Clinical pharmacology of atypical antipsychotics: an update

Abstract

This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.

Table 1. Proposed mechanisms of action of atypical antipsychotics (modified by Horacek et al., 2006)

Table 2. Potential clinical efficacy and benefits related to the mechanisms of action of antipsychotics (modified by Miyamoto et al., 2005)

Table 3. Pharmacokinetic characteristics of new oral antipsychotics (modified by Citrome, 2013)

Figure 1. Atypical antipsychotics: proposed mechanisms of action (modified by Seeman, 2002)

Figure 2. Simplified receptor binding affinity profiles for atypical antipsychotics

Blue, potentially therapeutics, red, potentially side effects, receptor binding affinities. The two receptors with asterisks 5HT_2C and D₂ should be both therapeutic and side effects inducing. The yellow line indicates the D₂ affinity level for each drug (modified by Cutler et al., 2008)