The great psychoanalyst Sigmund Freud thought that his favorite technique could
treat every mental disorder. He also often blamed parents – especially mothers –
for the psychiatric problems of patients. He was exaggerated, but psychoanalysis
can relieve neurosis, personality disorders and other mental problems.
recent decades, psychiatry has swung to the opposite end of the spectrum –
regarding mental illness as a biological disorder involving imbalance of
chemical brain messengers called neurotransmitters that can be relieved – even
if not perfectly without side effects – by medications.
“You don’t have
to throw the baby out with the bath water,” says Prof. Uriel Heresco-Levy, chief
of psychiatry at Jerusalem’s psychogeriatric Herzog Hospital.
mental problems that can benefit from psychotherapy, but there certainly are
patients with mental illness such as schizophrenia and depression who can
benefit from medications, and a new era to treat such psychiatric disorders with
drugs is ahead,” he told The Jerusalem Post
in a recent interview in his office.
Even Parkinson’s disease, which is a neurological disorder, seems to involve
psychiatric symptoms that can be relieved with “modulators” of
Clinical depression is clearly a problem of the
connectiveness of the synapses [gaps between neurons] in the brain. and
neurotransmitters apparently are involved in schizophrenia ,” said the Romanian-
born psychiatrist, who is director of Herzog’s schizoprenia research program.
Heresco-Levy, who also teaches at the Hebrew University-Hadassah Medical School,
has spent two decades doing pioneering investigations of the neurotransmitters
glutamate, glycine and D-serine.
Taken from the Greek words for “split”
and “mind,” schizophrenia 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.
Heresco-Levy, it may become routine for schoolchildren with serious behavioral
problems to be screened for early symptoms and markers of
Those found at risk may be given naturally occurring amino
acids to delay or even prevent the onset of this currently incurable psychiatric
In schizophrenia, patients have what are called “positive” and
“negative” symptoms can be alleviated with medications. “Positive symptoms are
not beneficial, despite the term,” said Heresco-Levy, but include phenomena
whose presence is abnormal such as hallucinations and thought disorganization,
while negative ones refer to deficits, or the lack of normal
There are also cognitive symptoms such as memory problems and
learning difficulties. Drugs that block the receptors of the neurotransmitter
known as glutamate mimic the positive and negative symptoms and cognitive
problems involved in schizophrenia. The positive symptoms include delusions and
hallucinations, while the negative ones include apathy, reduced emotion and lack
Anywhere from 0.4 percent to 1% of the population are
affected by schizophrenia, and it equally hits men and women of all races and
ethnic backgrounds. The cause of great suffering to patients and their families,
it is regarded as the most disabling mental disorder.
patients have a low socioeconomic status because the disease brings about
drastic impairment of social and occupational skills.
“When a child is
diagnosed with schizophrenia, his 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
earned his MD at Tel Aviv University’s Sackler Medical Faculty and specialized
in psychiatry at Herzog.
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
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. An agonist is
a chemical that binds to some receptor of a cell and triggers a response by that
cell. Agonists often mimic the action of a naturally occurring substance. While
an agonist causes an action, an antagonist blocks the action of the agonist.
Schizophrenics have average life expectancies that are 12 to 15 years less than
others because of higher suicide rates and physical problems for which they
don’t seek medical help.
The earlier generation of anti-psychotic drugs,
which were dopamine suppressors, came with Parkinson disease-like side effects.
Many institutionalized patients, recalled Heresco-Levy, were affected by
muscular stiffness, tremor and involuntary movements.
“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
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.
simplest type of amino acids found in the protein of all plants and animals, is
released into the synapse. 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
IN THE early 1990s, Heresco-Levy was doing a research
fellowship at Yeshiva University's Einstein School of Medicine in New York 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.”
worked on the drug phencyclidine, a “street drug” with hallucinogenic effects
that is also known as PCP or “angel dust.” PCP works mostly as an NMDA receptor
antagonist, which blocks the activity of the NMDA receptor and, like most
antiglutamatergic hallucinogens, is significantly more dangerous than other
categories of hallucinogens.
Glutamatergic drugs have been found to work
in some but not in all studies. These compounds 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 yet being marketed.”
He has no doubt that the
next generation of schizophrenia treatments will be drugs involving the action
of glutamate in which it functions as a transmitter. Heresco-Levy is also
convinced that such drugs can also help patients with chronic depression and the
motor and mental symptoms in Parkinson’s disease, which causes not only shaking
and difficulty walking but also a persistent feeling of sadness and loss of
“For years, there were not many new things in
psychopharmacology and the treatment of neuropsychiatric diseases,” said
“New drugs that were introduced during the last 20 or 30
years were ‘me-too’ medications based on the same mechanism of monoamines,
adrenalin, dopamine, acetylcholine and serotonin.
However, research he
and others have done on glutamate offers promising understanding of what causes
the diseases and new treatments.
“It’s surprising that this field hadn’t
been researched for so long.
It is very important but complicated, as it
involves different receptors systems in the brain,” the Herzog psychiatrist
“A large amount of glutamate is toxic in the brain and elsewhere in
the body, so there was reluctance to deal with it. We were among the first
researchers in the world into NMDA receptors.” Today, Javitt comes to Israel
from time to time and has two or three other research groups at Harvard and
Heresco-Levy conducts research on glutamatergic medications alone
“We have shown that schizophrenic patients who get NMDA
agonists, they show an improvement in their negative symptoms, such as apathy,
difficulty in personal relations and a lack of pleasure,” the Herzog
His most recent research, involving small patient
studies, were published in Movement Disorders and the International Journal of
Although they involved only a few dozen patients
each, they were clear cut and convincing.
Today, the Roche pharmaceutical
company is conducting phase III trials on glycine reuptake inhibitor for
schizophrenic patients. “The drug companies have no interest in natural
compounds because of patent difficulties, so they prefer new synthetic
compounds. This is good because we expect this approach will bring a revolution
in psychiatry, the first since the emergence of dopamine and serotonin drugs.
Our schizophrenia research on NMDA agonists affects not only negative symptoms
of the disease but also motor drug induced symptoms,” Heresco-Levy
AS FOR depression, this problem is major, as 30% or more of
sufferers don’t react well to anti-depression drugs. There is a critical time
lag, he said. “It takes weeks from the moment they are first taken until they
have an effect. This lag is critical, because they could be suicidal without
benefit from drugs. There is a new hypothesis that the problem is due to a
decline in the plasticity of a synapse’s connectiveness. We believe that NMDA
antagonists can help.”
At Yale, much attention was given to studies in
which ketamine – used as an NMDA receptor antagonist – was given intravenously
to the clinically depressed. This drug is used in both human and veterinary
medicine to induce and maintain general anesthesia, usually together with a
sedative. It is widely used including for treating pain, high blood pressure and
for asthma symptoms.
“The researchers found that depressive symptoms
declined significantly in a few hours, and the beneficial effects remained for
up to two weeks after it was administered one time,” he continued.
problem is that it is has side effects, and intravenously, it is not pleasant.
We thought that if NMDA antagonism is a mechanism against depression, if we
delivered it to other locations of the receptors, maybe we can make it
Heresco-Levy noted that there is an existing drug used as an
antibiotic for tuberculosis that was approved by the US Food and Drug
Administration for 40 years. Called cycloserine (its commercial name is
Seromycin), it was found serendipitously to be a partial agonist for NMDA. “We
took patients with treatment-resistant depression and added Seromycin – and they
were much improved. We showed that the mechanism against depression is
In the coming decade or two, Heresco-Levy concludes, the revolution
of glutaminergic drugs will be upon us. “Major companies work in this field
today. There will be fewer patients who have to be confined to psychiatric
hospitals. Today, most of the inpatients have schizophrenia resistant to drugs.
If we can find something better for them, it will change the whole mental health
system. We are still far from it now, but when it is shown effective and is
widely accepted, they will be able to live in the community and be employed in
Patients with schizophrenia and other disorders will have
much less stigma. Most treatment will be in the community.’
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