While levodopa is the mainstay treatment of Parkinson disease, long-term use of levodopa has many side effects [
A possible method of enhancing the action of dopaminergic therapy is to increase the sensitivity of dopamine D2 receptors that are the main targets for dopamine agonists [
For example, Alttoa et al. [
In another study [
These studies support the hypothesis that an increased number of D2 receptors in the high-affinity state correlates with increased motor behavior [
The present study examined whether an ultra-low daily dose of 40 micrograms of haloperidol could enhance the action of the patient’s daily dose of levodopa.
In order to establish the appropriate dose of haloperidol, the following estimates were made. For the treatment of psychosis, the recommended dose for oral haloperidol is 2–10 mg daily. It has been shown that subjects receiving 2 milligrams/day of haloperidol achieve plasma levels of about 1 to 1.5 nanograms per mL of plasma [
Before starting the study, the clinical study protocol, informed consent document, and all other relevant documents were submitted to and approved by the IEC/IRB (Internal Ethics Committee, and Internal Review Board) at the Alexandra Marine and General Hospital (AMGH). The documents were also submitted to and approved by the Therapeutic Products Program at Health Canada. The short name of the trial was CLR4001. At the start of the study, each subject was informed of the title of the study, that the study had been approved by the Therapeutic Products Program at Health Canada in Ottawa, the name of the drug (haloperidol) that would be added to their present medication, the dose of the medication, that the low dose of the added drug was far lower than is normally used for other clinical indications and was not expected to cause any muscle stiffness or related motor effects, and that the subject was free to stop taking the medication at any time. Informed signed consent was obtained from all participants. At the end of the study, the individuals were told by the study physician and the assistant whether the subject had any significant alterations in his/her clinical assessment.
This was a Phase IIa study intended to examine whether 40 micrograms of haloperidol per day would enhance the effectiveness of the regular daily dose of levodopa in treating Parkinson disease patients. The participants’ daily doses of levodopa ranged from 75 to 1,200 mg per day (in the forms of Sinemet or Apo-Levocarb) and were fixed during the study. The average levodopa dose for all patients was 502 mg/day. This procedure, therefore, had patients serve as their own controls. After approval by Health Canada and the AMGH review board, patients being treated for Parkinson’s disease were recruited by word of mouth from local general practitioners who had made the original diagnosis of Parkinson disease and had it confirmed by a neurologist using the standard UK Brain Bank criteria for Parkinson’s disease. The general nature of the study was described to potential participants by the study coordinator, and written consent was sought. Participants continued with their regular levodopa treatment throughout the course of the trial, and the dose was kept constant.
To be included, participants needed to have a clinical diagnosis of Parkinson’s disease. The diagnosis of Parkinson’s disease was made by the family doctor initially and confirmed by a consulting neurologist. While it would have been best in retrospect to select patients early in their illness to test the proof-of-principle for this study, it was decided to test all those who were eligible for the study.
Participants were evaluated at baseline and every week throughout the trial using the SPES/SCOPA scale for motor impairment [
Participants were treated with 40 micrograms of haloperidol per day for two weeks on a daily basis and returned weekly for assessment for a further four weeks. The liquid haloperidol medication was prepared by the hospital pharmacy (40
The specific steps were as follows.
Week 1: the study purpose and procedure, as above, were explained to the subject and the consent form was signed. A unique subject number was assigned, and the medical history and current medications were recorded. A SPES/SCOPA scale was scored. Each subject received fourteen vials, each of which contained 40 micrograms of haloperidol with instructions to take the contents of one vial at bedtime each evening for a period of two weeks. The subject’s number was recorded for each set of vials. Visit 2 was scheduled for 7 to 9 days later.
Week 2: after one week of medication, the SPES/SCOPA scale was scored, the signs, symptoms, and side effects were recorded, compliance was asked about, and the next visit was scheduled. The same was done at weeks 3 to 7, at which time the patients were thanked for their cooperation and received personal feedback.
Table
Patient data.
Subject | Age | M/F | Disease duration, years | SCOPA baseline at week 1 | Medication | L-DOPA dose/day |
---|---|---|---|---|---|---|
101 | 70 | M | 1 | 14 | Sinemet 100/25, 3/day | 300 mg |
102 | 59 | F | 2 | 25 | Levocarb 100/25, 1 qhs prn; Stalevo 150/37.5; 5/day | 850 mg |
103 | 81 | F | 31 | 42 | Sinemet cr 100/25, 5/day; Sinemet 100, 1/day | 600 mg |
104 | 80 | M | 9 | 26 | Levocarb 100/10 2 tabs, 5/day | 1000 mg |
105 | 76 | M | 10 | 23 | Pramipexole 200 mg, 3/day |
|
106 | 70 | M | 12 | 29 | Apo-Levocarb 100/25, 3 tabs, 4/day | 1200 mg |
107 | 81 | M | 4 | 20 | Apo-Levocarb 25 mg, 3/day | 300 mg |
108 | 65 | M | 10 | 27 | None | 0 mg |
109 | 61 | M | 3 | 16 | Levocarb 25 mg, 4/day | 100 mg |
110 | 67 | M | 8 | 16 | Levocarb 250/25 mg, 4/day; pramipexole 1 mg/day | 1000 mg |
112 | 72 | M | 6 | 30 | Apo-Levocarb 25 mg, 4/day | 100 mg |
113 | 61 | M | 6 | 21 | Sinemet, 100/25, 3/day | 300 mg |
114 | 63 | M | 12 | 28 | Sinemet 100/25, 2 tabs, 5/day | 1000 mg |
115 | 77 | F | 7 | 30 | Sinemet 100/25 | 700 mg |
117 | 92 | M | 15 | 13 | Sinemet cr 100/50, 2/day | 200 mg |
118 | 80 | M | 5 | 17 | Apo-Levocarb 100/25, 1/day | 100 mg |
|
||||||
Average | 72 | 8.8 | 23.6 | |||
s.e. | 1.9 |
SCOPA ratings at the end of each week.
Case | Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 |
---|---|---|---|---|---|---|---|
101 | 14 | 11 | 10 | 15 | 12 | 17 | 14 |
102 | 25 | 29 | 20 | 25 | 28 | 22 | 19 |
103 | 42 | 46 | 49 | 48 | 52 | 49 | 47 |
104 | 26 | 29 | 32 | 32 | 33 | 34 | 33 |
105 | 23 | 20 | 22 | 22 | 25 | 28 | 23 |
106 | 29 | 25 | 27 | 28 | 30 | 27 | 33 |
107 | 20 | 18 | 17 | 17 | 11 | 15 | 15 |
108 | 27 | 20 | 16 | 17 | 12 | 15 | 10 |
109 | 16 | 14 | 14 | 17 | 16 | 15 | 13 |
110 | 16 | 10 | 15 | 12 | 12 | 14 | 12 |
112 | 30 | 18 | 21 | 24 | 19 | 19 | 16 |
113 | 21 | 16 | 17 | 20 | 19 | 26 | 21 |
114 | 28 | 20 | 21 | 17 | 20 | 20 | 23 |
115 | 30 | 27 | 30 | 28 | 30 | 29 | 28 |
117 | 13 | 9 | 9 | 7 | 7 | 7 | 8 |
118 | 17 | 20 | 18 | 13 | 14 | 18 | 23 |
|
|||||||
Av. | 23.6 | 18.92 | 21.1 | 21.3 | 21.3 | 22.2 | 21.1 |
S.E. | 1.9 | 2.3 | 2.4 | 2.4 | 2.9 | 2.5 | 2.6 |
|
|||||||
Data for subgroup analysis: | |||||||
Av. | 20.8 | 17.1 | 16.7 | 17.1 | 16.25 | 18 | 16.4 |
S.E. | 1.7 | 1.6 | 1.2 | 1.5 | 1.8 | 1.6 | 1.5 |
|
0.007 | 0.0008 | 0.004 | 0.007 | 0.058 | 0.016 |
Four severe cases (and nonresponders; 104, 106, 103, and 115) were removed for the subgroup analysis.
The primary goal of the study was to obtain an estimate of the magnitude of the mean difference on the SPES/SCOPA scale between baseline and subsequent visits.
Based on the effect size in the prior animal work, a sample size of 16 subjects was calculated to provide 90% power to detect a difference at the 5% level, using MANOVA.
The results of the SPES/SCOPA scale on all 16 subjects in the low-dose haloperidol trial indicated a clear trend of improvement of Parkinson’s signs and symptoms, starting after one week of treatment, and continuing to improve over baseline throughout the duration of the trial, as shown in Figure
An add-on oral dose of 40
The SCOPA ratings shown in the top of Figure
In addition, we speculated whether there might be a sub-group of patients who might have benefitted from the low-dose haloperidol. This was done by omitting four outlier patients who were at the most advanced stage of Parkinson’s, as determined by neurological opinions stated in the clinical charts. These four patients (103, 104, 106, and 115) had been taking relatively high doses of levodopa (between 600 and 1200 mg/day, averaging 875 mg/day; the average levodopa dose for the other patients was 366 mg/day). The rationale was that these patients may have had extensive degeneration of their dopamine-sensitive neurons, thus precluding an elevation of D2High receptors secondary to haloperidol. In the remaining subgroup, the average SPES/SCOPA rating at week one (baseline) was
Comparing week 1 and week 3, that is, when the 2-week period of low-dose haloperidol was stopped, the results were even more significant. The average SPES/SCOPA rating at week 1 was
As indicated by the mechanism of action of low-dose haloperidol in elevating D2High receptors, the clinical response was highest at the end of the third week. The fall of 4 points on the Parkinson’s rating scale suggests a clinical improvement in the patients’ signs and symptoms.
The results showed a significant decline of freezing (episodes of inability to move; feet glued to the ground; feet frozen; freezing during speaking, eating, writing, or brushing teeth; freezing while getting out of bed, stepping forward, drinking, or even freezing when thinking) from Week 1 (a rating of 0.81) to Week 4 (one week after stopping treatment)—a rating of 0.50 (Figure
While continuing the daily dose of levodopa, the add-on low dose of 40
The ultra-low dose of 40
The add-on dose of 40 micrograms of haloperidol per day appeared to enhance the clinical action of levodopa, as shown in Figure
The synergism between the effect of haloperidol and levodopa is not surprising, because it has long been known that haloperidol can induce dopamine supersensitivity.
However, it should be noted that the haloperidol effect reported here may be within an “inverted U-shaped response.” That is, while very low doses of haloperidol are effective in causing dopamine supersensitivity, higher doses of haloperidol are well known to elicit the opposite effect and exacerbate the Parkinsonian signs.
Many additional patients are needed to extend the present findings and to determine the duration of the add-on effect. It is possible, for example, to give the add-on haloperidol for only one or two weeks each month to enhance the levodopa action.
In addition, a larger study with many more patients would need to examine the test-retest effect after three weeks off haloperidol, in order to see whether the haloperidol potentiation of levodopa action can be reinstated.
Moreover, a larger study will need to examine the period of time for which this haloperidol-add-on approach will continue to generate a positive response.
A longer and more extended study will also need to examine the stage of Parkinson’s disease for which this approach is likely to be effective.
Furthermore, the potentiation of the levodopa efficacy by the low-dose haloperidol may depend on the concomitant dose of levodopa. This aspect, too, needs to be examined in a more extended study with more subjects.
While the reduction of freezing (Figure
Overall, the apparent enhancement of the levodopa action by the low-dose haloperidol could in principle delay the progressive increases in the L-DOPA doses, which are usually found necessary in treating Parkinson diseased patients.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Craig J. Hudson made the study design and clinical assessments. Philip Seeman created graphs and assisted in the preparation of manuscript. Dr. Mary V. Seeman: Analysis of data, manuscript preparation.
The authors thank Heather Alce-Steffler and Alexander Cardno for excellent assistance. They thank Dr. James Hollingsworth, Dr. Don Neal, Dr. Samuel Appavoo, and Dr. Patrick Conlon for their excellent cooperation and support. Philip Seeman and Mary V. Seeman were supported by Clera Inc., which has patent applications for this method of treating Parkinson’s disease.