A new generation of drugs for schizophrenia

teaser

Michel Bourin
PharmD MD
Professor of Psychiatry
Neurobiology of Anxiety and Depression Unit
School of Medicine
University of Nantes
France
E:[email protected]

In 1952, the use of chlorpromazine in psychiatry marked the beginning of a new era in the treatment of schizophrenia. During the following 25 years, several neuroleptic drugs were launched. Although these drugs are all dopamine receptor antagonists, their clinical effects are different, which led to biochemical and clinical classifications. These drugs, which are effective in the treatment of schizophrenia, are associated with a wide range of side-effects; thus, minimal doses must be used. Furthermore, conventional neuroleptics are more effective on the productive symptomatology of schizophrenia than on the negative symptoms; in addition, 25% of patients are treatment- resistant (refractory schizophrenia). The development of new drugs for the treatment of schizophrenia has focused on molecules with lesser side-effects and improved action on the negative symptoms.(1)

Carlsson and Crow hypothesised that dopaminergic hyperactivity may be linked to the positive symptoms of schizophrenia, whereas dopaminergic hypoactivity would be linked to the negative symptoms of the disease. These hypotheses were demonstrated using other neuromediators, such as serotonin and glutamate. Serotonin control induces a negative feedback on dopamine secretion in some regions of the brain, whereas glutamate inhibits subcortical dopaminergic activity (one theory put forward is that schizophrenia results from a deficit in glutaminergic transmission in the brain).(2)

Other neuropeptides, such as cholecystokinin or neurotensin, may also be involved in the modulation of dopaminergic transmission.

Dopaminergic neurons, on which neuroleptic drugs act, can be classified according to the four following pathways:

• The nigrostriatal pathway, which is involved in the development of extrapyramidal effects. In the striatum, dopaminergic neurons are linked with cholinergic neurons. Dopaminergic D(2)-receptor blockade induces the stimulation of central cholinergic neurons.
• The mesolimbic pathway, with anterior sub-cortical projections, which could be implicated in mobility initiation and mood stabilisation. Hyperactivity in this area could be the main cause of the positive symptoms of schizophrenia.
• The mesocortical pathway, which projects to the frontal cortex and participates in amnesic and cognitive processes. Hypoactivity of this pathway could be responsible for the negative symptoms of schizophrenia.
• The tuberoinfundibular pathway, on the level of which dopamine inhibits prolactin secretion of the anterior hypophysis by stimulating D(2)-receptors. D(2)-receptor blockade by conventional neuroleptics on this pathway induces amenorrhoea– galactorrhoea syndrome and decreases libido.

The current biochemical hypothesis is based on a dopaminergic transmission deficit in the nigrostriatal and mesocortical pathways, contrasting with an excess of dopaminergic transmission in the mesolimbic area.(3) The different strategies used in the development of new antipsychotic drugs are focused not only on the discovery of specific antagonists of one dopaminergic receptor subtype but also on the synthesis of molecules with different effects depending on the region of the brain that is targeted.

Selective dopaminergic receptor antagonists
Until recently, only two types of dopaminergic receptors had been identified: D(1)-receptors, which activate adenylate cyclase (which inhibits cyclic AMP production and phosphatidylinositol turnover), and D(2)-receptors, which inhibit it. Five receptor subtypes have now been identified:

• D(1)- and D(5)-receptors, associated with a
• G(s) protein.
• D(2)- and D(4)-receptors, associated with a
• G(i) protein.
• D(3)-receptor, a presynaptic receptor involved in negative feedback.(4)

The dopaminergic receptor family has been extensively studied to develop selective antagonists and agonists for each receptor subtype and establish a clinical profile for each of them. Traditional neuroleptics, such as haloperidol, mainly block D(2)-receptors, whereas substituted benzamides are essentially D(2)/D(3)-blockers.(5) The fact that clozapine is a selective D(4)-receptor blocker could explain its efficacy in refractory schizophrenia.(6,7)

The wide distribution of the D(2)-receptors demonstrates their ubiquitous expression, particularly in the neostriatum and the hypophysis, where their blockade leads to the motor and neuroendocrinological side-effects observed with conventional neuroleptics. This blockade at limbic system level explains the therapeutic effects of these drugs on positive symptoms, hallucinations and delusions. However, these drugs also block dopaminergic transmission in other areas of the brain, which can lead to a worsening of the negative symptoms and can contribute to the development of tardive dyskinesia.

Studies on D(2)- and D(3)-receptor antagonists focus on the development of selective D(2)-receptor antagonists with a preferred mode of action through the mesolimbic pathway (rather than the nigrostriatal pathway). D(3)-receptors are localised in the limbic area and cannot be found in the hypophysis or the striatum. Substituted benzamides are selective D(2)- and D(3)-receptor antagonists.(8) Furthermore, compounds such as sulpiride preferentially block D(2) presynaptic autoreceptors at low dosages, which explains the bipolar activity of this type of compound. Clinical trials have demonstrated the efficacy of sulpiride as an antipsychotic, although its side-effect profile, particularly extrapyramidal symptoms and hyperprolactinaemia, does not seem to be in agreement with predictions based on dopaminergic selectivity at D(2)-receptor level.(9)

Studies showing an interaction between D(1)- and D(2)-receptors have demonstrated the importance of the D(1)-receptor subtype.(10) The affinity of thioxanthene derivatives (ie, flupenthixol and zuclopenthixol) and clozapine for this receptor is higher than that of phenothiazines. However, no selective D(1)-receptor antagonist is currently available.

Molecular studies have demonstrated that D(4)-receptors are mainly located in the limbic and mesocortical areas. D(4)-receptor antagonism could explain the efficacy of clozapine (Leponex) and olanzapine (Zyprexa) in refractory schizophrenia. Postmortem studies have shown a high density of this receptor subtype in schizophrenic patients. However, no link has currently been established between D(4)-receptor density and response to treatment, and it is not clear whether elevated D(4)-receptor density is a predisposing factor.(11)

D(2)- and 5-HT(2)-receptor antagonists
Serotoninergic neurons, which can be found in the raphe nuclei, exert an inhibitory effect on dopaminergic transmission in the nigrostriatal and mesocortical areas by decreasing dopamine synthesis and release. In schizophrenic patients, dopamine inhibition by serotoninergic control is increased, which could partly explain the dopaminergic hypo-activity observed in the nigrostriatal and meso-cortical areas.(2) This effect can be countered by using serotoninergic (5-HT) antagonists. New antipsychotic drugs are superior to traditional neuroleptics in that they are also 5-HT(2) antagonists. In nigrostriatal and frontal areas, 5-HT antagonists improve the negative symptoms and reduce extrapyramidal symptoms, while being associated with better tolerance. Some traditional neuroleptics, such as thioxanthene derivatives, exhibit weak 5-HT(2) antagonist activity (much lower than that observed with risperidone or clozapine). In the case of clozapine, 5-HT(2) antagonism is more important than D(2)-receptor blockade. Some authors have suggested a link between the 5-HT(2)/D(2) binding ratio and the efficacy of a compound on negative symptoms.

Risperidone is a benzisoxazole derivative with potent D(2)- and 5-HT(2)-antagonist activities. Double-blind studies comparing risperidone with haloperidol (20mg/day) and placebo in patients with chronic schizophrenia demonstrated the potent anti-psychotic effect of risperidone, with optimal efficacy between 4 and 8mg/day for negative symptoms. (12–14) A meta- analysis shows that risperidone is more efficacious than haloperidol on negative symptoms. Risperidone is associated with less extrapyramidal effects; some side-effects on prolactin secretion have also been observed with this drug. The efficacy of risperidone in refractory schizophrenia, however, has not yet been demonstrated.

Selective 5-HT-antagonists
Over the past decade, there has been an increase in interest for the serotoninergic system as evidence was being uncovered that 5-HT-receptors are involved in depression, anxiety and schizophrenia.(15) Numerous neuroleptics, such as thioridazine and clozapine, act as 5-HT(2)-antagonists; in addition, several selective 5-HT(2)-antagonists have recently been developed.

Multiple-receptor antagonists
Active drugs in refractory schizophrenia display antagonist activity for several receptors (usually dopaminergic, serotoninergic, alpha-adrenergic, muscarinic and histaminic [H(1)]-receptors). The 5-HT(2)/D(2) binding ratio is >1, and dopaminergic binding is mainly observed on limbic and mesocortical D(1)- and D(4)-receptors. Clozapine was the first such molecule available; olanzapine is also part of this family of compounds. Clozapine, a dibenzodiazepine derivative, was developed in the early 1960s. Its antipsychotic properties were demonstrated to be superior or similar to those of the neuroleptic drugs then available, with fewer associated extra-pyramidal symptoms and hyperprolactinaemia.(16) The drug does not contribute to the development of tardive dyskinesia and could be beneficial in the case of tardive dyskinesia induced by other neuroleptics. In the mid-1970s, clinical studies on clozapine were stopped in North America because the drug was shown to induce agranulocytosis. However, there was a revival of interest in this drug following results from a clinical study demonstrating that its efficacy was superior to that of other available drugs in 30% of patients with refractory schizophrenia. Clozapine has been granted marketing authorisation for the treatment of refractory schizophrenia in North America and Europe, with a warning on serious haematological side-effects such as agranulocytosis (observed in 0.8% of patients treated with clozapine) and a compulsory haematological monitoring associated with its use. In addition to its efficacy in the treatment of refractory schizophrenia, clozapine has a wider pharmacological profile than traditional neuroleptics, which could account for its beneficial effects on refractory schizophrenia. Clozapine is also claimed to have a beneficial action on cognitive defects and to improve verbal fluency and memory. Major side-effects include hypersialorrhoea (33% of patients), weight gain and dose-dependent convulsions (1–4.4% of patients).(17)

Olanzapine is more efficacious than haloperidol for both positive and negative symptoms. Clinical studies comparing the drug with haloperidol have also demonstrated its superiority in improving depressive symptoms and suicidal thoughts, as well as a better quality of life at 52 weeks in patients treated with olanzapine.(18) The drug may also have anxiolytic effects, as lower benzodiazepine consumption levels, dropout rates and anxiety–depression subscores have been observed in the olanzapine group.(19) Olanzapine presents a good side-effect profile, with few extrapyramidal effects and no tardive dyskinesia or agranulocytosis.(20)

Partial D(2)-receptor agonists
A new drug, aripriprazole, was launched in Europe in June 2004, following its first launch in the USA in December 2002. This compound is a partial agonist of D(2)-receptors in the high-affinity state. Thus, at presynaptic level, agonistic activity is dose-dependent. A presynaptic agonist can inhibit dopamine release when the dose is too high; if the levels of dopamine released are too low, the drug stimulates the release of the neuropeptide at postsynaptic level. As a partial agonist, the response induced by aripriprazole is similar, although of a lesser intensity, than that obtained with a full agonist. Furthermore, the drug has a high affinity for the receptor. That way, binding with the pre- or postsynaptic receptor is stronger than the binding of dopamine to this same receptor. However, because this partial agonist is in competition with the full agonist dopamine, it can be considered as an agonist or as an antagonist depending on the quantity of dopamine present in the synapse. A recent study shows that schizophrenia can be linked to pre-synaptic striatal dopamine dysfunction, and, if this is the case, the use of aripiprazole would be appropriate.(21) In the presence of reserpine, which depletes the storage of dopamine, aripiprazole continues to stimulate dopaminergic receptors, even in the presence of elevated levels of dopamine. Like buspirone, aripiprazole is also a partial 5-HT(1A)-receptor agonist. Clinical trials have demonstrated that the efficacy of aripiprazole starts at a dose of 10mg. Maximal efficacy is observed between 15mg and 30mg, with only very mild side-effects observed. Depending on the pathology, aripiprazole acts as a pre- or a postsynaptic agonist. Thus, dosages do not need to be adjusted. Thus, aripiprazole is a D(2)- and 5-HT(1A)-receptor agonist and a 5-HT(2) antagonist. As aripiprazole does not act as a receptor blocker but can inhibit dopaminergic activity if there is an excess of dopamine, this drug is indeed the first of a new generation of antipsychotics. Serotonin can act as a central dopaminergic receptor inhibitor, with the possibility for this interaction to be antagonised by 5-HT(2) receptors. Although traditional neuroleptics present this property, they are also D(2)-receptor antagonists.

Conclusion
At present, neurobiologists believe that the dopaminergic system is essential in the treatment of schizophrenia and that multiple modulations are possible at that level, probably depending on genetic factors. The degree of the interactions between  gamma-aminobutyric acid (GABA), the dopaminergic system and serotonin varies depending on brain structures, which could account for the hypofrontal syndrome that affects schizophrenic patients, which is the result of two different mechanisms: anomalies of glutaminic acid decarboxylase and dopamine/GABA/glutamate imbalance due to excessive blockade of D(2)-receptors.

Thus, modulators (such as aripiprozole) should be prescribed in the treatment of schizophrenia rather than inhibitors.

References

1. Möller HJ. Eur Neuropsycho-pharmacol 1993;3:1-11.
2. Kapur S, Remington G. Am J Psychiatry 1996;153:466-76.
3. Risch SC. Pharmacotherapy 1996;16:11-4.
4. Sokoloff P, Martres MP, Schwartz JC. Médecine/Sciences 1993;9:12-20.
5. Hollister LE. J Clin Psychopharmacol 1994;14:50-63.
6. Van Tol HH, Bunzow JR, Guan HC, et al. Nature 1991;350:610-4.
7. Kerwin RW, Collier D. Psychol Med 1996;26:221-7.
8. Coukell AJ, Spencer CM, Benfield P. CNS Drugs 1996;6:237-56.
9. Mauri MC, Bravin S, Bittetto A, Rudelli R, Invernizzi G. Drug Saf 1996;14:288-98.
10. Gerlach J, Peacock L. Int Clin Psychopharm 1995;10 Suppl 3:39-48.
11. Rietschel M, Naber D, Oberlander H, et al. Neuropsycho-pharmacology 1996;15:491-6.
12. Chouinard G, Jones B, Remington G, et al. J Clin Psychopharmacol 1993;13:25-40.
13. Borison RL. J Clin Psychopharmacol 1995 Suppl 1;15:24S-9S.
14. Marder SR, Meibach RC. Am J Psychiatr 1994;151:825-35.
15. Kane JM. N Engl J Med 1996;334:34-41.
16. Fitton A, Heel RC. Drug 1990; 40:722-47.
17. Buchanan RW. Schizophrenia Bull 1995;21:579-91.
18. Tollefson GD, Beasley CM Jr, Tran PV, et al. Am J Psychiatry 1997;154:457-65.
19. Weiden P, Aquila R, Standard J. J Clin Psychiatry 1996;57 Suppl 11:53-60.
20. Casey DE. J Clin Psychiatry 1996;57 Suppl 11:40-5.
21. McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Arch Gen Psychiatry 2004;61:134-42.