Psychopharmacologia (Berl.) 42, 135-137 (1975) 9 by Springer-Verlag 1975
Deanol in Tardive Dyskinesia: A Preliminary Report WILLIAM E. FANN Baylor College of Medicine, Houston, Texas JOHN L. SULLIVAN III and ROBERT D. MILLER Department of Psychiatry, Duke University Medical Center, Durham, North Carolina GERALD M. McKENZIE Department of Pharmacology, Wellcome Laboratories, Research Triangle Park, North Carolina Received December 23, 1974
Abstract. Deanol, a CNS stimulant and putative precursor of choline, has been given to 10 subjects with tardive dyski-
nesia. All subjects showed relief of symptoms of TD, possibly through enhancing CNS cholinergic mechanisms.
Key words: Movement Disorders - Dyskinesia - Acetylcholine - Dopamine.
Current theories of tardive dyskinesia (TD), a hyperkinetic disorder associated with long-term neuroleptic treatment, have identified it as a hyperdopaminergic condition (Fann etal., 1972a). Most therapeutic attempts have involved administration of dopamine (DA) blocking agents, but, since many of these agents have been implicated in the genesis of TD, this approach to therapy may ultimately constitute further aggravation of the condition, and, indeed, no effective treatment of T D has thus far been found. The neuroleptics, which antagonize the CNS effects of dopamine, may cause an increased synthesis of dopamine through a feedback mechanism, or by chronically blocking the dopamine receptor site, create a condition of functional denervation, making the postsynaptic D A neuron more sensitive to available D A (Klawans, 1973). Since the offending neuroleptics possess potent anticholinergic as well as antidopaminergic properties, another possibility in the genesis of T D involves a dysfunction of striatal cholinergic systems. Pursuant to this, we have given a putative metabolic precursor of ACh, deanol (2-methylaminoethanol) to subjects with TD. Deanol is theoretically intraneuronally N-methylated to form choline, which is then conjugated to an acetyl radical to yield acetylcholine (Pfeiffer et al., 1959).
Method Thirteen hospitalized, chronically mentally ill patients, diagnosed by 3 psychiatrists as having TD, were scored by these 3 physicians on 4 parameters: mouth-lip, tongue, hand-finger, feet. The rating was done on a 100 point scale with 0 reflecting no movement and 100 the worst the rater had ever seen. Each patient was escorted to a room with the 3 raters present and subjected to a standard rating procedure, previously described (Fann et al., 1972b). The subjects were rated before starting the drug and after 5 days on deanol, 500 nag per day in divided doses. The raters did not communicate their assessments to one another until the ratings were completed and the score sheets submitted. Because the possibility of investigator bias exists on an open trial, assessments of the three raters were subjected to the Kendall Coefficient of Concordance for determination of inter-rater reliability. No special laboratory work was conducted, in view of deanol's long history of safe clinical use in treatment of hyperkinesis. Blood pressure was monitored and recorded four times daily.
Results Ten subjects completed the five day course of therapy. One subject was dropped from the study because of an increase in systolic blood pressure, which returned to normal upon withdrawal of the drug. Two others dropped out, refusing to take the medication at all.
136
Psychopharmacologia (Berl.), Vol. 42, Fasc. 2 (1975) Table 1. Effects of deanol in tardive dyskinesia
Patient
Rater
Mouth-lip
Tongue
Hand-finger
Feet
Pre
Post
Pre
Post
Pre
Post
Pre
Post
1
A B C
50 50 70
10 20 15
40 50 70
10 0 5
20 35 30
10 0 10
10 10 5
0 0 0
2
A B C
30 25 30
10 0 15
10 25 10
10 0 0
0 0 20
10 0 5
0 0 5
0 0 0
3
A B C
0 0 10
0 20 0
5 0 10
0 0 0
15 25 10
0 20 0
4
A B C
50 50 30
10 25 5
10 10 20
5 0 0
5 0 20
5 0 0
0 0 10
0 0 0
7
A B C
0 0 15
5 20 10
20 10 35
5 0 0
20 0 10
5 0 0
9
A B C
0 0 20
0 0 0
20 25 30
0 0 0
0 0 0
5 15 ~t."
10
A B C
0 0 5
5 0 0
25 25 30
5 20 5
20 25 20
10 0 ~t. a
15 25 15
0 0 0
11
A B C
30 70 50
20 25 15
30 70 50
10 25 15
25 50 50
0 0 25
10 10 20
10 25 5
13
A B C
30 50 40
20 25 15
10 50 25
10 15 10
0 0 0
5 5 ~t. ~
0 0 10
0 0 0
14
A B C
10 0 0
5 25 10
0 0 0
5 10 0
a f.t. = Fast tremor. Values given by 3 raters to severity'of body part movement expressed in raw numbers, before drug and after 5 days on oral deanol, 500 mg/day. 100 = most severe hyperkinesia the rater has ever seen; 0 = no hyperkinetic movement.
This was a s s o c i a t e d w i t h t h e i r c h r o n i c s u s p i c i o n a n d hostility rather than with any discomfort caused by t h e s t u d y m e d i c a t i o n . T a b l e i shows t h e d e c r e a s e in d y s k i n e t i c m o v e m e n t s in the t e n c o m p l e t e d s u b j e c t s a f t e r t r e a t m e n t w i t h d e a n o l . A l l 10 a c h i e v e d s o m e o r t o t a l relief of t h e i r i n v o l u n t a r y m o v e m e n t s a f t e r 5 d a y s o n d e a n o l . D a t a was a n a l y z e d b y W i l c o x i n M a t c h e d P a i r s S i g n e d R a n k T e s t ( T a b l e 2). O n e s u b j e c t ( P a t i e n t 9) s h o w e d m i l d l y i n c r e a s e d s e v e r i t y of a slight p a r k i n s o n i a n t r e m o r of t h e h a n d .
Discussion D e a n o l , an o r a l l y a d m i n i s t e r e d c h o l i n e r g i c a g e n t , h a s b e e n p r e s c r i b e d to 10 p a t i e n t s with t a r d i v e d y s k i n e s i a
Table 2. Effects of deanol in tardive dyskinesia: level of significance
Hand-finger Tongue Feet Mouth-lip
Rater agreement a pre
Rater agreement a pre minus post
Improvement b
0.05 0.001 0.01 0.02
0.05 0.05 N.S. 0.01
N.S. 0.01 0.02 0.05
N.S. = Not significant. Kendall Coefficient of Concordance. b Wilcoxin Matched-Pairs Signed Rank Test.
W. E. Fann et al.: Deanol in Tardive Dyskinesia: A Preliminary Report for 5 days and has provided partial or complete symptom relief to all 10. The precise mechanisms for the action of deanol in TD remain undefined, but the findings that its administration is followed by suppression of hyperkinetic symptoms, and that it may aggravate parkinsonian symptoms, suggest that it is working through enhancement of the cholinergic system, probably in the striatum. Although the intensification of Patient 9's parkinsonism was not intentionally evoked, the phenomenon tends to corroborate our belief that deanol is a cholinergic agent acting to relieve a presumed hypocholinergic state in tardive dyskinesia. It is now generally accepted that the dopamine-dependent and acetylcholine-dependent neuronal systems in the striatum must be in balance for normal motor function (Klawans, 1973). Therefore, an initial suppression of DA by the neuroleptics would create a relative hypercholinergic condition early in treatment, with a consequent parkinson-like state (Ambani et al., 1973). Eventually, however, the dopamine system would adapt to the deficiency, allowing the anticholinergic effects of the neuroleptics to predominate, compromise the ACh-dependent systems, and create a hypocholinergic condition appearing clinically as dyskinesia. If deanol does indeed act as a cholinergic agent, this supposition would account for its apparent efficacy in treatment of tardive dyskinesia. In earlier trials, we have administered the anticholinesterase physostigmine to patients with TD. Physostigmine enhanced the CNS activity of acetylcholine and suppressed the patients' involuntary movements (Fann et al., 1972b). Ambani et al. (1973) reported that 6 of 10 patients who developed minimum rigidity or tremor or both during acute (8-16 days) phenothiazine therapy exhibited worsening of their neurological signs after injection of physostigmine. These investigators concluded that cholinergic hyperactivity or hypersensitivity or both occur in phenothiazine-induced parkinsonism and idiopathic Parkinson's Disease. In another related study, we found that methylphenidate, a CNS stimulant which acts through enhancement of noradrenergic and dopaminergic activity in the brain, aggravated TD (Fann et al., 1973). Deanol also demonstrates CNS stimulant properties, and the finding that another stimulant showed opposite action in TD would tend to isolate
137
the dopamine-acetylcholine systems as the central issue in the genesis and treatment of TD. Despite the preliminary nature of this study and the open model, we believe that a report of findings is in order to alert other clinical investigators to an interesting and apparently safe compound worthy of further clinical evaluation in the treatment of TD. We suggest precautionary daily blood pressure determinations, however, since I subject here and 2 others in an earlier pilot study (3 of 21 subjects) have shown unexplained increases in systolic blood pressure while receiving deanol. Pressure returned to normal when the drug was stopped; hypertension recurred in 1 subject when deanol was resumed and returned to normo-tensive levels when discontinued. A definite causal relationship has not as yet been established, however. We are currently undertaking further examination of this agent in treatment of TD, including chronic clinical efficacy studies and examination of CNS mechanisms in animal trials. Acknowledgements. The authors wish to express their grateful appreciation to Mr. Bruce Richman, who helped in collection and preparation of the data; Ms. Connie Ramey, who prepared the manuscript; Osvaldo N. Rd, M.D., Riker Laboratories, Inc., who furnished deanol; and especially to John I. Thornby, Ph.D., who helped with the statistical analysis. Supported in part by VA Grant No. 2600-04. References Ambani, L. M., Van Woert, M. H., Bowers, M. B.: Physostigmine effects on phenothiazine-induced extrapyramidal reactions. Arch. Neurol. (Chic.) 29, 444-446 (1973) Farm, W. E., Davis, J. M., Janowsky, D. S.: Tardive dyskinesia: Findings in two mental hospital populations. Dis. Nerv. Syst. 33, 182-186 (1972a) Fann, W. E., Lake, C. R., Gerber, C. J., McKenzie, G. M.: Cholinergic suppression of tardive dyskinesia. Psychopharmacologia (Berl.) 37, 101-116 (1972b) Fann, W. E., Davis, J. M., Wilson, I. C.: Methylphenidate in tardive dyskinesia. Amer. J. Psychiat. 130, 922-924 (1973) Klawans, H. L., Jr.: The pharmacology of tardive dyskinesia. Amer. J. Psychiat. 130, 82-86 (1973) Pfeiffer, C. C., Groth, D. P., Bain, J. A.: Choline vs. dimethylaminoethanol (deanol) as possible precursors of cerebral acetylcholine. In: Biological Psychiatry, J.H. Masserman, ed., p. 259. New York: Grune & Stratton, Inc. 1959
William E. Fann, M.D., Department of Psychiatry, Baylor College of Medicine 1200 Moursund, Houston, Texas 77025, U.S.A.
Deanol in Tardive Dyskinesia: A Preliminary Report WILLIAM E. FANN Baylor College of Medicine, Houston, Texas JOHN L. SULLIVAN III and ROBERT D. MILLER Department of Psychiatry, Duke University Medical Center, Durham, North Carolina GERALD M. McKENZIE Department of Pharmacology, Wellcome Laboratories, Research Triangle Park, North Carolina Received December 23, 1974
Abstract. Deanol, a CNS stimulant and putative precursor of choline, has been given to 10 subjects with tardive dyski-
nesia. All subjects showed relief of symptoms of TD, possibly through enhancing CNS cholinergic mechanisms.
Key words: Movement Disorders - Dyskinesia - Acetylcholine - Dopamine.
Current theories of tardive dyskinesia (TD), a hyperkinetic disorder associated with long-term neuroleptic treatment, have identified it as a hyperdopaminergic condition (Fann etal., 1972a). Most therapeutic attempts have involved administration of dopamine (DA) blocking agents, but, since many of these agents have been implicated in the genesis of TD, this approach to therapy may ultimately constitute further aggravation of the condition, and, indeed, no effective treatment of T D has thus far been found. The neuroleptics, which antagonize the CNS effects of dopamine, may cause an increased synthesis of dopamine through a feedback mechanism, or by chronically blocking the dopamine receptor site, create a condition of functional denervation, making the postsynaptic D A neuron more sensitive to available D A (Klawans, 1973). Since the offending neuroleptics possess potent anticholinergic as well as antidopaminergic properties, another possibility in the genesis of T D involves a dysfunction of striatal cholinergic systems. Pursuant to this, we have given a putative metabolic precursor of ACh, deanol (2-methylaminoethanol) to subjects with TD. Deanol is theoretically intraneuronally N-methylated to form choline, which is then conjugated to an acetyl radical to yield acetylcholine (Pfeiffer et al., 1959).
Method Thirteen hospitalized, chronically mentally ill patients, diagnosed by 3 psychiatrists as having TD, were scored by these 3 physicians on 4 parameters: mouth-lip, tongue, hand-finger, feet. The rating was done on a 100 point scale with 0 reflecting no movement and 100 the worst the rater had ever seen. Each patient was escorted to a room with the 3 raters present and subjected to a standard rating procedure, previously described (Fann et al., 1972b). The subjects were rated before starting the drug and after 5 days on deanol, 500 nag per day in divided doses. The raters did not communicate their assessments to one another until the ratings were completed and the score sheets submitted. Because the possibility of investigator bias exists on an open trial, assessments of the three raters were subjected to the Kendall Coefficient of Concordance for determination of inter-rater reliability. No special laboratory work was conducted, in view of deanol's long history of safe clinical use in treatment of hyperkinesis. Blood pressure was monitored and recorded four times daily.
Results Ten subjects completed the five day course of therapy. One subject was dropped from the study because of an increase in systolic blood pressure, which returned to normal upon withdrawal of the drug. Two others dropped out, refusing to take the medication at all.
136
Psychopharmacologia (Berl.), Vol. 42, Fasc. 2 (1975) Table 1. Effects of deanol in tardive dyskinesia
Patient
Rater
Mouth-lip
Tongue
Hand-finger
Feet
Pre
Post
Pre
Post
Pre
Post
Pre
Post
1
A B C
50 50 70
10 20 15
40 50 70
10 0 5
20 35 30
10 0 10
10 10 5
0 0 0
2
A B C
30 25 30
10 0 15
10 25 10
10 0 0
0 0 20
10 0 5
0 0 5
0 0 0
3
A B C
0 0 10
0 20 0
5 0 10
0 0 0
15 25 10
0 20 0
4
A B C
50 50 30
10 25 5
10 10 20
5 0 0
5 0 20
5 0 0
0 0 10
0 0 0
7
A B C
0 0 15
5 20 10
20 10 35
5 0 0
20 0 10
5 0 0
9
A B C
0 0 20
0 0 0
20 25 30
0 0 0
0 0 0
5 15 ~t."
10
A B C
0 0 5
5 0 0
25 25 30
5 20 5
20 25 20
10 0 ~t. a
15 25 15
0 0 0
11
A B C
30 70 50
20 25 15
30 70 50
10 25 15
25 50 50
0 0 25
10 10 20
10 25 5
13
A B C
30 50 40
20 25 15
10 50 25
10 15 10
0 0 0
5 5 ~t. ~
0 0 10
0 0 0
14
A B C
10 0 0
5 25 10
0 0 0
5 10 0
a f.t. = Fast tremor. Values given by 3 raters to severity'of body part movement expressed in raw numbers, before drug and after 5 days on oral deanol, 500 mg/day. 100 = most severe hyperkinesia the rater has ever seen; 0 = no hyperkinetic movement.
This was a s s o c i a t e d w i t h t h e i r c h r o n i c s u s p i c i o n a n d hostility rather than with any discomfort caused by t h e s t u d y m e d i c a t i o n . T a b l e i shows t h e d e c r e a s e in d y s k i n e t i c m o v e m e n t s in the t e n c o m p l e t e d s u b j e c t s a f t e r t r e a t m e n t w i t h d e a n o l . A l l 10 a c h i e v e d s o m e o r t o t a l relief of t h e i r i n v o l u n t a r y m o v e m e n t s a f t e r 5 d a y s o n d e a n o l . D a t a was a n a l y z e d b y W i l c o x i n M a t c h e d P a i r s S i g n e d R a n k T e s t ( T a b l e 2). O n e s u b j e c t ( P a t i e n t 9) s h o w e d m i l d l y i n c r e a s e d s e v e r i t y of a slight p a r k i n s o n i a n t r e m o r of t h e h a n d .
Discussion D e a n o l , an o r a l l y a d m i n i s t e r e d c h o l i n e r g i c a g e n t , h a s b e e n p r e s c r i b e d to 10 p a t i e n t s with t a r d i v e d y s k i n e s i a
Table 2. Effects of deanol in tardive dyskinesia: level of significance
Hand-finger Tongue Feet Mouth-lip
Rater agreement a pre
Rater agreement a pre minus post
Improvement b
0.05 0.001 0.01 0.02
0.05 0.05 N.S. 0.01
N.S. 0.01 0.02 0.05
N.S. = Not significant. Kendall Coefficient of Concordance. b Wilcoxin Matched-Pairs Signed Rank Test.
W. E. Fann et al.: Deanol in Tardive Dyskinesia: A Preliminary Report for 5 days and has provided partial or complete symptom relief to all 10. The precise mechanisms for the action of deanol in TD remain undefined, but the findings that its administration is followed by suppression of hyperkinetic symptoms, and that it may aggravate parkinsonian symptoms, suggest that it is working through enhancement of the cholinergic system, probably in the striatum. Although the intensification of Patient 9's parkinsonism was not intentionally evoked, the phenomenon tends to corroborate our belief that deanol is a cholinergic agent acting to relieve a presumed hypocholinergic state in tardive dyskinesia. It is now generally accepted that the dopamine-dependent and acetylcholine-dependent neuronal systems in the striatum must be in balance for normal motor function (Klawans, 1973). Therefore, an initial suppression of DA by the neuroleptics would create a relative hypercholinergic condition early in treatment, with a consequent parkinson-like state (Ambani et al., 1973). Eventually, however, the dopamine system would adapt to the deficiency, allowing the anticholinergic effects of the neuroleptics to predominate, compromise the ACh-dependent systems, and create a hypocholinergic condition appearing clinically as dyskinesia. If deanol does indeed act as a cholinergic agent, this supposition would account for its apparent efficacy in treatment of tardive dyskinesia. In earlier trials, we have administered the anticholinesterase physostigmine to patients with TD. Physostigmine enhanced the CNS activity of acetylcholine and suppressed the patients' involuntary movements (Fann et al., 1972b). Ambani et al. (1973) reported that 6 of 10 patients who developed minimum rigidity or tremor or both during acute (8-16 days) phenothiazine therapy exhibited worsening of their neurological signs after injection of physostigmine. These investigators concluded that cholinergic hyperactivity or hypersensitivity or both occur in phenothiazine-induced parkinsonism and idiopathic Parkinson's Disease. In another related study, we found that methylphenidate, a CNS stimulant which acts through enhancement of noradrenergic and dopaminergic activity in the brain, aggravated TD (Fann et al., 1973). Deanol also demonstrates CNS stimulant properties, and the finding that another stimulant showed opposite action in TD would tend to isolate
137
the dopamine-acetylcholine systems as the central issue in the genesis and treatment of TD. Despite the preliminary nature of this study and the open model, we believe that a report of findings is in order to alert other clinical investigators to an interesting and apparently safe compound worthy of further clinical evaluation in the treatment of TD. We suggest precautionary daily blood pressure determinations, however, since I subject here and 2 others in an earlier pilot study (3 of 21 subjects) have shown unexplained increases in systolic blood pressure while receiving deanol. Pressure returned to normal when the drug was stopped; hypertension recurred in 1 subject when deanol was resumed and returned to normo-tensive levels when discontinued. A definite causal relationship has not as yet been established, however. We are currently undertaking further examination of this agent in treatment of TD, including chronic clinical efficacy studies and examination of CNS mechanisms in animal trials. Acknowledgements. The authors wish to express their grateful appreciation to Mr. Bruce Richman, who helped in collection and preparation of the data; Ms. Connie Ramey, who prepared the manuscript; Osvaldo N. Rd, M.D., Riker Laboratories, Inc., who furnished deanol; and especially to John I. Thornby, Ph.D., who helped with the statistical analysis. Supported in part by VA Grant No. 2600-04. References Ambani, L. M., Van Woert, M. H., Bowers, M. B.: Physostigmine effects on phenothiazine-induced extrapyramidal reactions. Arch. Neurol. (Chic.) 29, 444-446 (1973) Farm, W. E., Davis, J. M., Janowsky, D. S.: Tardive dyskinesia: Findings in two mental hospital populations. Dis. Nerv. Syst. 33, 182-186 (1972a) Fann, W. E., Lake, C. R., Gerber, C. J., McKenzie, G. M.: Cholinergic suppression of tardive dyskinesia. Psychopharmacologia (Berl.) 37, 101-116 (1972b) Fann, W. E., Davis, J. M., Wilson, I. C.: Methylphenidate in tardive dyskinesia. Amer. J. Psychiat. 130, 922-924 (1973) Klawans, H. L., Jr.: The pharmacology of tardive dyskinesia. Amer. J. Psychiat. 130, 82-86 (1973) Pfeiffer, C. C., Groth, D. P., Bain, J. A.: Choline vs. dimethylaminoethanol (deanol) as possible precursors of cerebral acetylcholine. In: Biological Psychiatry, J.H. Masserman, ed., p. 259. New York: Grune & Stratton, Inc. 1959
William E. Fann, M.D., Department of Psychiatry, Baylor College of Medicine 1200 Moursund, Houston, Texas 77025, U.S.A.
