The Quest for Better Schizophrenia Treatment
Serendipity and Science
By Hakon Heimer
About Hakon Heimer
In the early 1950s, a chance discovery helped transform schizophrenia from
mystical affliction to medical disorder. French psychiatrists discovered that
chlorpromazine, a drug used to make surgical patients less anxious, also
relieved the symptoms of psychosis. The subsequent discovery that
chlorpromazine targeted a brain messenger molecule called dopamine kicked off a
large research effort into dopamine dysfunction in schizophrenia.
A half-century later, another avenue of research has yielded exciting results.
Two recent studies—one a clinical drug trial and another a basic science study
in laboratory mice—have helped turned the focus to a different messenger
molecule, or neurotransmitter, called glutamate. In September 2007, researchers
at Eli Lilly published a study showing that an experimental compound that
inhibits glutamate signaling was able to reduce psychosis.1 Although the trial
awaits confirmation, and it remains to be seen whether this particular compound
will be any more effective or have fewer side effects than the older drugs, the
results validate the basic neuroscience research and purposeful drug
development that offered up the first successful new drug target in more than
half a century.
Reinforcing this new emphasis on non-dopamine causes of schizophrenia,
researchers at the University of California, San Diego, reported in December
2007 that interfering with glutamate signaling in their mouse model also
disrupted brain cells that use yet another neurotransmitter, this one called
gamma-aminobutyric acid (GABA).2 The fact that the GABA cell alterations
mimicked those seen in schizophrenia may help to unite two prominent, and
competing, theories of schizophrenia causation.
Schizophrenia Without Drugs
Although chlorpromazine (later sold as Thorazine in the United States) rescued
schizophrenia sufferers from failed treatment strategies such as electroshock
therapy, induced insulin shock, and frontal lobotomy, it did not restore full
functionality to patients, as disabling cognitive and motivational symptoms
persisted. Indeed, even today researchers are only in the infancy of
understanding a disorder that was reported in historical texts as early as
Pharaonic Egypt.
An important turning point in understanding psychotic disorders came around the
turn of the twentieth century, when the German psychiatrist Emil Kraepelin
distinguished two types of disorders featuring delusions, hallucinations, and
other thought disruptions. The major distinction between “dementia praecox” and
“manic depression,” Kraepelin postulated, was that although people with manic
depression (now called bipolar disorder) might experience psychosis during
manic periods, they return to relatively normal cognitive function when they
come down from the mania. For people with dementia praecox, later termed
“schizophrenia” by Kraepelin’s countryman Eugen Bleuler, psychosis is an
ongoing state, often accompanied by profound deterioration in the ability to
process information or interact socially.
The modern diagnosis of schizophrenia requires the persistence of psychotic,
also called “positive,” symptoms for at least six months, without evidence of
mood cycling. However, psychosis is not the only symptom of schizophrenia. Most
people with the disorder also exhibit poor working memory (information stored
temporarily during a task) and are unable to quickly recognize new situations
and rules, an ability termed cognitive “flexibility.” These cognitive features
contribute greatly to the chronic disability of most patients, as does a third
symptom domain, that of “negative” symptoms. Negative symptoms describe aspects
of normal behavior that are subtracted by the disease process—typically
motivation, the display of emotion, or the desire to interact with other
people. Thus, the most severely afflicted find themselves in a constant state
of confusion about the events going on around them, without the capacity to
have normal social
interactions.
The Chlorpromazine Puzzle
The work of the German classifiers and their contemporaries had no direct
benefit for people with schizophrenia and other psychotic disorders. Indeed,
the next half-century saw some horrifically misguided attempts to alleviate the
suffering of patients and their families. Treatments such as the surgical
disconnection of major brain pathways with frontal lobotomy were the result of
physicians’ moving forward with slim scientific evidence.
Finally, in the second half of the twentieth century, antipsychotic drugs
provided a logic and a strategy for looking for chemical or structural changes
in the brains of people with schizophrenia. If a single
molecule—chlorpromazine—could reduce and in some cases eliminate the complex
manifestations of schizophrenia, then it stood to reason that there was a
chemical imbalance in the brain.
The Swedish scientist Arvid Carlsson had discovered dopamine in the early
1950s, and a decade later he and his colleagues determined that antipsychotic
drugs worked by blocking dopamine from attaching to its receptor molecules.
This finding dovetailed with another serendipitous finding: as early as the
1930s, it had been noted that amphetamine could cause psychosis. Amphetamine
and other psychostimulants, it turns out, boost the activity of dopamine. Thus,
the “dopamine hypothesis” of schizophrenia was born.
For the next several decades, researchers focused on trying to understand how
dopamine systems were disturbed in the disorder. However, despite some
significant refinements to chlorpromazine, especially reductions of some side
effects, this line of research has been disappointing. According to Joseph
Coyle of Harvard University, one of the first schizophrenia researchers to turn
their attention to glutamate, 70 to 80 percent of patients with schizophrenia
treated with dopamine drugs remain profoundly impaired by cognitive and
negative symptoms. Moreover, neither a clear understanding of how blocking
dopamine receptors curbs psychosis nor any new molecular targets have emerged
from this line of research. Most psychiatry researchers are currently of the
opinion that the dysfunction of dopamine neurotransmission in schizophrenia
results from, or compensates for, a more fundamental or “upstream” disturbance
of the nervous system, perhaps in glutamate
signaling.
The Biggest Little Neurotransmitter You’ve Never Heard Of
While the public has had many opportunities to learn about the important role
of dopamine in the brain, especially in regard to Parkinson’s disease and the
rewarding effects of sex, drugs, and chocolate, glutamate remains relatively
unknown. In fact, it is the most common neurotransmitter in the brain and the
signaling molecule of choice of the powerful pyramidal neurons. So named for
their shape, these cells send information shooting around the cerebral cortex
and other brain areas that control behavioral functions, rapidly combining
sensory input with stored information and emotions.
One reason for glutamate’s anonymity in the public mind is that its status as a
neurotransmitter was demonstrated only some twenty years ago. Researchers had
long known that it was abundant in the brain, but it is involved in numerous
other cell activities as well. In order to qualify glutamate as a true
neurotransmitter, scientists had to establish that it was released by nerve
cells at the ends of long fibers called axons. Researchers also showed that
glutamate, like dopamine and all other neurotransmitters, crosses a narrow
space beyond the axon called the synapse and binds to receptor molecules on the
surface of other neurons, triggering rapid electrical or chemical activity in
the second cell.
Once scientists had established the status of glutamate, especially in the
cortex, they were quick to explore the possibility of glutamate dysfunction in
schizophrenia. Here another bit of serendipity came into play. As with
amphetamine and the dopamine hypothesis, it involved a drug that caused
psychosis.
Remarkably, the drug phencyclidine was another gift from the anesthesiologists.
Developed as an anesthetic in the 1950s, phencyclidine (PCP, called “angel
dust” as a street drug) was soon pulled from regular use because it caused
psychotic symptoms during recovery. But whereas amphetamine produces only the
positive (psychotic) features of schizophrenia, PCP and chemically similar
anesthetics such as ketamine produce both negative and cognitive symptoms as
well. David Lodge and colleagues at the University of London supplied the link
to glutamate in 1983, when they found that PCP and ketamine bind to one
particular type of glutamate receptor called the N-methyl-D-aspartate (NMDA)
receptor.
Researchers soon began to advance theories about how glutamate dysfunction
might play a role in schizophrenia, led by Daniel Javitt of the Nathan Kline
Institute in New York in 1987, as well as Joseph Coyle and his colleagues and
John Olney of Washington University in St. Louis. If PCP and ketamine produced
a schizophrenia-like state by interfering with normal NMDA receptors, then
perhaps these receptors were performing poorly in the disorder. Evidence
emerged from studies of postmortem brain tissue—some, but not all, such studies
have found modest evidence of alterations in glutamate-related molecules in the
brains of people with schizophrenia. The glutamate hypotheses have also gained
support from genetic research—among the genes that have the strongest support
as schizophrenia susceptibility candidates are several that code for proteins
that influence glutamate signaling. In particular, a meta-analysis of genetic
studies, by Lars Bertram and
colleagues at Massachusetts General Hospital and published in 2008, found that
variation in one of the subunits that makes up the NMDA receptor increases the
risk for the disease.3
Researchers, particularly Javitt and Coyle, have conducted clinical trials to
boost the function of NMDA receptors. Although negative and cognitive symptoms
improved in these small preliminary trials, the results were not strong enough
to induce the pharmaceutical industry to pursue drug development efforts.
However, a breakthrough at the turn of the new millennium has led to a
revitalizing of these approaches.
A Different Window onto the Glutamate Synapse
While Coyle, Javitt, and others were focused on modulating the NMDA receptor
directly, Bita Moghaddam at Yale University had turned her attention to a
different class of glutamate receptor. Called metabotropic glutamate receptors
(mGluRs), they do not rapidly convey information at glutamate synapses, as NMDA
receptors do. Rather, they influence how the glutamate synapse operates in
various and subtle ways. In a paper published in 1999, Moghaddam and colleague
Barbara Adams took advantage of the fact that PCP and other NMDA-interfering
drugs can be used in animal models, where they produce effects strikingly like
the negative and cognitive symptoms of schizophrenia patients.4 When they gave
rats a drug that activates only mGluRs, the researchers found that the
cognitive effects of PCP—e.g., working memory impairment—were significantly
reduced. In 2005, John Krystal of Yale University and his colleagues replicated
this finding in humans, showing that
the same mGluR receptor drug could reverse the cognitive effects of ketamine
in healthy volunteers.
These studies set the stage for Eli Lilly to try the mGluR drug in people with
schizophrenia. As the Lilly researchers reported in their 2007 paper in Nature
Medicine, in a double-blind, placebo-controlled trial conducted in Russia with
nearly 200 patients, they found that the experimental drug was significantly
better than the placebo in treating positive symptoms, the first non-dopamine
blocker to achieve this distinction.1 They did not report on whether they had
found effects on cognitive measures, as Moghaddam and Krystal had in their
experiments. The study is now being repeated in a different group of patients,
with different doses of the mGluR drug. The Lilly trial provides not just proof
of concept evidence for the target, but also proof of concept evidence that the
strategy can yield new drugs that may turn out to be effective, according to
David Lewis of the University of Pittsburgh’s Western Psychiatric Institute,
one of the researchers who
had demonstrated changes in glutamate-related molecules.
It’s Not All Excitatory
Another significant glutamate study published in 2007 pointed out both the
significant advances and the remaining challenges in understanding
schizophrenia pathology. Margarita Behrens, Laura Dugan, and their colleagues
at the University of California, San Diego, reported in Science that
interfering with glutamate NMDA signaling in mice can reproduce one of the most
well-supported findings in schizophrenia: disruptions of cells called
interneurons, which signal using the neurotransmitter GABA.2
GABA is the yin to glutamate’s yang. While glutamate is the neurotransmitter of
choice for the pyramidal neurons, which use it to excite electrical activity in
the neurons they contact, GABA is typically employed by a more modest group of
cells, the interneurons. These cells confine their axons to their local areas,
in which their bursts of GABA inhibit the activity of the pyramidal neurons.
Researchers including David Lewis, Francine Benes at McLean Hospital in
Belmont, Massachusetts, and others have found changes in GABA-related proteins
in schizophrenia but only in a select population of interneurons. A recent
study in genetically altered mice also points to GABA cell problems in
schizophrenia. Akira Sawa and colleagues inserted a mutant form of the
schizophrenia susceptibility gene called “disrupted in schizophrenia 1” (DISC1)
into mice.5 When they examined the brains of the mice, the researchers found
that the same interneurons affected in
schizophrenia are altered in the mice with mutant DISC1. The researchers
described their work in a 2007 paper in Proceedings of the National Academy of
Sciences.
Lewis and his collaborators are now testing a drug that may normalize GABA
interneuron function in the brain of people with schizophrenia, perhaps with a
beneficial effect on symptoms.
However, Behrens, Dugan, and colleagues’ intriguing finding is that the NMDA
blocker ketamine selectively damages this same group of GABA interneurons. The
researchers suggest that the glutamate deficit might therefore be “more
primary,” or “upstream” of the GABA deficit. The intermediate step, their
report suggests, may be the production of destructive molecules called “free
radicals.” These results have not been confirmed, so the conclusions vis-à-vis
schizophrenia remain speculative. But in 2008 Behrens, working with John Lisman
of Brandeis University, added supporting evidence for the link between
glutamate and GABA disruptions.6 As they reported in the Journal of
Neurophysiology, they were able to directly record altered electrical activity
in GABA interneurons that had been disrupted with an NMDA receptor blocker.
Searching Between Drugs and Behavior
The results of Behrens and colleagues highlight the need to work out the
complex set of relationships between the different types of neurons in the
brain, said Coyle. The strategy of giving different compounds to animals or
people and studying how their behavior changes, which has been so productive in
the case of the NMDA-blocking drugs, still leaves a fuzzy area between the drug
input and the behavior output. In addition to the ongoing debate on the
relative importance of glutamate versus GABA disruption in schizophrenia,
researchers disagree on whether the neurons of most interest are those in the
higher-reasoning areas of the cortex, in areas that connect the cortex with
sensory or movement regions of the brain, or both.
Scientists will now attack the neuronal circuits from different entry points:
they will explore metabotropic glutamate receptors (of which eight variations
have been identified), as well as the manipulation of other glutamate receptors
and molecules that help control the amount of glutamate floating about in
synapses. Researchers will also focus on the cells on the receiving side of
glutamate neurotransmission, principally the GABA interneurons and their
connections back to the glutamate-releasing pyramidal cells. Other
neurotransmitters, such as dopamine, acetylcholine, and serotonin, will receive
attention because they subtly alter communication between glutamate and GABA
cells. It remains to be seen whether any single approach will lead to a drug
that effectively treats schizophrenia, or whether different compounds,
targeting separate neurotransmitter systems for the different symptom domains,
will be needed.
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