The recent article from Tabatabaei Dakhili et al. (1) describes some elegant studies that indicate that the antipsychotic diphenybutylpyridine (DPBP) drugs, particularly pimozide, can alleviate obesity-induced type 2 diabetes. They use in vitro, in vivo, and in silico techniques to demonstrate a noncanonical action of these dopamine 2 (D2) receptor antagonists in reducing hyperglycemia via a reduction of succinyl CoA:3-ketoacid CoA transferase (SCOT) activity. They conclude that this indicates the potential for drug repurposing of the DPBPs, as they “appear relatively safe in humans,” a conclusion reiterated by Max Bingham’s editorial (2).

However, this conclusion is misleading. Pimozide and the other DPBPs have been largely replaced by newer drugs in the treatment of psychosis for three main reasons. Like other conventional (older) D2 antagonists, they can induce acute (e.g., parkinsonism) and enduring (tardive dyskinesia) motor side effects. They may also induce hyperprolactinemia through their antagonism of D2 receptors on pituitary lactotrophs. Most importantly, pimozide is liable to increase the QT interval through HERG (KCNH2) potassium channel inhibition with a Ki of 18 nmol/L (3), resulting in a documented risk of potentially fatal arrhythmias (4). These severe adverse effects are all dose dependent.

The experiments of Tabatabaei Dakhili et al. (1) employed drug concentrations in vitro of approximately 1 μmol/L, 100 or more times higher than is required for D2 receptor antagonism and, in vivo, at least 10-fold higher than is used to model antipsychotic action and motor side effects of these drugs (5,6). This implies the need for clinically effective antiglycemic doses of pimozide to be far in excess of those currently permitted, which would result in complete blockade of, among other sites, D2 receptors and HERG ion channels (3), with consequent effects likely to include motor dysfunction, hyperprolactinemia, and QT prolongation. While SCOT is convincingly demonstrated to be a valuable target for potential therapy in type 2 diabetes, the suggestion that DPBPs “may have utility in being repurposed for the treatment of [type 2 diabetes]” is, at best, unsupported by current evidence.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Tabatabaei Dakhili
SA
,
Greenwell
AA
,
Yang
K
, et al
.
The antipsychotic dopamine 2 receptor antagonist diphenylbutylpiperidines improve glycemia in experimental obesity by inhibiting succinyl-CoA:3-ketoacid CoA transferase
.
Diabetes
2023
;
72
:
126
134
2.
Bingham
M
.
In this issue of Diabetes
.
Diabetes
2023
;
72
:
1
2
3.
Kongsamut
S
,
Kang
J
,
Chen
XL
,
Roehr
J
,
Rampe
D
.
A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs
.
Eur J Pharmacol
2002
;
450
:
37
41
4.
Haddad
PM
,
Anderson
IM
.
Antipsychotic-related QTc prolongation, torsade de pointes and sudden death
.
Drugs
2002
;
62
:
1649
1671
5.
Arnt
J
.
Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade
.
Acta Pharmacol Toxicol (Copenh)
1982
;
51
:
321
329
6.
Fujiwara
H
.
Comparative studies of sulpiride and classical neuroleptics on induction of catalepsy, locomotor activity, and brain dopamine metabolism in mice
.
Pharmacol Biochem Behav
1992
;
41
:
301
308
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