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 receptors.

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 D3 receptor.

Sanofi-Synthélabo is developing its compound SR-125047 that modulates a brain site called the central sigma receptor, 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 schizophrenia 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.