Clera Inc.

Because increased dopamine neurotransmission occurs with most antidepressants, and because antipsychotics cause behavioural supersensitivity to dopamine, short-term low-dose antipsychotic treatment was tested on depressed patients with an expectation of clinical improvement in the supersensitive phase following drug withdrawal.

This was a randomized, double-blind, placebo-controlled study of 48 patients who met criteria for DSM-IV(®) Major Depressive Disorder, were in a Major Depressive Episode, and had a Hamilton Depression Rating Scale (HAMD) rating of ≥14. Half the participants received 0.25mg oral haloperidol each day for 7 days, after which they received placebo daily for 4 weeks. The other half received placebo throughout the trial.

One week after stopping the medication, the HAMD ratings of the drug-treated patients fell by 9.96 points, as compared to a reduction of 8.73 points in the placebo-treated patients, when comparing visits 1 and 4. There was no such difference when comparing visits 2 and 4. The differences were not significant, but indicated a trend. One week after the medication was stopped, the Clinical Global Index fell 1.64±0.18 units for the medication-treated patients, compared to 1.12±0.26 units for the placebo group (P=0.05). The regimen was well tolerated.

Seven days of an ultra-low dose of 0.25mg haloperidol, followed by withdrawal of haloperidol, resulted in clinical depression improvement greater than placebo and significantly decreased psychomotor retardation, consistent with haloperidol-induced behavioural supersensitivity to dopamine.

The sample was small. More patients are needed in a future study.

Dopaminergic stabilizers are recognized as compounds that can either enhance or antagonize dopamine (DA)‐dependent behaviors depending on the prevailing dopaminergic tone. The dopaminergic stabilizer ASP2314 is being tested clinically and has been reported to have antipsychotic effects in a clinical trial as an add on medication. To elucidate the mechanisms of action of this dopaminergic stabilizer, its potency on the functional dopamine D2High receptors was examined. In competition with D2 receptors selectively labeled by [3H]domperidone, ASP2314 had a dissociation constant, KiHigh, of 1.62 μM for D2High in human cloned D2Long receptors and 0.83 μM for rat homogenized striata. Using the D2 agonist ligand [3H](+)‐4‐propyl‐3,4,4a,5,6,10b‐hexahydro‐2H‐naphtho[1,2‐b][1,4]oxazin‐9‐ol ((+)PHNO), ASP2314 had a high‐affinity Ki of 32 nM for D2High for rat homogenized striata. ASP2314 stimulated the incorporation of [35S]GTP‐γ‐S into rat striata by 50% at 43 nM, and into the cloned D2Long membranes by 50% at 3.2 μM (compared to 100% stimulation by 10 μM dopamine). With similar concentrations of ASP2314 inhibiting the binding of ligands at D2High and stimulating [35S]GTP‐γ‐S incorporation, the data indicate that the dopaminergic stabilizing action of ASP2314 may be related to the selectivity for the D2high state of the D2 receptor. Synapse 63:930–934, 2009. © 2009 Wiley‐Liss, Inc.

Although dopamine supersensitivity is a fundamental aspect of diseases such as schizophrenia and Parkinson's disease, the molecular basis of dopamine supersensitivity is not known. Because behavioral dopamine supersensitivity is associated with a marked elevation of striatal dopamine D2Highreceptors in vitro, it is important to develop methods to measure D2Highreceptors in vivo. The presentex vivostudy found that the dopamine agonist NPA ([‐]‐N‐propyl‐norapomorphine) inhibited the binding of the agonist [3H](+)PHNO to rat striatal D2 receptors significantly more than the D2 antagonist [3H]raclopride, when NPA was coinjected i.v. with each radioligand. These results suggest that the greater sensitivity of [3H](+)PHNO to inhibition by the coinjected NPA reflects in vivo competition at D2Highreceptors. Using rats that had been sensitized to amphetamine, thisex vivomethod found that the specific binding of [3H](+)PHNO that was displaced by 10 μg/kg of NPA was 2.4‐fold higher than that for control rats. These data agree with in vitro data showing a marked increase in D2Highsites after amphetamine sensitization. Therefore, it is recommended that this method of coinjecting the D2 radioligand and the dopamine agonist displacer be used in human positron tomography to detect D2Highreceptors in health and disease. Synapse 63:186–192, 2009. © 2008 Wiley‐Liss, Inc.