¹National Taiwan University Hospital and National Taiwan University College of Medicine, Psychiatry, Taipei, Taiwan, ²National Taiwan University College of Medicine, Graduate Institute of Anatomy and Cell Biology, Taipei, Taiwan

Background: Patients in remitted psychosis wish to stop medications but facing increased risks of relapse if doing so. Dopamine-supersensitivity during withdrawal period after chronic antipsychotics administration is supposed to explain this phenomenon. To minimize such hazards, we have adopted a hyperbolic (in contrast to linear) tapering algorithm with a pre-requisite of 6-month stabilization before next dose reduction [1] and we have demonstrated that a proportion of patients could reduce 58.5% of their baseline dose and endorsed improved functioning and quality of life after 2 years [2]. However, the protracted course of tapering renders it inconvenient to apply to clinical practice. We also need more evidence from benchworks to support and optimize bedside approaches.

Aims & Objectives: Aim 1: Characterize the role of dopamine D2 receptor (D2R) and striatal D2R-expressing medium spiny neuron (D2-MSN) in hypothetical haloperidol-induced dopamine supersensitivity. Aim II: Test the efficiency of antipsychotic tapering protocol and evaluate the effect of n-acetylcysteine (NAC) cotreatment on the reduction of dopamine supersensitivity induced by pretreatment with haloperidol. Aim III: Test if NAC add-on can help patients with remitted psychosis to taper down antipsychotic doses faster and safer.

Method: First, using heterozygous Disc1 mutant (Disc1 Het) mice as an animal model of schizophrenia [3], we administer saline or haloperidol (0.5 mg/kg) with various durations to wild type (WT) and Disc1 Het mice, test its effects on striatal D2R and D2-MSN, and establish a behavioral model by demonstrating if there is haloperidol-induced dopamine supersensitivity using amphetamine challenge test to simulate the reactions while discontinuing antipsychotics of patients after chronic treatment. Second, after establishing dopamine-supersensitivity by administering haloperidol 0.5 mg/kg, we will reduce the dose step-by-step to test the biological responses and behavioral reactions of mice. And then test if co-administration of NAC during tapering of haloperidol will ameliorate the aforementioned responses and reactions of mice. Third, 20 patients with remitted psychosis under stable antipsychotic treatment will be recruited in a pilot dose tapering clinical trial to test if add-on of NAC 1200 or 2400 mg/d can help to half the pre-requisite of stabilization to 3 months smoothly, without increased risk of relapse after 1 year compared to the 2-year results of GARMED trial [4].

Results: The preliminary results of amphetamine challenge test on 4 groups, 6 mice in each group pretreated with either saline or haloperidol on WT vs. Disc1 Het, revealed significant hyperlocomotion, a behavioral reaction suggesting dopamine supersensitivity, and it seems more prominent on the mutant mice. Besides, 4 remitted patients have participated in the pilot trial, all well-tolerable to NAC add-on so far. The protective effect of NAC on Disc1 Het mice will be tested further.

Discussion & Conclusions: We designed a project connecting benchwork and a pilot trial to test the hypothetical theory, mitigating negative impact of dopamine supersensitivity by NAC pretreatment on mice and clinical patients while undergoing antipsychotic tapering. We anticipate it to become a model for testing feasibility of tapering psychotropics, not only antipsychotics but also antidepressants or hypno-sedatives, with adjuvant neuroprotective agents (not exclusively with NAC) for patients who have already reached remitted states.