures. Psychologists and at least one doctor designed or recommended coercive interrogation methods including sleep deprivation, stress positions, isolation, and waterboarding. The military’s Behavioral Science Consultation Teams evaluated detainees, consulted their medical records to ascertain vulnerabilities and advised interrogators when to push harder for intelligence information. Psychologists designed a program for new arrivals at Guantnamo that kept them in iso­lation to “enhance and exploit” both their “disorientation and disorganization.”

Medical officials monitored interrogations and ordered medical interventions so they could continue even when the detainee was in obvious distress. In one case, an interrogation log obtained by 

magazine shows a medical corps-man ordered intravenous fluids to be administered to a dehydrated detainee even as loud music was played to deprive him of sleep.

We cannot dismiss the psychiatrists who participated in interrogations in Guantanamo and the mental health professionals who helped devise the abusive practices as mere rogues or outliers. They were actors on a much larger stage. They were swept up by a pervasive and persuasive attitude that subsumed the country and energized a military plan to “hunt down the criminals wherever they may be hiding.” The Department of Defense issued policy accordingly, and the Office of the Assistant Secretary for Health Affairs contended that the legitimate objective of fighting terrorism trumps the ethical responsibility of the healing practitioner. In their eyes, “the ends justify the means” and a few brutalized prisoners were a small price to pay for protecting the citizens of the United States.

But, in truth, the use of torture and the practice of cruel, inhuman, and degrading treatment detracted from the military mission and compromised the international stature of our country. It undermined the effectiveness, credibility, and ethical foundations of the medical professionals. Torture and abuse harmed the victims, damaged the perpetrators, and weakened national security. My findings and opinions reflect hundreds of hours of clinical interviews with detainees in Guantanamo and hundreds more reviewing medical records and reports of interrogations. Both the interviews and records expose the techniques of harsh interrogation, including stress positions, extremes of temperature, long-term isolation, waterboarding, sleep deprivation, instilling fear through the use of dogs, threats of death or severe harm, bombardment by loud music, severe humiliation, and physical force.

Research studies, direct clinical observations, and reviews of medical records document the adverse and harmful effects of enhanced interrogation. Sleep manipulation contributes to cognitive impairment and disruption, with psychotic features emerging within 1 week, and it can lead to self-harm, including symptoms resembling paranoid schizophrenia. Sensory deprivation, including hooding and isolation, leads to severe anxiety, depression, and psychotic-like thinking, with serious health consequences. Repetitive exposure to frightening and life-threatening circumstances contributes to debilitating PTSD.

Victims of abusive interrogation suffer with anxiety and depressive disorders, manifest brief psychotic disorders such as delusions and hallucinations, develop obsessive-compulsive disorder, and are at greater risk for suicide. Many are demoralized and hopeless. Statements made by detainees in an impaired mental state when interrogated have not been admissible in court proceedings.

Standing up for human rights has come front and center, as both a matter of national strategy and a measure of human decency. Historically, the human rights stance against torture has been unequivocal, one of the few absolutes in human rights law: It is never permitted, never excused, never to be balanced against national needs or interests-even in cases of national emergency. Torture is forbidden under the laws of war. It is considered a war crime under the Geneva Conventions.

By reflecting on the ethical principles and traditions of our healing professions, a stronger case for national security can be put forward against torture and mistreatment:

 Victims of torture and mistreatment breed political instability and discontent, weakening governments and societies.

 Torture and mistreatment violate the intents and purposes of medical healers, and participation in any way corrupts the ethical foundations of the practitioners and professions.

 Physicians are not interrogators, any more than they are fighter pilots or infantrymen. The military and other government agencies have other professionals to do those tasks, and calling on physicians to fill such roles is irresponsible and ineffective.

Physicians enjoy special trust and confidence across almost all societies. That trust is undermined with participation in harmful, coercive, and abusive conduct that is neither doctor-like nor appropriate.

In 1947, our nation and its allies tried and sentenced the Nazi physicians who violated basic principles of medical ethics. In 2003, the political dynamics and national sentiment induced physicians, including psychiatrists, a well as other health care professionals to commit actions that violated core ethics. Much has improved since the dark days of 9/11, but our nation has been damaged. Where once the symbol of our great democracy was the Statue of Liberty, it has now become the image of that poor hooded man in detention with wires strung from his hands and feet. We have damaged the lives of thousands of people who will suffer the consequences for many decades to come. Our men and women on the front lines are endangered because of the increased risk of retaliatory measures. We are not safer because of these misguided policies and how we have acted as a country. Physicians have a collective duty to oppose torture and abuse-to uphold historically shared beliefs and convictions.

Thomas J. Mental health professionals in the “enhanced” interrogation room. 

Rubenstein LS, Xenakis SN. Doctors without morals. 

http://www.nytimes.com/2010/03/01/opinion/01xenakis.html?scp=1&sq=doctors%20without%20morals%20march%201%202010&st=cse

 The plain fact is that nothing that has been claimed in the name of defending our country can justify cruel, inhuman, and degrading treatment of another man or woman. Torture, in any form-light or heavy-is not a tool of interrogation or useful for gathering good intelligence. 

Condemning Torture and Abuse: A Call to Action

The theory of the role inflammation in the etiology of schizophrenia was formulated more than 100 years ago and has recently gained momentum with numerous new data that support this theory. For example, it is well known that the integrity of the blood-brain barrier reduces entry of inflammatory cells and antibodies into the brain. Usually only a few mononuclear cells, activated T cells, and macrophages migrate into the CNS.

 Comparison of cerebrospinal fluid samples from patients with schizophrenia and from control patients revealed that the proportion of mononuclear macrophages is significantly higher in patients with schizophrenia.

The importance of macrophages and T lymphocytes, and the cytokines produced by them, has been highlighted in the macrophage–T-cell theory of bipolar disorder and schizophrenia.

According to this theory, chronically activated macrophages, microglia, and T cells synthesize inflammatory compounds that destabilize the brain and lead to schizophrenia.

 Monocytes, also known as the mononuclear phagocyte system, differentiate into macrophages or dendritic cells on activation. They originate in the bone marrow, migrate in the blood vessels, and penetrate all organs. Monocytes carrying CD54 receptors bind to intracellular adhesion molecules (ICAMs), which are important factors in the transmigration of monocytes through endothelial cells in the blood vessels.

Levels of soluble ICAMs have been shown to be increased in patients who have schizophrenia.

Of great interest are findings that microglial cells-the macrophages of the brain-are activated during psychosis.

 Cells visualized with a positron emission tomography tracer (PK11195) that binds to peripheral benzodiazepine receptors, an indicator of microglia activation, were found to have greater receptor expression in patients with recent-onset schizophrenia.

 Activated microg-lia stimulate astrocytes to produce S100B, a marker of inflammation that is considered to be the equivalent of C-reactive protein in the brain.

 Serum S100B levels are elevated in patients with schizophrenia, and antipsychotics such as haloperidol and clozapine have been shown to decrease S100B release from glial cells.

Under certain environmental conditions, such as exposure to infectious agents or ischemic conditions, macrophages produce inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor Î± (TNF-Î±), IL-6, and chemokine (CC motif) ligand 2.2 Levels of these molecules repeatedly have been shown to be elevated in schizophrenia patients.

Mice models of immune challenge have shown that maternal viral and bacterial infections during pregnancy lead to behaviors in offspring that are considered rodent analogues of schizophrenia-like symptoms: deficits in prepulse inhibition, novelty-induced hyperactivity, and cognitive impairments.

 These behavioral alterations are thought to be caused by imbalances in proinflammatory and anti-inflammatory cytokines.

 Proinflammatory cytokines, such as IL-1Î², IL-6, and TNF-Î±, can signal through the endothelial cells to cause alterations in the tight junction structure, leading to increased permeability of the blood-brain barrier and alterations in brain structure and function.

Supporting the animal model research, studies in humans suggest that gestational exposure to infection may contribute to the etiology of schizophrenia.

 Moreover, there is extensive literature that supports the role of infectious agents in schizophrenia etiology.

 A very interesting review in 2008 discussed how some strong schizophrenia candidate genes, including immune system genes, play direct roles in regulating the life cycle of several pathogens and how understanding the interplay between gene function and pathogen exposure may help explain the role of gene-environment interactions in schizophrenia development.

Association of immune system genes with schizophrenia

Schizophrenia is a very heterogeneous disorder with a wide array of symptoms and extraordinary variety among individuals. The impingement of different environmental factors in genetically susceptible individuals probably determines the overall expression pattern and severity of the illness. Furthermore, schizophrenia probably is not caused by mutations in just a few specific genes but rather is caused by the disruption of any number of genes involved in key developmental signaling pathways, such as the immune system pathway.

Understanding how genetic makeup, in combination with environmental stimuli, modulates expression of immune system genes and, in turn, regulates brain function and behavior, and how this could lead to the occurrence of mental disorders is an area of much research. In the past few years, several studies have demonstrated the association between genetic variants in immune system genes and schizophrenia, which further supports the hypothesis that immune system dysregulation plays an important role in the etiology of schizophrenia (

Two controlled studies of patients with schizophrenia found significant associations between variants mapping to the region of chromosome 6 that forms part of the major histocompatibility complex (MHC) and increased risk of schizophrenia.

 The MHC has also been associated with increased risk of autoimmune disorders.

 A large study in Denmark found that a family history of any autoimmune disorder is associated with a 45% increased risk of schizophrenia.

In a genome-wide association study, Lencz and colleagues

 found evidence that 2 immune system genes, colony-stimulating factor 2 receptor Î± and IL-3 receptor Î± (

), are associated with schizophrenia. Two later studies further support the finding of the association between 

 A single-nucleotide polymorphism in the first intron of the interferon Î³ gene was found to be associated with a 1.66-fold higher risk of paranoid schizophrenia in males, but not in females.

 An evaluation of genes in the IL-18 pathway revealed associations between schizophrenia and herpes simplex virus seropositivity.

Significant differences in both genotype and allele frequencies of 

 p40 gene promoter variants were found between patients with schizophrenia and controls.

 gene promoter polymorphism and schizophrenia was also found.

 gene promoter has also been associated with schizophrenia.

 receptor antagonist) and susceptibility to schizophrenia has been reported recently.

), one of the strongest schizophrenia candidate genes currently identified, have been shown to interact synergistically with 

polymorphisms to increase the risk of schizophrenia.

Our group recently reported evidence of an association between 

 and immune dysregulation. A valine to leucine mutation in the transmembrane region of 

 which was previously identified to be associated with schizophrenia, was found to be associated with higher levels of proinflammatory cytokines in plasma and increased production of proinflammatory cytokines in lymphoblastoid cell lines.

 This is the first report of the association be-tween an 

Stress and immune system reactivity play a major role in the development and exacerbation of psychotic symptoms in schizophrenia.

 First-time outbreaks of psychosis and schizophrenia are more frequent in individuals who are exposed to high levels of stress, such as newly recruited military personnel.

 Evidence suggests that with increasing life events or situational stress, psychotic symptoms increase, possibly because of the overactivation of the immune system and overexpression of inflammatory cytokines.

-methyl-d-aspartate (NMDA) receptor, which is caused by excessive cytokine-induced glutamate release from astrocytes. Increased inflammation in the CNS also leads to impaired function of oligodendrocytes, which are damaged as a consequence of overexposure to cytokines such as TNF-Î±; this leads to impaired myelination.

 These processes have been shown to be altered in patients with schizophrenia.

Findings from these studies suggest that exposure to stress or immune challenges (either through stressful life events or infections) produces a host of biological processes that in genetically susceptible individuals can lead to the development of psychiatric disorders, such as schizophrenia.

Levels of proinflammatory cytokines have been shown to be increased not only in patients with schizophrenia but also in patients with bipolar disorder. Overlapping but distinct gene expression patterns have been found in the monocytes of patients with schizophrenia and bipolar disorder. By performing a comprehensive analysis of inflammatory molecules involved in schizophrenia and bipolar disorder, it may become possible to identify specific disease signatures, which will provide valuable clues to understanding the progression to a particular disease.

It is possible that dysregulation of a particular set of cytokines may lead to schizophrenia, while another set may lead to depression or bipolar disorder. Similar to transcriptome arrays for the analysis of inflammatory cytokines, proteomic arrays are designed to detect specific inflammatory fingerprints and may help identify psychiatric patients who will benefit from adjunctive anti-inflammatory therapy. For example, by analogy, patients treated with TNF antagonists (monoclonal antibodies against TNF) for immune diseases, such as psoriasis, Crohn disease, and rheumatoid arthritis, describe improvement not only in somatic symptoms but also in depression scores and quality of life.

It was recently reported that immunomodulation therapy can change aberrant monocytes that cause inflammation and the production of cytokines by restoring the monocytes/macrophages to their neuroprotective state, therefore reducing inflammation and normalizing the cellular environment of critical nerve cells.

 This approach was used in a phase 1 clinical study of the immunomodulator NP001 for the treatment of amyotrophic lateral sclerosis.

 Studies such as this are a source of optimism that immunomodulation may open up an alternative method for treatment of schizophrenia.

A number of different theories have been proposed to explain the wide range of symptoms in schizophrenia, including alterations of the dopaminergic and/or glutamatergic systems, abnormal neurodevelopment, and the theory of immune system imbalance.

 While all these theories are supported by a strong body of evidence, it is possible that they are not mutually exclusive and in fact may be interconnected. For example, recent studies indicate that the kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids, is activated by proinflammatory cytokines.

 It has been shown that these acids regulate NMDA receptor activity and may also be involved in dopamine regulation.

 Therefore, although the possibility of the interrelationship between the currently proposed schizophrenia theories remains to be demonstrated, a unifying theory that explains all the different lines of evidence may soon start to emerge.

 Silverman AJ, Sutherland AK, Wilhelm M, Silver R. Mast cells migrate from blood to brain. 

 NikkilÃ¤ HV, MÃ¼ller K, Ahokas A, et al. Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. 

 Drexhage RC, Knijff EM, Padmos RC, et al. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. 

 Smith RS. A comprehensive macrophage-T-lymphocyte theory of schizophrenia. 

 Lawson C, Wolf S. ICAM-1 signaling in endothelial cells. 

 van Berckel BN, Bossong MG, Boellaard R, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C] PK11195 positron emission tomography study. 

 Sen J, Belli A. S100B in neuropathologic states: the CRP of the brain? 

Zhang XY, Xiu MH, Song C, et al. Increased serum S100B in never-medicated and medicated schizophrenic patients. 

 Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. 

 Of mice and mental illness [editorial]. 

 Nawa H, Takei N. Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines. 

 Ek CJ, Dziegielewska KM, Stolp H, Saunders NR. Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (

 Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. 

 Yolken RH, Torrey EF. Viruses, schizophrenia, and bipolar disorder. 

 Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to 

 in patients with schizophrenia: a meta-analysis. 

 Carter CJ. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and 

 Stefansson H, Ophoff RA, Steinberg S, et al. Common variants conferring risk of schizophrenia. 

 Li T, Li Z, Chen P, et al. Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese. 

 van Heel DA, Franke L, Hunt KA, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. 

 International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley JB, AlarcÃ³n-Riquelme ME, Criswell LA, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. 

 Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. 

 Lencz T, Morgan TV, Athanasiou M, et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. 

 Sun S, Wang F, Wei J, et al. Association between interleukin-3 receptor alpha polymorphism and schizophrenia in the Chinese population. 

On the wide range of symptoms in schizophrenia, including alterations of the dopaminergic and/or glutamatergic systems, abnormal neurodevelopment, and the theory of immune system imbalance.

The Link Between Immune System Dysregulation and Schizophrenia

Newly developed blood tests for schizophrenia and for depression designed to augment current diagnostic approaches have attracted increased attention at recent major scientific meetings.

At this year’s American Psychiatric Association’s annual meeting in Hawaii, Professor Sabine Bahn, MD, PhD, MRCPsych, Director of the Cambridge Centre for Neuropsychiatric Research (CCNR) and Director/Cofounder of Psynova Neurotech Ltd, described her 15-year search for biomarkers of neuropsychiatric disorders and the development of VeriPsych-reportedly the first blood-based diagnostic test to confirm the presence of recent-onset schizophrenia. It is not a genetic test, but rather an automated test that uses a single serum sample to identify 51 protein biomarkers. It is designed to help mental health professionals arrive at a diagnosis.

Psynova Neurotech, established in 2005 by Bahn and Chris Lowe, PhD, Director of Cambridge University’s Institute of Biotechnology, is a spin-off company created to commercialize CCNR’s findings. Psynova then partnered with the Rules-Based Med-icine (RBM) of Austin, Tex, a CLIA-certified testing laboratory known for its Multi-Analyte Profiling technology platform. In recent months, Psynova Neurotech became a wholly owned subsidiary of RBM, and RBM became a wholly owned subsidiary of Myriad Genetics, taking the name Myriad RBM, Inc.

For Bahn, who is also Chair of Translational Neuroscience at Erasmus Medical Centre in Rotterdam, the Netherlands, the search for biomarkers in psychiatric disorders is a personal pursuit. Her father had bipolar disorder.

Biomarkers have multiple applications, Bahn explained to APA attendees. These include the identification of high-risk individuals and disease subgroups that could serve as target populations for intervention trials; facilitation of “objective” diagnosis; monitoring of patient response to drug treatments; and assessment of patient compliance.

According to Bahn, she and the more than 20 scientists at CCNR are seeking to develop molecular diagnostics for major neuropsychiatric disorders and to determine the cellular mechanisms that regulate the expression of biomarker molecules altered in these states so as to develop novel therapeutic approaches.

CCNR’s lab, she said, uses ad-vanced molecular profiling techniques (microarrays, proteomics, lipidomics, and metabolomics) to globally investigate abnormalities in gene/protein/metabolite/lipid “expression” in postmortem human brain tissue and in blood and other samples derived from patients and matched controls, to establish evidence-based hypotheses.

For example, Bahn told APA attendees that in the team’s examination of postmortem brain tissue of patients with schizophrenia, they found evidence of abnormal glucose utilization. Schizophrenia, she said, might be considered “diabetes of the brain.”

Bahn and her team then moved to cerebrospinal fluid (CSF) in living patients “to see if we could identify the same changes as seen in the postmortem brain.”

The team studied CSF samples from drug-naive or minimally treated patients with first-onset paranoid schizophrenia and demographically matched healthy controls.

“Our findings suggest alterations in glucoregulatory processes in CSF of drug-naive patients with first-onset schizophrenia. Short-term treatment with atypical antipsychotic medication resulted in a normalization of the CSF disease signature in half the patients well before a clinical improvement would be expected,” she said.

Bahn’s team discovered a set of 51 biomarkers with linkages to  schizophrenia and to various biochemical pathways, including  inflammation and metabolism, as well as cell-to-cell signaling. 

The results also suggest that the initiation of antipsychotic treatment during a first psychotic episode may influence treatment response and/or outcome.

 Newly developed blood tests for schizophrenia and for depression designed to augment current diagnostic approaches have attracted increased attention at recent major scientific meetings.

Paranoid Schizophrenia

A Potential Schizophrenia Treatment Trial Falls Short

Eliciting the Phenomenon of Schizophrenia From an Autobiographical Narrative

Condemning Torture and Abuse: A Call to Action

The Link Between Immune System Dysregulation and Schizophrenia

Blood Tests for Diagnosis of Schizophrenia and Depression?

Traumatic Brain Injury Among Veterans Returning From Afghanistan and Iraq

Asking the Right Question

Inflammation, Psychosis, and the Brain

Patient Advocacy-and a Deadly Outcome

Psychiatric Testimony and the Insanity Defense