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German Journal of Psychiatry

ISSN 1433-1055

Congress Report

Review of the New Wave of Atypical Neuroleptics: Bewildering Neurotransmitter Profiles and New Choices for the Clinician
Jan M. Keppel Hesselink


From the Institute of Pharmacology, University of Witten/Herdecke, Germany Corresponding author: Prof. Dr. Jan M. Keppel Hesselink, abfab@jmulder.demon.nl

German J Psychiat 1998;2:69-75

Received: November 8, 1998

Published: December 10, 1998


Introduction

At the recent European Congress for Neuropsychopharmacology (ENCP), held in Paris in November 1998, much information was shared about the atypical neuroleptics, a reason to review this class of drugs.

Chlorpromazine, the first phenothiazine neuroleptic, began the revolution in the treatment of schizophrenia in the early 1950s. However, this drug has many troublesome side effects, limiting its use. Haloperidol, the next step in treating schizophrenia has since its introduction been used to treat millions of patients of all ages over nearly 4 decades.

The launch of clozapine on the world market in 1990 led to the establishment of a new group of neuroleptics that for the time being are referred to as the atypical neuroleptics.

Atypical neuroleptics are all said to be able to reduce positive and negative symptoms of schizophrenia, without inducing EPS, for which enough proof exists (1). These drugs have generally been found to be more effective than conventional antipsychotics against the totality of negative symptoms. The usefulness of the typical neuroleptics in the treatment of the negative symptoms of schizophrenia has always been a weak point of these agents.

Atypicality has been ascribed to 5-HT2/D2 antagonism, although the exact pharmacological mechanism underlying the efficacy of the atypical neuroleptics is not yet known. Furthermore, they have serotonin, adrenergic, histamine, and acetylcholine receptor blockade effects that may be involved with the antipsychotic effect (2).

Since the introduction of clozapine, a drug with a ten-fold higher affinity for D4 compared to D2 or D3 receptors and the gold standard in treating neuroleptic-refractory schizophrenic patients, a large number of new atypical neuroleptics have been tested and introduced into clinical use or are about to be launched: risperidone, olanzapine, zotepine, ziprasidone, sertindole and quetiapine. Many other compounds are still in the early clinical pipeline: LU 111995, a D4 and 5HT2A antagonist (phase IIa) and BTS 79018, a D3 and 5HT1A agonist, M100907, a selective 5-HT2A receptor antagonist, and novel benzothiazepine derivatives with affinity for 5-HT2, D2, and D3 receptors (preclinical phase), to mention only a few.

Recent data on the degree of dissociation at the D2 receptor show that antipsychotic drugs which induce parkinsonism (trifluperazine, chlorpromazine, haloperidol, fluphenazine) bind more strongly than dopamine to D2, while those antipsychotic drugs which elicit little or no parkinsonism (melperone, quetiazepine, clozapine, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors (3)

There is further evidence that some of the atypical neuroleptic activity might be due to H3 autoreceptor antagonism, thus increasing the histamine levels in the brain (4).

The atypical neuroleptics can also be of use to treat violent behaviour. This occurs in nearly 13% of schizophrenic patients, and occurs often in the context of positive psychotic symptoms (i.e., delusions or hallucinations)(5). A common side effect of all atypical neuroleptics is weight gain, and dependent on the compound can be up to 4 kg (6). Various atypical agents, such as olanzapine, risperidone, and sertindole, seem to cause tardive dyskinesias, but at a much lower rate than haldol (1% vs. 5%). Only clozapine does not seem to cause any TD.

Zotepine (Knoll)

Zotepine, a tricyclic compound, structurally similar to clozapine, was presented at the recent ECNP by Knoll scientists as a broad spectrum antipsychotic drug with high affinity for D1 and D2 receptors, as well as for 5HT2, 5HT6 and 5HT7 receptors (7). A unique feature of this drug was claimed to be its NA-reuptake inhibition in the nanomolar range, which could have clinical relevance for the treatment of comorbid affective states. Zotepine elevates dopamine in the frontal cortex of rats, as measured by the microdialysis method (8). Zotepine, clozapine as well as haloperidol were reported to elevate enkephaline mRNA levels in the limbic area, a property suggested to be relevant to its neuroleptic activity (9). In 3 double-blind, placebo controlled trials, a dose range between 75 and 450 mg was tested against haloperidol and chlorpromazine. Cooper presented data of a recurrence prevention study in 121 patients, treated with 50-100 mg tid. The risk of recurrence over a 25-week period was significantly reduced in the patients treated with zotepine. Somnolence and weight gain were the most frequent side effects. Specific details on dose-finding, side effect profile and data of the individual trials were not presented. An intramuscular formulation and a liquid formulation are under development. Market launch in Germany and Austria is expected in November, according to a spokesperson of Knoll.

Olanzapine (Lilly) and Risperidone (Janssen)

Risperidone and olanzapine were the first 2 new atypical neuroleptics introduced on the market. It is clear that this is one of the reasons why the first direct comparative trials testing these two compounds are now being reported. Some of these direct comparisons were presented at the ECNP, but the details of the methodology used in these trials was not released. Thus, a final judgement on whether one of these compounds is superior to the other is still outstanding. However, the overall efficacy will most probably be comparable. It may be that one or other compound will have certain advantages for a certain type of patient.

Olanzapine has a broad receptor profile similar to that of clozapine. It is as effective as haloperidol against the positive symptoms of schizophrenia, and more effective against negative symptoms, with significantly fewer extrapyramidal side effects. Side effects include somnolence and weight gain. New data on the efficacy and safety were presented of trials comparing risperidone and olanzapine.

During a Lilly-sponsored symposium Stuart Montgomery (UK) presented preliminary data from a double-blind, placebo-controlled, international trial in over 300 patients were olanzapine (10-20 mg) was compared to risperidone (4-12 mg). He presented the PANSS depression scores: olanzapine was superior to risperidone.

Some anecdotal data were presented based on case studies suggesting that one could use risperidone to boost the efficacy in partially refractory patients treated with olanzapine or clozapine (10).

In a separate poster Grainger and colleagues from Eli Lilly presented further data of 339 schizophrenic patients, using a quality of life scale, without detecting significant differences between the two therapies, although some trends in favour of olanzapine were described in subscales (11). Total costs per patient over the 28 weeks of exposure were higher for risperidone.

These data were not replicated in a Canadian pharmacoeconomic study, based on a retrospective chart review of 60 patients treated with either olanzapine or risperidone. In that study significantly higher acquisition costs for olanzapine over a 17-week treatment period were documented. A methodologically less complicated comparison between risperidone (2-6 mg/day) and olanzapine (5-20 mg/day) in 407 patients was presented by Conley of the University of Maryland, Baltimore, USA at a Janssen sponsored satellite. Approximately 80 % of the patients for both drug groups were outpatients. The mean daily dose was 4.8 mg for risperidone and 12.5 mg for olanzapine, in line with the average doses used in actual practice. Both drugs showed comparable efficacy in reducing negative symptoms and EPS rates were comparable low. Risperidone however, was more effective in reducing the positive and anxiety/depression related symptoms. Olanzapine treated patients gained significantly more weight (risperidone15% vs. olanzapine 30%). As methodological details were not presented (e.g. ITT population vs. observed case), interpretation of these findings will await final publication in a peer reviewed journal.

Ziprasidone (Pfizer)

Ziprasidone is an atypical neuroleptic with affinity for the 5HT1A, 5HT1D, 5HT2 and D2 receptors, and has moderate inhibition of serotonin and noradrenaline re-uptake. At a poster Sprouse and colleagues from Pfizer demonstrated that a strong reduction took place of dorsal raphe firing after IV application of ziprasidone, clear proof of in vitro 5HT1A agonistic properties (12), These effects could be abolished by the application of a selective antagonist. Furthermore ziprasidone and clozapine significantly increased dopamine release in the prefrontal cortex, without increasing the levels in the striatum. This property may be beneficial for the amelioration of negative symptoms, improving cognitive functioning, with a low liability for inducing extrapyramidal side effects (EPS).

In a fixed dose trial, testing 4 different doses of ziprasidone versus haloperidol 15 mg/day, ziprasidone 160 mg/day (80 mg bid) has been recently reported to be as effective as haloperidol, and concomitant benztropine use at any time during the study was nearly four times less in the patients treated with ziprasidone compared to the those treated with haloperidol (1). Prolactin levels did not change during treatment with ziprasidone.

During the ECNP the drug was reported to be available in a rapid intramuscular formulation by Tensfeldt from Pfizer in a poster, as well as during a Pfizer satellite symposium. Phase III trials demonstrated efficacy and acceptable safety. According to Pfizer researchers, positive data were also generated in a small pilot trial in patients suffering from Tic disorder (14).

In a double-blind placebo-controlled study 12 patients treated with placebo were compared to 16 patients treated with ziprasidone, initiated at 5 mg/ day and increased in steps of 5 mg up to 40 mg/day as a maximal dose. Ziprasidone was significantly better compared to placebo on a variety of endpoints (Yale Global Tic Severity Scale, Yale-Brown Obsessive Compulsive Scale and a global scale.

Swift from Pfizer also presented the validation of a new scale, the BARS, behavioural activity rating scale, a scale to assess activity in agitated patients. The efficacy of ziprasidone IM was also evaluated using this instrument: 20 mg IM induced a rapid and sustained reduction in agitation up to 4 hours after injection.

Quetiapine (AstraZeneca)

Quetiapine, a 5HT2/D2 antagonist, with affinity for H1 and alpha 1 receptors was reported to have a significant positive impact on health cost by company researchers, based on pharmacoeconomic analysis, especially due to decreased hospital stay (Langham). During a sponsored symposium, data on over 500 patients were presented, and quetiapine showed an important improvement on all measures for aggression and hostility in a 600 mg/day dose. A Zeneca spokesperson said that an extended release formulation is currently being tested in phase I. The pivotal trials have already been presented in peer reviewed journals, so no new clinical data on quetiapine were presented at ECNP (15, 16, 17)

Sertindole (Lundbeck)

Sertindole has high affinity for 5-HT2 receptors, D2 receptors, and a1-adrenoceptors. The affinity for D1, alpha-2, H1, and sigma receptors is low, and there is no affinity for the 5-HT1A, muscarinic, cholinergic, or b-adrenoceptors. Binding experiments indicate a limbic preference vs. striatal D2 receptors (18). In a recent single photon emission computerised tomography (SPECT) study sertindole-treated patients demonstrated significantly lower levels of striatal D2 binding compared to those treated with haloperidol and risperidone, but significantly higher levels compared to clozapine (19). In an animal model for tardive dyskinesia, sertindole did not produce these moments significantly more often compared to placebo (20).

The safety and efficacy of sertindole have been demonstrated in three double-blind randomised studies (21). These trials showed that sertindole was as effective as haloperidol in controlling positive symptoms, and was superior to placebo in reducing negative symptoms, whereas haloperidol was not. At 12-24 mg/day, sertindole was not associated with EPS, and they were significantly lower compared to haloperidol. The highest dose, 24 mg, might induce some EPS. Slight prolongation of the Q-T interval was seen with sertindole in early clinical trials and its use is contraindicated in patients suffering from cardiac diseases. Most of the other adverse events reported for sertindole are based on the alpha, antagonistic activity.

Conclusion

Many new atypical neuroleptics have been introduced into clinical use during the past years and many more will become accepted over the next decade. However, it is still unknown what kind of receptor profile a neuroleptic drug superior to clozapine would have. Many of the new atypical drugs have profiles based on the 'dirty' profile of clozapine. We still do not exactly understand why clozapine is such an effective drug, neither is our insight into the pathogenesis of schizophrenia deep enough to pursue a rational approach to designing new atypical agents. The new wave of neuroleptic drugs all follow the receptor profile of clozapine in one way or another.

At the ECNP the results of the first trials comparing atypical neuroleptics to each other were reported (olanzapine, risperidone, clozapine). The methodology of these comparative trials was not reported in detail and final conclusions on the value of the various compounds in treating schizophrenia await publication in peer reviewed journals. The results of various pharmacoeconomic studies suggested some advantages of certain neuroleptics over others, but also here the various methodologies used do not yet allow a final conclusion. The efforts to produce sigma ligands (e.g. panamesine [EMD 57445]) with efficacy in schizophrenia seem to have stalled. The atypical neuroleptics clearly have a lower risk of EPS, but other side effects can be bothersome, such as sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only)(22). Neuroleptic malignant syndrome can also occur in patients treated with atypical antipsychotics (23). Given the normal side-effect profile of these drugs, the clinician should be aware of suboptimal compliance on the part of patients, even when they are treated with new, atypical agents.

References

  1. Gibson MD, Tandon R. A summary of new research findings on the new antipsychotic drugs. Essential Psychopharmacology. 1: 27-37, 1996.
  2. Meltzer HY. The mechanism of action of novel antipsychotic drugs. Schizophrenia Bull 1991;2:263-87
  3. Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998;3:123-34
  4. Morisset S et al. Clozapine and other atypical neurleptics enhance histamine neuron activity. European Neuropsychopharm, 1998,8(suppl2):S242
  5. Taylor P, Butwell M, Gray C, et al. Schizophrenia, violence, clozapine and risperidone: A review. British Journal of Psychiatry 1996; 169 (Suppl 31): 21-30,
  6. Allison DB et al. Weight gain associated with conventional and newer neuroleptics. European Neuropsychopharm, 1998,8(suppl2):S216.
  7. Hind ID et al. Zotepine pharmacokinetcs. European Neuropsychopharm, 1998,8(suppl2): S306
  8. Rowley HL et al. Zotepine elevates dopamine in the frontal cortex of rats. European Neuropsychopharm, 1998,8(suppl2):S241
  9. Marksteiner J. et al. Differential alterations in enkephaline mRNA expression in rat brain. European Neuropsychopharm, 1998,8(suppl2): S240
  10. Mannokakis I et al. Risperidone augmentation of clozapine or olanzapine in refractory schizophrenia. European Neuropsychopharm, 1998,8(suppl2):S233.
  11. Grainger D. et al. Resource use and quality of life of olanzapine compared to risperidone. European Neuropsychopharm, 1998,8(suppl2):S225.
  12. Sprouse JS, Rollema H, Lu Y et al. Ziprasidone: in vitro evidence of a central 5HT1A agonist activity. European Neuropsychopharm, 1998,8(suppl2):S246
  13. Goff DC, Posever T, Herz L. et al. An exploratory haloperidol-controlled dose finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharm 1998;18:296-304.
  14. Chappell P. Sallee F. The tolerability and efficacy of ziprasidone in the treatment of children and adolescents with Tourette's syndrome. European Neuropsychopharm, 1998,8(suppl2):S216.
  15. Gray R Quetiapine: a new atypical antipsychotic for the treatment of schizophrenia. Ment Health Care 1998 ;1:163-4
  16. King DJ, Link CG, Kowalcyk B. A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. Psychopharmacology (Berl) 1998;137:139-46
  17. Peuskens J, Link CG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997;96:265-73
  18. Hyttel J, Arnt J, Costall B et al. Pharmacological profile of the atypical neuroleptic sertindole. Clin Neuropharm 1992;15 (suppl 1):267A-268A.
  19. Kasper S, Tauscher J, Kufferle B, Barnas C, Hesselmann B, Asenbaum S, Podreka I, Brucke T. Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123I-IBZM SPECT study. Psychopharmacology 1998 Apr;136(4):367-73
  20. Gao XM, Sakai K, Tamminga CA. Chronic olanzapine or sertindole treatment results in reduced oral chewing movements in rats compared to haloperidol. Neuropsychopharmacology 1998;19:428-33.
  21. Hale AS. A review of the safety and tolerability of sertindole. Int Clin Psychopharmacol 1998;13 Suppl 3:S65-70
  22. Collaborative Working Group on Clinical Trial Evaluations. Adverse effects of the atypical antipsychotics. J Clin Psychiatry. 1998;59 Suppl 12:17-22.
  23. Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry 1998;155:1113-6