By the 1970’s, several related compounds had been discovered.
1976, it was learned that there is a direct linear relationship between
the strength with with the compounds bind at the dopamine D2 receptor,
and the clinical potency of the drug.
Molecular Psychiatry (1998)3, 123-124]
The discovery of this direct relationship was taken as
for the relationship between dopamine receptor blockade and therapeutic
effect. Some even went so far as to say that this proved that
dopamine excess was the cause of schizophrenia, but that was a bit of a
stretch. In any event, therapeutic research focused primarily
the D2 receptor for decades.
Researchers and astute clinicians knew, however, that there was more to
Some people would respond well to one drug, but not another,
though the two drugs both blocked the same D2 receptors.
There had to be
more to the story. There were too many things like that,
that tickled the intuition, for well-informed persons to feel confident
that dopamine was the whole story.
One of the unsettling observations was the unparalleled efficacy of
Clozapine was first developed in 1961, and was found to be remarkably
more efficacious than any other antipsychotic
drug. Something else was going on, something other
than blockade of the D2 receptor.
We know now that this is partly due to the effect that clozapine has on
blocking 5HT2 receptors (a subtype of serotonin receptor).
line of study led to the expansion of what is now an entire family of
Now, firstname.lastname@example.org is, somewhat uncharacteristically, gushing over a
recent phase-II trial of a different kind of antipsychotic medication.
hopes for new schizophrenia drugs
Drug trial hailed as first major breakthrough for 50 years.
Published online: 2 September 2007; doi:10.1038/news070827-9
Psychiatrists have welcomed the unveiling by a US drug
company of the first new class of schizophrenia drugs since the 1950s.
According to early clinical-trial data, the prototype drug —
codenamed LY2140023 and produced by Eli Lilly researchers in
Indianapolis, Indiana — seems to be as effective as
olanzapine, the best currently available drug. The drug’s developers
hope that it will offer psychiatrists a new alternative for treating
their patients, and one that may offer greater benefits in relation to
the side effects…
LY404039 is a selective agonist for
glutamate 2/3 (mGlu2/3) receptors. It turns on the
receptors, which lowers the activity of glutamate in the synapse.
(LY2140023, the drug in the study, is a prodrug that is
metabolically changed into LY404039.)
The study that the news article is based upon is this one:
of mGlu2/3 receptors as a new approach to treat schizophrenia: a
randomized Phase 2 clinical trial. The authors
studied mice. They also studied 196 humans, which admittedly
does add to the clinical validity of the study.
Patients were randomized to receive olanzapine (an atypical
antipsychotic), placebo, or LY2140023:
After 4 weeks of treatment, both the
LY2140023 group (32.0%, P less than 0.001) and the olanzapine group
(41.2%, P less than 0.001) showed significantly greater response rates
than the placebo group (3.2%).
That is a good result. The reason I am sounding
skeptical is that it is hard to think of this as “a major
breakthrough.” Many phase-II drugs never make it to market;
we have seen many disappointing fizzled products.
Even if it is a major breakthrough, it would not count as the “first
major breakthrough” unless you disregard the introduction of clozapine,
not to mention rel="tag">risperidone and possibly depot href="http://en.wikipedia.org/wiki/Fluphenazine">fluphenazine.
If this does work out as is hoped, it will be a welcome advance.
That is for two reasons. One, hardly anyone gets a
fully satisfactory response from the current medications.
Therefore, any new approach is likely to help some people who
could not be helped before. Or it might bring a greater
degree of improvement in people who have unsatisfactory responses to
Two, the new drug appears to have a much lower adverse effect burden
than existing antipsychotic medications. Drugs are useful
only if they cause more benefit than harm, and they are useful only if
people actually are willing to take them. Having a lower
adverse effect burden would make both outcomes more likely.
However, given the very small number of humans who have been
exposed to LY2140023, and the short time scale of the study, it would
be wise to withhold judgment on this point.
If this does work out, Lilly will make a lot of money from it, and they
will deserve it. I just hope they start working on a depot
formulation right away, rather than making us wait forever. I
also hope they start work on the possible efficacy for bipolar
disorder, rather than conducting those studies as an afterthought.
(Or playing patent-life games by getting a second indication
years after the first.)