Dyskinesias and their treatment with essential fatty acids: a review

Prostaglandins, Leukotdenes and Essential Fatty Acids (1996) 55(1 & 2), 89-94 © PearsonProfessionalLid 1996

D y s k i n e s i a s and t h e i r t r e a t m e n t w i t h e s s e n t i a l f a t t y acids: a r e v i e w Krishna Vaddadi Clinical Research Unit and Movement Disorders Clinic, Maroondah Hospital, Mt Dandenong Road, East Ringwood, Victoria 3135, Australia.

INTRODUCTION

Dyskinesia means 'abnormal movement'. Terms like dyskinesis and hyperkinesia are used rather loosely by clinicians. Tremor, chorea, tic, myoclonus and dystonia are all abnormal movements. Movement disorders are frequently a complication of drug therapy. Dyskinesias induced by levodopa in Parkinson's disease and neuroleptic induced tremor are examples. This paper will focus on tardive dyskinesia and Huntington's disease in relation to essential fatty acid therapy. Essential fatty acids play important structural and functional roles in neurons, yet there is very little scientific literature in the field of essential fatty acids and prostaglandins in relation to dyskinesias. ESSENTIAL FATTY ACIDS

Neurons are surrounded by plasma membranes and these membranes have an important role in regulating neuronal activity. In membranes, which are largely composed of phospholipids and cholesterol in various forms, are embedded various proteins such as receptors, ion channels, enzymes and components of second messenger systems. Essential fatty acids (EFAs) are polyunsaturated fatty acids and must be taken in the diet as the body cannot make them? There are two types of EFAs, the n-6 series derived from linoleic acid (18: 2, n-6) and n-3 series derived from alpha-linolinic acid (18: 3, n-3). EFAs constitute approximately 20% of the solid matter in the brain? They have two major roles: in forming the structure of the cell membrane and in the biosynthesis of a variety of short-lived derivatives such as eicosanoids, prostagwlandins (PGs) and leukotrienes. They confer on membranes properties of fluidity and flexibility and modulate receptors, ATPases and ion channels. A number of studies have shown that non-esterified or 'free' forms of fatty acids regulate ion channels.3,4 PGs modulate nerve Correspondence to: K. Vaddadi

conduction, neurotransmitter release and post-synaptic transmitter release and post-synaptic transmitter actions? EEAs are characterized by the presence of several double bonds in the carbon skeleton. This confers a considerable degree of instability to the molecule. EFAs are rapidly oxidized in the presence of oxygen with the formation of lipid peroxides and toxic free radicals and they are protected by the body's own deactivating systems. A major defence of the cell against free radicals and other oxidative damage includes the antioxidant vitamins, such as alpha-tocopherol and ascorbate, enzymes, such as catalase and superoxide dismutase, and compounds such as glutathione.5,16 Alpha-tocopherol (vitamin E) is lipid soluble and concentrated in the cell membrane. The role that EFAs and PGs might play in dyskinesias has not been adequately researched and has not received the merit that it probably deserves. For example, phospholipids and cholesterol esters in cell membranes provide a framework for receptors. Chorea can be induced in healthy women by oral contraceptives which resolves after withdrawal or fluctuates with the menstrual cycle. Estrogen administration has complex effects on dopamine transmissionY There is evidence to suggest that fatty acids regulate in vivo some steps of the steroid hormone message.8 These complex interactions in the mesostriatal and mesolimbic dopamine system and with estrogen might well be primarily related to the changes or abnormalities of EFAs and PG production in these areas where receptors are situated, rather than due to the direct effect of estrogen on dopamine transmission. This indicates the importance of studying fatty acids in the cell membranes as they effect the function of the receptors. Studies on the effects of EFAs and PGs on dyskinesias

Phospholipid abnormalities in the membranes were first reported by Stevens in 1972.18 Abdulla et a112found that platelets from schizophrenic patients were severly defective in their ability to make PGE1 when stimulated with 89

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ADP. Horrobin first suggested that a deficiency of prostaglandins (PGE~) may play an important role in the pathogenesis of schizophrenia based on some empirical observations/4 He suggested that resistance to pain and rare occurrence of rheumatoid arthritis in schizophrenia might well be explained by reduced PGE1 production. Therefore attempts were made the raise PGE~ synthesis in the brains of schizophrenic patients by giving penicillin which stimulates PG formation2' and by supplementing their diet with essential fatty acids and penicillin. 2° Some therapeutic success was reported in these early studies. During these studies the author of this article (KSV) first made observations that when schizophrenic patients who developed tardive dyskinesia were given EFAs to improve their mental state there was a significant reduction in their neuroleptic-induced abnormal involuntary movement called tardive dyskinesia.TD Patients with tardive dyskinesia have by definition been exposed to at least three months of neuroleptic medication and exhibit stereotypic repetitive pursing, chewing, smacking orofacial and choreoathetoid tongue movements. There can be abnormal movements in other parts of the body such as in limbs, muscles of respiration, etc. 22 Sometimes these movements can be irreversible. Supersensitivity of post-synaptic dopamine receptors due to up-regulation induced by neuroleptic receptor blockade has been postulated to play a role in the development of tardive dyskinesia. This is supported by the superficial similarity between tardive dyskinesia and levodopa-induced dyskinesias in idiopathic Parkinson's disease. However, the exact mechanism of TD is not known. Not all patients who take neuroleptics develop TD and only in a small proportion of patients does TD become irreversible. Damage to the neuronal membrane through free radical generation has been postulated.23,24 However, a recent study by McCreadie and others suggests increased free radical activity in schizophrenia but no differences were found in patients with or without TD in their lipid peroxide levels and vitamin E levels.25 The initial empirical observation of the therapeutic role of EFA in reducing tardive dyskinesia led me to some animal model experiments of tardive dyskinesia. Animal model studies of EFAs, PGs ans dyskinesia

The effect of 2-(N,N-dipropyl)amino-5,6-dihydroxytetraline (tetralin) in inducing perioral movements in guinea pigs has been suggested as a suitable model of dyskinesia.26 These movements induced by tetralin consist of repetitive head movements, oro-facial grimacing, tongue protrusion, etc. Using this model we were able to demonstrate that essential fatty acid-treated guinea pigs by intraperitoneal route showed significantly reduced perioral movements induced by tetralin. Essential fatty acid treat-

ment completely abolished tongue protrusion and there was a reduction in grimacing and munching behaviour. These were small but significant changes.27 Costall, Kelly and Naylor28 studied the antidyskinetic action of dihomo-gamma-linolenic acid (DGLA)in the rodent model of dyskinesias that were induced by tetralin and dopamine. They were clearly able to demonstrate the antidyskinetic effect of DGLA when injected into the straium of the rat of given in the diet. Dopamine and tetralin-induced dyskinesias in guinea pigs were abolished or reduced by DGLA given intraperitoneally. Aspirin, by inhibiting cyclooxygenase enxymes, inhibited the antidyskinetic effect of DGLA. The authors suggest that incorporation of DGLA into lipid membranes and conversion to PGs as the possible mechanism of action. These important animal model results led us to do some clinical studies. Human studies of EFA supplementation and dyskinesias

Kaiya15 in open studies in schizophrenic patients used intravenous PGE1 to improve their mental state. He noticed the disappearance of drug-induced extrapyramidal symptoms. A double blind placebo-controlled study of essential fatty acid supplemantation in a group of psychiatric patients with tardive dyskinesia was conducted in the UK) ° We used Efamol evening primrose oil capsules. Each capsule contains linoleic acid (360 rag) and gamma-linolenic acid (45 mg), and vitamin E (10 IU) is added as an antioxidant. A group of psychiatic patients, primarily schizophrenics (81.3%), who exhibited abnormal involuntary movements were given either active Efamol or placebo for a period of 16 weeks with a cross over at the end so that patients who received active Efamol first were given placebo capsules and those who received placebo capsules first were given active Efamol for a further 16 week period. At the end of the final 16 week period all patients entered an open phase of the trial for 4 weeks and they were given active Efamol. In addition they were also given Efavit tablets, containing ascorbic acid (125 rag), pyridoxine hydrochloride (25 mg), nicotinic acid (7.5 mg) and zinc sulphate (4.4 rag). These micronutrients are known co-factors in the metabolism of EFAs to prostaglandins. RBC fatty acid analysis was done. Table 1 shows the mean values of RBC membrane EFA levels in phospholipids of these patients. All patients had values of RBC membrane c/s-linoleic acid (n-6 series) below those of normal controls and patients who had severe tardive dyskinesia as assesed by abnormal involuntary movement scale (total AIMS greater than 12) had the lowest values of n-3 and n-6 series EFAs

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Dyskinesias and their treatment with essential fatty acids: a review 91

Table I M e a n values of RBC m e m b r a n e EFA levels in phospholipids

n--3 series (mean + SD) Severe tardive dyskinesia (total AIMS 12) n = 14, mean age = 50.3 years M o d e r a t e tardive dyskinesia (total AIMS 1 0 - 1 2 ) n = 11, mean age = 52.4 years Mild tardive dyskinesia (total AIMS <10) (n = 12, mean age = 50.9 years Psychiatric controls n = 17, mean age = 43.1 y e a r s Normal controls n = 20, mean age = 52.3 years

n-6 series (mean + SD)

4.41 + 4.39 a*,b,c 9.12 + 7.14 a*,b*

7.37 + 5.02 a

14.03 + 8.19 a*

8.37 + 4.48 a

14.50 + 7.28 a*

7.72 + 4.62 ~

16.00 + 7.28 ~

11.17 + 1.74

22.00 + 2.42

a M e a n significantly lower than normal control, P < 0.05; a,p < 0.01. b Mean significantly lower than psychiatric control, P < 0.05; b*P < 0.01. c M e a n significantly lower than mild tardive dyskinesia, P < 0.05.

when compared to psychiatric control patients without TD and normal controls. Since 81.3% of these patients had schizophrenia the results suggest a close association between schizophrenia, tardive dyskinesia and EFA levels. Supplementation with EFA alone did not improve TD in this study but produced a significant improvement in Weschler memory scale scores of these patients. However, addition of micronutrients in the final open phase of the trial to Efamol caused improvement in movement disorder and in Weschler memory scale scores. The relative failure in this trial of EFAs in improving movement disorder could be due to low dosage, inadequate length of the trial and chronicity and irreversibility of tardive dyskinesia. In a group of 16 male patients with tardive dyskinesia who were given 600 mg of gamma-linolenic acid in a double blind trial, Wolkin and others 31 found no significant effect of gamma-linolenic acid in reducing movement disorder rating scale scores. Short duration of trial and small numbers make the drawing of definite conclusions difficult. A study was conducted by Vaddadi and others 33 in Australia of 72 patients with the diagnosis of schizophrenia and schizoaffective disorder to examine the relationship between tardive dyskinesia, mental status and RBC membrane and plama fatty acids. These patients were clinically assessed and rated in 1987-1988 and followed up again four and half years later, 1992-1993. The only consistent findings were that lower levels of RBC membranes linoleic acid (LA) and higher levels of dihomogamma-linolenic acid characterized the patient population compared with controls. There was a considerable variability in patients EFA profile over time. However, we found a considerable stability in linoleic acid levels in our © Pearson Professional Ltd 1996

normal sample over a four and a half year period. The LA to DGLA ratio appears to be reduced in schizophrenics as a group and somewhat more so in patients with tardive dyskinesia. DGLA was elevated in both RBC and plasma on both measurement occasions. Accumulation of DGLA in the RBC membranes might reflect an impaired metabolic pahtway from DGLA to PGE1. Reduced platelet production of PGE1 when stimulated with ADP has been reported? 2 Evidence for a subsensitivity of PGE~ receptors has also been reported? 4 This subsensitivity could also lead to DGLA accumulation as it is a PGE~ precursor. Plasma EFA levels have been reported to be lower in schizophrenic patients from different geographic locations such as England, Ireland, Scotland and Japan. lz37'3s The considerable stability of linoleic acid levels in our normal samples levels over a long period of time and lowered levels of LA in schizophrenic patients across the different geographic locations make dietary factors as an explanation for these findings very unlikely. Some studies suggest that phenothiazines can inhibit the incorporation of fatty acids into cholesterol esters) 5 although there is no evidence that drug therapy is associated with changes in EFA levels in psychiatric patients. 33,36,39 Our own unpublished data looking at the relationship between neuroleptic medication dosages and EFA levels in RBC membranes do not support the hypothesis that the changes in EFA levels observed are related to medication effects. In another study, RBC membrane fluidity was not found to be effected by haloperidol treatment but decreased fluidity correlated with increased psychoses. 29 Horrobin and others 4° have shown that fatty acids in the phosphotidylethanolamine (PE) fraction of frontal cortex scrapings of autopsy brains from schizophrenic patients showed below normal levels of 18 and 20 carbon fatty acids with some compensation from very highly saturated 22 carbon EFAs. The abnormality was localized to the cortex and not observed in the cerebellum. The prevalence of TD in schizophrenic patients on neuroleptics is approximately 13.9%. The interesting observations of membrane lipid abnormalities in schizophrenia and tardive dyskinesia are indicative of the need for long-term clinical trials of EFAs in patients treated with neuroleptics. HUNTINGTON'S DISEASE - A ROLE FOR ESSENTIAL FATTY ACIDS

Huntington's disease is an autosomal dominant neuropsychiatric disorder for which there is no known definitive cure. Dopamine receptor blockers such as haloperidol are most commonly used to control chorea and associated behavioural disturbances. I here report clinical improvement in chorea and cognitive functioning in a woman with Huntington's disease, who was treated

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with essential fatty acids in addition to haloperidol. The patient is a Caucasian woman born in 1912 and has 12 children and several grandchildren. She was referred to our Movement Disorders Clinic by her general practitioner as her movements were worsening. She was living in a nursing home. She had been having unsteady gait and several falls over the past 13 years. In 1991, the geriatrician felt she had short-term memory deficits, recall deficits and a lack of insight into her problems. In addition, she was also disgnosed as having non-insulindependent diabetes mellitus and arthritis of the spine. She walked with a wide-based unsteady gait. In 1992, she was seen by a consultant physician, whose clinical impression was early dementia with athetoid movements and some degree of cerebellar degeneration. She was non-compliant with diabetes mellitus treatment. In 1992, she sustained a hip fracture following a fall and was hospitalized, and then seen by a neurologist, who suspected that she had Huntington's Disease. She was commenced on haloperidol, which continued until December 1993. She became depressed and suicidal and was taken off the haloperidol, but her chorea and speech became worse, and she was recommenced on haloperidol six weeks later and continued ever since. The continuation of haloperidol was reported by her daughter, although clear documented evidence of the dates of drug therapy was difficult due to poor documentation and nursing home notes. According to her daughter even when she was on a regular dose of haloperidol (0.5 mg), she had abnormal involuntary movements with impaired speech. She was referred to our Clinical Research Unit & Movement Disorders Clinic on the 13 April 1994, for treatment of chorefform movements. She had received 1 mg of haloperidol daffy, that had been discontinued, according to the notes from her general practitioner nursing home notes, but the dangther believed that it was being given. Her medication at that time was: Clonazepam Temazepam Dothiepin

0.5 mg twice daffy 10 mg nocte 50 mg nocte

From the history we obtained, her father died at age 78 years, but had no dementia or chorea. Her mother died at age 48 years from a stroke. One sister died having developed dementia and her son died at age 56 of a brain tumour. Her two daughters and one son have recently been genetically tested and are positive for Huntington's disease. She was assessed by myself [KSV] and the clinic's Neurologist [JM]. She was in a wheelchair, with severe abnormal movements of the trunk, the neck the upper limbs and had marked dysarthria, with the movements so severe that she was unable to sit even in the wheelchair. She could tell her age, but was unable to tell us the

day, date or year. She was thought to have Huntington's disease with severe cognitive impairment or Alzheimer's disease with severe chorea. Due to the exposure to neuroleptics, a possibility of tardive dyskinesia was also considered. Initially her medication was commenced on haloperidol 0.25 mg mane and mianserin 10 mg nocte; the dothiepin was stopped. She initially responded with some reduction in her abnormal movements, but the movements became severe and the haloperidol was increased to 0.5 mg twice daily. Due to her age and severe debilitated condition and the severity of her movement disorder, a CT scan of the brain could not be performed. DNA test for Huntington's disease was positive. The number of CAG repeats observed were 16 and 41 for two alleles. In addition to haloperidol 0.5 mg twice daily, she was also commenced on gamma-linolenic acid (45 mg per capsule x 8 capses were given orally). She was then seen again in September 1994, as her daughter reported that after starting her on gamma-linolenic acid supplementation, for approximately 8 weeks, there was a marked noriceable reduction in her abnormal involuntary movements and some memory improvement (we did not do any specialized neuropsychological testing at baseline due to the severity of her condition and her inability to participate in any testing). She was, however, video-taped at baseline. This marked improvement in her abnormal involuntary movements, some improvement in speech, general improvement in her memory and interaction with other relatives has been meintained some 19 months later. She has also gained weight and no deterioration in her condition has taken place. There is a marked improvement reported by the patient herself, and this improvement is confirmed by both her daughters who visit her regularly in the nursing home. Her abnormal involuntary movements were video-taped on three subsequent occasions and the tapes were rated blindly by a Consultant Neurologist, who had not seen this patient before, and he rated the pre- and post-treatment tapes on global severity of chorea and again noticed a marked improvement of chorea. This patient had take haloperidol in the past, according to her daughter, and the abnormal movements continued. However, the addition of gamma-linolenic acid, in our opinion, has made a sustained and remarkable improvement over 19 months. The exact mechanism of action of EFAs in improving and arresting clinical deteriortion that would have been otherwise been expected in this patient is open to speculation. Neuroleptic drugs are often used in Huntington's disease (HD) to treat chorea and behavioural disturbance. However, evidence that neuroleptic drugs favourably infulence the course of HD is lacking. 13,41 There are reports that as the functional capacity of patients worsens in HD chorea seems to lessen and dystonia intensifies.

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Dyskinesias and their treatment with essential fatty acids: a review 93

However, in this patient there was a marked reduction in chorea and some objective and subjective improvement in her functioning. Essential fatty acids are important for m e m b r a n e structure and exert a wide range of actions at second messenger levels. 42 Receptor proteins behave differently when embedded in saturated or unsaturated fatty acids. Both n-3 and n-6 series polyunsaturated fatty acids are essential to maintain the normal dopaminergic function in the cat caudate nucleus? 2 Excitotoxicity involving amino acid neurotransmitters has been implicated in the pathogenesis of HD. 9-]1 Under certain conditions the NMDA receptor will open and admit b o t h sodium and calcium. Glutamate is normally compartmentalized in presynaptic terminals. Release of glutamate into synapses will result in the activation of excitatory amino acid receptors. Large excess of calcium entering into the cells by excessive activation of NMDA receptors may cause cell death. Arachidonic acid (AA) is a major second messenger at the NMDA receptors. It has been shown that the NMDA receptors of cerebral granule cells are modulated directly by AA.43 Changes in the availability of essential fatty acids and AA will have an important influence on the functioning of NMDA receptors. Evidence of selective loss of striatal NMDA receptors in the post m o r t e m brain of patients who died rather early with HD has been reported. In HD there is a selective loss of NMDA receptor containing neurons in the striatum with relative sparing in the hippocampus. ]3 It has been suggested that whatever the cause, improper availiability of EFAs to maintain the neuroarchitecture and physiological functioning would lead to an impairment in the functioning of NMDA receptor in HD and produce neurodegneration through excitotoxicity. Selective abnormalities in EFA metabolism in different areas of the brain might lead to selective loss of NMDA receptorcontaining neurons. Additionally it can also be conceptualized that through an unknown mechanism, a rapid loss of structural lipids in certain parts of the brain m a y occur in HD; therefore it is suggested that replacement of these EFAs by free fatty acids through supplementation may normalize the fatty acid pool and prevent this neurodegeneration. There is now evidence for a substantial phenotypic variation in HD. 44 It is therefore tempting to suggest that a subgroup of late-onset HD patients m a y respond to EFA supplementation in addition to a very low dose of haloperidol. CONCLUSION

RBC m e m b r a n e abnormalities have been observed by several researchers working independently in the field of schizophrenia. The prevalence of TD in neuroleptictreated schizophrenic patients is approximately 13.9%. We have been able to show that there are RBC m e m b r a n e © Pearson Professional Ltd 1996

EFA abnormalities in schizophrenic patients without TD, and slightly more so in schizophrenic patients with TD. Therefore further research in this area of movement disorders and membrane lipid abnormalites is needed. Clinical improvement in HD with LA and GLA supplementation is a novel finding and the involvemnt of NMDA receptors and EFAs has been discussed. It has also been suggested that in individuals at early stages of HD or individuals at risk of developing HD, if given EFAs probably of both n-6 and n-3 series on a long-term basis might delay the onset of HD. However, this is highly speculative at this stage. We are currently conducting a double blind placebo-controlled trial of Efamol in HD subjects in Australia.

ACKNOWLEDGEMENTS

I would like to thank Mrs Efleen Soosai (research nurse) and Mr Gantam Vaddadi (medical student) for their help.

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