Atypicals are not just D2 receptor blockers

What’s the difference between an atypical and a typical antipsychotic? Quite a lot as Herbert Meltzer, USA, explained. Generally, typical antipsychotics are a single class of drugs – D2 receptor blockers - with secondary actions causing dose-related extrapyramidal symptoms (EPS) e.g. parkinsonism and tardive dyskinesia, at clinically effective doses. They act mainly to improve positive symptoms.

Typical antipsychotics are D2 receptor blockers - with secondary actions causing dose-related extrapyramidal symptoms at clinically effective doses

Atypicals – a class or a mixed bunch?

Atypical antipsychotics, on the other hand, cause minimal EPS, but some are associated with prolactin increases at clinically effective doses and some cause weight gain – a serious drawback. Generally, they are a more disparate ‘class’ than the typical antipsychotics but have in common their potent direct and indirect 5-HT2A partial agonistic effects rather than being solely D2 receptor antagonists.

Indeed, studies show atypicals to be multifaceted in their receptor interactions, not solely with different serotonergic but also with muscarinic, nicotinic and other neuroreceptors. Atypicals also influence neurogenesis and synaptic maturation, formation and dissolution. Overall, they are a heterogeneous bunch. Thus, atypicals show multiple actions, some unique, that add to their efficacy as well as to their side-effect profiles. They generally improve positive symptoms, some improve cognition and some reduce suicide risk.

Atypicals show multiple actions, some unique, that add to their efficacy as well as to their side-effect profiles

As Prof Meltzer stated, atypicals have made an outstanding contribution to enhancing our understanding of schizophrenia through identifying new drug targets.  The potential for personalized medicine is just coming on line. With all these receptor targets available, shouldn’t we be matching patients to an individual drug?

NeSSy - a tailored approach

And this seems to be precisely what Gerhard Gründer, Germany, has been doing. He described the multicentre, randomized, double-blind Neuroleptic Strategy Study (NeSSy) clinical trial.

Quality of life was statistically and clinically significantly more improved with atypical antipsychotics only when the antipsychotic was tailored for each patient

In this trial quality of life (QoL) was statistically and clinically significantly more improved with atypical compared to typical antipsychotics but only when selection of the antipsychotic was tailored for each specific patient. However, in terms of psychopathology rated by psychiatrists, no significant differences were noted.

So, like CATIE, no benefit in primary outcome was noted in NeSSy. But, unlike CATIE, benefit was seen when atypical agent was matched to patient. Might it be there is something lacking in psychiatric clinical trials?

What’s lacking?

CATIE, despite conforming to accepted best practice, might have yielded some positive benefits for atypicals, compared to typicals, if the heterogeneity of both the study population and each drug’s mechanism of action had been incorporated into its design.

CATIE might have yielded some positive benefits for atypicals, if heterogeneity of population and mechanism of action had been incorporated into its design

Taking the patient’s perspective into consideration when determining study endpoints might also have been beneficial. Considering QoL, social function and patient well-being are meaningful patient-orientated goals. However, Professor Grunder suggested, from the patient’s perspective, studies to investigate the longer term effects of antipsychotic exposure on brain structure should also be considered. Less exposure to drug may in itself be beneficial.

References and further reading

1. The main references for CATIE and NeSSy are cited below:
2. Lieberman JA & Stroup TS. Guest editor’s introduction: what can large pragmatic clinical trials do for public mental health care. Schizophrenia Bulletin 2003;29:1-6.
3. Stroup TS et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project: schizophrenia trial design and protocol development. Schizophrenia Bulletin 2003;29:15-31.
4. Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005;353:1209-1223.
5. McEvoy JP et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006:163;600-610.
6. Stroup TS et al. Effectiveness of olanzapine, quetiapine, risperidone and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006:163;611-622.
7. Gründer G et al. Effects of first- versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind randomised study. Lancet Psychiatry 2016 (in press)
8. Schulz C et al. Patient-oriented randomisation: a new trial design applied in the NeSSy study. ClinTrials 2016 (in press)