Journal of Psychopharmacology | 2021
Individualizing tapering antipsychotic schemes considering D2 blockade dynamics
Abstract
To the editor, Tapering antipsychotic dose in schizophrenia treatment is good clinical practice, as current guidelines suggest using a minimum effective dose to reduce the burden related to adverse effects (Barnes et al., 2020), but controversial, as the withdrawal process may be associated with relapses, whether due to the chronic characteristics of psychotic disorders or attributed to neural adaptations to antipsychotic exposure (Horowitz et al., 2020). In a viewpoint, the authors indicate that when reduction is appropriate, the concept of neuroadaptation should guide the rationale leading to adopting a slow, hyperbolic titration (Horowitz et al., 2020). This view goes in a different direction from the standard procedure of using fixed intervals (linear reduction), possibly increasing relapse risk, since usual minimum doses still induce high D2 blockade – based on in vivo molecular studies (Lako et al., 2013). We agree with this rationale; however, some additional issues concerning D2 blockade adaptation and schizophrenia treatment can help plan individualized schemes. Neuroadaptation can vary according to the duration of treatment and the differences between antipsychotics for D2 receptor affinity (Thompson et al., 2020). Antipsychotics with lower affinity and higher dissociation rates from the D2 receptor tend to induce less dopamine supersensitivity (Servonnet and Samaha, 2020) and can lead to a faster recovery of the neuroadaptation processes. Thus, different affinities may account for distinct time intervals during titration. Regarding antipsychotic exposure, patients at first-episode seem more sensitive to D2 blockade, whereas patients with multiple episodes and prolonged treatment can be more sensitive to withdrawal (Yin et al., 2016). In addition, although some antipsychotics have lower D2 affinity, such as quetiapine and clozapine, their short half-lives may be associated with withdrawal symptoms, including rebound psychosis, also demanding slower tapering (Chouinard et al., 2017). Also, antipsychotics have multiple targets – such as serotonergic, histaminergic, and cholinergic – which can be affected when stopping medications. For instance, cholinergic rebound can be mistaken for exacerbation of psychosis. Acknowledgedly, empirical support varies for each statement mentioned above, but overall, these particularities demand more caution. Tapering antipsychotic treatment is subject of debate among schizophrenia experts. Even reduction to a minimum effective dose in the maintenance phase is usually postponed when not simply disregarded in clinical practice. The possibility of discontinuing the medication has implications at different levels, specifically for patients. Up to 20% of individuals who fulfill schizophrenia spectrum disorders criteria will not present a second psychotic episode (Hui et al., 2019). Although this remains to be determined, it is possible that more than 20% of them will not have a second episode if medications are tapered off slowly enough, which can take months to years, as proposed by Horowitz et al. (2020). How to tell who will benefit if it is not timely and precisely executed? The idea of a general scheme is useful, especially in clinical trials, but specific characteristics of patients and medications can affect the risk of relapse exclusively towards neuroadaptation. To individualize, we suggest considering antipsychotic affinity, duration of treatment, and other variables – such as non-dopaminergic targets and half-lives of antipsychotics – until further research provides data to better inform decision-making.