Combined treatment with a selective PDE10A inhibitor TAK‐063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic‐like effects without affecting plasma prolactin levels and cataleptic responses in rodents

Abstract

Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK‐063 [1‐[2‐fluoro‐4‐(1H‐pyrazol‐1‐yl)phenyl]‐5‐methoxy‐3‐(1‐phenyl‐1H‐pyrazol‐5‐yl)pyridazin‐4(1H)‐one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK‐063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK‐063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK‐063 enhanced N‐methyl‐D‐aspartic acid receptor‐mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway‐specific markers revealed that coadministration of TAK‐063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK‐063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine‐ or MK‐801‐induced hyperactivity in rats and MK‐801‐induced deficits in prepulse inhibition in mice. TAK‐063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK‐063 may produce augmented antipsychotic‐like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents.

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

“…TAK‐063 at this dose did not exacerbate plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK‐063 may produce augmented antipsychotic‐like activities in combination with antipsychotics without exacerbating side effects in rodents …”

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…According to the pharmaceutical manufacturer (Avineuro) [227] Further development stopped because the primary endpoint of the assay was not reached [228] Selective dopamine D [274,275] Negative results from a phase II study [276] In one additional neuroimaging study on healthy male participants, TAK-063 attenuated ketamine-induced changes in…”

“…Up to now, these efforts have resulted in 12 reported clinical candidates and four clinically validated PDE10A PET ligands [ 273 , 274 ]. Following positive preclinical studies [ 275 ], which indicated efficacy in the treatment of positive and cognitive schizophrenia symptoms, the selective PDE10A inhibitor TAK-063 was investigated in a phase II study (20 mg/day, n = 83). Despite not meeting the primary endpoint, the authors stated that the results might be suggestive of antipsychotic activity [ 276 ].…”

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives

“…Upregulation of cyclic nucleotide levels in indirect pathway MSNs could be an alternative approach for novel antipsychotics [ 20 , 21 ], whereas activation of direct pathway MSNs could be associated with improvement of cognitive functions. Thus, in contrast to the marketed antipsychotics, phosphodiesterase inhibitors (PDEIs) influence both the indirect and direct pathways, and the additional action of these compounds on the direct pathway could help distinguish them clinically from D 2 antagonists [ 22 ]. Moreover, PDEIs may have potential therapeutic utility in the treatment of cognitive impairment associated with schizophrenia or may be useful as an adjunctive treatment for negative symptoms in patients with schizophrenia [ 19 ].…”