A startling new approach to schizophrenia

Predicting the onset and even heading off this terrible psychosis is the goal of this Jerusalem psychiatrist.

Uriel Heresco-Levy (photo credit: Judy Siegel)
Uriel Heresco-Levy
(photo credit: Judy Siegel)
Someday, it may become routine for schoolchildren with serious behavioral problems to be screened for early symptoms and markers of schizophrenia. Those found at risk would be given naturally occurring amino acids to delay or even prevent the onset of this currently incurable psychiatric disorder. That is the dream of Prof. Uriel Heresco-Levy, head of the psychiatric branch and director of the Schizophrenia Research Program of Jerusalem's Herzog Hospital, who also teaches at the Hebrew University-Hadassah Medical School. The veteran psychiatrist and neuropsychopharmacology researcher has spent nearly two decades doing pioneering investigations of glutamate, glycine and D-serine - vital neurotransmitters (chemical messengers) produced in the brain that seem to be involved in the disease. Drugs that block glutamate (such as ketamine and phencyclidine) have also been found to mimic the "positive" and "negative" (deficit) symptoms and cognitive problems involved in schizophrenia. The "positive symptoms" include delusions and hallucinations, while the " negative" ones include apathy, reduced emotion and lack of initiative. The cognitive symptoms involve reduced attention, learning abilities and executive function, he explains. "Patients may be violent in reaction to delusions or hallucinations, but this is not very common. Schizophrenia patients are not serial killers." If early (prodromal) screening tools became available, pupils whose grades, concentration and class performance have declined or who seem depressed or socially withdrawn - difficulties that could easily hint at familial, social and other causes - could undergo tests to determine whether they are likely to develop schizophrenia. This would be particularly true for children or teenagers who have relatives suffering from schizophrenia or brain-tissue deficits demonstrated by imaging techniques. It's a very complex disease, says Heresco-Levy during an interview in his modest office overlooking bushes and cats - dozing in the sun on a chair - that have "adopted" the psycho-geriatric hospital. Not only genetics is involved; the risk for schizophrenia is also apparently affected by a child's early environment (maybe even in the uterus), psychology, neurobiology and social influences. Taken from the Greek words for "split" and "mind," it has nothing to do with to multiple personality disorder, in which a patient adopts different personas. Schizophrenia is a psychosis with disorganized thinking and incoherent speech, abnormal perception or expression of reality, auditory hallucinations, paranoid or bizarre delusions and major social and occupational dysfunction. Delusions, by the way, are affected by the cultural and social environment. In Israel, some patients think they are the Messiah, "while in the southern US, patients may think they are Elvis Presley," the Herzog doctor says. Anywhere from 0.4% to 1% of the population are affected by schizophrenia, and it hits men and women of all races and ethnic backgrounds equally. The cause of great suffering to patients and their families, it is regarded as the most disabling mental disorder. "Most schizophrenia patients have a low socioeconomic status, but this is not because schizophrenia preferentially targets the poor, but mainly because it brings about drastic impairment of social and occupational skills," says the psychiatrist, who was born in Romania and came on aliya in 1973. Symptoms usually appear between the age of 15 and 25. Some patients may also suffer from depression, anxiety, alcoholism and drug addiction. Studies of identical twins raised in separate families, says Heresco-Levy, have shown that if one twin has schizophrenia, the other is more likely to get it, but it is far from a sure thing. Thus while there is a genetic component to the disorder, there is not one gene or two that, if inherited, doom children to schizophrenia. ALTHOUGH it was once thought that overbearing, control-freak parents - especially mothers - drive children to schizophrenia, Heresco-Levy says this does not create schizophrenia. "When a child is diagnosed, such parents feel guilty. Today we speak about a biological disease involving brain development. Expressed emotions such as criticism, rejection and emotional overinvolvement don't cause the disease, but once it occurs, such factors can make it more serious," added Heresco-Levy, who did his BA at the Hebrew University in the social sciences, served in the Israel Defense Forces, went to Tel Aviv University to study medicine and specialized in psychiatry at Herzog. "It's hard to find the moment that symptoms first appear, but a first psychotic episode is usually easily recognized." In Herzog's two active psychiatric departments with a total of 70 beds (one department for men and one for women), about 70% of inpatients suffer from schizophrenia. Improved psychotropic drugs over the past decade or two have minimized the number of patients with depression, bipolar disease, obsessivecompulsive disorder, allowing them to have better lives, with treatment and social support in the community. "We are glad that more patients live outside now - even if their disorder continues - as they have a higher quality of life and make a contribution to society," says Heresco-Levy. Some with schizophrenia can also be in the community. He points to John Forbes Nash, a Nobel-Prize-winning economist mathematician whose life with schizophrenia was depicted in the book and movie, A Beautiful Mind. But he is an exception, and schizophrenia is tightly bound with stigma. "The more seriously ill patients are in the wards." In the early 1950s, chlorpromazine (Thorazine) - originally an anti-nausea treatment that also alleviated psychotic symptoms - was the first anti-psychotic drug, but it was not specifically meant for schizophrenia. Working as an "antagonist" to dopamine, it blocks dopamine receptors on the ends of nerve cells and was found to improve "positive" symptoms significantly but not the "negative" and cognitive ones. The earlier generation of anti-psychotic drugs, which were dopamine suppressors, came with Parkinson disease-like side effects. Many institutionalized patients, recalls Heresco-Levy, were affected by muscular stiffness, tremor and involuntary movements. Early second-generation anti-psychotic drugs such as clozapine, resperidone and olanzpine each has a unique mechanism. Their effects on patients were better compared with the earlier drugs but the conclusions on what were more effective is not clear. Some may affect the motor nervous system, others may cause havoc with the metabolic system. "Today, we are far from having an ideal treatment, which causes frustration among psychiatrists. That is a major reason why I like to combine research and clinical work." Among the many types of neurotransmitters that make brain activity possible, amino acids such as glutamate, glycine and D-serine were chosen by Heresco-Levy for his laboratory and clinical studies. Sixty percent of neurons use glutamate as their main neurotransmitter. Glycine, the simplest type of amino acids found in the protein of all plants and animals, is released into the synapse (the gap between neurons, as nerve cells in the brain are not directly connected). Glutamate, glycine and D-serine affect the function of the N-methyl-d-aspartate (NMDA) receptor. This type of glutamatergic receptor is found to be abnormally low in number in the brains of autopsied schizophrenic patients. Furthermore, it plays a crucial role in brain development and cardinal brain functions such as synaptic plasticity, learning and memory. He notes that PCP - originally a type of surgical anesthesia that became an illegal "street drug" used by addicts (and known as "angel dust") - is able to block NMDA receptors. This drug was known to cause not only "positive" but also "negative" and cognitive schizophrenia-like behavior. As schizophrenia is a human disease, and there are no good animal models for it, PCP effects served as a human model for the disease. "In the early 1990s, I was doing a research fellowship at Yeshiva University's Einstein School of Medicine with Prof. Daniel Javitt, a world pioneer in glutamate research.While studying antagonists of NMDA-type glutamate receptors, we reasoned that if NMDA antagonists cause schizophrenia-like symptoms, enhancing the functions of such receptors might help against schizophrenia." He has since used a combination of regular antipsychotic drugs combined with glycine and D-serine, which are natural amino acids in the brain and stimulate NMDA function. "The results were interesting; there were fewer negative symptoms." TODAY'S CLINICAL research is aimed at finding a drug that works on novel mechanisms, and on giving drugs much earlier in the hope they will bring symptoms to a halt or delay their onset, he explains. "So far, glutamatergic drugs have been found to work in some but not in all studies. This compound seemed to work better with treatment-resistant schizophrenia patients, and the pharmacological industry is now developing synthetic drugs that mimic glycine and D-serine actions, but no glutamatergic drugs are being marketed." But giving natural amino acids to teenagers is a problem. One vitamin supplement company sells glycine for improving moods and causing relaxation, but if you took the amount hypothesized to work on prodromal symptoms, you'd have to swallow nearly a bottleful a day. "If you tell parents that their children are at high risk of becoming schizophrenic, they will not easily accept it. Preventive treatment is an entirely new concept in psychiatry and involves clinical as well as ethical dilemmas. We need more solid data before this concept will become fully accepted.We don't know if glutamatebased drugs may prevent the disease or just postpone it - but they can reduce symptoms." He has no doubt that the next generation of schizophrenia treatments will be glutamatergic drugs. "Furthermore, this type of medication may also be relevant for other disorders. We recently performed clinical trials that found evidence that glutatamergic drugs can help not only schizophrenia but also depression, posttraumatic stress disorder and Parkinson's disease. Yet these possible treatments are not established and certainly not in the health fund basket. It is research for the future."