The results of this 12-week prospective, open-label study suggest that TJ-54 may be effective and well tolerated for children, adolescents and adults with PDD-NOS and Asperger’s disorder. Although the drug may also be effective in patients with PDD-NOS and Asperger’s disorder, our small sample size limits interpretation of data in these PDD subtypes.
In order to clarify the mechanism underlying the amelioration of aggressiveness by TJ-54, the effects of this medicine on the aggressive behaviour observed in rats treated with a serotonegic neurotoxin, para-chloroamphetamine, were investigated. TJ-54 ameliorated the aggressive behavior as effectively as a serotonin (5-HT) 1A receptor agonist or 5-HT2A receptor antagonist
. From these results, we hypothesized that this effect of TJ-54 may be due to 5-HT1A receptor antagonism
An in vitro binding study demonstrated that TJ-54 showed agonistic binding to 5-HT1A and dopamine (DA) 2 receptors. A further in vitro binding test to clarify the active compound showed that geissoschzine methyl ether (GM), an alkaloid in uncaria hook, a galencial constituent of TJ-54, had a similar potent binding to 5-HT1A and DA2 receptors
[25, 41, 42].
Treatment with TJ-54 at dosages from 2.5 to 7.5 g/day associated with significant amelioration of irritability, including aggression, self-injury, tantrums, lethargy, stereotypy, hyperactivity, and inappropriate speech. In light of research suggesting that a disregulation of DA and 5-HT contributes to maladaptive behavior in PDDs
, TJ-54’s unique mechanism of action as a partial D2 agonist, 5-HT1A agonist, and 5-HT2A antagonist
, may prove important for both its effectiveness and tolerability in PDD-NOS and Asperger’s disorder.
The significant reduction on the ABC-I subscale from baseline to end point is noteworthy in that the subjects in this study had higher baseline irritability subscale scores than those in the RUPP Autism Network study of risperidone for irritability in autism
. This finding highlights the fact that youths with PDDs other than autism, such as PDD-NOS, often suffer from a significant degree of similar symptomatology
Although highly speculative, these positive changes in socialization may be due to TJ-54’s mechanism of action as a partial 5-HT1A agonist
. A putative association has been hypothesized between partial agonism at 5-HT1A receptors and improvements in anxiety and depression, as well as the negative symptoms of schizophrenia
. Thus, it is possible that TJ-54 targets these symptoms, thereby potentially resulting in subjects’ increased ability and/or interest in interacting with others. It also may be that by decreasing irritability, the children and adolescents were better able to improve their social functioning over time. Overall, TJ-54 was well tolerated, with no severe or serious adverse effects associated with the drug.
The preliminary results of this study suggest that TJ-54 has the potential to be an effective and well-tolerated treatment for severe irritability in pediatric patients with PDD-NOS, and possibly in Asperger’s disorder. PDD or autism spectrum disorder, range from a severe form, called autism, to a mild form, AD and PDD-NOS. In previous studies almost AD and PDD-NOS children were not mentally retarded (high-functioning). To reduce the bias by heterogeneity of the PDD, in this study, we include mild form PDD, AD and PDD-NOS, and exclude moderate or severe form of PDD, autism.
Given the design characteristics of this trial, the present findings should be taken cautiously. Study limitations include its open design, lack of a control group, and small sample size. In an open-label study, both placebo effects and the role of previously prescribed medication prior to wash out cannot be ruled out as explanations for the observed improvement. Furthermore, regression to the mean is a ubiquitous phenomenon in repeated data that should always be considered as a possible cause of an observed change
. However, the rapid improvement in symptoms over several weeks observed here is consistent with a response related to therapeutic dosages of TJ-54. In this study, diagnoses were made by child and adolescent psychiatrist experienced in the diagnosis of PDDs using DSM-IV-TR criteria. However, it will be important to incorporate additional diagnostic instruments into future studies to augment the diagnostic assessment of individuals with subtypes of PDDs, such as the Autism Diagnostic Interview-Revised
. Finally, one might consider this sample as not completely representative of the whole population of PDD-NOS and Asperger’s disorder clients because only outpatients not suffering at present from axis I disorders were included, and no subjects had IQ below 70. On the other hand, PDD-NOS and Asperger’s disorder is a heterogeneous condition, and given the present small sample size, treatment efficacy data were better interpreted in a sample that was as homogeneous as possible. In summary, our trial suggests that TJ-54 therapy is a well-tolerated and effective remedy that improves the symptoms of PDD-NOS and Asperger’s disorder. This study has several limitations that could potentially impact the reliability and validity of these findings. Because of its open-label design, bias as well as a placebo effect could be a factor in our findings of improvement in irritability, as well as having provided socialization opportunities to these relatively high functioning individuals every 2 weeks. The number of subjects in this study was relatively small. In addition, the absence of a control group limits the conclusions that can be definitively drawn regarding the safety and tolerability of TJ-54 in this population.