Possible future developments
It will have become clear that the atypical antipsychotic
medicines cannot provide all the answers to schizophrenia.
They do not work in some people, suggesting that other brain
areas may be involved. Almost certainly, other chemical abnormalities
exist in some other people and research already suggests
that other receptor types may contribute to schizophrenia.
These include some serotonin receptor sub-types, as well
as others called muscarinic, cannabinoid, kainate, and sigma
There are a number of experimental medicines still at an
early stages of development that act on the 5HT and dopamine
receptors. Two, EMR-62218, under investigation by Merck Pharmaceuticals,
and eplivanserin (Sanofi-Synthélabo), appear to be
selective inhibitors of the 5HT2A receptor with no dopamine
blockade. Their progress will be interesting to watch, especially
as MDL-100907 (also a 5HT2A blocker) did not show activity
in the clinic. They are in Phase 1 and Phase 2 trials respectively.
Sanofi-Synthélabo is also assessing SSR-181507, a
mixed dopamine D2/5HT2A antagonist, while GlaxoSmithKline
has progressed an antagonist of the 5HT6 receptor (SB271046)
into Phase 1 clinical trials. This should give us some indication
of the role this particular receptor plays in schizophrenia.
Pharmacia has a compound PNU-177864 in early development
which is a highly selective partial blocker of the dopamine
Sanofi-Synthélabo is developing its compound SR-125047
that modulates a brain site called the central sigma
to which haloperidol has also been shown to bind. It is a
potent and very specific inhibitor of this binding site and
will provide interesting information on its role in schizophrenia.
It has yet to enter clinical trials. Another new target being
explored by Sanofi-Synthélabo is the neurokinin receptor.
Neurokinins are chemical compounds called peptides found
in the substantia nigra and striatum regions of the brain.
They are involved in movement control which may be relevant
to some of the side effects of neuroleptic medicines. Sanofi-Synthélabo
is investigating a neurokinin-3 (NK3) blocker, osanetant,
which has now entered Phase 3 clinical trials, while GlaxoSmithKline
also has an NK3 antagonist, talnetant (SB223412), in Phase
2 clinical trials.
Sanofi-Synthélabo also has rimonabant (formerly SR-141716)
in Phase 3 trials, a blocker of yet another receptor, the
cannabinoid receptor. Users of cannabis can develop a state
resembling hebrephenic schizophrenia with predominant negative
symptoms. Also, a Swedish study has shown that cannabis use
before the age of 18 raises by six-fold the incidence of
schizophrenia. Finally, a Japanese study indicates that in
people with schizophrenia, errors are to be found in a gene
known as CNR-1 which codes for the cannabis receptor, CB-1,
suggesting that some people may have increased susceptibility
to the condition. For these reasons, the clinical effect
of rimonabant will be watched with great interest.
An entirely different approach to schizophrenia is the testing
of inhibitors of a brain enzyme responsible for the breakdown
of polyunsaturated fatty acids in cell membranes. A compound
of this type, LAX-101d from Laxdale Pharmaceuticals is in
Phase 2 studies, with Phase 3 trials planned for late 2003.
This inhibitor may cause changes in the functioning of neuroreceptors
and neurotransmitters in nerve cells.
In developing this new approach, it has been pointed out
that some neuroleptic medicines, including chlorpromazine,
inhibit to some extent the same enzyme as LAX-101d, and that
treatment with clozapine causes a dramatic rise in concentrations
of fatty acid-related products in red blood cell membranes.
Research suggests that the primary action of clozapine may
therefore be on these components of the cell membranes, rather
than on neurotransmitter receptors. LAX-101d should test
this theory which, if it can be proved, implies that the
basis of schizophrenia may actually be a relatively minor
biochemical defect that can be corrected.
The unmet needs of many people with schizophrenia continue
to drive physicians to examine existing medicines. For example,
diazoxide (already available for some extreme forms of high
blood pressure and for the control of low blood sugar) may
act on potassium channels that may be defective in people
with schizophrenia. When given together with haloperidol,
the combination was significantly superior to haloperidol
alone against positive symptoms. Amoxapine, a tricyclic antidepressant
has shown activity in animal models similar to the atypical
antipsychotics. A small study in people with acute psychosis
has shown significant improvement in both positive and negative
symptoms with no weight gain, though there was some prolactin
elevation. D-cycloserine has a weak stimulatory effect at
NMDA receptors at the ‘glycine site’ and can
improve negative symptoms when used with older compounds
in schizophrenia. A recent study has shown that it has similar
worthwhile actions when added to risperidone treatment, though
the dose range is critical. Another compound acting at the
glycine site is milacemide. Studies such as these may not
represent major breakthroughs in themselves but they do,
perhaps, provide clues for the future.
Of course, unravelling the complexities of a disease such
as schizophrenia is fraught with difficulties and pitfalls.
Nevertheless, our knowledge continues to grow as new discoveries
are made. For instance, only in early 2003, the discovery
of a new group of proteins was announced called ‘multiple
receptor-interacting proteins’ (DRIPs for short).
One, NCS-1, is present in the frontal cortex of people with
at levels 50 per cent higher than well individuals. It also
binds strongly with the dopamine D2 receptor suggesting that
it might prove yet another target for medicines development.