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Balancing efficacy and tolerability to personalize treatment choices in schizophrenia

The Precision Medicine Initiative was launched in 2015 in the United States. This approach to disease prevention and treatment takes into account individual differences in patients’ genes, environments and lifestyles. It is proving success in many areas of medicine, and this EPA2020 satellite symposium discussed how the principles are being applied to treatment choices in schizophrenia.

Why do we need a choice of antipsychotics? 

Neuroadaptive mechanisms may improve cognitive function, boost resilience and facilitate functional recovery

Schizophrenia is a multifactorial disorder, with no ‘magic bullet’ regarding treatment, explained Marco Riva (University of Milan, Italy). The spectrum of symptoms is related to dysfunction of different neural circuits1 involving a variety of receptors2.

Available antipsychotic drugs have heterogeneous pharmacological profiles, differing in receptor profile. Key to the effect of antipsychotics on psychotic symptoms has been modulation of dopamine D2 receptors, but drugs vary regarding 5HT2a/D2 affinity ratio, prolonged blockade versus fast dissociation, partial agonism versus antagonism, and functional selectivity. Furthermore, second-generation antipsychotics have multireceptor profiles that are not limited to the D2 receptor.

The receptor signature of antipsychotics goes beyond modulation of neurotransmitter release to wider synaptic effects3  which lead to neuroadaptive mechanisms4. In the long-term, these neuroadaptive mechanisms may improve cognitive function, boost resilience and facilitate functional recovery of patients with schizophrenia4,5.

How to choose between antipsychotics regarding efficacy and safety

Balance efficacy and tolerability as much as possible

Christoph Correll (Zucker School of Medicine, New York, USA) considered treatment options for different stages of the disease. For first episode psychosis, second-generation antipsychotics are more efficacious than first-generation, with no significant difference between them, suggesting that adverse event profile will guide treatment choice6.

For multi-episode acute treatment, network meta-analysis comparing 32 antipsychotics showed that adverse event differences were more marked than efficacy differences7, and meta-analysis of second-generation antipsychotics for maintenance treatment demonstrated no consistent superiority of any agent regarding efficacy or tolerability8.

Prof Correll stressed that efficacy and tolerability must be balanced as much as possible. Further developments in precision medicine, measurement based care and novel mechanisms of action would aid decision-making.

Which drug for which patient?

Antipsychotic choice needs to be tailored to patient characteristics and needs

Andrea Fagiolini (University of Siena, Italy) discussed how individualized treatment choices can be made in clinical practice. Patients differ regarding symptoms and comorbidities, priorities and goals of treatment, and degree of acceptance of particular adverse events. Differences between antipsychotics in terms of target receptor profile9.10 will influence efficacy and tolerability11,12,13 and therefore the functional outcome:

  • D2 antagonism -  efficacy on positive symptoms, but extrapyramidal symptoms (EPS) and endocrine effects will be observed
  • 5HT2A antagonism -  efficacy on negative symptoms and reduced EPS
  • High 5HT2A/D2 affinity ratio - antipsychotic efficacy and reduced EPS (compared to D2 alone)
  • 5HT1A agonism - antidepressant and anxiolytic activity, improved cognition and reduced EPS
  • 5HT1D and 2C antagonism - antidepressant activity
  • α1 antagonism - postural hypotension will be observed
  • H1 antagonism - sedation and weight gain will be observed
  • M1 antagonism - anticholinergic effects (e.g., cognitive impairment) will be observed

Until we have reliable intra-individual response predictors, antipsychotic choice needs to be tailored to patient characteristics and needs, considering:

  • Different efficacy profiles
  • Different tolerability profiles
  • Individual patient characteristics influencing antipsychotic pharmacological actions
  • Individual patient preference

Educational financial support for this Satellite symposium was provided by Angelini.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Williams LM. Lancet Psychiatry 2016;3:472-80
  2. Aringhieri S, et al. Pharmacol Ther 2018;192:20-41
  3. Li J, et al. Schizophr Res 2018;192:194-204
  4. Luoni A, et al. Int J Neuropsychopharmacol 2015;18:puy061
  5. Calabrese F, et al. J Psychopharmacol 2020;34:420-8
  6. Zhu Y, et al. Lancet Psychiatry 2017;4:694-705
  7. Huhn M, et al. Lancet 2019;394:939-51
  8. Kishimoto T, et al. World Psychiatry 2019;18:208-224
  9. Gareri P, et al. Clin Interv Aging 2014;9:1363-73
  10. Correll CU, et al. Trends Mol Med 2011;17:92-107
  11. Zom SH, et al. Interactive Monoaminergic Brain Disorders 1999;377-93
  12. Tandon R, et al. J Serotonin Res 1997;4:159-77
  13. Leucht S, et al. Am J Psychiatry 2017;174:927-42
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