Balancing efficacy and tolerability to personalize 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 5HT_2a/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 schizophrenia^4,5.

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 profile^9.10 will influence efficacy and tolerability^11,12,13 and therefore the functional outcome:

• D₂ antagonism -  efficacy on positive symptoms, but extrapyramidal symptoms (EPS) and endocrine effects will be observed
• 5HT_2A antagonism -  efficacy on negative symptoms and reduced EPS
• High 5HT_2A/D₂ affinity ratio - antipsychotic efficacy and reduced EPS (compared to D₂ alone)
• 5HT_1A agonism - antidepressant and anxiolytic activity, improved cognition and reduced EPS
• 5HT_1D 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.