PROLONGED QTc IN A POPULATION OF ADULT PATIENTS WITH MENTAL RETARDATION.

Jeanne E. Girardy, MD

BACKGROUND AND INTRODUCTION: Hunterdon Developmental Center (HDC) is a New Jersey State residence facility for 650 adults with neurodevelopmental disorders. These neurodevelopmental disorders are the result of a variety of diagnosis including chromosomal abnormalities, birth trauma, infections, etc and many of the residents of this facility have an unknown etiology for their disorder. Their disorders have resulted in conditions such as mental retardation, cerebral palsy and other neuromuscular conditions, severe abnormal behaviors, and seizures.

Recently, a large number of residents at Hunterdon Developmental Center have been noted to have QT prolongation on EKG. This study was designed and intended in order to gain understanding regarding the possible cause of this finding and its significance.

As noted above a significant number of residents of the HDC were noted to have prolonged QTc. This study hoped to address a few particular questions. The first was whether the residents at the Developmental Center did in fact have a higher QTc than the general population. The second question to be addressed was whether, in light of the recent Black Box Warning by Novartis, Mellaril has a more significant affect on the Qtc than the other neuroleptics. The third question entertained was whether there could be any other reason (other than those already known) that could explain QTc prolongation in this population of persons.

METHODS : All data was collected at the Hunterdon Developmental Center (HDC) from the HDC EKG books for the years 1999 and 2000 available in the Clinic Department. These data books include the information of Resident name, age, date of EKG, current medications, and list of medical conditions for each resident at the time of their EKG. These books did not record any recent laboratory data.

For each EKG, the RR interval and QT interval were measured. These numbers were recorded along with the resident's information as listed above. The QTc for each EKG was then calculated based on Bazett's formula. For this study, the upper limits of normal for Qtc were to be 0.42 msec for men and 0.43 msec for women. Although information on every EKG was recorded during data collection only the most recent EKG for each resident was used during statistical analysis.

RESULTS:

All data below are preliminary results and statistical significance has not yet been determined.

627 Residents of HDC 210 Residents had an EKG between 1/ll99 and 8/1l00 (33.5%) Of the 210 residents with EKG's: Average age = 45 years {Range 20-83) 79/210 Women (38%) - Average age 44 (Range 26-81 ) 131 /2l 0 Men {62%) - Average age 46 (Range 20-83)

89/2l0 {42%) had prolonged QTc {defined as women with QTc> 0.43 and men with QTc > 0.42) Of these 89 with prolonged Qtc: 47/89 (53%) had no identifiable reason for having a prolonged QTc (as determined by the list of medications and medical conditions listed above that have been shown to lead to prolonged Qtc) 23/89 {26%) were on Mellaril with or without another QTc prolonging medication/medical condition 16/89 ( 18%) had Mellaril as the only recognizable reason for QTc prolongation 30/89 (34%) had recognized reason (medication or medical condition) other than Mellaril for QTc prolongation.

Of the 210 residents with EKGs: 100/210 (48%) received a medication or had medical condition recorded that may lead to prolonged QTC. The average QTc for these residents was 0.43 msec. 110/210 (52%) had no recorded condition or medication recorded that may lead to prolonged QTc. The average QTc for these residents was 0.42 msec.

Of the 210 residents with EKGs: 42/210 (20%) were on Mellaril +/- another neuroleptic at the time of the EKG. The average QTc for this group was 0.43 msec. 168/210 (80%) were not on Mellaril at the time of their EKG. The average QTc for this group was 0.42 msec.

Of note: according to the list distributed by HDC pharmacy, as of 8/1/00: 98/627 residents { 16%) were on Mellaril Of these 98 residents: 56/98 (57%) did not have an EKG between l/1/99- 8/1/00.

In attempt to determine if different medication groups were associated with prolonged QTc's, the 210 residents with EKG's were separated into categories based on the rnedications they were taking at the time of the EKG. Each resident was placed into only one category. The order in which the categories were determined is the same order in which they are listed. For example, if a resident was taking a neuroleptic they were placed into that category regardless of what other medications they were taking. If a resident was taking an anti-epileptic medication and a GI medication they were placed in the category of anti-epileptic.

Medication Category # of Residents in Category Average QTc (milliseconds)

Neuroleptic 85 427 Anti-epileptic 58 417 GI 34 430 No Meds 16 398 Misc. 17 418 TOTAL 210 420

* * * *From this calculation it was also determined that the average QTc for the 2 l 0 HDC Residents with an EKG between l/1/99 and 8/1/00 was 0.42.

To further differentiate the Neuroleptic group to see if any one neuroleptic had a greater effect on the QTc than another, this group was divided based on neuroleptic. Of the 85 people in this category,14 Residents were on more than one neuroleptic and so were not used in this analysis. Of the 71 residents who were on a single neuroleptic, the following table lists the number of residents in each category and the average QTc for the category.

Neuroleptic # of Residents Average QTc (milliseconds) Mellaril 34 430 Zyprexa 13 410 Risperdal 13 420 Thorazine 8 420 Haldol 3 440

To further investigate whether one neuroleptic had more effect on QTc prolongation than another neuroleptic, a few patients were identified who had EKGs on different drug regimens. Although only their most recent EKG was utilized for all the above analysis, the following information is of interest as each of these residents serve as their own control. The residents listed below are those who were on a single neuroleptic and then switched to another single neuroleptic or were taken off of all neuroleptics. I did not include the residents identified who were on more than one neuroleptic and then switched to single neuroleptic treatment because of the possibility of confounding variables.

In the below table the residents are identified by a number. Of the 210 residents with EKG's that were used for this study, each resident was assigned a number 1-210.

Medication switch: Mellaril to Zyprexa: Patient ID # QTc on Mellaril QTc on Zyprexa 44 0.55 0.40 130 0.50 0.40 172 0.45 0.41

Medication switch: Mellaril to No Neuroleptic: Patient ID # QTc on Mellaril QTc on No Neuroleptic 107 0.44 0.43 161 0.43 0.41

Medication switch: Thorazine to No Neuroleptic: Patient ID # QTc on Thorazine QTc on No Neuroleptic 119 0.45 0.42

As noted above, the Gastro-intestinal category had a higher mean QTc than the Neuroleptic category. To further investigate the GI category, an attempt was made to separate the residents based on which GI medication they were taking. Residents in this category were on a variety of GI related medications including: Propulsid, Prilosec, Prevacid, Axid, Pepcid, Zantac, Pericolace, Colace, Reglan, Sennakot, Dulcolax, and Mylanta Gas. Due to the multiple different combinations of the various medications that the residents were on it was impossible to categorize them. However. it should be noted that only 8 residents in this group were on Propulsid (known to cause prolonged QT) and the average Qtc for this group was 0.426 (lower than the groups mean).

DISCUSSION: This study hoped to answer a few questions. The first of which was whether thrs population has a significantly higher QTc than the general population. Although there is debate even in the general population about the normal QTc, it appears that the QTc of 0.40 for the residents in this study that were taking MVI only or no medications falls within the normal range for the general population.

The next question addressed by this study was whether Mellaril had a more significant affect on QTc than other neuroleptics. The answer to this question appears to be yes. The group on Mellaril had a higher QTc mean than the groups on other neuroleptics (with the exception of the group on Haldol). This is also evident by the few cases identified of residents that were taken off of Mellaril and subsequently had a dramatic decrease in QTc.

The next question addressed by this study was whether there may be an alternative explanation (beside the explanations already known) to explain why this population may have a prolonged QTc. Although one may attempt to explain the mean QTc for this population of 0.42 strictly by medication effect, as found in this study, 52% of those residents that had a prolonged QTc had no identifiable reason, either by medication or medical history. It still remains a question whether chronic brain dysfunction is the common reason for this population as a whole to have upper normal QTc values.

One new question raised by this study is why the Gastro-intestinal medication group should have a higher than mean QTc. As stated earlier, this observation cannot be explained by the few patients that were taking Propulsid because their mean was lower than the groups mean. It is possible that this finding may be related to autonomic dysfunction. It is one possibility that the group of residents needing GI medication may have a higher rate of autonomic dysfunction and that this dysfunction may also cause them to have a prolonged QTc. This area should be further investigated in the future

Some clinical recommendations can be made on the basis of this study. The first is that the developmentally disabled population should have a baseline EKG done regardless of medication history and prior to and after addition of any new medication. This is due to the fact that there were such a high percentage of unexplained QTc prolongations in this population. The second recommendation is that mellaril be used only with extreme caution in this population and only when other neuroleptic regimens have faiIed. The last recommendation is that the subset of patients with GI conditions should be monitored especially closely for QT prolongation. As mentioned earlier the relationship of GI dysfunction and prolonged QT may be a good area of future research.