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LECITHIN TREATMENT FOR TARDIVE DYSKINESIA:

A CLINICAL EVALUATION

DISSERTATION

Presented to the Graduate Council of the

North Texas State University in Partial

Fulfillment of the Requirements

For the Degree of

DOCTOR OF PHILOSOPHY

By

Lynn Aikin Price, M,S,

Denton, Texas

December, 1982

Price., Lynn Aikin, Lecithin Treatment for Tardive

Dyskinesia; A Clinical Evaluation. Doctor of Philosophy

(Ecological and Behavioral Medicine), December, 1982,

136 pp., 23 tables, 8 figures, references, 78 titles.

Tardive dyskinesia is an insidious and debilitating

extrapyramidal side effect of neuroleptic drug treatment.

Recent research has suggested that lecithin has been

effective in treating tardive dyskinesia.

Lecithin's effects were evaluated under double-blind

placebo controlled conditions in 45 male inpatients.

Treatment conditions included a placebo control group, a

lecithin treatment group, and a no-treatment control group.

Fifteen subjects were randomly assigned to each group.

Subjects in the lecithin group received 60 gms/day of

lecithin (33 gins of phosphatidylcholine) . Subjects in the

placebo group received a similar mixture which contained

no lecithin. Subjects received mixtures for 9-11 days.

Treatment effectiveness was determined by subjective,

objective, and global evaluations. All subjects were

evaluated 3 to 4 days prior to treatment and following

9 to 11 days of treatment.

Data were analyzed using a factorial analysis of

covariance. Treatment conditions, age, and length of

neuroleptic treatment were the classification variables.

For each treatment measure, pretest score was the covariant

and posttest score was the variant.

Results indicated that few measures demonstrated

treatment effects. Symptom severity measures showed no

significant differences for any of the classification

variables.

Of the measures assessing motor performance ability,

only dominant hand finger oscillation measures showed a

significant reduction due to lecithin's effects. The inter-

action of treatment conditions and age suggested that only

younger subjects responded to lecithin's effects by

reducing dominant hand finger oscillation. The interaction

of treatment conditions and length of neuroleptic treatment

indicated that shorter-term treated subjects were more

responsive to lecithin's effects.

No significant effects of lecithin were reflected in

measures assessing sensory-motor integration or speech

sounds articulation. Subjective global evaluations of

treatment were determined by researcher and subjects.

Results indicated that global evaluations were not signif-

icantly related to treatment conditions.

Overall, results did not demonstrate lecithin's

effectiveness in reducing symptom severity or improving

motor performance. These findings did not support

lecithin's claim as an effective treatment for tardive

dyskinesia.

TABLE OF CONTENTS

Page

LIST OF TABLES vii

LIST OF ILLUSTRATIONS ix

LECITHIN TREATMENT FOR TARDIVE DYSKINESIA: A CLINICAL TREATMENT

Introduction 1

Cholinomimetic Treatment Effects on TD Physostigmine treatment Choline treatment Lecithin treatment

Method 52

Subjects Measures Procedures

Results 57

Discussion 66

Appendices 90

References 127

V I

LIST OP TABLES

Table Page

1. Antipsychotic Agents . . . . . . . . . . . . . 89

2. Differential Diagnostic Categories for Tardive Dyskinesia go

3. Relative Sequence of Onset of Extrapyramidal Side Effects 16

4. Studies Using Physostigmine in tne Treatment of Tardive Dyskinesia 92

5. Studies Using Choline Chloride in the Treatment of Tardive Dyskinesia , . ? , . , . 94

6. Studies Using Lecithin in the Treatment of Tardive Dyskinesia . . . . . . . . . . . . . . 96

7. Summary of Analysis of Covariance for Total Score on Simpson Tardive Dyskinesia Rating Scale H I

8. Summary of Analysis of Covariance for Total Number of Scored Items on Simpson Tardive Dyskinesia Rating Scale . 112

9. Summary of Analysis of Covariance for Bucco-Lingual-Masticatory Symptoms on Simpson Tardive Dyskinesia Rating Scale . . 1 1 3

10. Summary of Analysis of Covariance for Total Score on Selt-Report Tardive Dyskinesia Rating Scale . , » . . . . . 114

11. Summary of Analysis of Covariance for Dominant Hand Finger Oscillation Rate , . . t 115

12. Summary of Analysis of Covariance for Non-Dominant Hand Finger Oscillation Rate , , 1 1 6

13. Summary of Analysis of Covariance for Purdue Pegboard Test 117

vii

Table Page

14. Summary of Analysis of Covariance for Minnesota Rate of Manipulation Test . . . . . . 118

15. summary of Analysis of Covariance for Line Tracing Task . . . . . . . , , . , . . . 119

16. Summary of Analysis of Covariance for Bender-Gestalt Total Score 120

17. Summary of Analysis of Covariance for Bender-Gestalt Category Score . . . . . . . . . 121

18. Summary of Analysis of Covariance for Digit Symbol Test 122

19. Summary of Analysis of Covariance for Trails A Test . . . . . . . . . . . . . . . . 123

20. Summary of Analysis of Covariance for Speech Sounds Test . . . . . . . . . . . . . . 124

21. Subjects Assigned to Treatment Response Categories by Self-Evaluation . . . . . . . . . 64

22. Subjects Assigned to Treatment Response Categories by Researcher's Evaluation . . . . . 65

23. ANCOVA Distribution of Subjects to Cells . . . 125

viii

LIST OF ILLUSTRATIONS

Figure Page

1. Striatal DA/ACh Activity in Acute EPS Disorders 14

2. Striatal DA/ACh Activity in Tardive Dyskinesia 15

3. Presumed Functioning of Pre- and Post-Synaptic Dopaminergic Neurons in the Nigrostriatal System 21

4. Direct Inhibitory Action of DA Neurons of the Nigrostriatal Pathway on ACh Neurons of the Striatum 29

5. Reciprocal Interaction Between Dopamine and Cholinergic Neurons in the Striatum 31

6. Pathophysiology and Cholinergic Treatment Effects on Striatal Neurons 37

7. Interaction of Treatment Conditions and Age for Dominant Hand Finger Oscillation 60

8. Interaction of Treatment Conditions and Length of Neuroleptic Treatment for Dominant Hand Finger Oscillation 62

IX

LECITHIN TREATMENT FOR TARDIVE DYSKINESIA:

A CLINICAL EVALUATION

Tardive dyskinesia, an insidious and debilitating

extrapyramidal side effect of drug treatment in major

psychiatric disorders, has been the cause of considerable

concern in the long-term use of neuroleptics (Ayd, 1977;

Crane, 1968). The concern has centered around the issue of

whether the benefits derived from long-term maintenance

doses of neuroleptics outweigh the risk of developing tardive

dyskinesia (TD). Because the demographics of this disorder

have been illusive, risk factors associated with TD were

only marginal predictors of who would develop TD. Hence,

medical judgment usually favored continued neuroleptic

treatment at the expense of increasing the likelihood of TD.

To date, research efforts aimed at disclosing salient

and highly predictable risk factors which herald the onset

of the disorder have been disappointing. The risk factors

revealed by these research efforts have proved to be signif-

icant only for population demographics and essentially poor

predictors of TD for any given individual. Hence, for the

individual on neuroleptic therapy, risk factors have been

largely ignored in favor of continued pharmacotherapy for

the major psychiatric disorder. In view of these consider-

ations, it seems both plausible and practical to pursue

research efforts aimed at a treatment for tardive dyskinesia.

In the late 1950s, the syndrome of oral-lingual-

masticatory movements in patients treated with phenothiazines

was first described (Hall, Jackson, & Swain, 1956;

Schonecker, 1957; Sigwald, Bouttier, Raymondeau, & Piot,

1959). A striking predilection for involuntary and

repetitive movements that typically affect orofacial

structures has been noted in tardive dyskinesia (TD).

Because facial movements were the most obvious and frequently

encountered disorder of TD (Crane, 1968), additional terms

such as "orofacial dyskinesia" and "bucco-linguo-masticatory

syndrome" (BLM) were used interchangeably with tardive

dyskinesia (Kobayashi, 1977).

Movement disorders in other areas of the body were also

frequently noted. Druckman, Seelinger, and Thulin (1962)

noted continuous jerky movements of the extremities

(particularly of the fingers, toes, wrists, and ankles), and

tonic contraction of neck and back muscles.

Symptoms characteristic of tardive dyskinesia have been

graphically described by numerous writers (Ananth, 1980;

Carpenter & Rudo, 1979; Casey, 1978; Crane, 1968, 1973;

Jeste & Wyatt, 1979; Klawans, 1973; Kobayashi, 1977; Quitkin,

Rifkin, Feld, & Klein, 1977; Schiele, Gallant, Simpson,

Gardner, & Pole, 1973; Sovner, 1978). Symptom characteristics

presented by the American College of Neuropsychopharmacology

Food and Drug Administration Task Force (Schiele et al.,

1973) have become the established standard for the syndrome.

In older chronic patients, TD has been characterized by

stereotyped, repetitive, involuntary movements of the mouth,

lips, and tongue. Sometimes these movements were accompanied

by choreiform movements of the limbs and trunks. The most

commonly described symptoms which made up the "bucco-linguo-

masticatory" triad consisted of sucking and smacking

movements of the lips, lateral jaw movements, puffing of

cheeks, and tongue thrusting, rolling, or fly-catching

movements. Occasionally, the BLM triad was heralded by

tick-like, grimacing movements of the lips and eyes.

Additionally, the extremities have shown choreiform movements

that were variable, purposeless, involuntary, and quick.

Frequently, athetoid movements which were continuous,

arrhythmic, worm-like, slow movements in the distal parts

of the limbs have been associated with choreiform movements.

Together, these movements comprised the choreoathetoid

postural movements characteristic of TD. Trunkal movements

either in an anterior-posterior direction, or from side to

side have been observed in some patients.

The symptom severity and the configuration of symptoms

displayed at any given time have been reported to be quite

variable (Ananth, 1980; Carpenter & Rudo, 1979,* Crane, 1968;

Jeste & Wyatt, 1979; Schiele et al., 1973). In general,

severity of movements correlated with the general level of

arousal. Movements tended to worsen under emotional tension

and increased activity, to abate in state of relaxation and

quiesence, and to disappear altogether during sleep

(Crane, 1968; Schiele et al., 1973). Additionally, voluntary

activity of affected areas, often (but not always) has been

associated with reduce abnormal movements (Crane, 1968).

Likewise, fewer abnormal movements have been associated with

volitional control (Crane, 1968).

The configuration of abnormal movements in various body

parts has been shown to vary in intensity (mild to severe)

from one body part to another as well as from one time to

another within the same body part (Crane, 1968). For

example, tongue protrusion has been observed to be severe

at one time and mild to absent at another time, while

choreoathetoid movements of fingers may be mild in the first

instance and severe in the second. Knowledge of the patho-

physiology of dyskinetic movements has thus far been

inadequate to account for the variability in symptom

characteristics.

Tardive dyskinesia has been intimately associated with

the use of neuroleptic drugs (Crane, 1968), Though the

cause of TD has not been completely understood, epidemiologic

evidence has implicated neuroleptic drugs as a major, (but

neither necessary nor sufficient) cause of the syndrome

(Carpenter & Rudo, 1979). The role of neuroleptic drugs has

been considered insufficient to show causality because not

all patients chronically administered neuroleptics display

the syndrome. Moreover, neuroleptics have been considered

unnecessary to the development of the BLM dyskinetic

syndrome because it occasionally occurs spontaneously in

aging (Faurbye, Rasch, Petersen, Brandberg, & Rakkenberg,

1964). However, since TD has been operationally defined as

late or tardive onset of dyskinetic movements due to long-

term neuroleptic treatment (Crane, 1968? Faurbye, 1970),

neuroleptics have been considered necessary but not

sufficient to account for the syndrome.

Faurbye et al. (1964) first observed dyskinetic

manifestations in patients treated with phenothiazines and

related compounds. Drugs of this type have become known as

antipsychotics, major tranquilizers, or neuroleptics (see

Table 1, Appendix A).

It has been well established that the onset of symptoms

was insidious. In early stages, symptoms have appeared as

vermicular ripples of the tongue, inability to protrude the

tongue without retraction, or inability to sustain protrusion

(Carpenter & Rudo, 1979; Schiele et al,, 1973). Because of

the insidious onset, most often tardive dyskinesia has been

noticed only after the syndrome was fully established

(Crane, 1968).

A primary consideration in the diagnosis of tardive

dyskinesia has involved the duration of neuroleptic treatment

and changes in neuroleptics associated with the appearance

of the dyskinetic manifestations. For patients maintained

on neuroleptics, the emergence of tardive dyskinesia has

been reported to occur as early as 90 days from the onset

of neuroleptic therapy. If dystonic movements were noted to

occur earlier in drug treatment, most likely they were due

to other extrapyramidal disorders (Carpenter & Rudo, 1979).

Often TD manifestations appeared or became intensified

following termination or reduction of neuroleptic dosage

(Crane, 1968, 1973; Faurbye et al., 1964). Conclusively,

the role of neuroleptic involvement in the etiology of TD

has been well established.

The course of TD has not been completely understood.

Present evidence has indicated that in some instances TD

was reversible, while in other instances it appeared to be

irreversible or persistent. Most researchers have

acknowledged that it was quite probable that both subtypes

existed (Carpenter & Rudo, 1979; Casey, 1976, 1978? Crane,

1968, 1972, 1973, 1977; Jeste & Wyatt, 1979; Kobayashi, 1977;

Marsden, Tarsy, & Baldessarini, 1975; Quitkin et al., 1977; &

Simpson, 1980b). Although persistence of TD, even after the

discontinuation of neuroleptics, has been a characteristic

feature (Crane, 1968, 1972, 1973, 1977; Kobayashi, 1977),

spontaneous remission following drug withdrawal has been

reported. Estimates of spontaneous remission have varied

greatly and ranged from 2-40% by Kobayashi (1977), approx-

imately 30% by Marsden et al. (1975), and from 0-90% by

Simpson (1980b).

Most researchers have agreed that symptomatology

decreases over a period of several months following discon-

tinuation of the neuroleptic and have advocated drug

withdrawal at first signs of tardive dyskinesia (Carpenter &

Rudo, 1979; Crane, 1968, 1972, 1973, 1977; Jeste & Wyatt,

1979; Quitkin et al., 1977). Several researchers have

concluded that the major variable in the reversibility of

TD may be the length of time that symptoms have persisted

prior to drug withdrawal and not the age at onset of the

symptoms (Carpenter & Rudo, 1979; Casey, 1978; Quitkin

et al., 1977). Jeste and Wyatt (1979) maintained that

withdrawal of neuroleptics resulted in spontaneous remission

in younger and non-BD patients. For cases of persistent

dyskinesia, evidence has indicated that following drug

withdrawal the condition does not usually progress in

severity (Schiele et al., 1973).

There has been some belief that persistent dyskinesia

reflected Irreversible brain damage (Jeste & Wyatt, 1979).

Consistent with this view were the findings of Christiansen,

Moller, and Faurbye (1970). The investigation of 28 brains

8

from patients who at the time of death had persistent oral

dyskinesia in comparison to brains from a control group

matched for age and sex, revealed lesions of the substantia

nigra in combination with midbrain and brain stem lesions

were characteristic of the tardive dyskinesia group.

Whether persistent tardive dyskinesia reflects a permanent

change in brain function and structure is an issue requiring

further validation.

As noted in the preceding discussion, the course of TD

has been believed to be either persistent or reversible.

Casey (1978) has proposed that a more parsimonious explana-

tion of the course of TD is that it occurs along a continuum

of persistence. Symptoms that resolve may reflect a

temporary alteration in CNS function, while those that

persist may reflect a permanent change in CNS function.

Factors predisposing to tardive dyskinesia have been

widely studied, but the results are conflicting. Probably

the most convincing risk factors have involved age, duration

of neuroleptic use, and quantity of neuroleptics. A more

comprehensive overview of risk factors has recently been

published in a task force report on tardive dyskinesia

(Baldessarini, Cole, Davis, Simpson, Tarsy, Gardos, &

Preskorn, 1980). Age was probably the single most important

risk factor (Ezrin-Waters, Seeman, & Seeman, 1981).

Patients above 50 were at greater risk for TD than were

younger patients (Carpenter & Rudo, 1979; Crane, 1968, 1973).

Some studies have also demonstrated a correlation between

age at the time of diagnosis or age at the onset of neuro-

leptic treatment and tardive dyskinesia (Crane, 1973; Jus,

Pineau, Lachance, Plechat, Jus, Pires, & Villeneure, 1976).

Another group of factors which correlated with

increased incidence of TD has included the duration, quantity,

and type of drugs used by the patient. Several researchers

have concluded that the number of years of neuroleptic

treatment are correlated with the occurrence of TD

(Carpenter & Rudo, 1979; Crane, 1968, 1973; Ezrin-Waters

et al., 1981). It also has been reported that large doses

of neuroleptics were more likely to produce TD (Carpenter

& Rudo, 1979; Crane, 1977) especially among older patients

(Crane, 1977). Types of drugs associated with increased

incidence of TD were Haldol, Depot drug (Ezrin-Waters et al.,

1981) and antiparkinson medications (Carpenter & Rudo, 1979).

Other factors, including organic brain damage, sex,

and earlier acute extrapyramidal disorders, have been less

widely accepted as risk factors. Several researchers have

maintained that organic brain damage is predictive of TD

(Carpenter & Rudo, 1979; Crane, 1968; Klawans, 1973).

Others (Ananth, 1980; Carpenter & Rudo, 1979) have discussed

sex as a risk factor. Females have been reported to be at

greater risk of developing TD than males. The emergence of

10

acute extrapyramidal disorders early in neuroleptic treatment

also has been reported to correlate with TD. Conclusively,

these factors are believed to reflect an inconsistent

relationship with TD.

Overall, the risk factors presented in this section

have been reflected in the demographics of the population of

patients studied. Nevertheless, they have not been shown

to be reliable predictors of TD for individual patients.

Surprisingly little is actually known about the

prevalence of tardive dyskinesia among patients who have

undergone neuroleptic therapy. In chronic care hospitals,

reports on prevalence have ranged from 0.5% to 56% (Jus et

al., 1976). In an outpatient clinic a recent report has

found about 40% of patients on long-term neuroleptic

treatment show some degree of TD (Ezrin-Waters et al., 1981).

In a review on the prevalence of TD, Kazamatsuri et al.

(1972) concluded that the following factors are responsible

for the variability in prevalence estimates: (1) lack of

common criteria in recording the presence or absence of TD,

(2) the possibility that neuroleptics suppress TD, (3) the

highly variable definition of TD. Other considerations

accounting for the variability in prevalence estimates have

included: (1) different criteria for diagnosis of TD,

(2) difference in the severity of TD for diagnosis, (3) the

population in which the survey took place, (4) inclusion of

li

other extrapyramidal disorders, and (5) the age of the

population. Judging from the number of variables encountered

when attempting to assess the prevalence of TD, one is not

surprised to find such a wide range of variability.

The diagnosis of tardive dyskinesia has been suspected

when the classical BLM movements and also choreiform

movements of the extremities and trunk were observed following

months or years of neuroleptic use, or following discontinua-

tion or reduction of neuroleptic drugs. However, before a

definite diagnosis of TD could be made, it was necessary to

differentially rule out other diagnostic categories. Major

differential categories have included (1) spontaneous

dyskinesias, (2) dyskinesias related to neurological

disorders, (3) psychoneurological dyskinesias, (4) dyskinesias

due to metabolic disorders, (5) dyskinesias of other extra-

pyramidal side effects, (6) dyskinesias produced by drugs

other than neuroleptics, (7) dyskinesias produced by

electroconvulsive therapy, (8) prostetically induced

dyskinesias. In addition to giving due consideration to an

accurate differential diagnosis, it has been advisable to

consider the possibility of mixed syndromes of dyskinesias.

In these syndromes some of the dystonic movements could have

been due to tardive dyskinesia while other dystonic

mannerisms could have been due to differential syndromes.

A detailed outline of differential diagnostic categories for

TD is presented in Table 2 (see Appendix B).

12

Probably the most difficult differential category

noted has been that of spontaneous dyskinesias. Because

all patients within the population studied have had a

history of neuroleptic treatment, it has been most difficult

to differentiate between BLM tardive dyskinesias and

spontaneous dyskinesias. Moreover, differential diagnosis

has become increasingly difficult with the elderly

psychiatric patient, since the BLM syndrome may be related

to senile chorea (Klawans, 1973) rather than to TD. In

younger patients treated with neuroleptics, spontaneous

cases of dyskinesias have been infrequent as compared to

drug related ones. Berger (1980) reported estimates that

from 1-20% of TD patients actually suffer from spontaneous

dyskinesia. Kobayashi (1977) reported that among a mixed

population of psychiatric patients, 3 - 6% were estimated

to suffer from spontaneous rather than drug induced TD.

Contrastingly, estimates of spontaneous dyskinesia among

elderly, chronically institutionalized patients were reported

to be as high as 40%. Conclusively, differential diagnosis

ruling out the possibility of spontaneous dyskinesias in the

elderly psychiatric patient has been, at best, tenuous.

Differential diagnosis of dyskinesias related to

neurological disorders have not posed such a perplexing

diagnostic problem. Both medical history and diagnostic

criteria associated with the neurological disorder have

13

facilitated a differential diagnosis from tardive dyskinesia.

Psychoneurological dyskinesias have been rather

difficult to distinguish from TD. Chronic schizophrenic

mannerisms and stereotypes have been reported to resemble TD.

Though the stereotyped movements of schizophrenia include

many of the BLM dyskinetic movements, choreoathetoid

movements present in TD rarely have been observed in

schizophrenia. Additionally, in schizophrenia, abnormal

movements have been associated with disjointed speech,

sounds, or utterances and symbolically charged movements.

Also, schizophrenic mannerisms have been associated with

akinetic and bizarre posturing of body parts, rather than

choreoathetoid postures (Carpenter & Rudo, 1979).

Dyskinesias due to metabolic disorders have been

easily ruled out by appropriate laboratory tests.

Dyskinesias of this type have been infrequently encountered

and pose few problems in differential diagnosis.

Other extrapyramidal disorders which also result from

neuroleptic treatment have posed a major differential

diagnostic problem. These have included (1) pseudo-

Parkinsonism, (2) akathisia, (3) acute dystonic reaction,

(4) Pisa syndrome, (5) rabbit syndrome. Despite the super-

ficial similarity of the abnormal movements, these disorders

have been considered the neurochemical obverse of TD.

Theoretically, these disorders represented a reduction in

1.4

striatal dopaminergic (DA) activity and a concomitant

enhancement of cholinergic (ACh) activity. Hypothetically,

they were early manifestations of dopamine receptor

blockade caused by the administration of the neuroleptic.

These disorders responded to treatment with anticholinergic

drugs by reestablishing the DA/ACh balance (Carpenter &

Rudo, 1979; Kobayashi, 1977; Schiele et al., 1973). The

relationship between dopaminergic and cholinergic activity

DA

treatment with DA ACh anticholinergic*' |

agents .ACh

acute reaction restored to DA receptor homeostasis blockade

Figure 1. Striatal DA/ACh in Acute EPS Disorders

in the striatum for these types of disorders is depicted

graphically in Figure 1.

In contrast to these syndromes which were viewed as

manifestations of DA receptor blockade, tardive dyskinesia

was believed to represent a hypersensitivity of post-synaptic

dopamine receptors (Klawans, 1973); wherein an increase in

striatal dopaminergic activity and a concomitant decrease in

cholinergic activity has occurred. These disorders responded

to treatment with cholinergic drugs by reestablishing the

DA/ACh balance (Carpenter & Rudo, 1979; Kobayashi, 1977;

Schiele et al., 1973). The neurotransmitter imbalance

15

believed to be responsible for TD is shown in Figure 2.

Tardive dyskinesia has been shown to respond to treatment

with cholinergic drugs (Davis, Berger, & Hollister, 1975;

Davis, Hollister, Barchas, & Berger, 1976; Growdon, Hirsch,

Wurtman, & Weiner, 1977; Tamminga, Smith, Ericksen, Chang,

& Davis, 1977). The relationship between dopaminergic and

cholinergic activity in the striatum is presented in Figure 2

ACh treatment with DA ACh cholinergic I

DA y S | agents

tardive (late) restored reactions to homeostasis hypersensitivity of DA receptors

Figure 2. Striatal DA/ACh Activity in Tardive Dyskinesia

Another primary difference between initial and tardive

manifestations of abnormal movements in the course of neuro-

leptic therapy has been the time between the initiation of

neuroleptic treatment and the appearance of symptoms

(Carpenter & Rudo, 1979). As indicated in Table 3, acute

dystonic reactions have been noted during the first few days

of neuroleptic therapy. Akathisias have been observed several

days after the initiation of treatment. Pseudo-Parkinsonism

has been reported to develop from approximately one week to

three months following the beginning of neuroleptic treatment.

16

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Tardive dyskinesia has not been shown to develop prior to

three months of neuroleptic treatment.

Other characteristic differences between tardive

dyskinesia and other extrapyramidal syndromes have been

related to the discontinuation or change in dosage.

Researchers have found that tardive dyskinesia has either

appeared for the first time or has become worse following

discontinuation or reduction of neuroleptics (Crane, 1968).

In contrast, they have noted that other extrapyramidal

disorders have improved or abated altogether shortly

following dose reducation or discontinuation (Carpenter

& Rudo, 1979). Accordingly, researchers have evidenced

that an increase in the dosage of neuroleptics has alternated

or masked symptoms of TD and augmented symptoms of other EPS

disorders (Crane, 1968; Schiele et al., 1973).

Dyskinesias produced by drugs other than neuroleptics

have included 1-dopa and antihistamine decongestants. The

mode of action of these drugs has indicated that they produce

a pseudo-tardive dyskinesia effect. Accordingly, it is

believed that the underlying neurochemical mechanism of these

drugs may be identical to that of tardive dyskinesia. In

support of this contention, it has been demonstrated that

antihistamines have an anticholinergic effect

(Schiele et al., 1973) which shifts the balance of striatal

dopamine and acetycholine in the same directions as does TD.

18

L-dopa, a precursor of dopamine, enhances dopaminergic

activity and attenuates cholinergic activity.

ECT induced dyskinesias have presented little problems

in differential diagnosis because this information is readily

available in the medical records.

The oromandibular chewing syndromes also has presented

little problems for differential diagnosis of TD. When the

patient has obtained dentures which fit well, this syndrome

has disappeared.

The mixed syndromes of tardive dyskinesia have posed a

considerable problem for both accurate diagnosis and assess-

ment of treatment results in TD. Research efforts have been

well advised to eliminate the mixed syndromes altogether

or risk invalid results. Conclusively, a detailed and

extensive consideration of differential diagnosis of tardive

dyskinesia has been deemed imperative in both clinical and

research efforts.

The search for the underlying pathophysiological

mechanisms of TD has been fervently pursued during the past

decade. Despite these efforts, the state of empirical

findings has left many inferences open to conjecture and

speculation. In the following discussion, several hypothe-

tical models of the pathophysiology of TD will be presented

as they evolve chronologically in the literature.

19

The search for the underlying pathophysiological

mechanisms of tardive dyskinesia began with the observation

that TD was intimately associated with the long-term use of

neuroleptics (Crane, 1968? Faurbe et al., 1964). Initially,

the mode of action of the neuroleptic on central nervous

system's neurons and neurotransmitters was investigated as

a mechanism for the pathophysiology of TD.

Neuroleptics, known to block the action of dopamine in

the limbic system, were also believed to interfere with

dopamine transmission in the nigro-striatal pathway and the

striatum (Carlsson, 1970). Neuroleptics, by instituting

a blockade of dopamine (DA) striatal receptors, have been

shown to produce a "chemical denervation" of these receptors

in the striatum (Carlsson, 1970). Research efforts have

revealed that homeostatic mechanisms in the DA neurons and

post-synaptic dopaminergic receptor sites were engaged in an

effort to overcome the neuroleptic blockage imposed on the

DA receptors by increasing DA synthesis and turnover

(Prange, Sisk, & Wilson, 1972) and by increasing the

sensitivity or number of post-synaptic DA receptor sites

(Klawans & Rubovits, 1972). The compensatory increase in

the sensitivity of the receptors has been termed "denervation

hypersensitivity" and has been proposed by Klawans (.1973) as

a hypothesis accounting for the hyperkinetic manifestations

of tardive dyskinesia. Herein, Klawans (1973) has proposed

2Q

that a reduction in dopaminergic neurotransmission caused by

antidopaminergic treatment, resulted in a compensatory

increased sensitivity of the receptors. It has seemed quite

\*ArAr/\/~ Normal

Neuroleptic Action

Tardive Dyskinesia

mum Figure 3. Presumed functioning of pre- and post-synaptic

dopaminergic neurons in the nigrostriatal system. (1) Under normal conditions, (2) during neuroleptic blockade ot DA receptors, (3) during hypersensitivity of DA receptors with TD.

likely that TD may be an overt manifestation of the abnormal

responses of such neurons. Figure 3 illustrates this

hypothesis.

Although both increased synthesis and turnover of

dopamine and denervation hypersensitivity have been shown to

be likely compensatory mechanisms for overcoming neuroleptic

blockade of DA receptors, probably the former mechanism has

21

functioned more in earlier stages of neuroleptic treatment

(Davis, Berger, & Hollister, 1979), and has not seemed to be

an important mechanism of abnormal neuronal responses in TD

(Carlsson, 1975; Davis, Berger, & Hollister, 1979; Klawans,

1973; Marsden & Jenner, 1980). However, dopamine receptor

hypersensitivity was present along with a disappearance of

DA receptor antagonism between six months and a year

following the initiation of neuroleptic drug treatment.

In this period, dopamine produced excessive stimulation of

adenylcyclase and the number of DA receptors increased above

control levels. Six months following drug withdrawal,

adenylcyclase activity remained enhanced but DA receptor

numbers tended to return toward baseline. Hence, it has

appeared that hypersensitivity of dopamine receptors in

the striatum was an important factor in the pathophysiology

of tardive dyskinesia.

Pharmacological effects of drugs on tardive dyskinesia

has contributed support to the denervation hypersensitivity

hypothesis. In general, drugs which have decreased dopa-

minergic activity in the striatum have reduced the dyskinetic

manifestations, and drugs which have enhanced activity have

augmented these symptoms. Since it is beyond the scope of

the present work to detail research in this area, the reader

is referred to several comprehensive literature reviews

(Jeste & Wyatt, 1970; Kazamatsuri et al., 1972; Kobayashi, 1977)

22

Drugs which reduce dopamine transmission in the CNS

have been divided into two principal classes: (1) dopamine

depleting drugs and (2) dopamine blocking drugs. Researchers

have demonstrated that dopamine depleting drugs acted by-

preventing intraneuronal storage in presynaptic vesicles.

Because these drugs do not block postsynaptic receptors,

they have not led to the denervation hypersensitivity

produced by dopamine blocking drugs. Among the dopamine

depleting drugs, reserpine and tetrabenzine have been widely

used in the treatment of TD. It has been demonstrated in

numerous studies that they were useful in the treatment of

TD due to their ability to reduce striatal dopaminergic

activity. However, these drugs have produced deleterious

side effects and therefore, they have not been recommended.

It has been demonstrated that dopamine blocking drugs

antagonize dopamine receptors by interfering with cell

membrane function and the respiratory enzymes of cyclic AMP

(Faurbye, 1970; Marsden & Jenner, 1980). Among dopamine

blocking drugs, the neuroleptics pimozide, phenothiazine,

thioxanthene, and butyrophenone, have been widely used in

the treatment of major psychiatric disorders. Their clinical

effectiveness in the treatment of both psychiatric disorders

and tardive dyskinesia has been reported to be due to

reduction in dopaminergic activity. Paradoxically, neuroleptic

drugs which caused TD have attenuated symptoms by

23

reestablishing the dopamine blockade which has been overcome

by compensatory mechanisms of the neurons. Such a treatment

strategy has been shown to perpetuate a vicious cycle between

ever increasing hypersensitivity and higher doses of neuro-

leptics required to reduce symptoms. Thus, it has been viewed

contrary to common sense to treat a syndrome with the drug

that caused it (Casey, 1978).

Other drugs which have been shown to reduce dopaminergic

activity have also been shown to be effective in reducing

symptoms of tardive dyskinesia (Kazamatsuri et al., 1972;

Kobayashi, 1977). These drugs have included lithium carbonate,

alphamethylparatyrosine, papaverine, and alphamethyldopa.

Essentially, drugs which have reduce dopaminergic

activity via depleting stores of DA, blocking DA receptors,

or some other mode of action, all have tended to reduce the

availability of DA to hypersensitive receptors and thereby

have attenuated dyskinetic manifestations of TD. This

evidence has supported the denervation hypersensitivity

hypothesis of tardive dyskinesia.

Other evidence in support of the present hypothesis has

concerned drugs which increase dopaminergic activity in the

striatum. Drugs such as 1-dopa (a dopamine precursor)

(Gerlach, Reisby, & Randrup, 1974) and amphetamine (a drug

which increases DA activity) (Growdon, Hirsh, Wurtman, &

Weiner, 1977), have exacerbated tardive dyskinesia movements.

24

This has been considered further evidence that TD reflected

dopaminergic hypersensitivity (Crane, 1973; Klawans, 1973).

A hypothesis for denervation hypersensitivity of

dopaminergic receptors of the striatum has been presented and

evidenced by pharmacological manipulation of drugs which

have affected these receptors. Despite the expected correla-

tion of drug effects on the dystonic manifestation of tardive

dyskinesia, this model has been unable to account for the

drug effects which have affected cholinergic neurotransmitter

systems and TD. Conclusively, a simple model of hyper-

sensitivity in DA striatal neurons has been inadequate to

fully account for the pathophysiological mechanisms of TD

(Klawans, 1973; Klawans & Rubovits, 1974).

Strategies for cholinergic manipulation of tardive

dyskinesia came about as a result of the observation that

Parkinsonism and TD seemed to be at opposite ends of an

extrapyramidal spectrum of excessive or insufficient dopa-

minergic activity. Based on observations that Parkinson's

Patients benefitted from treatment with 1—dopa and anti-

cholinergic drugs (i.e., increasing the DA/ACh ratio) and

that these strategies worsened or precipitated TD,

researchers reasoned that treatment strategies aimed at

increasing cholinergic activity would be beneficial for TD

(Gerlach et al., 1974; Klawans, 1973; Klawans & Rubovits,

1974) . Hence, Parkinsonism and TD seemed also to be at

opposite ends of the cholinergic spectrum.

25

In initial attempts to demonstrate a cholinergic

involvement, Klawans and Rubovits (1974), Gerlach, Reisby,

and Randrup (1974), and Fann, Lake, Gerber, and McKenzie

(1974), demonstrated that i.v. physostigmine (an anticholine-

sterase inhibitor) improved abnormal movements in patients

with tardive dyskinesia. By augmenting cholinergic

functioning, these studies presented evidence for hypo-

cholinergic functioning in the pathophysiology of TD.

Pharmacological evidence has supported the hypothetical

role of cholinergic activity in tardive dyskinesia.

Numerous studies employing cholinergic agents such as

physostigmine, deanol, choline chloride, and lecithin have

demonstrated effectiveness in the treatment of TD (reviewed

by Casey and Tepper (1979) and Jeste and Wyatt (1979).

Accordingly, anticholinergic drugs such as scopolamine or

benaotropin have worsened TD symptoms in the majority of

patients treated (Gerlach et al., 1974; Klawans & Rubovits,

1974).

The hypothesis for hypocholinergic functioning in the

striatum has been supported by pharmacological studies.

Hence, the inadequacy of a single neurotransmitter model of

TD has been established. Further, research has indicated

that there is a reciprocal balance between cholinergic and

dopaminergic activity (see Figure 1 and 2). From these

conclusions, it has been deduced that there were two

26

pharmacological alternatives for the treatment of TD:

(1) strategies which decrease DA activity and (2) strategies

which increase ACh activity. As previously noted, it has

been deemed unwise to choose the former tactic, since this

could worsen the condition in the long run. Obviously,

strategies aimed at increasing cholinergic activity has been

the treatment of choice.

Hypocholinergic/hyperdopaminergic pathophysiological

mechanisms of tardive dyskinesia have been proposed and

evidenced by pharmacological manipulations. Additionally,

the apparent reciprocal relationship between DA and ACh

activity has been established. However, a neuroanatomical

model whereby these transmitter systems can interact in

order to establish this self-regulatory modulating effect

will further illuminate and support the role of these

biochemical mechanisms in the pathophysiology of TD.

Tardive dyskinesia has been shown to be an extrapyramidal

disorder of the basal ganglia. The striatum comprised of the

caudate nucleus and the putamen has been found to be

principally involved in this disorder. Afferent connections

to this region have been shown to arise principally from

dopamine synthesizing cells in the substantia nigra via the

nigrostriatal pathway and to project to dopamine sensitive

cells in the striatum. Many cells in the striatum have been

shown to be sensitive to cholinergic stimulation. Their

27

afferents are also believed to arise from dopamine synthe-

sizing cells in the substantia nigra. It has been demonstrated

that efferent pathways from the striatum enter the globus

pallidus, the chief motor outflow of the corpus striatum,

and project via the various multi-synaptic pathways of the

extrapyramidal motor system to motor neurons by way of the

rubrospinal, reticulospinal, or vestibulospinal tracts

(Gardner, 1975).

The simplest neuronal model to explain the reciprocal

relationship between dopamine and acetylcholine in the

striatum has been one where the DA neurons of the substantia

nigra send their inhibitory axonal processes rostrally to

terminate on dendrites of small cholinergic interneurons

of the striatum. The only biochemical afferents thus far

identified for this population of cholinergic interneurons

have been the dopaminergic nigrostriatal tract (McGeer,

Grewaal, & McGeer, 1974). The work of McGeer and associates

(1974) suggested that some DA receptors are located on

cholinergic neurons. Moreover, this work suggested that DA

neurons exert a direct inhibitory action on cholinergic

neurons. Hence, the post-synaptic receptors on cholinergic

neurons have been found to be inhibitory. Consequently,

increased activity of dopaminergic activity in the substantia

nigra, due to denervation hypersensitivity, has been shown

to result in inhibition of cholinergic neurons in the striatum.

2:8

This mechanism is illustrated in Figure 4. However, this

mechanism has also been found to be inadequate to fully

account for the reciprocal relationship between DA and ACh

activity. In order to fully account for this reciprocal

Substantia Nigra

via Nigrostriatal Pathway

DA neurons

•\ h Striatum

ACh neurons

iMAMA/ls Figure 4. Direct inhibitory action of DA neurons of the

Nigrostriatal Pathway on ACh neurons of the striatum. (1) Excitatory DA receptors promote depolarization in substantia nigra neurons. (2) Inhibitory DA receptors promote hyper-polarization in striatal cholinergic neurons.

interaction, the model must also provide a means for

cholinergic neurons to influence dopaminergic activity.

In order for cholinergic treatment to modify the

activity of DA neurons, it was reasoned that cholinergic

systems must have input onto DA neurons (Kobayashi, 1977).

Tarsy (1977) has demonstrated that cholinergic agents affect

synthesis, turnover, and release of DA in the basal ganglia.

The mechanism mediating this effect has been shown to be via

a GABA feedback mechanism (Groves, Wilson, Young, & Rebec, 1975)

29

These researchers have demonstrated that striatal cholinergic

interneurons synapse with gabanergic cell bodies on which

they have an excitatory effect. Other researchers have

confirmed that the post-synaptic effects of ACh in the

striatum are mediated by excitatory muscarinic cholinergic

receptors (Kobayashi, 1977; Macintosh, 1979; Tune & Coyle,

1980).

The overall effect of cholinergic suppression of DA

neurons in the substantia nigra have prompted researchers to

formulate a more complete neuronal model of regulatory

mechanisms of DA/ACh modulation (Davis, Berger, & Hollister,

1979; Groves et al., 1977; Tune & Coyle, 1980). This model

is shown in Figure 5. It can be seen from this model that

dopaminergic and cholinergic activity are reciprocally

related through GABA regulatory feedback mechanism.

The pharmacological rationale for cholinergic treatment

of tardive dyskinesia has been established with the validation

of the hypocholinergic hypothesis. Several therapeutic

strategies aimed at increasing the activity of acetylcholine

in the striatum have been presented. These strategies have

been divided into acute versus chronic cholinomimetic action

due to differences in their mode of action on acetylcholine

augmentation (Casey & Tepper, 1979) . The mode of action has

been expressed in view of the mechanisms of synthesis and

degradation of the acetylcholine molecule.

30

(3)

GABA

B

W - / a

Figure 5. Reciprocal interaction between dopamine and cholinergic neurons in the striatum. (A) illustrates that increases in DA activity produce decreases in ACh activity. (1) Depolarization of DA neurons results in hyperpolarization of ACh neurons due to inhibi-tory properties of post-synaptic DA receptors of synapse. (2) Consequently, excitatory ACh transmitter activity is reduced at synapse and (3) inhibitory GABA transmitter activity is reduced at synapse. Hence, DA neurons are free from gabanergic inhibition. (B) shows that increases in ACh activity produce decreases in DA activity. (2) Depolarization of GABA neuron due to the excitatory properties of the post-synaptic ACh receptors at synapse. (3) Inhibitory properties of GABA post-synaptic receptors at synapse promote hyperpolarization of the DA neuron. Hence, ACh neurons are free from dopaminergic inhibition.

31

The following equation represents these reactions:

cholineacetylas^

acetyl Coenzyme A + choline ACh + Coenzyme A

acetylcholinesterase

It has been demonstrated that physostigmine acts in an acute

manner by preventing the degratory enzyme, acetylcholine-

sterase, from breaking up the ACh molecule (Casey & Tepper,

1979). Since these reactions occur only within the neuron

and its adjacent synapse, physostigmine is believed to act

rapidly and directly upon CNS mechanisms. Cholinomimetic

drugs such as deanol, choline chloride, and lecithin have

been considered to act chronically due to increased delay of

therapeutic effects and enhanced central cholinergic tone

(Casey & Tepper, 1979).

Metabolic effects of cholinomimetic treatment has

suggested that their clinical effectiveness was due to

increased cholinergic activity in the striatum. Since it

has been demonstrated that de novo synthesis of choline does

not take place in the brain, brain choline must be derived

from plasma-free choline and lysophosphatidyl choline

(Aquilonious & Eckernas, 1975). Numerous studies have

demonstrated that elevations in plasma-free choline, brain

choline, central ACh levels, and cerebrospinal fluid (CSF)

choline correlate with therapeutic effects of cholinomimetics.

Elevations in plasma-free choline have been demonstrated

following choline chloride administration using both

intraperitoneum injections in rats (Cohen & Wurtman, 1975),

oral administration in rats (Cohen & Wurtman, 1976), and in

humans (Aquilonius & Eckernas, 1975). Further, increased

concentration of brain choline (Cohen & Wurtman, 1976) and

brain acetylcholine levels has been reported in rat studies

(Cohen & Wurtman, 1976; Hirsch, Growdon, & Wurtman, 1977)

and inferred in human studies by a perfect correlation

between physostigmine and choline chloride effects on

tardive dyskinesia (Davis, Hollister, Barchas, & Berger, 1976)

Finally, evidence indicating increase in CSF choline

content (Growdon, Cohen & Wurtman, 1977) has suggested an

increased breakdown of central ACh activity due to an

increase in cholinergic tone, because the net effect of

choline transport has been found to be from the brain to

the CSF.

Just as orally administered, choline chloride has

increased plasma-free choline, so has lecithin. Moreover,

evidence indicated that orally administered choline equiv-

alents of lecithin have produced greater increases in plasma-

free choline (265% over baseline compared to 86%) and longer

lasting effects (24 hours compared to 12 hours) than has

equivalent oral doses of choline chloride (Wurtman, Hirsch,

& Growdon, 1977) .

In conclusion, chronically administered cholinomimetics,

deanol, choline chloride, and lecithin have been assumed to

33

reflect increased central cholinergic activity due to their

correlation with physostigmine treatment (Davis et al.,

1976) and the correlation between the metabolic effects and

treatment effects. Nevertheless, there has been some dispute

whether increased cholinergic tone reflects precursor or

agonist properties of these drug effects.

There has been little dispute concerning the mode of

action of physostigmine effects in tardive dyskinesia.

Contrastingly, the mode of action of the chronic cholinomi-

metics has been controversial. One view maintained that

these drugs act as precursors of ACh (Cohen & Wurtman, 1976;

Hirsch, Growdon, & Wurtman, 1977), while the other held that

they act as agonists which directly stimulate the muscarinic

post-synaptic receptors (Jenden, 1979; Macintosh, 1979).

Increases in free choline and plasma-free choline in

whole brain and caudate regions in rats were taken as evidence

that choline intake into the CNS affects ACh concentration by

accelerating synthesis of ACh (Cohen & Wurtman, 1976).

A later study demonstrated increased ACh activity at the

site of cholinergic terminals following administration of

choline chloride (Hirsch et al., 1977). These results were

interpreted as evidence of enhanced release of the transmitter,

thereby inferring increased synthesis and release of ACh.

Conclusions contrary to these were evidenced by the

transport kinetics of choline into the neuron (Jenden, 1979;

Macintosh, 1979). Choline for ACh synthesis enters the

34

neuron via a choline transport system which was unsaturated

at normal plasma levels of choline. Jenden (1979) and

Macintosh (1979) agreed that 10-fold increases in plasma

choline would have very little (less than 10 percent)

effect on the rate of choline transport. Additionally, they

agreed that only during extreme synaptic activity, which is

certainly not the case in TD, could choline become the

rate limiting factor for ACh turnover (Macintosh, 1979).

Both researchers have concurred that most likely choline

acts as an agonist rather than a precursor.

That choline acts as an agonist is a more tenable

position for several reasons. First, evidence offered in

support of the precursor mode of action has not been

incompatible with agonist effects. An increase in brain

or plasma choline and increased post-synaptic activity would

also occur if the cholinomimetic acted as an agonist.

Second, stores of ACh in synaptosomes of striatal neurons

have been shown to be increased significantly in TD due to

inhibition of the neurons (McGeer et al., 1974). Consequently,

there is no need for increased synthesis to further increase

these stores. Third, transport affinity constants have

suggested that choline is not likely to be taken into the

cell. Fourth, agonist effects have offered a more parsimon-

ious explanation of treatment effect.

35

In Figure 6, a mode of treatment effects in TD which is

consistent with the known pathophysiology of TD as well as

with agonist effects of cholinomimetics is proposed. It is

readily observable that agonist effects on cholinergic post-

synaptic receptors offer a plausible and parsimonious

mechanism for drug action (Figure 6c). It is interesting

to note from this model that treatment does not affect

cholinergic neurons but rather indirectly attenuates the

hyperactive DA neuron via a GABA feedback loop.

Cholinomimetic Treatment Effects on TD

Treatment studies employing physostigmine, choline

chloride, and lecithin are summarized in Tables 4, 5, and

6 respectively. Treatment effects of these drugs will be

reviewed in the following discussion.

Physostigmine treatment. Physostigmine, an anticholiner-

terase agent, was the first drug used to test whether increases

in acetylcholine activity would be effective in reducing

tardive dyskinesia symptoms. Although Fann, Lake, Gerber,

and McKenzie (1974) were actually first to report positive

effects, their initial reports were for the most part

confirmed by their colleagues (Davis et al., 1975, 1976;

Gerlach et al., 1974; Klawans & Rubovits, 1974; Moore &

Bowers, 1980; Tamminga, Smith, Ericksen, Chang, & Davis, 1977).

In contrast, to reports demonstrating effectiveness, Tarsey,

Leopold, and Sax (1974) found no improvement in any of seven

36

s//.|DA

GABA

Figure 6. Pathophysiology and cholinergic treatment effects on striatal neurons. (A) Initial effects of neuroleptic treatment. (1) DA receptor blockade at synapse and (2) facilitates firing of ACh neurons and (3) a consequent inhibition of DA neurons via GABA feedback at synapse. Acute dystonic reactions may result. (B) Late effects of neuroleptic treatment. (1) Hypersensitivity of DA receptors at synapse and (2) inhibits firing of ACh neurons and (3) facilitates firing of DA neurons due to inhibition of GABA feedback at synapse. Tardive dyskinesia may result. (C) Treatment effects in tardive dyskinesia. (2) Cholinomimetics may directly stimulate cholinergic post-synaptic receptors on GABA neurons and consequently inhibit firing of DA neurons via GABA inhibitory post-synaptic receptors at synapse. (3) In turn, reduced firing of DA neurons facilitates firing of ACh neurons. Improvement in dyskinetic symptoms may result.

37

patients treated with physostigmine. A summary of the

results obtained in these studies is presented in Table 4

(see Appendix C).

Of the 55 patients treated with intravenous injection

of physostigmine, 36 patients showed improvement (i.e., 65%)

within about 60 minutes. Improvements were maintained for

up to 24 hours. One of these studies (Fann et al., 1974),

demonstrated a statistical difference between baseline and

treatment measures for severity of symptoms. Conversely,

two other studies (Gerlach et al., 1974; Moore & Bowers,

1980), using a statistical analysis of the data, found no

significant overall treatment effects, but, nevertheless,

reported treatment effectiveness in some of the patients

treated. Several studies (Gerlach et al., 1974; Klawans &

Rubovits, 1974; Tamminga et al., 1977) employed some type

of placebo control strategy. Together, these studies

indicated that 77% of these patients have benefitted from

treatment. The only double blind placebo controlled study

{Tamminga et al., 1977) showed an 83% improvement ratio.

Contrary to expectations, the percentage of patients improved

in open trials (55%) has been considerably less than that

obtained for combined placebo controlled studies (77%).

Although apparent inconsistencies in the expected

effects of control measures on the percentage of patients

improved by physostigmine treatment have been noted, overall,

38

there has been sufficient improvement in patients (65%) to

evidence the beneficial effects of cholinergic enhancement

in the treatment of tardive dyskinesia. However, as a

practical means of long-term treatment, physostigmine has

been inadequate because of the marked peripheral side effects,

the short duration of effectiveness, and the inconvenient

mode of administration. In search of a more practical means

of cholinergic treatment, research efforts have explored

the effectiveness of choline chloride treatment.

Choline treatment. Choline, a precursor of acetyl-

choline, was first used in the treatment of tardive dyskinesia

by Davis, Berger, and Hollister (1975). Following initial

reports of effectiveness, choline treatment has been

investigated in several other studies (Davis et al., 1976;

Gelenberg, 1979; Gelenberg, Doller-Wojcik, & Growdon, 1979a,b?

Growdon, Hirsch, Wurtman, & Weiner, 1977; Tamminga et al.,

1977). These studies are summarized in Table 5 (see

Appendix D).

The total number of patients treated with choline

chloride in these studies is 34. Overall, 59% of the

patients have benefitted from this treatment. Four of the

five studies presented do not employ placebo control measures.

One study (Growdon et al., 1977) employed a double blind

crossover design and reported that 45% of the patients were

improved. This figure is in marked contrast to the 59%

39

improvement ratio reported when all studies were considered

together, and in even greater contrast to the reports of the

combined open studies, which reported a 79% improvement ratio.

Notably, in this instance the design of the study has had

considerable effects on the results.

The daily dose of choline chloride varied from a maximum

of 13.5 grams per day to 20 grams. The study which showed

the lowest percentage of improvement also had the lowest

maximum daily dose of choline (13.6 grams) (Growdon et al.,

1977). Maximum daily doses of choline chloride in the other

studies ranged from 16 to 20 grams per day. In comparing

the treatment results of these studies, variability in

dosage may be one factor which could have accounted for

differences in the percentage of patients improved. However,

it is likely that the single most significant factor

accounting for the difference in percentage of improvement

obtained by Growdon and associates (1977) and the other

researchers has been due to the design employed in the study.

In comparing these studies, another interesting issue

has concerned the use of concurrent medications. In five

of the six studies cited in Table 5, the neuroleptic status

of the patient was unchanged. In contrast, in one study

(Tamminga et al., 1977) all neuroleptic medication was

discontinued two weeks prior to the study. This strategy

has been controversial. Advocates of this method have

40.

maintained that concurrent medications could interact with

treatment effects and thereby obscure results (Jeste &

Wyatt, 1979). However, as evidenced by the number of

studies in which concurrent neuroleptics were unchanged,

most researchers have maintained that discontinuing

neuroleptics worsened the TD symptoms displayed and overall

affected the stability of the baseline measure.

Another point which merits consideration has been that

of discontinuing concurrent anticholinergic medication

(Growdon et al., 1977). This strategy has seemed justifiable

because anticholinergics counter the increases in cholinergic

effects produced by the cholinergic treatment.

A final issue has concerned the treatment duration.

Although the duration of treatment has varied greatly

(from 8 - 6 0 days), beneficial treatment effects were obtained

after eight days of treatment by Davis (1975). Other

researchers have confirmed that this duration is adequate to

obtained treatment effects (Tamminga et al., 1977). The fact

that therapeutic benefits were obtained for up to eight weeks

has suggested that long-term treatment effects are possible.

Overall, choline chloride has seemed to be an effective

and possibly long-term treatment of tardive dyskinesia for

a considerable percentage of patients. However, several

studies have reported adverse side effects due to this

treatment (Davis et al., 1976; Growdon et al., 1977;

Tamminga et al., 1977). Side effects noted were: dizziness.

41

depression, nausea, stomach cramps, diarrhea, increased

salivation, lacrimination, blurred vision, anorexia, and a

fishy body odor. These adverse effects have imposed limits

upon the feasibility of choline chloride treatment of

tardive dyskinesia.

Lecithin treatment. Lecithin or phosphatidylcholine,

is a phospholipid which has been found to occur naturally

in all tissues of the body (Fox, Betzing, & Lekim, 1979).

Moreover, it has been determined that it is the normal

dietary source of choline. As such, this phospholipid-bound

choline has been shown to be a major source of brain choline,

and therefore, has therapeutic potential for tardive

dyskinesia. As previously noted, lecithin has been shown

to produce greater and longer lasting effects on plasma

choline elevations than does choline chloride (Wurtman et al.,

1977) and to increase brain acetylcholine levels (Hirsch &

Wurtman, 1978).

The effects of lecithin on tardive dyskinesia were

first tested by Growdon and associates (Growdon, Gelenberg,

Doller, Hirsch, & Wurtman, 1978). Of the three patients

treated, all showed improvement. Validation of these

results were obtained in later studies (Barbeau, 1978, 1979?

Gelenberg, 1979; Gelenberg, Doller-Wojcik, & Growdon, 1979a, b;

Jackson, Davis, Cohen, & Nuttall, 1981; Jackson, Nuttall,

Ibe, & Berez-Cruet, 1979). A summary of these studies is

presented in Table 6 (see Appendix E).

42

The total number of cases of tardive dyskinesia treated

with lecithin has been 20. These studies have concurred

that all patients treated with lecithin have shown improve-

ment. Conclusions drawn from a cursory overview of these

reports have indicated that lecithin has been an effective

treatment for tardive dyskinesia in all patients. However,

a more critical evaluation should be undertaken before these

reports are accepted.

Overall, the demographic features of the patients

studied represented a heterogeneous group. Sex was

relatively equally represented (7 males and 8 females

reported). Age ranged from relatively young patients (27-32)

(Gelenberg et al., 1979) to middle-aged (mean of 57) (Jackson

et al., 1979, 1981) to relatively elderly (Mean of 64)

(Barbeau, 1979). Collectively, age factors tended to be more

representative of the middle-aged to moderately elderly age

groups (i.e., 67% of patients studied were in this group).

However, the age distribution in this sample, was, overall,

representative of that occurring in the population of patients

with TD, since older patients are at greater risk of

developing TD (Baldessarini et al., 1980; Jeste & Wyatt, 1981),

Essentially, the demographic variables represented in this

sample did not differ from those of the population. Hence, it

is unlikely that treatment effectiveness has been biased by

demographic sampling errors.

4 3

In contrast, several methodological issues may have

biased reported results of treatment effectiveness. The

first issue has concerned the small number of patients in

the sample. The second issue has involved the criteria

used to determine whether the treatment was effective. The

third issue has considered the use of placebo controls.

The fourth issue has regarded methods of assessing treatment

effects.

Statistical sampling is based on the assumption that

the sample is not characteristically different from the

population. When the number in the sample is small, the

statistical probability of sampling error increases. Due

to the small sample reported, lecithin treatment may have

been more effective when applied to this particular sample

than when applied to all patients with TD. Judging from

the percentage of patients improved by other cholingergic

strategies, it appears that lecithin treatment effectiveness

may have been overstated in part due to the small number of

patients thus far treated.

The criteria used to determine whether a treatment is

effective could have significantly biased the results.

In only one study, researchers have performed a statistical

analysis of the data (Jackson et al., 1979). Using a

double-blind crossover design, this study has demonstrated

by use of a one-tailed paired student's t-test, that

44

severity ratings showed a significant difference between

treatment and placebo following eight days of lecithin

treatment (£<.05). This difference was maintained for a

10-day period following discontinuation of treatment.

Although, Jackson and associates (.1981) utilized the same

study as Jackson and coworkers (1979), different schedules

for assessing changes in severity of TD produced consistent

results. Although the latter researchers did not perform

a statistical analysis of their data, an analysis of

variance with repeated measures on one variable (undertaken

by the present author) demonstrated that between day 7 and

day 14 of lecithin treatment a significant (JD < .05) reduction

in symptoms occurred between treatment and placebo groups.

The criteria used to determine effectiveness in all

other studies (see Table 6, Appendix E) was based upon the

percentage of change from baseline scores or upon unstated

criteria. Although such means of assessing changes seemed

to reflect basic overall trends for individuals, it has not

accurately reflected whether treatment effects among the

group treated were of a significant magnitude to demonstrate

that these trends were not a chance occurrence. For example,

Gelenberg and coworkers (1979), using percent of change

from baseline measures, reported improvement in severity

of symptoms for all five patients treated. However, an

analysis of variance with repeated measures on one variable

45

(performed by the present author) disclosed that treatment

effects for these patients were insignificant (jd = 2.5) .

In defense of nonstatistical assessment methods, group

data employed in statistical analysis could have obscured

treatment effects when some patients respond differently to

treatment than others. Some researchers have maintained

that subtypes involving different pathophysiological

mechanisms may exist in TD (Carroll, Curtis, & Kokmen, 1977;

Casey, 1978; Casey & Tepper, 1979; Crane, 1968; Fann et al.,

1977; Gelenberg et al., 1979b; Gerlach et al., 1974; Moore &

Bowers, 1980). If this is shown to be the case, then

statistical measures could have obscured valuable treatment

effects for that subset of patients who responded favorably

to treatment. Nevertheless, it is likely that nonstatistical

analysis of treatment effects in 70% of the patients treated

has contributed greatly to an overstatement of lecithin's

effectiveness.

A third issue has regarded the use of appropriate

placebo controls. Only one study has employed placebo

controls (Jackson et al., 1979, 1981). Although this study

used a double-blind crossover design, these results did not

differ from those obtained in open trials. Despite the

fact that this design has ruled out placebo effects (i.e.,

a positive response to random treatments), it was unable to

evaluate spontaneous fluctuations in symptoms as they occur

4 6

when no treatment is offered, or to detect a general trend

of improvement over time. The importance of assessing change

over time is a viable consideration because there have been

reports of spontaneous rates of remission between 19 - 40%

even when patients continued on neuroleptics (Ananth, 1980).

Moreover, it has been reported that TD could subside spon-

taneously after only a period of a few weeks (Kazamatsuri

et al., 1972), although this was uncommon. Without adequate

control measures, variability in the symptom array and spon-

taneous remission rates could confound drug response results

(Berger, 1980; Casey & Tepper, 1979; Quitkin et al., 1977;

Tamminga et al., 1977). For the reasons stated, it is

beneficial to employ a no treatment control group as well as

a placebo control group. This additional control would

further distinguish placebo and treatment effects from

spontaneous variability or remission.

A fourth issue has regarded the methods of assessing

treatment effects. In the studies reviewed, only two methods

of assessment have been used. One method has been to

assess changes in the frequency of dyskinetic movements.

The other has been to assess severity on tardive dyskinesia

rating scales.

Although the rating scale methods are qualitative rather

than quantitative measures of symptoms, these seemed

preferable for several reasons. First, because frequency

47

measures required videotaping, patients were made very aware

that their symptoms were being obtrusively observed.

Because patients usually have voluntary control over their

symptoms for brief periods of time, they may have self-

consciously limited their movements (Fann et al., 1974;

Kuzamatsuri et al., 1972). In contrast, rating scales could

be completed when the patient was entirely unaware that his

symptoms were being assessed. Second, frequency measures

required the selection of one or two prominent symptoms,

which were reassessed upon each assessment period. Due to

the marked variability in symptoms from time to time, the

researcher could be recording spurious data which did not

reflect the ubiquitous displays of the symptoms. Conversely,

the use of rating scales has permitted evaluation of movements

in all parts of the body. Hence, spurious inconsistencies

reflected in the variability of movements in different body

parts from one assessment period to another has little effect

on the overall rating score. A third problem with counting

movements per minute was the short duration of time sampled.

This method was judged to be far from accurate since rates

of movements oyer a short period of time could vary greatly

from one time to another (Kazamatsuri et al., 1972). A

further problem with this method has been the technical

problem encountered with videotaping. Often shadows obscured

the movements and the three-dimensional characteristics of

48

the movement were lost to the two-dimensional display

(Kazamatsuri et al., 1973). Overall, methods of assessing

treatment effects could have contributed to biased reports

of lecithin's effectiveness.

In addition to the possibility that reports of

lecithin's effectiveness have been biased by various question-

able methodologies, these studies also have failed to

consider a number of other important means of evaluating

treatment effects. Among these were the following:

1. A global assessment of treatment effects as

measured by both researcher's and subject's overall

evaluation;

2. A detailed self-report assessment of symptom

array and severity as measured by the subjects' responses

to the Self-Report Tardive Dyskinesia Rating Scale;

3. An evaluation of subjects' fine and gross motor

performance abilities as measured by several motor tasks;

4. An assessment of speech articulation as measured

by subjects' ability to articulate speech sounds.

In summary, although the present literature has shown

lecithin to be an effective treatment for tardive dyskinesia,

questions have been raised which challenge the validity of

lecithin's reported effectiveness. Overall, the demographic

distribution of the sample of patients studied has not

differed from that of the population. However, other

49

considerations offered have challenged the reports of

lecithin's effectiveness. The small number of patients

sampled could have biased treatment effects by reporting on

a subset of patients with TD. The appropriateness of the

data analysis has been questioned. Overall, a more

conservative statistical analysis of the data seems necessary

in order to substantiate reports of lecithin1s effectiveness

which were obtained largely from nonstatistical data analysis.

The use of inadequate placebo control measures has also been

considered. It has been suggested that an additional

control measure which could reflect spontaneous fluctuation

and/or remission of symptoms would be beneficial. Assessment

measures which assess treatment effects both subjectively

and objectively have been offered as a means of demonstrating

lecithin's effectiveness. Finally, it has been suggested

that additional research is much needed in this area in

order to clarify lecithin's proposed effectiveness in treating

tardive dyskinesia.

The purpose of the present study was to more extensively

examine the effects of lecithin treatment on tardive

dyskinesia with due regard given to the objectionable

methodologies employed in previous studies. The objective

of this study was to evaluate the effects of lecithin

administered under double—blind, placebo controlled conditions

and to compare statistically these treatment effects with

5Q

no-treatment control measures. Further, a more extensive

clinical assessment of treatment effects which employs

subjective, objective, and global evaluations as dependent

measures has been suggested and was believed to be significant

in more thoroughly evaluating the effects of lecithin on

tardive dyskinesia. In accordance with the stated objective,

the following hypotheses were adopted in order to test

lecithin's effectiveness.

1. Symptom severity measures as determined by the

Simpson Tardive Dyskinesia Rating Scale will demonstrate that

lecithin treated subjects, as compared to subjects in the

placebo or no treatment control groups, will show signif-

icantly reduced symptoms subsequent to treatment.

2. Symptom severity measures as assessed by the Self-

Report Tardive Dyskinesia Rating Scale will show a signif-

icant reduction for subjects treated with lecithin as

compared to those in the placebo and no-treatment control

groups.

3. Motor performance as measured by (a) the Finger

Oscillation subtest from the Halstead-Reitan Battery,

(b) the Purdue Pegboard Test, (c) the Minnesota Rate of

Manipulation Test, and (d) a line tracing task will reveal

that subjects in the lecithin group, as compared to those in

the two control groups, will show a significant improvement

subsequent to treatment.

51

4. Integrative sensory motor performance as evaluated

by (a) the Bender-Gestalt Visual Motor Test, (b) the Digit

Symbol subtest from the Wechsler Adult Intelligence Scale,

and (c) the Trails A subtest from the Halstead-Reitan Battery

will show a significant improvement for subjects in the

lecithin group as compared to subjects in the two control

groups.

5. Speech articulation as measured by a modification

of the Speech Sounds Perception subtest of the Halstead-

Reitan Battery will demonstrate that subjects treated with

lecithin show significantly improved speech articulation

while those in the two control groups will show no signif-

icant change.

6. An overall global evaluation of treatment effects

as determined by both researcher and subjects will indicate

that lecithin treated subjects will show significant overall

improvement while subjects in the two control groups will

show no change.

Method

Subjects

Subjects were 45 volunteer male inpatients from the

Veterans Administration Medical Center in Waco, Texas, who

displayed symptoms of tardive dyskinesia. The population

was comprised of the following major psychiatric diagnoses:

schizophrenia (68.9%), organic brain syndrome (28.9%), and

52

bipolar affective disorder (2.2%). Subjects ranged in ages

from 26 to 77. The mean age of the subjects was 56.15

(standard deviation = 9.7). Years of neuroleptic treatment

ranged from 2 to 26 years. The mean length of treatment was

17.29 (standard deviation = 8.5) years.

Criteria for including subjects into the study were

the following:

1. Visible dyskinetic movements of the choreoathetotic

variety, occurring in the orofacial regions and/or in the

extremities following a prolonged exposure to neuroleptics;

2. A duration of tardive dyskinesia lasting at least

3 months, i.e., stable and chronic;

3. No family history of hedepodegenerative disease

that involves dyskinetic movements;

4. No exposure to medicines, other than neuroleptics,

or other treatments that could account for the dyskinetic

movements;

5. A thorough discriminating evaluation of the disorder

to rule out other extrapyramidal disorders and other

differential diagnostic categories.

Criteria for excluding subjects from the study were

the following:

1. Physical disorders in which there is a contraindi-

cation of increased lipid content in the diet, e.g., coronary

heart disease or arteriolsclerosis;

53

2. Physical disorders affecting the gastrointestinal

tract which could be worsened by constituents of the

treatment, e.g., gastric, duodenal ulcers, or chronic

gastritis;

3. Other acute or chronic illness which would prevent

patients from participating in the study.

Details of the experimental study were explained to

subjects randomly selected to be in lecithin or the placebo

treatment group. Following this explanation, each subject

was asked if he would be willing to participate in the study.

Those who chose to participate gave their informed consent

(see Appendix E) and were included in the study according

to the provision of a protocol on tardive dyskinesia

previously approved for the Beckham (1981) lecithin treatment

study by the North Texas State University Use of Human

Subjects Review Board and the Veterans Administration

Medical Center (VAMC) Human Studies Subcommittee. For the

subjects in the no-treatment group, a similar induction

procedure approved by the VAMC Human Studies Subcommittee

was followed (see Appendix G). These subjects were neither

informed of nor offered any treatment.

Subjects evaluated in the present study overlap with

those included in the Beckham (1981) study. Approximately

60% of the subjects participating in the present study had

been included in the Beckham study.

54

Measures

Twelve assessment devices were used to evaluate all

subjects from 3 to 4 days prior to the initiation of treatment

and after 9 to 11 days of treatment. The following measures

were used:

1. Measures assessing symptoms severity include the

Simpson Tardive Dyskinesia Scale (Appendix H) and the Self-

Report Tardive Dyskinesia Rating Scale (Appendix I);

2. Measures evaluating motor performance ability

include: (a) the Finger Oscillation subtest from the

Halstead-Reitan Battery, .(b) Purdue Pegboard Test,

(c) Minnesota Rate of Manipulation Test, and (d) a line

tracing task;

3. Assessment of performance on integrative sensory-

motor tasks include: (a) the Bender-Gestalt Visual Motor

Test, (b) Digit Symbol subtest from the Wechsler Adult

Intelligence Scale (WAIS), and (c) Trails A subtest from

the Halstead-Reitan Battery;

4. Assessment of speech articulation was measured by

using a modification of the Speech Sounds Perception Test

of the Halstead-Reitan Battery (Appendix J);

5. A global overall measure of treatment effects was

obtained by both researcher's and subject's evaluation of

whether or not the treatment had been effective in reducing

dyskinetic symptoms.

55

Procedure

Subjects were randomly assigned to the three conditions

(15 in each group) in an effort to avoid systematic bias due

to subject age, duration of exposure to neuroleptics,

symptom severity, or diagnostic factors. Although the

subjects assigned to one of the treatment groups were

informed that they would receive either the lecithin treat-

ment or a placebo control treatment, neither the patients

nor the researcher knew to which group any individual had

been assigned.

Neuroleptic medication was unchanged in all subjects

participating in the study (N - 41). Those subjects taking

no neuroleptics (N = 4) were maintained on this status.

Anticholinergics were discontinued approximately 3 days

prior to baseline measures for 7 of the subjects. It was

clinically unfeasible to discontinue anticholinergics in

7 other patients. However, only one of these patients was

assigned to lecithin treatment group.

All subjects received their usual diet. No attempts

were made to increase the calorie intake of the patients

in the no-treatment control group.

Lecithin granuals (Lethicon, American Lecithin

Corporation) containing approximately 55% phosphatidylcholine

(see Appendix K) were mixed with 8 oz. of milk. The placebo

substance consisted of a mixture of corn oil and crushed

56

graham crackers. The placebo substance resembled the

lecithin mixture in taste, appearance, and thickness.

These mixtures were dispensed by the hosptial pharmacy and

administered to the subjects in the two treatment groups

twice daily. Subjects in the lecithin treatment group

received a daily dose of 60 grams of the lecithin compound

(33 grams of phosphatidylcholine). Doses were administered

to the subjects by the ward nurse who observed that they

consumed all of the mixture. At the final session, each

subject was informed that the research project was concluded

and thanked for his participation in the research.

Results

A one-way analysis of avariance was performed on

subject variables to determine if there were initial

differences among the groups. These analyses show no

significant differences for age (JD>.2), duration of

neuroleptic treatment (JD >.2), or initial symptom severity

(p- >.2). A chi square analysis of diagnostic categories

demonstrates no significant difference among the groups

(X = 4.8, df = 4, £ >.5). Therefore, random assignment

of subjects to treatment conditions is an effective means of

eliminating systematic bias due to initial differences in

the distribution of subjects among the groups.

Treatment effects are analyzed using a factorial

analysis of covariance. Treatment conditions, age, and

57

length of neurolpetic treatment are the classification

variables. The treatment conditions include a placebo

control group, a lecithin treatment group, and a no-treatment

control group. Age factors are determined by dividing the

subjects according to a median split (median = 56 years)

into younger or older halves. Duration of neuroleptic

treatment factors are determined by dividing the subjects

according to a median split (median = 19 years) into shorter

or longer halves. For each treatment measure, the pretest

score is the covariant and the posttest score is the variant.

Effects of the independent variable, lecithin treatment,

are assessed in terms of a number of dependent measures.

Measures assessing symptom severity include the Simpson

Tardive Dyskinesia Rating Scale (STDRS) and the Self-Report

Tardive Dyskinesia Rating Scale (SRTDRS). Examiner ratings

which employ the Simpson scale show no significant effects

of treatment conditions for the total score (see Table 7,

Appendix L), the total number of scored items (see Table 8,

Appendix M), or the bucco-linguo-masticatory triad (see

Table 9, Appendix N). Subjects' evaluations are measured

by the Self-Report Tardive Dyskinesia Rating Scale. This

measure also demonstrates no significant effect of treatment

conditions. Statistical values determined for this measure

are listed in Table 10 (Appendix 0). Neither examiner nor

subject rating scale measures show any significant change

in symptom severity due to lecithin treatment.

58

Only one measure evaluating motor performance ability

shows significant treatment effects. Measures recorded for

the finger oscillation task are the average score on three

triads of ten second duration. The finger oscillation test

with the dominant hand shows significant effects of lecithin

treatment. The ANCOVA indicates that there is a significant

overall effect of lecithin treatment (p. < .05). Regardless

of the affects of age or duration of neuroleptic treatment,

there is an overall significant reduction in dominant hand

tapping speed. The Newman-Kuels post hoc analysis indicates

that the lecithin group is significantly different from

the placebo control and the no-treatment control groups

(JQ < .05). Statistical values obtained for dominant hand

finger oscillation measures are listed in Table 11

(Appendix P).

Further, the ANCOVA shows that age has a significant

overall effect on dominant hand tapping speed (p.< .0001).

Older subjects are slower regardless of treatment conditions

or duration of neuroleptic treatment.

A significant interaction of treatment conditions and

age is evidenced by the ANCOVA (p <.05). This interaction

is graphically illustrated in Figure 7. Adjusted means for

dominant hand tapping speed for younger and older subjects

are plotted across treatment conditions. The Tukey A post

hoc analysis reveals that the significant difference is

59

CD 4-> rd Ph

o •p (d r-t i—I •H 0 to a

a> 01 a •H

c to <D S t> CD •P 05 S3 T T3 <

50

48

46

44

42

40 -

38 -

36

34

32

30

Figure 7.

A *

X Placebo Lecithin No-Treatment

Control

Interaction of treatment conditions and age for dominant hand finger oscillation rate.

found between younger and older subjects of the placebo group

and younger and older subjects of the no-treatment control

group (£< .05). Younger and older subjects in the lecithin

group do not differ significantly on dominant hand tapping

speed.

6Q

The ANCOVA reveals another significant interaction

between treatment conditions and duration of neuroleptic

treatment. Adjusted group means of short- and long-term

neuroleptic treatment plotted across the three treatment

conditions are shown in Figure 8. The Tukey A post hoc

analysis shows a significant difference between short- and

long-term treated subjects in the placebo group (p< .04).

In summary, the analysis indicates four significant

findings. First, there is an overall significant effect of

treatment conditions on dominant hand tapping speed.

Specifically, tapping speed is reduced in the lecithin group.

Second, there is an overall age effect. Older subjects

perform this task slower than do younger subjects. Third,

treatment conditions and age show a significant interaction.

Lecithin effectively reduces dominant hand tapping speed in

younger subjects. Fourth, duration of neuroleptic treatment

and treatment conditions also interact significantly. The

complexities of this interaction are more difficult to

interpret definitely because the no-treatment control group

measure does not confirm that response differences are due

to duration of neuroleptic treatment factors.

The only factor significantly affecting nondominant hand

finger oscillation is age. Regardless of treatment conditions

or length of neuroleptic treatment, older subjects have a

slower tapping speed (p < .01). Statistical values obtained

for this measure are shown in Table 12 (Appendix Q).

61

CD -P fd Pd

£ o +> d t—i i—i •H O CO O u a> O* d •H Pm £ rd <D s-n3 (L) •P CO 3 *r~l <c

48

46 ~

44 -

42

40

38

36

34

32 -

30

Figure 8.

• • shorter

• longer

JL Placebo Lecithin No-Treatment

Control

Interaction of treatment conditions and length of neuroleptic treatment for dominant hand finger oscillation rate.

The Purdue Pegboard Test measures consist of the total

number of pegs placed in holes for three consecutive trials

of thirty seconds duration. The three trials include

dominant hand performance, nondominant hand performance,

and performance of both hands working together in a

6 o

coordinated fashion. No significant effects are found among

the experimental conditions, nor are age or duration of

neuroleptic treatment effects evident. Table 13 (Appendix R)

lists statistical values obtained for this measure.

The Minnesota Rate of Manipulation Test measures

recorded are the fastest of two dominant hand trials in

which the subject is able to fill all the holes with pegs.

The analysis indicates that there is an overall effect for

duration of neuroleptic treatment (jd < .05) . Regardless of

the treatment conditions, subjects with shorter duration of

neuroleptic treatment perform this task faster. The ANCOVA

indicates no difference among the adjusted means for the

three treatment conditions. Statistical values for these

measures are listed in Table 14 (Appendix S).

The line tracing task measures the total number of

deviations from a straight line of ten inches. The subject's

ability to perform this task is not influenced by treatment

conditions. In Table 15 (Appendix T), statistical values

are listed for this measure.

None of the integrative sensory-motor performance task

reflect differences among the treatment conditions. The

Bender-Gestalt measures recorded are the scores obtained

by use of the Hain's scoring method. Both total score and

categore scores are used in the analysis. Results indicate

no significant effect of treatment. In Tables 16 and 17

63

(Appendixes U and V), statistical values obtained for this

measure are listed. The Digit Symbol subtest and the Trails

A subtest do not show any differences due to treatment

conditions. In Tables 18 and 19 respectively (Appendices

W and X), statistical values obtained for these measures

are listed.

The subject's ability to articulate speech sounds does

not reflect any differences due to treatment conditions.

Statistical values obtained for this measure are shown in

Table 20 (Appendix Y) .

Subjective global measures of treatment effects assessed

by both examiner and subject indicate no globally recognized

difference among the three experimental conditions. A chi

square analysis of the subject's estimate of whether he has

benefitted, not changed, or has become worse indicates that

these evaluations are not significantly related to treatment

conditions (x2 = 1-31, df. = 2, £ < .75, (j>_ = .21) . In the

placebo group 12 of 15 subjects report no change in their

dyskinetic movements, and 3 subjects believe that they are

improved. In the lecithin group, 1 subject reports being

worse, 10 report no change, and 4 report improvement.

Table 21 lists the number of subjects assigned to various

treatment response categories as determined by subjects'

global evaluation of treatment effects. Overall, 67% of the

subjects in the lecithin treatment group report no change

64

in their symptoms. In the placebo group, 80% report no

change.

Table 21

Subjects Assigned to Treatment Response Categories by Self-Evaluation

Treatment Response Categories

Group Worse No Chanae Improved

Placebo 0 12 3

Lecithin 1 10 4

A chi square analysis of the researcher's estimate of

change due to treatment indicates no significant relation

between treatment groups and global assessment (X-2 = 1.05,

df = 4, £ < .95, = .11). The research reports that

13 of 15 subjects in the placebo group show no change and 3

subjects appear improved. In the lecithin group, 12 subjects

show no change, 2 appear improved, and 1 appears worse. In

the no-treatment control group, 12 subjects are unchanged,

2 show improvement, and 1 subject is worse. In Table 22,

the number of subjects assigned to various treatment response

categories by the researcher's global evaluation are shown.

Overall, the researcher assesses that 87% of the subjects

in the placebo control group show no change and 80% of the

subjects in the lecithin group and the no-treatment control

group show no change.

65

Table 22

Subjects Assigned to Treatment Response Categories by Researcher's Evaluation

Treatment Response Categories

Group Worse No Change Improved

Placebo

Lecithin

No-Treatment Control

0

1

13

12

12

2

2

A chi square analysis undertaken to determine whether

the subject and the researcher concur on their global

evaluation of treatment effects indicates that their

evaluations are not significantly related (x2 = -007, df =1,

p = .93, <j>_ = .01). Nevertheless, they are in agreement on

67% of the evaluations.

Discussion

Overall, results of the study do not support the

prediction that lecithin treated subjects will show signif-

icant reduction in dystonic movements and increased control

over voluntary movements and speech articulation. The only

significant finding suggests that lecithin modulates response

rate for rapid dominant hand finger osciallation. The finding

that lecithin treated subjects show attenuated dominant hand

volitional response rates may suggest that lecithin reduces

66

the extrapyramidal motor activity which in turn influences

peripheral motor neuron activity.

Although lecithin treatment is shown to have significant

overall effect in reducing dominant hand finger oscillation,

interesting differential effects of lecithin treatment are

shown by the interaction of age and the duration of

neuroleptic treatment.

The interaction of lecithin treatment and age (see

Figure 7) suggests that younger subjects respond to lecithin

treatment with reduced dominant hand finger oscillation rate,

but older subjects do not. Further, regardless of treatment

conditions, younger subjects perform faster on this task

than do older subjects. Despite this overall effect of age,

the performance of younger and older lecithin treated

subjects does not differ significantly as does the performance

of younger and older subjects in both the placebo and

no-treatment control groups. Hence, due to lecithin effects,

younger subjects' performance becomes nonsignificantly

different from that of older subjects.

The interaction of lecithin treatment and duration of

neuroleptic treatment (see Figure 8) shows that dominant

hand finger oscillation rate differs for short- and long-term

treated subjects in the placebo group. Because there is no

difference in performance between short- and long-term

treated subjects in the no-treatment control group, the

67

significance of this interaction becomes more speculative.

Nevertheless, some trends reflected in this interaction may

be important.

For example, short-term treated subjects of the

lecithin treatment group show a marked reduction in tapping

speed which is notably less, but not significantly different

from the responses of longer-term treated subjects. For those

subjects who were offered no treatment, shorter- and longer-

term treated subjects perform essentially the same on this

measure.

Duration of neuroleptic treatment is not a significant

factor on performance of this task as evidenced by the

performance of the no-treatment control group. However,

shorter-term treated subjects tend to respond with reduced

tapping speed in response to lecithin treatment. In

comparison to responses of shorter-term treated subjects in

the placebo control group, shorter-term treated subjects in

the lecithin group show a markedly diminished tapping rate.

Overall, Figure 8 shows a marked variability in

response to treatment effects in shorter-term treated

subjects. There is virtually no difference in treatment

response for longer-term treated subjects. Hence, it is

possible that duration of neuroleptic treatment affects

subjects' responsiveness to lecithin treatment. That is,

shorter-term treated subjects respond to lecithin by a

68

suppression of dominant hand finger* oscillation while

longer—term treated subjects do not show this response.

Persistence or reversibility of tardive dyskinesia

symptoms represents a conceptual framework in which these

results can be examined. Researchers maintain that TD

occurs along a continuum of reversibility (Casey, 1978,*

Jeste & Wyatt, 1979; Quitkin et al., 1977). When neuro-

leptics are withdrawn, symptoms that resolve are believed

to reflect a temporary alteration in CNS function. Those

which persist are viewed as an indication of permanent

change in the CNS function (Casey, 1978). The reversibility

of TD symptoms by drug withdrawal has been demonstrated in

patients who have taken drugs for a relatively short period

of time (Quitkin et al., 1977) as well as in younger,

nonbrain damaged patients (Jeste & Wyatt, 1979). On the

other hand, persistent TD is believed to reflect irreversible

brain damage (Christensen et al., 1970? Jeste & Wyatt, 1979).

Although the effects of the present study do not

produce remission of TD symptoms, treatment response to

lecithin is specific for a certain subset of subjects who

are younger and have had a shorter duration of neuroleptic

treatment. These results may suggest that for those subjects

who demonstrate a response to treatment, the underlying

pathophysiology represents a temporary alteration in CNS

function. For those who show no treatment response, it is

59

likely that pathophysiology represents a permanent change

in CNS function.

The biochemical mechanism for cholinergic intervention

is believed to be acetylcholine receptors located on post

synaptic gabinergic neuron which feedback onto dopamine

(DA) neurons of the substantia nigra. The effect of this

mechanism is to attentuate the hyperactivity of these DA

neurons. In younger and shorter-term treated subjects,

lecithin treatment effects imply that this CNS regulatory

mechanism is intact, while lack of treatment effects obtained

among older and longer-term treated subjects suggests that

this feedback mechanism is not functional. This model seems

consistent with present findings because, in younger and

shorter-term treated subjects, extrapyramidal outflow

(evidenced by reduced dominant hand finger oscillation) is

attenuated most likely due to suppression of DA neurons.

In older and longer-term treated subjects, DA neurons

apparently are not suppressed and consequently, extra-

pyramidal outflow remains unchanged.

Age and duration of neuroleptic treatment influence

results obtained from three dependent measures. First, age

is an overall significant factor in dominant hand finger

oscillation. Regardless of treatment conditions, younger

subjects perform faster than do older subjects. Overall,

this finding seems to be an indication of a more intact

70

extrapyramidal system. Even when younger subjects show-

response to treatment by reduced finger oscillation rate,

these measures are greater than those of older subjects

under any treatment condition (see Figure 7). Hence, age

effects are displayed ubiquitously and likely reflect the

integrity of the extrapyramidal motor outflow of the CNS.

Second, age is also a significant factor in nondominant

hand finger oscillation. Similarly, younger subjects

perform this task at a faster rate than do older subjects.

Third, duration of neuroleptic treatment is shown to

affect subjects' performance on the Minnesota Rate of

Manipulation Test. Regardless of treatment conditions or

age, subjects who have received shorter-term neuroleptic

treatment perform this task faster. In accordance with

these findings, longer-term neuroleptic treatment may produce

disintegration of this motor system and be reflected in

overall diminished response rates.

Overall, lack of treatment effectiveness seems to be

accurately reflected in the dependent measures. Nevertheless,

possible short-comings of the study should be acknowledged.

Although subjects were randomly assigned to treatment condi-

tions, subjects were not matched for equal distribution of

age and length of neuroleptic treatment factors because this

was unfeasible due to limited number of available subjects.

There is an unequal distribution of these factors. The distri-

bution of subjects to cells in the ANCOVA is shown in Appendix Z,

71

The unequal distribution of subjects could be

problematic for accurate interpretation of interaction

effects. Interpreting 3-way interactions would be

particularly problematic because they represent the greatest

disproportion in cell frequencies. Since no significant

3—way interactions are obtained, this does not affect

present findings. Although less problematic, 2-way inter-

actions may reflect bias due to unequal distribution among

cell frequencies. The ANCOVA indicates a significant

difference in response to lecithin for younger and older

subjects. The particular distribution of subjects to cells

in this interaction (see Appendix Z) does not, however,

suggest the likelihood of strong bias due to disproportional

cell frequencies. The ANCOVA further indicates a signif-

icant difference between the response of short-term and

long-term treated subjects. Herein, the particular

distribution of subjects to cell is more disporportionate

(see Appendix Z). This may have biased results somewhat.

The finding that lecithin attenuates dominant hand

finger oscillation among younger and shorter-term treated

subjects may be regarded only as exploratory data. Because

no other dependent measure showed significant treatment

effects, it is possible that these findings represent a

violation of statistical probability (i.e., finding

significance where none actually exists). Further research

7 2

is necessary before a definitive assertion regarding

lecithin effects on dominant hand finger oscillation rate

can be accepted.

Findings of the present study are in marked contrast

to those of previous studies that found lecithin effective

in reducing dyskinetic movements. A number of experimental

factors may account for these discrepant findings.

Differences in subject population may contribute to

these differences. Subjects' age, duration of neuroleptic

treatment, symptom severity, chronicity, differential

diagnosis, and psychiatric diagnosis may effect treatment

effectiveness.

To determine whether age factors contribute discrepant

findings reported here, mean age and age range reported in

previous studies are examined and compared with those of

this study. The mean age for subjects in this study is 56

(standard deviation = 9.7) years. Ages range from 26 to 77.

In only one study, are age factors notably different from

those reported here (see Table 6, Appendix E) (Gelenberg

et al., 1979a, b). In this study, subjects' ages range from

27 to 32. It is likely that younger subjects are represen-

tative of those patients who exhibit reversible TD. Therefore,

they likely would be more responsive to treatment. Other

studies report beneficial effects of lecithin among

subject populations with age ranges comparable to those

73

of this study. Four subjects with a mean age of 63.7

(standard deviation = 5.8) years (Barbeau, 1979) and six

subjects with a mean age of 57 years and a range from 49

to 60 (Jackson et al., 1979, l98l) all show beneficial

effects of lecithin treatment. Thus it is difficult to

conclude that age is a significant factor which accounts

for the reported differences.

The length of neuroleptic treatment is another factor

which may be significant for treatment effectiveness.

Because patients treated for longer periods do not show

reversibility of dyskinetic symptoms when neuroleptics are

discontinued (Quitkin et al., 1977), it is reasonable to

infer that these patients would De less responsive to

lecithin treatment. Present findings suggest that long-term

treated subjects do not show response to lecithin treatment.

Jackson et al.. (i979, 1^81; reported that the 6 subjects

treated had received neuroleptics virtually continuously for

at least 4 years, although the range was from 4 to 23 years.

Their results indicate that all patients showed a significant

reduction in dyskinetic movements. In the present study,

the average length of neuroleptic treatment is 17,3

(standard deviation = 8.5) years. The range is from 2 to 26

years. Based on similar length of of treatment between

previous reports and the present, it is unlikely that the

duration of neuroleptic treatment can account for the

reported differences.

74

Severity of the tardive dyskinesia may also be a

factor accounting for discrepant reports. In the present

study, average initial severity of TD (measured by the

Simpson scale) is moderate. The range is from mild to

severe. A comparison to previous reports (Table 6,

Appendix E) reveals that the initial severity of TD reported

in other studies does not differ from those reported here.

Hence, initial severity measures do not seem to be a

significant factor which accounts for the reported

differences.

Duration of the tardive dyskinesia measures are largely

speculative because symptom onset is insidious. Because the

course of TD is progressive, severity measures are often

more reliable estimates of symptom chronicity than are

speculations as to its onset. In the present study and in

several others (Barbeau, 1978? Growdon et al., 1978; Jackson

et al./ 1979, 1981), researchers have disregarded the

importance of tne duration of the TD as a crucial factor

affecting the results. Hence, duration of TD is an

unreliable measure and cannot be used as a factor which

accounts for treatment effects.

Criteria for establishing a differential diagnosis of

TD from other extrapyramidal disorders could account for

discrepant findings. However, the criteria for establishing

a diagnosis of TD are believed to have judiciously excluded

75

subjects with other extrapyramidal syndromes in both this

and previous studies.

Psychiatric diagnosis within the subject population may

also influence results. Tardive dyskinesia is more

prevalent in patients with diagnosed organic brain syndromes

(OBS). Reports suggest that these patients are unlikely to

demonstrate reversibility of TD when neuroleptics are

withdrawn (Jeste & Wyatt, 1979). In previous reports,

(Gelenberg et al., 1979a, b; Jackson et al., ±979, 1981) no

subjects had a diagnosis of OBS. In the present study,

within the lecithin treatment group, three subjects (20%)

have this diagnosis. Although it is unlikely that such a

smail number of subjects have significantly affected

results, it is possiDle that including subjects with OBS

may have influenced the present results. Nevertheless, it

seems unlikely that marked discrepancies reported in this

study are fully accounted for by the inclusion of these

subjects.

Other likely considerations which may account for these

differences involve experimental procedures such as, dosage,

length of lecithin treatment, and concurrent medications

are considered.

Dosage is an important consideration when evaluating

response to treatment. Previous research suggests that

lower doses of cholinomimetics, presumed to act as agonists

76

on Gabanergic post synaptic receptors, may be more effective

than higher doses. According to Macintosh (1979),

muscarinic receptors are activated by lower concentrations

of cholinomimetics than are nicotinic receptors. At higher

doses nicotinic receptors are also activated; thereby

promoting both activating and blocking effects. Consequently,

smaller doese may be more effective than larger doses. In

partial support of this contention, Gelenberg et al. (1979b)

reported that larger doses (21 gms per day) of lecithin

for shorter periods (2 weeks) do not produce the positive

effects seen after smaller doses over longer duration

(6 - 8 weeks). However, the interaction of dose and duration

does not necessarily indicate that large doses have blocking

effects. It is more likely that the duration of lecitnin

treatment xs more significant tnan dose size.

Reports of lecithin effectiveness have evidenced a wide

range of dose effectiveness. It can be seen from Table 6

(see Appendix E) that dosages ranging from 2.4 gms per day

to 35 gms per day of lecithin close equivalents have been

reported effective in reducing dyskinetic manifestations.

The present study uses a dose of 33 gms per day which is

within the range of those previously found effective.

Hence, dosage does not appear to be a significant factor

which accounts for the lack of treatment effectiveness.

77

The length of lecithin treatment may affect the

results. Jackson et al. (1979) have demonstrated that

after 8 days of lecithin treatment, lecithin effects were

shown to significantly reduce aystonic movements* However, .

these researchers noted continued improvement through the

i4th and final day of their study. Geienberg et al.

(1979a, b) have noted continued improvement throughout eight

weeks of treatment. Both research teams have, therefore,

advocated continued long-term lecithin treatment intervention,

In previously reported studies, the duration of

lecithin treatment ranged from 2 weeks to 20 weeks (see

Table 6, Appendix E). Statistically significant differences

in severity of TD were noted after 8 days of treatment. In

the present study, treatment lasts from 9 to li days.

According to the findings reported by Jackson et al. (1979)

the length of treatment employed in the present study should

be adequate to obtain significant reduction in dyskinetic

movements. However, since beneficial effects are not

obtained, it is worthwhile to consider that lack of treatment

effectiveness is in part due to the relatively short duration

of lecithin treatment.

Concurrent medications may also be considered a factor

influencing the results of this study. In studies

previously undertaken ana the present, the neuroleptic

medication status remained essentially unchanged.

7:8

However, changes in anticholinergic drugs are called for in

order to assure that these drugs do not counter the effects

of cholinergic treatment. Discontinuation of anticholiner-

gics was notea by Jackson et al. (1979, 1981) and also

employed in the present study. Overall, continued neuro-

leptic medication assures stability of baseline measures as

well as contributes to the efficacy of lecithin effectiveness,

In the present study, the procedures regarding the use of

concurrent neuroleptic medications seem appropriate.

Anticholinergics were discontinued in all but one subject

in the lecithin group. However, it is doubtful that this

has significantly affected the results. Overall, results

are not likely due to variable effects of other medications.

Adequate design is crucial to obtaining clear and

unbiased data. When appropriate control measures are

instituted, experimental error due to experimenter bias and

to placebo effects is reduced considerably. Although

design has been shown to signficantly affect choline

treatment results by reducing the percentage of subjects

improved in open trials from 79% to 45% in a double blind

study (Growdon et al., 1977), design thus far has not been

demonstrated to affect results of lecithin treated subjects.

Studies employing double-blind crossover design to test the

effects of lecithin report improvement in all six patients

treated (Jackson et al., 1979, 1981). Present results,

79

however, offer a challenge to reports of lecithin's

effectiveness obtained in controlled sutdies.

Jackson et al. (1979, 1981) have demonstrated an

impressive differential response to lecithin treatment in

a double-blind crossover, placebo controlled study. The

present study, using a double-blind placebo controlled

design reports no such differences.

Design of the present study, using both a placebo

control measure and a no-treatment control measure, necessi-

tates that treatment effects must differ from both control

measures. Use of a second control measure further reduces

experimental error and increases validity of the results

more than does a design which utilizes a single control

measure.

Other considerations which may account for reported

differences include dependent measures such as subjective

severity ratings and global evaluations.

Means of subjectively assessing treatment effects include

the Simpson Tardive Dyskinesia Rating Scale, the Self-Report

Tardive Dyskinesia Rating Scale, and overall global

assessments of subjects and researcher. None of these

measures evidence beneficial effects of lecithin.

Severity rating scales are commonly used to evaluate

treatment effects. Previous studies (Gelenberg et al.,

1979a, b; Jackson et al., 1979, 1981) have reported reduced

80

severity of dyskinetic movements reflected in these measures.

Present results do not confirm these reports. However, it

is possible that differences in the scales used account for

some of these discrepancies.

Previous studies (Gelenberg et al., 1979a, b? Jackson

et al., 1979, 1981) have used the Abnormal Involuntary

Movement Scale (AIMS). The present study uses the Simpson

Tardive Dyskinesia Rating Scale (STDRS). Differences in

reports of lecithin's effectiveness may be attributable in

part to differences in what the scales measure. First, the

AIMS distinguishes between the severity of the movement on

a 5 point scale. The STDRS uses a 6 point scale. Second,

only 7 grossly localized areas are distinguished by AIMS

and only one rating is made for each affected area. The

STDRS lists 34 discrete localized movement disorders and

allows rating on each individual type of dystonic movement.

Third, the AIMS uses overall global evaluation. Three of

the 12 items on the scale are used to evaluate these global

measures. No global measures are reported by the STDRS.

Essentially, the main difference in the scales is that

the AIMS yields a very global and nondiscrete estimate of

the severity of dystonic movements, while the STDRS permits

a very discriminating evaluation of the symptom array.

Further, it is likely that the specificity which the STDRS

permits encourages the rater to carefully evaluate in a

81

methodological manner, the presence or absence and severity

of each dystonic movement displayed. In contrast, the rater

using the AIMS is forced to make gross generalizations about

the severity of movements in fairly large body areas.

Overall, a more precise evaluation is possible with the STDRS.

It is contrary to common judgment that an instrument

which permits largely global evaluations would be more

revealing of treatment effects than would one which allows

discrete evaluation of subtle movement characteristics.

Thus, the lack of treatment effectiveness found in the

present study cannot be accounted for by weakness of the

STDRS to reflect changes in movements. Overall, the ability

of the STDRS to precisely and distinctly assess the array of

diskinetic movements is judged superior to that of the AIMS

scale. This must be taken into account when comparing the

results obtained from the STDRS with those obtained form

the AIMS.

Differences in the way the severity rating scales are

used may also account for the discrepant findings. The

length of the rating period may contribute to differences.

Longer rating periods would naturally increase the total

number of symptoms displayed as well as the overall reliability

of symptoms noted. Because the interval of the symptom

occurrence may exceed the length of the rating period, a

problem associated with using shorter rating periods is the

82

considerable variability of symptoms displayed. Accordingly,

Jackson et al. (1979, 1981) noted that AIMS subscores do not

demonstrate consistent differential change. This is likely

since the short duration of assessment would likely not

reveal a ubiquitous display of the total symptom array.

The longer rating period is superior because ample time is

allowed for assessing symptoms and establishing a reliable

baseline of symptom array. The present study demonstrates

reliability of differential components which is evidenced

not only in the no-treatment control group, but in both the

lecithin treatment group and the placebo control group.

Increased level of extrapyramidal outflow may also

contribute to reported differences. Severity of dystonic

movements increases with increased levels of arousal. Since

in the present study symptom severity ratings are assessed

during states of motor activity on timed performance tasks,

it is possible that lecithin treatment effects which might

be demonstrated at lower levels of motor activity are masked

at higher levels of EPS activity.

In support of this supposition, some researchers

(Tamminga et al., 1977) have suggested that cholinomimetics

may act as a generalized sedative. If lecithin acts through

a generalized reduction in EPS outflow, possibly at increased

levels of motor activity, sedative effects are counteracted.

Thus, the discrepant reports of lecithin's effectiveness may

83

be attributable to differential effects of lecithin which are

due to the level of activity of the extrapyramidal motor

system.

Subjects' awareness can also affect severity ratings.

As previously noted, subjects can volitionally control

dystonic movements for short periods of time. Accordingly,

subjects' awareness of rating procedures in noncontrolled

studies (Gelenberg et al., 1979a, b) is likely to affect

results. However, in highly controlled studies (Jackson

et al., 1979, 1981), it is unlikely that results are

attributable to subject awareness. Therefore, subject

awareness is not a likely factor which accounts for discrepant

reports of lecithin's effectiveness.

The preceding discussion has addressed issues concerned

with reported differences of lecithin's effectiveness as

assessed by symptom severity measures. Studies assessing

lecithin's effectiveness in terms of frequency measures have

not been considered because changes in symptom severity are

not necessarily related to change in frequency. Therefore,

results of this study neither address nor preclude the

validity of findings that lecithin reduces the frequency of

dyskinetic movements. To the contrary, it is quite possible

that lecithin's effects produce changes in the frequency of

movements without affecting the severity (i.e., amplitude)

of the movement.

84

Self-report measures are another means of evaluating

treatment effectiveness. The Self-Report Tardive Dyskinesia

Rating Scale and a global evaluation indicates that subjects

in the present study are not aware of improvement in their

dyskinetic movements. In contrast, Barbeau (1979) in a

noncontrolled study notes that subjects report a marked

improvement in muscle tension felt in the face and neck.

It is likely that these reports are confounded by the

positive expectancies of subjects, since no controls were

instituted.

Studies which employ self-report measures (Barbeau,

1979; and the present study) find that these measures concur

with the overall reported effectiveness of lecithin.

Essentially, subjects* reports appear to be a valuable means

of assessing treatment effects provided that adequate control

measures are used. However, subjects' reports of treatment

effectiveness in noncontrolled studies may reflect subject

expectancy and thus account in part for discrepant reports.

Data analysis is one of the most important factors

affecting treatment results. Of the lecithin treatment

studies only the study undertaken by Jackson et al. (1979,

1981) demonstrated a statistically significant difference

between lecithin and placebo control groups. All other

studies have interpreted their results from a non-statistical

percentage of change from baseline.

85

According to Davis et al. (1976), results of any study

evaluating treatment effects on tardive dyskinesia must be

interpreted with great caution because TD is characterized

by extreme variability from day to day. They reported that

day-to-day fluctuation in symptomatology can vary by 25% in

either direction which makes reports based on percentage of

change from baseline subject to a great deal of experimental

error. Of the total number of patients thus far treated

with lecithin, 70% of the reported findings are based on

this type of analysis. Further confounding these results,

it should be noted that all of these studies employ no

control measures to rule out positive expectancy. Hence,

results reported for most patients are subject to viable

criticism regarding experimental error due to spontaneous

fluctuations in symptoms.

Using a one-tailed paired student's t-test, the Jackson

study demonstrates a significant difference (JD <. .05) in

mean total AIMS scores following eight days of treatment.

The greatest difference is demonstrated on the 14th and

final day of treatment (p < .01). The double-blind corss-

over design lends further credibility to this report

because placebo effects and researcher bias are effectively

eliminated. Differences in subjects' responses to treatments

are impressively demonstrated in this repeated measures

design. The present study reports finding to the contrary,

despite the fact that statistical methods are appropriate.

86

The difference in reported treatment effects obtained from

these two studies does not seem to be due to statistical

error. Nevertheless, the lack of statistical analysis in

70% of the cases reported may account for some of the

reported differences.

Summary and Conclusions

Present findings do not indicate that lecithin is an

effective treatment for tardive dyskinesia. Findings

suggest that lecithin has an attenuating effect on dominant

hand finger oscillation for some subjects with tardive

dyskinesia. This suggests that lecithin may have an overall

effect of diminishing the rate at which extrapyramidal

motor outflow influences peripheral motor neurons.

A number of factors which may explain the lack of

treatment effectiveness have been explored. Although most

of the factors discussed are ruled out as plausible consider-

ations accounting for lack of treatment effectiveness,

several variables may be significant. If, indeed, lecithin

is an effective treatment for tardive dyskinesia, it is

possible that the inclusion of subjects with organic brain

syndromes and the short duration of lecithin treatment have

obscured treatment effectiveness. Since subjects with

known central nervous system lesions may manifest irreversible

tardive dyskinesia, lack of responsiveness in these subjects

could have concealed overall treatment effectiveness, but

87

this is doubtful. Because all of these subjects fell into

the older age grouping, statistical analysis would have

partitioned out this subtest of subjects and distinguished

them from younger subjects who were more likely to respond

to treatment. It is unlikely that the inclusion of QBS

subjects contributes significantly to lack of treatment

effectiveness. The short duration of lecithin treatment

may contribute to the lack of treatment effectiveness.

Although previous studies report beneficial effects after

8 days of treatment, continued improvement is reported for

up to 2 months. Longer treatment would likely promote

large, more discernible changes. This issue seems to be

a valid point of criticism of this study.

If, on the other hand, lecithin is actually not an

effective treatment for tardive dyskinesia, several factors

may be responsible for reducing experimental error, and

thereby, demonstrating that lecithin is ineffective in

treating tardive dyskinesia. The double-blind design which

employs both placebo control and no-treatment control groups

considerably reduces experimental error due to subject

expectancies, researcher bias, and baseline variability of

the syndrome. The Simpson Tardive Dyskinesia Rating Scale

reflects precise characteristics of the disorder and

demonstrates reliability of baseline measures. Longer rating

periods are effective in reducing experimental error due to

88

variability of symptom displayed over shorter rating sessions,

By use of appropriate statistical measures, the probability

of drawing erroneous conclusions is greatly reduced.

Another possibility is that lecithin effectiveness is

contingent upon the level of extrapyramidal arousal.

Perhaps, lecithin effects are notable during quiescence, but

not during states of increased extrapyramidal arousal.

These results suggest that during states of increased

extrapyramidal activation, dystonic movements remain

essentially unchanged from baseline measures.

In conclusion, results do not support previous findings

that lecithin is an effective agent in reducing tardive

dyskinesia. Due to the many variables involved in comparing

the results of this study with those reported previously,

a definitive conclusion regarding the efficacy of lecithin

treatment becomes an issue of conjecture which must be

addressed in future research efforts. The findings of this

study raise valid questions regarding the beneficial

effectiveness of this treatment. Hopefully, these findings

will contribute to more realistic evaluations of lecithin

treatment effectiveness and stimulate further investigation

of more effective means of treating tardive dyskinesia.

89

Appendix A

Table 1 Antipsychotic Agents

Commercial Name Generic Name

Phenothiazines: Compazine Etrafon (Triavil) Largon Levoprome* Mellaril Phenergan Proketazine Prolixin (Permitil) Quide Repoise Serentil Sparme Stealzine Thorazine Tindril Torecan Trilafon Vesprin

Butyrophenones: Haldol Innovar*

Thioxanthenes: Navane Teractan

Prochlorperazine Perphenazine and amitriptyline Propiomazine Methotrimeprazxne Thioridazine Promethazine Carpenazine Fluphenazine Piperacetazine Butaperazine Mesoridazine Promazine Trifluoperazine Chlorpromazine Acetophenazine Thiethylperazine Perphenazine Tr i f1uproma z ine

Haloperidol Droperidol

Thiothixene Chlorprothixene

*Not marketed as an antipsychotic (Schiele et al., 19/3)

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O (0 GJ c • H >1 W 0 Q d u • H « •H 0) 4-> 0 u WOE O c fl> 0) P CO d D» o C TJ 'H 0) d p •HOC U • H T» ^ U 0 0 o G to ft to o E w >i C • H <U o r—1 T J W - H c E $-i d >i O 4 0 O *0 •H i—l •o -H 4 U c -p r—1 Q> +J d d to H3 N c d O QiCu • H C « 0 o p <1) 1 50 TJ >i k * H TD H O •H to +» QJ c C CD£ <U • H 4-4 0> •H 3 +i d 4-1 u> D (U d 3 (0 X5 • H 0 oi a> w 0 * H d Q u P S C U C < & I OS

d Q M

o H 00 r-ON ON rH

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«

U * >i U 0 JS 43 QJ C O U 43 G d P O d 43 d P EH 0-I fa w

to d •H W4J to d g Q) -H d G 10 -P •HOW X c o K-H D >*x c T3 W O O •CO (D d) TD •P T3 d OJ 0) "HOC QJ P -H U 13 E G (0 0>-H -p 3 tQ i-l d *H Q ft43 O -H M T 3 4-> 0 I G

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to d •H Q> C •H X 10 >i T3 13 QJ O 3 *0 G •H

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- P

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d

TS <D 43 (0

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P u o •> QJ "0 £ G 3 d c o; .c O O QJ 00 CD b U ON O* (D

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•H P (0 Q P 0) to 6H Q G d v« £H •H •H w8 CO QJ ws to a) C ft G O >i QJ u •H •H •P E JJ O O to 0 QJ M QJ o to

>i d M T3 QJ o to Q Q o QJ G P 0 EH k4 •P >i •O E 4-i to W C O O w» CJ Q •H M •H EH O G T3 to E G •H *H t*. C Q) W O c d rH >i E •H -P QJ 4 rH t0 O G to d M XJ d U O >i-H 43 o o> TJ to T3 to ft O • H c c G •H O -H +J -H >i •H <D 43 N G Q) > CO -P • H d rC QJ H 3 d 43 tJ» +J 43 H 3 to UA: o u W o 0 ft < < w o 0 X M • H CU 2

92

Appendix C

Table 4 Studies Using Physostigmine

in the Treatment of Tardive Dyskinesia

Study Subjects TD Characteristics

Number

Duration of

Age Sex TD

Severity Maximum of Daily TP Dose

Fann, Lake, Gerber 7 & McKenzie (1974)

55-70 1M chronic mild 40 mg/kg i.v. to with meth-

severe scopolamine

Gerlach, Reisby, & Randrup (1974)

44.7 5M 25 N.S. 1 mg i.v. (20-69) months with meth-

(2-96) scopolamine

Klawans & Rubovits 12 55.8 5M (1974) (39-71)IF

N.S. N.S. 1 mg i.v. with meth-scopolamine

Tarsy, Leopold, & Sax (1974)

47-67 6M IF

chronic 1-1.5 mg i.v. with meth-scopolamine

Davis, Berger, & Hollister (1975)

39 1M N.S. N.S. 3 mg i.v.over. 30 min. with

methscopolamine

Davis, Hollister, Barchos, & Berger (1976)

N.S. 4M 3 chronic N.S. (1-2 years) 1 recent (3 months)

3 mg i.v. with meth-scopolamine

Tamminga, Smith, Ericksen, Chang, & Davis (1977)

25-73 3M N.S. moderate 0.5-2 mg to with meth-

severe scopolamine

Moore & Bowers (1980)

10 N.S. 2M at least N.S. 8F 6 months

2 mg i.v. with meth-scopolamine

93

Table 4--Continued

Procedures Data Results

Duration of

Treatment

Design Concurrent of Medications Study

Assessment Measures Analysis

acute reaction (24 hrs.)

all continued open severity

t-test 6 a l b

(signif-icant)

acute reaction

all continued

single blind scopolamine

frequency Wilcoxon & severity test (non-5 a

combined signif-formula icant)

3 b

acute reaction (60 min.)

8 continued 4 off medi-cations

single blind scopolamine performance non- 10a

edrophonium task statis-controls tical

2 b

acute reaction

5 continued 2 off medi-cations

open 0 a 7 b

acute reaction

N.S. open frequency non- 10a

statis-tical

2 b

acute reaction

1 continued 3 off medi-cations

open frequency non-statis-tical

4 a 0 b

acute discontinued reaction 2 weeks

pretrial

double blind neostigmine & methexital controls

severity non-(Smith statis-Scale) tical

5 a 1 b

acute all continued reaction medications

open frequency per 1 min.

5 a 5 b paired t-test (not significant)

Improved

'unimproved

94

Appendix D

Table 5 Studies Using Choline Chloride

in the Treatment of Tardive Dyskinesia

Study Subjects TD Characteristics

Number Acre

Duration of

Sex TD

Severity Maximum of Daily TD Dose

Davis, Berger, & Hollister (1975)

1 39 1M N.S. N.S. 16 gms

Davis, Hollister, Barchas, & Berger (1976)

4 N.S. 4M 3chronic N.S. (1-2 yrs.) 1 recent (3 months)

16-20 gms

Tamminga, Smith, Ericksen, Chang & Davis (1977)

4 45 2M N.S. moderate to

severe

18 gms

Growdon, Hirsch, Wurtman, & Weiner (1977)

20 N.S. 5M stable, N.S. about chronic 13.6 gms

(200 mg/kg)

Gelenberg, 5 27-32 5M chronic mild Dollerwojcik, (1-5 yrs) to Growdon (1979a, b) severe

12-17 gms

Appendix D—Continued 95

Table 5—Continued

Procedures Data Results

Duration of Concurrent

Treatment Medications

Design of

Study Assessment Measures Analysis

8 days N.S. open frequency non- la

statistical 0b

15-21 days 1 continued 3 off medi-cations

open frequency Mann-per 45 Whitney

2 failed test

3a lb

15-21 days discontinued 2 weeks pretrial

open severity non- 2a

(Smith statistical Scale)

2b

14 days 13 continued double with 7 off medica- blind 10-day tions, discon- cross washout tinued anti- over

ACh medication

cL 3D frequency non- 9 11 per 30 statistical

6-8 weeks (42-56 days)

4 continued 1 off medi-cation

open severity (AIMS SCALE)

non-statistical {% change fm baseline)

5a 0 b

Improved

^Unimproved

96

Appendix E

Table 6 Studies Using Lecithin in the Treatment of Tardive Dyskinesia

Study Subj ects TD Characteristics

Duration Severity Maximum of of Daily

Number Acre Sex TD TD Dose

Growdon, Gelenberg, 3 N.S. N.S.N.S. N.S. 40 gms @ 16% Dollerwojcik, 8 0 gms @ 4% Hirsch, & Wurtman 60 gms @ 4% (1978)

Barbeau (1978) 2 N.S. N.S.N.S. N.S. 49 gms @ 20%

Gelenberg, 5 27-32 5M chronic mild 105 gms @ 20% Dollerwojcik, to & Growdon severe (1979a, b)

Barbeau (1979) 4 63.7 1M chronic N.S. 49 gms @ 20% (±5.8) 3F (7.2+2. 1 (±5.8)

years)

Jackson, Nuttall, 6 57 1M N.S. moderate 50 gms @ 70% Ibe, & Perez- to Cruet (1979) severe

Jackson, Davis, 6 57 1M N.S. moderate 50 gms @ 70% Cohen, & Nuttall (49-60) to (1981) (reported on severe same study as Jackson et al., 1979a)

Appendix E—Continued 97

Table 6—Continued

Procedures Data Results

Duration Design of Concurrent of Assessment

Treatment Medications Study Measures Analysis

2 weeks to 2 continued open frequency non- 3a ok 2 months 1 off per 30 sec. statistical (14-60 medication (% change fm days) baseline)

N.S. N.S. open frequency non- 2a 0b

per 5 min. statistical

6-8 weeks 4 continued open severity non- 5a 0b

(42-56 days) 1 off (AIMS statistical medication Scale)

average of N.S. open frequency non- 4a 0b

20 weeks per 5 min. statistical (140 days) avg. max.

final improvement

14 days 5 continued double severity paired 6a ob

with 10 day 1 discontinued blind (AIMS students washout medications cross- Scale) t-test period 2 weeks prior, over signif-

discontinue anti- icant ACh medications

14 days (same as double severity non- 6a ob

with 10 day previous blind (AIMS statistical washout study) cross- Scale) period over

Improved

^Unimproved

98

Appendix F

Information about Lecithin Therapy for Tardive Dyskinesia

Tardive dyskinesia is a well recognized side-effect of a large number of medications used in psychiatric treatment. Tne disorder usually involves involuntary movements in the mouth, face, tongue, or hands. Movements often persist for months to years after the medication which causes the diosrder nas been discontinued.

There is no known treatment for the disorder. However, recent research has suggested that lecithin, a nutrient found in eggs and soybeans, may be a treatment for tardive dyskinesia. This study is being undertaken to investigate the effectiveness of lecithin as a treatment for tardive dyskinesia.

If you participate in this study, you would take an addi-tional medication in the morning tor two weeks. The medication, which will be mixed in a glass of milk, would either be lecithin or another substance which has no effect on tardive dyskinesia symptoms. Neither you, your doctor, nor the experimenter would know which substance you had taken until the experiment is over.

You would also be videotaped four times—once before and once after the study, as well as twice while you were taking the study medication, uach tape will last about 5 minutes. You would be taped here at the hospital and the tapes will toe rated by people assisting in this research. Your identity as a participant would not be revealed in any puDlished or oral presentation of the results of this study. The tapes will be destroyed after they are rated.

The experimental medication may make your tardive dyskinesia symptoms worse, better, or may have no effect at all. The effects of the experimental medication probably will not last after you are no longer taking it. No side effects are expected, but if any occur, you would notify your ward nurse or doctor immediately. All your other medications and therapies would continue as usual. You would be free to withdraw from the study at any time.

The experimenter is available to answer any questions you have about this study and you may also wish to consult your doctor. After the study is over, the experimenter will be

Appendix F—Continued 99

available to tell you wnicn substance you took and to explain the outcome of the study.

In the unlikely event you are injured as a result of participation in this study, the Waco VAMC will furnish medical care as provided oy Federal statute. Compensation for such injury may be available to you under the provis-ions of Title 38, United States Code, Section 351, and/or the Federal Tort Claims Act. For further information, contact the VA District Legal Counsel at 756-6511, ext. 626,

I' certify that the above written summary was discussed and explained fully to me by Lynn A. Price on this date.

Date Subj ect

Witness

Witness

100.

Appendix G

Information about Variability in the Short-Term Re-Evaluation of Symptom Severity

in Tardive Dyskinesia

Tardive dyskinesia is a well recognized side effect of a large number of medications used in psychiatric treatment. The disorder usually involves involuntary movements in the mouth, face, tongue, or hands. Movements often last for months to years after the medications which cause the disorder have been discontinued. Perhaps you have noticed some of these movements in your body.

Because we do not know how you are affected by the extra movements, we are going to be testing some patients in the hospital so that we can find out more about tardive dyskinesia. If you participate in this study, you will be asked some questions about how you have been feeling and whether you have noticed or are bothered by the extra movements that you may have noticed. Also, you will be asked to do a few simple things with your hands to listen and repeat some sounds. If at any time you wish to with-draw from the study, you may do so. If you participate in this study, your identity as a participant will not be revealed in any published or oral presentation of the results of this study. The results will be incorporated in a doctoral dissertation to be deposited in the library of North Texas State University.

If you have any further questions, the experimenter or the staff psychologist will be available to answer your questions,

In the unlikely event you are injured as a result of parti-cipation in this study, the Waco VAMC will furnish medical care as provided by Federal statute. By participating in this program you will not waive any legal rights or remedies available to you, nor will you waive any VA benefits to which you may be entitled.

I, , certify that the above written summary was discussed and explained fully to me by Ms. Lynn Price on this date.

Date Subject

Witness Experimenter

Appendix H

The Simpson Tardive Dyskinesia Rating Scale (Full Scale)

101

Patient

Date

Setting

FACE

1. Blinking of eyes 1 2 3 4 5 6

2. Tremor of eyelids 1 2 3 4 5 6

3. Tremor of upper lip 1 2 3 4 5 6 (Rabbit syndrome)

4. Pouting of lower lip 1 2 3 4 5 6

5. Puckering of lips 1 2 3 4 5 6

6. Sucking movements 1 2 3 4 5 6

7. Chewing movements 1 2 3 4 5 6

8. Smacking of lips 1 2 3 4 5 6

9. Bon bon sign 1 2 3 4 5 6

10. Tongue protrusion 1 2 3 4 5 6

11. Tongue tremor 1 2 3 4 5 6

12. Choreoathetoid movements of the tongue 1 2 3 4 5 6

13. Facial tics 1 2 3 4 5 6 14. Grimacing 1 2 3 4 5 6 15. Other (describe)

1 2 3 4 5 6 16. Other (describe)

1 2 3 4 5 6 NECK AND TRUNK

17. Head nodding 1 2 3 4 . 5 6 18. Retrocollis 1 2 3 4 5 6 19. Spasmodic torticollis 1 2 3 4 5 6

Appendix H—Continued 102

20.

21. 22. 23.

Torsion movements (trunk)

Axial hyperkinesia (copulat

Rocking movement

Other (describe)

24. Other (describe)

CD U <u > CD W (U >i S-i rH <D

(D (1) > -P -P (D -p fd (0 (Q

G CD •0 0) 0) >i to 1—1 S-l •Q •H 0 O (D

a a 2 >

1 2 3 4 5 6

:i 2 3 4 5 6

i 2 3 4 5 6

i 2 3 4 5 b

i 2 3 4 5 6

EXTREMITIES (upper)

25. Ballistic movements

Choreoathetoid movements-fingers

Choreoathetoid movements-wrists

2 6 .

27.

28.

1

1

1

Pill-rolling movements or finger counting

29. Caressing or rubbing face and hair

30. Rubbing of thighs

31. Other (describe)

32. Other (describe)

(lower)

l

1

2

2

2

2

2

2

2

3 4

3 4

3 4

3 4

3 4

3 4

3 4

3 4

5

5

5

5

5

5

5

6

6

6

6

6

6

6

33. Rotation and/or flexion of ankles 1 2 3 4 5 6

34. Toe movements 1 2 3 4 5 6

35. Stamping movements-standing 1 2 3 4 5 6

36. Stamping movements-sitting 1 2 3 4 5 6

37. Restless legs 1 2 3 4 5 6

38. Crossing/uncrossing legs-sitting 1 2 3 4 S 6

39. Other (describe) 1 2 3 4 5 6

Appendix H—Continued 103

40. other (describe)

ENTIRE BODY

41. Holokinetic movements

42. Akathisia

43. Other (describe)

1 2

X 2

3 4

3 4

5 b

5 6

5 6

COMMENTS

104

Appendix I

Self-Report Tardive Dyskinesia Rating Scale

Name

I.D. #_

Date

Pre ( ) Post ( )

Below are listed some feelings which you may or may not have. Read each one carefully then answer by placing a circle around one of the numbers on the right. The meaning of each number is described below.

1.

2,

3.

4.

0 =

1 =

2 =

3 =

4 =

Absent. This feeling or symptom is one which you do not have. Mild or. slightly present. This feeling or symptom may be present but it is so mild that it is difficult to determine whether you really have it or not. Moderate. This feeling or symptom is one that you definitely have. Moderately severe. This feeling is present much of the time. It may prevent you from doing things you would like to do. Very severe. This feeling or symptom is present almost all of the time. It causes you great difficulty in doing the things you would like to do.

My hands and feet feel cold.

I have trouble sleeping.

I have had difficulty eating.

I am aware of lip movements such as smacking or sucking.

+•> G d) w Q (0

0

0

0

a> u

4-> £ a) > D* •H

CD W CD H >i U W H CD CD CD > U 4-> •P CD 0 fd fd W

u u nd CD CD >s i—[ <3 d u

0 0 0 £ e B >

1 2 3 4

1 2 3 4 1 £ 3 4

1 2 3 4

Appendix I—Continued 105

0) <D

5.

6. 7.

b.

9.

•P > rC <D tn U1

*H CD rH >i U W rH (D

CD CD > U -P •P <D

•p o m rd CO £ u u CD CD CD > i CQ HI nS U

sx •H 0 O CD rd S e 6 >

I wake up feeling tired in the mornings.

I have a poor appetite.

I feel that I can't control some of my movements.

Movements in parts of my body annoy me.

0

0

0 My speech is affected by uncontrollable movements of my mouth.0

10. I am troubled by constipation. 0

11. I have had attacks of nausea and vomiting lately. u

12. I am troubled by uncontrollable movements which interfere with what I am trying to ao. 0

13. I am troubled by hand movements when writing. 0

14. I become distracted by uncontrollable movements when I am watching T.V. or reading so that I lose track of what 0 is going on for a moment.

±5. I am bothered by stomach acid. 0

±6. Swallowing is difficult for me. 0

17. My physical health is a s good as tnat of most of my friends. o

18. i am bothered by pains over the heart and in my chest. 0

1

1

1

1

1

1

2

2

2

2

A

2

2

2

3

3

3

3

3

3

4

4

4

4

4

4

1 2 3 4

1 2 3 4

1 2 3 4

1 2 3 4

Appendix I—Continued 106

CD u 0)

4-> > & CD t n CO

*H 0) r—{ u CO rH Q)

CD <D U - p • P 0)

4-> 0 (0 rd CO a u u 0) CD Q) > 1 CO i H * 0 u

XX - H O 0 0) (0 £ £ S >

19. My chewing is affected by the uncontrollable mouth movements. 0 i 2 3 4

20. My breathing is affected by sudden movements in my body. 0 1 2 3 4

21. Parts of my body often have feelings like burning, tingling, or crawling, or like going to 0 1 2 3 4 sleep.

22. I have had difficulty in starting

or holding my bowel movements. 0 1 2 3 4

23. I have trouble walking. 0 1 2 3 4

24. Movements which I cannot control

make me self-conscious. 0 1 2 ^ 4

25. I feel pain in the back of my neck. 0 i 2 3 4

26. I am troubled by discomfort in the pit of my stomach. 0 1 2 3 4

27. I have trouble with my muscles twitching or jumping. U 1 2 3 4

28. There seems to be a fullness in my head or nose. 0 1 Z 3 4

29. I have noticed a change in my walking rhythm or gait. 0 1 2 3 4

30. X feel that other people act differently towards me because of my uncontrollable movements. 0 1 2 3 4

.51. I have difficulty in keeping my balance. 0 1 2 3 4

3.2. I have noticed uncontrolled move-ments in one or both my arms. 0 1 2 3 4

Appendix I—Continued 10?

33. I stroke or rub my face or hair

CD &-I 0)

- P > rG a>

w -H <D H > i to r~i <D

<D 0) > Ul •P • p 0)

- p 0 fd rtf 01 £ k a> TJ cu 0) > i (0 1—i Tf "O & H o O <u fd E E g >

without meaning to do it. 0 1 3 4

34. ± feel as if there were a tight band about my head. u 1 2 3 4

35. I have stomach trouble. 0 1 2 3 4

36. I have vomited blood or coughed up blood. 0 1 2 3 4

37. During the past few years I have not been well. 0 ± 2 3 4

38. I am troubled by movements of my eyelids or eyebrows. u 1 2 3 4

39. My fingers seem to move about more now than they used to. 0 1 2 3 4

40. I seem to be gaining or losing weight. 0 1 2 3 4

41. The top of my head sometimes feels tender. 0 1 2 3 4

42. I seem to tire quicKly. 0 1 2 3 4

43. I have dizzy spells. 0 1 2 3 4

44. I have noticed unnecessary movements in my jaw. 0 1 2 3 4

45. It is difficult for me to sit or stand still. 0 1 2 3 4

4b. When I read my eyes seem to tire easily. 0 1 2 3 4

47. I feel weak all over. 0 1 2 3 4 48. I have headaches. 0 1 2 3 4

49. My hands seem to fidget when I'm not doing anything with them. 0 1 2 3 4

Appendix I—Continued 108

0 M 0)

4-> > r C CU Cn CQ *ri 0 ) t—I >i u w i—f CD

CD Q> P> u • P - P CD 0 rd rd W

u M 0) Q) >i

- i *0 u - H o O CD £ e £ >

-p c <D w A nJ

50. I am troubled by the uncontrolled

movements in parts of my body. 0 1 2 3 4

51. At times X feel like swearing. 0 1 2 3 4

52. I notice my heart pounding and shortness of breath, 0 1 2 3 4

53. I get angry sometimes. U 1 2 3 4

54. I have noticed that I cross and uncross my legs while sitting more than most people do. 0 1 2 3 4

55. I dislike some people. 0 1 2 3 4

b6. If I don't feel well, I sometimes

become cross. 0 l 2 3 4

57. My body hurts all over. . 0 1 2 3 4

58. I have movements in my body wnich are difficult for me to control. 0 1 2 3 4

59. I have numbness in one or more

regions of my skin. 0 1 2 3 4

60. Sometimes I feel hate for someone, 0 i 2 3 4

61. I am annoyed by the unnecessary movements in my body, 0 i 2 3 4

62. I notice my ears ringing or buzzing. U i 2 3 4

63. I am annoyed by unnecessary movements in my face. 0 1 2 3 4

10.9

Appendix J

Speech Sounds Perception and Articulation

Name

I.D.#

Date

Pre ( ) Post ( )

Score

1.

2. 3.

4.

5.

6.

7.

8. 9.

10. 11. 12.

13.

14.

15.

16. 17.

18.

19.

20,

Theeks

Weej

leeg

teest

freeb

preeb

sheecti

neek

wheesh

preet

preem

f eez

sheez

veeth

theela

preet

teep

steeks

preet

zeend

21. 22. 23.

24.

25.

2 b.

27.

28.

29,

3u.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

deeld

weef

theer

meeld

seet

heek

meem

theer

heez

theep

wheep

keem

neek

sheem

theep

wee Id

teed

theez

weev

leeng

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

b4.

b5.

56,

57,

58,

59,

60,

sheen

geerd

geen

weeng

teed

teets

zeet

beet

teer

deeb

heem

theer

feeth

reek

yeed

deet

deez

teeld

meer

wheem

110.

Appendix K

Compositional Data on Lethicon

Phosphatidyl Choline 51 - 55 Phosphatidyl Ethanolamine 19 - 22 Monophsphatidyl Inositol 1 - 3 Lysosphosphatidyl Choline-Lysophosphatidyl Ethanolamine 2 .5 . 3

Phosphatidic Acid 2 .5 - 4 N-Acetyl-Phosphatidyl Ethanolamine 3 — 4 Glyceryl Phosphoryl Choline 0 .5 -

Free Fatty Acid 1 - 2

Sterolglycoside esters b — 7 Sterolglycoside 0 .5 - 1 Free Sterols 1 — 2 Monodiglyceride 0 .5 — 1 Triglyceride 2 - 3 Moisture 1 — 1.! Ethanol 0 .3 — 0.' D-Alpha-Tocopherol 0 .1 — o.;

% % %

% %

°/ /o

°/ 7o

°/ so

%

%

Ill

Appendix L

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112

Appendix M

to e 0 P M *0 O u o u CQ 0 U-l H 0 (0 u u w

0 £ D> £ G P *H 2 «P fO rH Ctf ro -P nj 0 *H t-i W a

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Appendix N

113

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G G HJ G •H *H o u A; rH <0 « > J>I G O Q rH u JQ G fO 4-1 > H 0 *H "0 IQ U *h rd to e-i >1 rH P rd G Q < ft

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•P c to c •Hi £ 0 Q

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117

Appendix R

a fij Eh

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118

Appendix S

U O -P W 0 0 Eh U G G r0 O •H -H U -P its ro > '—! O P O 04 -H M-i G 1—1 O ro S 0) w

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119

Appendix T

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120

Appendix U

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Appendix V

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122

Appendix W

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123

Appendix X

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124

Appendix Y

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125

Appendix Z

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b

126

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