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1992.
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NEUROLEPTIC-INDUCED MOVEMBNT DISORDERS AND BODY IRON STATUS PERMINDER SACHDEV Neuropsychiatric Institute, The Prince Henry Hospital University of New South Males, Sydney, Australia (Final form, July 1991) Contents 1. 2. 2.1. 2.2. 2.3. 2.4. 3.
Abstract Introduction Brain Iron Dysfunction and the NIMD Tardive Dyskinesia Drug-Induced Parkinsonism Akathisia Neuroleptic Malignant Syndrome Conclusions Acknowledgements References
641 641
649 650 650 650 651 651 651 651
Abstract Sachdev, Perminder: Neuroleptic-Induced Movement Disorders and Body Iron Status. Prog. Neuro-psychopharmacol. & Biol. Psychiat. 1992, 1615): 647-653. 1.
2. 3.
The distribution of iron in the human brain, what is known about its biological functions, and the interaction of neuroleptics with iron suggest that this trace metal may play an important role in the pathogenesis of neuroleptic-induced movement disorders (NIMD). The availability of magnetic resonance imaging has made some of the hypotheses testable in human subjects. This article is a brief overview of the current literature on the association between NIMD and brain iron.
akathisia, drug-induced parkinsonism, iron, neuroleptics, Keywords: neuroleptic malignant syndrome, tardive dyskinesia. blood brain barrier(BBB), dopamine (DA), gamma-aminobutyric Abbreviations: acid (GABA), iron deficiency (ID), magnetic resonance imaging (MRI). monoamine oxidase [MAO), neuroleptic-induced movement disorder (NIMD), neuroleptic malignant syndrome (NMS), serotonin (S-HT), spin-spin relaxation time (T2), tardive dyskinesia (TD).
l.Introduction Iron has recently received increasing attention for its possible etiological role in the development of neuroleptic-induced movement disorders (NIMD) Iron is the most abundant metal in the human body for a number of reasons. (Pollitt and Leibel, 19821, and its concentration in the brain is relatively high, being about one-quarter that in the liver, the principal storage organ (Hallgren and Sourander, 1958; Hoeck et al, 1975). It is unevenly distibuted in the brain, being highest in the globus pallidus, followed by the red 847
848
P.Sschdev
nucleus, subs tantia nigra pars reticulata, putamen and dentate nucleus (table 1) (Hallgren and Sourander, 1958). In the globus pallidus, its concentration is comparable to that in the liver. This morphological distribution is important for two reasons: i) the organs with high concentrations have a demonstrated role in the pathogenesis of movement disorders, and ii) these areas of the brain have a-high-content of dopamine (DA), gamma-aminobutyric acid (GABA), serotonin (SHT) and neuropeptides (Hill, 1988), neurotransmitters important in movement disorders and psychiatric illnesses. Table
1
The distribution of non-heme iron in human brain (autopsy data. age 30-100 years) * Organ
Iron content Mean (*SD) mg/lOOg fresh weight 21.3 19.5 18.5 13.3 10.4 9.3 3.8 3.6 2.9 1.4 1.0 13.4
Globus pallidus Red nucleus Substantia nigra Putamen Dentate nucleus Caudate nucleus Parietal cortex Cerebellar cortex Prefrontal cortex Medulla oblongata Meninges Liver * adapted from Hallgren and Sourander,
(k3.5) (k6.9) (k6.5) (k3.4) (k4.9) (k2.1) (kO.7) (20.9) (to.4) (&1.2) (*o-3) (29.4)
1958.
Recent findings on the biological role of iron in the body suggest that morphological distribution of iron may not be without a reason. IrOn is associated with many enzymes involved in the metabolism of neurotransmitters. Monoamine oxidase (MAO) is associated withiron, although the exact nature of the association is uncertain (Oreland, 1971). Iron deficiency (ID) leads to an increased concentration of brain 5HT and other 5-hydroxyindole compounds in animal studies (Mackler and Finch, 1982), while the concentrations of GABA and the excitatory glutamate are decreased (Tanjela et al, 1986). In addition to its metabolic role, iron is important for the dopamine D2 receptor function,. Evidence from a number of sources suggest that ID leads to a subsensitivity Of D receptors (Ashkenazi et al, 1982; Youdim et al, 1983). Iron may be part O$ the receptor site. or alternatively important for the formation of D2 protein or the confirmation of the membrane (Youdin et al, 1986). Increased iron, on the other hand, due to a direct injection of FeC13 into the brain, ID can disrupt the leads to the development of D2, receptor supersensitivity. blood-brain barrier(B%%) and, In addition, alter the content of proteins in some areas of the brain. A further important role for iron is as a catalyst The basal gangalia in oxidation, hydroxylation and peroxidation reactions. and the hippocampus are particularly susceptible to iron-mediated lipid peroxidation (Czernansky et al, 1983). Iron also promotes the generation of hydroxyl radicals, with their associated toxicity, from hydrogen peroxide. Alongside the increased knowledge of the biological functions of brain iron, it has become known that ID is not uncommon even in developed countries (Hallberg et al, 1979). It is also recognized that ID may affect tissue functions before or in concert with decrease in hemoglobin production (Pollitt and Leibel, 1982). Since the turnover of brain iron is low, the brain resists depletion, matched by a reduced rate of repletion upon therapy (Dallman et al, 1975). The BB% protects the brain against the acquisition of excess iron (Youdim etal, 1989). Iron overloading of the body, as occurs in hematochromatosis, does not lead to iron overloading of the brain. For the above reasons, serum iron status may not be an accurate reflection of brain this
Neuroleptlc-inducedmovcmentdlsorders
649
Several studies have suggested that magnetic resonance imaging (MRI) iron. Particles of iron may be useful in the evaluation of brain iron in vivo. and iron storage compounds (ferritin and hemosiderin) reduce T. relaxation while producing little effec f on Th (Drayer times of the surrounding tissues, While the form of iron that is responsible for T2 sho tening et al, 1986). point to the potential for the is debated (Chen et al, 1989), most reports use of MRI to study brain iron. Table 2 BIOLOGICAL
1.
Catalytic
A.
role
FUNCTIONS
in enzymatic
Tricarboxylic
cycle
succinate
OF
BRAIN
IRON
processes
enzymes:
dehydrogenese*
aconitase* B. Oxidative e.g. C. Amino
phoyphorylation
cytochrome acid
and
enzymes:
oxidase
C*
neurotransmitter
metabolism
enzymes: Phenylalanine Monoamine Aldehyde
hydroxylase*
oxidase
(MAO)*
oxidase
Aminobutyric Glutamate
acid
transaminase
dehydrogenase
receptor
2.
Effect
on D2
3.
Effect
on other
function
neurotransmitters:
GABA 5HT Opiate-peptides
4.
Role
in peroxidation,
oxidation
and
hydroxylation
reactions
5.
Other
possible i) Role ii)
*brain enzyme (Pollitt and
Role
functions
(not
in protein in maintenace
levels remain Leibel, 1982)
established):
synthesis of blood-brain
unchanged
in iron
barrier deficiency
2. Brain Iron Dysfunction and NIMD Support for the role of iron in NIMD comes from several sources. The relationship of iron with the DA receptor, GABA and neuropeptides, and its involvement in the metabolic pathways of neurotransmitters make this role likely. The possible significance of iron for Parkinson's disease(Jenner, 1989) further suggest such a role. There is increasing evidence that neuroleptics influence ferrokinetics, and this may be relevant for their
650
P. Sachdcv
beneficial and toxic effects (Rajan et al, 1974). directly examined the iron status of patients with
Finally, NIMD.
some
studies
have
2.1. Tardive Dyskinesia(TD) Indications for the possible role of iron in TD were first provided bv the Hunter et al (1968) Geport of increased iron content in the-basal ganglia of a patient with this disorder. A more recent case has been reported with similar neuropathological findings (Campbell et al, 1985). Neurological disorders such as Huntington's disease and Hallervorden-Spatz disease, with dyskinesia as one of their manifestations, have raised brain iron. The study of brain iron in TD is, therefore, of potential interest. In a recent MRI study(Bartzokis et al, 1990). 9 TD patients were found to have a significantly shortened left caudate T2 when compared with 5 non-TD schizophrenic controls. Further studies are clearly required. If iron‘is increased in some parts of the brain in TD, what is the pathogenesis and the significance of such an increase? As already noted, the BBB protects the brain from iron overload under ordinary circumstances. How, then, does the increase in brain iron come about? Of note here is the property of phenothiazines to act as chelators of i on. Borg and Cotzias (1962) reported that phenothiazines reacted with Fe 5 + to form a coloured reaction product as a semiquinone radical iron. Of all metals, the strength of binding of chlorpromazine was found highest for ion. It is possible that neuroleptics either mobilize iron from peripheral tissuesinto the brain, or decrease iron turnover in the brain leading to its accumulation (Ben-Shachar and Youdim, 1987). Long-term administration of chlorpromazine to the pig has been shown to increase the iron content of the caudate nucleus(Weiner et al, 1977). The metal chelating activities of the phenothiazines have significance for their action on the catecholaminergic systems (Rajan et al, 1974). DA receptor supersensitivity, which is considered one possible mechanism for the development of TD, may involve neuroleptic-related altered iron metabo: lism, as direct injection of FeC13 into the brain leads to D receptor Further, t&e ligation of supersensitivity (Ben-Shachar and Youdim, 1987). phenothiazines with transaction metal ions can produce free radical species (Rajan et al, 1974) with the potential to cause cell damage. Recent reports of the association of TD with negative symptoms and cognitive impairment in schizophrenia have resulted in speculation on the role of oxidative damage in the pathogenesis of TD (Casey, 1991). and neuroleptic-iron interaction is of interest in this regard. The irreversibility of TD in a proportion of patients is also better explained by brain damage than supersensitivity which is a reversible phenomenon, at least in animals (Jenner and Marsden, 1986). If the role of increased brain iron is indeed established in TD, it would suggest the following potential treatment strategies: reduction of iron using iron chelators (Gutteridge et al, 1979). prevention of iron-catalyzed free radical damage with free radical scavengers (Lohr et al, 1988). or preventing oxidation by using MAO inhibitors such as deprenyl used in Parkinson's diseaOne study (Lohr et al, 1988) did report that se (Tetrud and Langston, 1989). scavenger, improved TD in some alpha-tocopherol (vitamin E), a free radical especially those with a shorter history. patients,
2.2 Drug-induced Parkinsonism This results from DA blockade, producing the equivalent of DA deficiency responsible for symptoms in Parkinson's disease.(tiornykiewicz,'1975). Since ID leads to a sibsensitivity of D2 receptors, it should arguably worsen drug-induced parkinsonism. O'Loughlin et al, 1991, while examining akathisia primarily, found no differences in the iron status between Parkinsonian and non-Parkinsonian patients. The hypothesis, however, has not been adequately examined empirically. 2.3. Akathisia The role of ID in the pathogenesis of drug-induced akathisia has, on the These studies were prompted by in some studies. other hand, been examined the observations that ID can cause motor restlessness in rats (Weinberg et to hyperactivity in children (Webb and Oski, al. 1980) and may contribute The symptoms of akathisia resemble those of restless legs syndrome. 1974).
NeumleptIc4nduced movement disorders
651
a disorder that is more common in individuals with ID (Ekbom, 1960). A study that examined the association of serum iron status with the propensity to develope acute neuroleptic-induced akathisia reported negative results (Sachdev and Loneragan, 1991). Two studies using chronic (tardive) akathisia patients (Brown et al, 1987; Barnes et al, 1990) reported conflicting results. The pathophysiology of tardive akathisia may, however, be distinct from that of acute akathisia and be more akin to TD (Sachdev and Chee, 1990). The. issue, therefore, needs further examination. 2.4.Neuroleptic Malignant Syndrome Rosg&sh and Stewart (1989) reported a low serum iron level in 18 (95%) of their 19 neuroleptic malignant-syndrome (NMS) patients in whom it was determined, with a level of 20 mg/dl or less (normal range 52-180) in 7 This finding, though needing confirmation, is consistent with the patients. D2 receptor blockade hypothesis for the pathophysiology of NMS (Henderson and Wooten, 1981). The authors (Rosebush and Mazurek, 1991) reported, however, that serum iron levels fell precipitously in the first week after the onset of the syndrome, an adequate explanation for which is lacking. 3.Conclusions The role of iron in the pathogenesis of NIMD,and indeed other neuropsychiatric Further studies are clearly disorders, is only beginning to be investigated. indicated as preliminary studies increase our interest in neuropsychiatry of trace metals. Acknowledgements The National Health and Medical Research Council of Australia, Ramaciotti and the Rebecca F Cooper Foundationsfor financial support. C. Loneragan for assistance with literature search. References ASHKENAZI, R., BEN-SHACHAR, D. and YOUDIM, M.B.H. (1982). Nutritional iron and dopamine binding sites in the rat brain. Pharmacol Behav. -17 (Suppl), 43-47. BARNES, T.R.E., HALSTEAD, S.M. and LITTLE, P. (1990). Akathisia variants: Prevalence and iron status in a inpatient population with chronic schizophrenia. Schiz. Res., 3, 79(Abs). BARTON, A., ROWIE, A., and ELIMEIER, K. (1990). Low plasma iron status and akathisia. J. Neurol. Neurosurg. Psychiatry, 53, 671-674. BARTZOKIS, G., GARBER, H.J., MARDER, S.R. and OLENDORF, W.H. (1990). MRI in tardive dyskinesia: Shortened left caudate T2. Biol. Psychiatry.28, 10271036. BEN-SHACHAR, D. and YOUDIM, M.B.H. (1987). Neuroleptic induced receptor supersenstivity and tardive dyskinesia may involve altered brain iron metabolism (Abstr). (1962). Interaction of trace metals with BORG, B.C. and COTZIAS, G.C. phenothiazine drug derivatives, Parst 1.11 and III. Proc. Natl. Acad. Sci. USA,.e, 617-652. BROWN, K.W., GLEN, S.E. and WHITHE, T. (1987). Low serum iron status and akathisia. Lancet, 1, 1234-1236. CAMPBELL, W.G., RAST(IND, M.A., GORDON, T. and SHAW, C.M. (1985). Iron pigment in the brain of a man with tardive dyskinesia. Am. J. Psychiatry, 142, 364-365. CASEY, D.E. (1991). Neuropsychiatry of involuntary movement disorders: tardive dyskinesia. Curr. Opin. Psychiatry, 4, 86-89. CHEN, J.C., HARDY, P.A., CLAUBERG, M., JOSHI, J.G., PARRAVANO, J., DECK, J.H.N., HENKELMAN, R.M.. BECKER, L.E. and KUCHARCZYK, W-(1989). T2 values in the human brain: Comparison with quantitive assays of iron and ferritin. Radiology, 173, 521-526. CZERNANSKY, J.G., HOLMAN, C.A., BONNETT. K.A.. GRABOWSKY. K. KING, R. and HOLLISTER, L. (1983). Dopaminergic suoersensitivity at distant sites following induced epileptic foci. Life Sci.,z, 385-390. DALLMAN, P.R., SIIMES, M.A. and MANIES, E.C. (1975). Brain iron: persistant
P.Sachdev deficiency following short-term iron deprivation in the young rat. Brit. J. Haematol., 2. 209-215. DRAYER, B., BURGER, P.. DARWIN, R., RIEDERER. S., HERFKENS, R. and JOHNSON, G.A. (1986). Magnetic resonance imaging of brain iron. AJNR.;?, 373-380. EKBOM, K.A. (1960). Restless legs syndrome. Neurology, lo, 868-873. GUTTERIDGE, J.M.C., RICHMOND, R. and HALLIWELL, B. (1979). Inhibition of the iron-catalysed formation of hydroxyl radicals and of lipid peroxidation by desferrioxamine. Biochem. .I., 184, 469-472. HALLBERG, L., BENGTSSON, B., GARBEY, L., LENNATSSON, .I., ROSSANDER, L. and TIBBLIN. E. (1979). An analysis of factors leading to a reduction in iron deficiency in Swedish women. Bull. WHO, 57, 947-954. HALLGREN. B. and SOURANDER, P. (1958). The effect of age on the non-haemin iron in the human brain. J. Neurochem., 3_, 41-51. HENDERSON, V.W. and WOOTEN, G.F. (1981). Neuroleptic malignant syndrome: a pathogenic role for dopamine receptor blockade. Neurology, 31, 132-137. HILL, J.M. (1988). The distribution of iron in the brain. In: Brain Iron: neurochemistry and behavioural aspects, M.B.H. Youdim. (Ed) pp. l-24. London: Taylor and Francis. HOECK, A., DENMEL, U., SCHICHA. S.. KASPEREK, K. and FEINENDEGEN, L.E. (1975). Trace element concentration in human brain. Brain, E, 49-64. HORNYKIEWICZ, 0. (1975). Parkinsonism induced by dopaminergic antagonists. In: Advances in Neurology. Volume 9, D.B. Caine, T.N. Chase and A. Barbeau (Bds). PP. 155-164. New York:Raven Press. HUNTER. R., BLACKWOOD, W., SMITH, M.C. and CUMMINGS, J.N. (1968). Neuropathological findings in three cases of persistent dyskinesia following phenthiamine medication. J. Neurol.Sci., 1, 263-273. JENNER, P. (1989). Clues to the mechanism underlying dopamine cell death in Parkinson's disease. 3. Neurol. Neurosurg. Psychiatry., Special Suppl, 22-28. JENNER, P. and MARSDEN, C.D. (1986). Is the dopaminergic hypothesis of tardive dyskinesia completely wrong? (letter). Trends Neurosci.. 2, 259. LOHR, J.B., CADET, J.L., LOHR, M-A., LARSON, L.. WASLL, E., WADE, L., HYLTON. R.,VIDONI,C., JESTE, D.V. and WYATT, R.J. (1988). Vitamine E in the treatment of tardive dyskinesia: The possible involvement of free radical mechanisms. Bull., 14, 291-296. MACKLER. 8. and FINCH, C. (1982). Iron in central nervous system oxidative metabolism, In: Iron deficiency:brain biochemistry and behaviour, E. Pollitt and R.L. Leibel (Eds).pp. 31-38. New York: Raven Press. NEMES, Z.C.. ROTROSEN, J., ANGRIST,B., PESELOW, E., and SCHIENTAG, R. (1991). Serum iron levels and akathasia Biol. Psychiatry, _29_,411-413. O'LOUGHLIN, v., DICKIE, A.C. and ELIMEIER, K.P. (1991). Serum iron and transferrin in acute neuroleptic induced akathisia: J. Neurol. Neurosurg. Psychiatry. 54, 363-364. ORELAND, L. (1971). Purification and properties of pig liver mitochrondrial monamine oxidase. Arch. Biochem. Biophys., 146, 410-421, POLLITT, E. and LEIBEL, R. (Eds) (1982). Iron deficiency: Brain biochemistry and behaviour. New York: Raven Press. R.L. (1974). Studies on RAJAN, K.S., MANIAN, A.A., DAVIS, J.M. and NIXON, metal chelation of chlorpromazine and its hydroxylated metabolites. Adv. Biochem. Psychopharmacol., 2. 571-591. ROSEBUSH, P.I. and MAZUREK, M.F. (1991). Low serum iron levels and neuroleptic malignant syndrome: a reply (letter). Am. J. Psychiatry, 148. 148-149. ROSEBUSH, P. and STEWART, T. (1989). A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am. J. Psychiatry, 146, 717-725. SACHDEV, P.S. and CHEE, K-Y. (1990). Pharmacological characterization of tardive akathisia. Biol. Psychiatry, 2, 809-818. SACHDEV, P.S. and LONERAGAN. C. (1991). Acute drug-induced akathisia is not associated with low serum iron status. Psychpharmacology, 103, 138-139. TANEJA, V., MISHRA, K. and AGARWAL, K.N. (1986). Effect of early iron deficiency in rate on the gala-aminobutyric acid shunt in brain. J. Neurochem., 46, 1670-1674. TETRUD, J.W. and LANGSTON, J.W. (1989). The effect of Deprenyl (Selegiline) on the natural history of Parkinson's disease. Science, 245, 519-522. WEBB, T.E. and OSKI, F.A. (1974). Behavioural status of young adolescents with iron deficiency anemia. .I. Spec. Educ., 8, 153-156. WEINBERG, J., DALLMAN, P.R. and LEVINE, S. (1980). Iron deficiency during early development in the rat: Behavioural and physiological consequences.
Neuroleptic-fnducedmovamentdisordars
653
Pharmacol. Biochem. Behav., 12, 493-502. WEINER, J.W., NAUSIEDA, P.A. and KLAWANS, H.L. (1977). Effect of chlorpromazine on central nervous system concentrations of manganese, iron and copper. Life Sci., g, 1181-1186. YOUDIM, M.B.H., BEN-SHACHAR, D. and YEHUDA, S. (1989). putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behaviour. Am-J. Clin. Nutr.. 50, (Suppl), 607-617. YOUDIM, M.B.H., BEN-SHACHAR, D., ASHKENAZI, R. and YEHUDA, S. (1983). Modulation of brain receptor.in stratum by iron: behavioural and biochemical correlates. In: Advances in Neurology. Vol 40. A. Hassler and C.J. Christ (Bds), PP. 159-173. New York: Raven Press. YOUDIM, W.B.H., SILLS, M-A., HEYDORN, W.E., CREED, G.J. and JACOBOWITZ, D.H. (1986). Iron deficiency alters discrete protein in rate caudate nucleus and nucleus accumbens. J. Neurochem., 47, 794-799. Inquiries and reprint requests should be addressed Dr. Perminder Sachdev Neuropsychiatric Institute The Prince Henry Hospital P-0. Box 233 Matraville 2036 New South Wales Australia
to:
a 8bl Ehitain.
All
PS~
1992.
vd. 16. pp.
or76
647-66s
- 6646/92
s15.00
olesz~~nPrCMLtd
xl&to Raerved
NEUROLEPTIC-INDUCED MOVEMBNT DISORDERS AND BODY IRON STATUS PERMINDER SACHDEV Neuropsychiatric Institute, The Prince Henry Hospital University of New South Males, Sydney, Australia (Final form, July 1991) Contents 1. 2. 2.1. 2.2. 2.3. 2.4. 3.
Abstract Introduction Brain Iron Dysfunction and the NIMD Tardive Dyskinesia Drug-Induced Parkinsonism Akathisia Neuroleptic Malignant Syndrome Conclusions Acknowledgements References
641 641
649 650 650 650 651 651 651 651
Abstract Sachdev, Perminder: Neuroleptic-Induced Movement Disorders and Body Iron Status. Prog. Neuro-psychopharmacol. & Biol. Psychiat. 1992, 1615): 647-653. 1.
2. 3.
The distribution of iron in the human brain, what is known about its biological functions, and the interaction of neuroleptics with iron suggest that this trace metal may play an important role in the pathogenesis of neuroleptic-induced movement disorders (NIMD). The availability of magnetic resonance imaging has made some of the hypotheses testable in human subjects. This article is a brief overview of the current literature on the association between NIMD and brain iron.
akathisia, drug-induced parkinsonism, iron, neuroleptics, Keywords: neuroleptic malignant syndrome, tardive dyskinesia. blood brain barrier(BBB), dopamine (DA), gamma-aminobutyric Abbreviations: acid (GABA), iron deficiency (ID), magnetic resonance imaging (MRI). monoamine oxidase [MAO), neuroleptic-induced movement disorder (NIMD), neuroleptic malignant syndrome (NMS), serotonin (S-HT), spin-spin relaxation time (T2), tardive dyskinesia (TD).
l.Introduction Iron has recently received increasing attention for its possible etiological role in the development of neuroleptic-induced movement disorders (NIMD) Iron is the most abundant metal in the human body for a number of reasons. (Pollitt and Leibel, 19821, and its concentration in the brain is relatively high, being about one-quarter that in the liver, the principal storage organ (Hallgren and Sourander, 1958; Hoeck et al, 1975). It is unevenly distibuted in the brain, being highest in the globus pallidus, followed by the red 847
848
P.Sschdev
nucleus, subs tantia nigra pars reticulata, putamen and dentate nucleus (table 1) (Hallgren and Sourander, 1958). In the globus pallidus, its concentration is comparable to that in the liver. This morphological distribution is important for two reasons: i) the organs with high concentrations have a demonstrated role in the pathogenesis of movement disorders, and ii) these areas of the brain have a-high-content of dopamine (DA), gamma-aminobutyric acid (GABA), serotonin (SHT) and neuropeptides (Hill, 1988), neurotransmitters important in movement disorders and psychiatric illnesses. Table
1
The distribution of non-heme iron in human brain (autopsy data. age 30-100 years) * Organ
Iron content Mean (*SD) mg/lOOg fresh weight 21.3 19.5 18.5 13.3 10.4 9.3 3.8 3.6 2.9 1.4 1.0 13.4
Globus pallidus Red nucleus Substantia nigra Putamen Dentate nucleus Caudate nucleus Parietal cortex Cerebellar cortex Prefrontal cortex Medulla oblongata Meninges Liver * adapted from Hallgren and Sourander,
(k3.5) (k6.9) (k6.5) (k3.4) (k4.9) (k2.1) (kO.7) (20.9) (to.4) (&1.2) (*o-3) (29.4)
1958.
Recent findings on the biological role of iron in the body suggest that morphological distribution of iron may not be without a reason. IrOn is associated with many enzymes involved in the metabolism of neurotransmitters. Monoamine oxidase (MAO) is associated withiron, although the exact nature of the association is uncertain (Oreland, 1971). Iron deficiency (ID) leads to an increased concentration of brain 5HT and other 5-hydroxyindole compounds in animal studies (Mackler and Finch, 1982), while the concentrations of GABA and the excitatory glutamate are decreased (Tanjela et al, 1986). In addition to its metabolic role, iron is important for the dopamine D2 receptor function,. Evidence from a number of sources suggest that ID leads to a subsensitivity Of D receptors (Ashkenazi et al, 1982; Youdim et al, 1983). Iron may be part O$ the receptor site. or alternatively important for the formation of D2 protein or the confirmation of the membrane (Youdin et al, 1986). Increased iron, on the other hand, due to a direct injection of FeC13 into the brain, ID can disrupt the leads to the development of D2, receptor supersensitivity. blood-brain barrier(B%%) and, In addition, alter the content of proteins in some areas of the brain. A further important role for iron is as a catalyst The basal gangalia in oxidation, hydroxylation and peroxidation reactions. and the hippocampus are particularly susceptible to iron-mediated lipid peroxidation (Czernansky et al, 1983). Iron also promotes the generation of hydroxyl radicals, with their associated toxicity, from hydrogen peroxide. Alongside the increased knowledge of the biological functions of brain iron, it has become known that ID is not uncommon even in developed countries (Hallberg et al, 1979). It is also recognized that ID may affect tissue functions before or in concert with decrease in hemoglobin production (Pollitt and Leibel, 1982). Since the turnover of brain iron is low, the brain resists depletion, matched by a reduced rate of repletion upon therapy (Dallman et al, 1975). The BB% protects the brain against the acquisition of excess iron (Youdim etal, 1989). Iron overloading of the body, as occurs in hematochromatosis, does not lead to iron overloading of the brain. For the above reasons, serum iron status may not be an accurate reflection of brain this
Neuroleptlc-inducedmovcmentdlsorders
649
Several studies have suggested that magnetic resonance imaging (MRI) iron. Particles of iron may be useful in the evaluation of brain iron in vivo. and iron storage compounds (ferritin and hemosiderin) reduce T. relaxation while producing little effec f on Th (Drayer times of the surrounding tissues, While the form of iron that is responsible for T2 sho tening et al, 1986). point to the potential for the is debated (Chen et al, 1989), most reports use of MRI to study brain iron. Table 2 BIOLOGICAL
1.
Catalytic
A.
role
FUNCTIONS
in enzymatic
Tricarboxylic
cycle
succinate
OF
BRAIN
IRON
processes
enzymes:
dehydrogenese*
aconitase* B. Oxidative e.g. C. Amino
phoyphorylation
cytochrome acid
and
enzymes:
oxidase
C*
neurotransmitter
metabolism
enzymes: Phenylalanine Monoamine Aldehyde
hydroxylase*
oxidase
(MAO)*
oxidase
Aminobutyric Glutamate
acid
transaminase
dehydrogenase
receptor
2.
Effect
on D2
3.
Effect
on other
function
neurotransmitters:
GABA 5HT Opiate-peptides
4.
Role
in peroxidation,
oxidation
and
hydroxylation
reactions
5.
Other
possible i) Role ii)
*brain enzyme (Pollitt and
Role
functions
(not
in protein in maintenace
levels remain Leibel, 1982)
established):
synthesis of blood-brain
unchanged
in iron
barrier deficiency
2. Brain Iron Dysfunction and NIMD Support for the role of iron in NIMD comes from several sources. The relationship of iron with the DA receptor, GABA and neuropeptides, and its involvement in the metabolic pathways of neurotransmitters make this role likely. The possible significance of iron for Parkinson's disease(Jenner, 1989) further suggest such a role. There is increasing evidence that neuroleptics influence ferrokinetics, and this may be relevant for their
650
P. Sachdcv
beneficial and toxic effects (Rajan et al, 1974). directly examined the iron status of patients with
Finally, NIMD.
some
studies
have
2.1. Tardive Dyskinesia(TD) Indications for the possible role of iron in TD were first provided bv the Hunter et al (1968) Geport of increased iron content in the-basal ganglia of a patient with this disorder. A more recent case has been reported with similar neuropathological findings (Campbell et al, 1985). Neurological disorders such as Huntington's disease and Hallervorden-Spatz disease, with dyskinesia as one of their manifestations, have raised brain iron. The study of brain iron in TD is, therefore, of potential interest. In a recent MRI study(Bartzokis et al, 1990). 9 TD patients were found to have a significantly shortened left caudate T2 when compared with 5 non-TD schizophrenic controls. Further studies are clearly required. If iron‘is increased in some parts of the brain in TD, what is the pathogenesis and the significance of such an increase? As already noted, the BBB protects the brain from iron overload under ordinary circumstances. How, then, does the increase in brain iron come about? Of note here is the property of phenothiazines to act as chelators of i on. Borg and Cotzias (1962) reported that phenothiazines reacted with Fe 5 + to form a coloured reaction product as a semiquinone radical iron. Of all metals, the strength of binding of chlorpromazine was found highest for ion. It is possible that neuroleptics either mobilize iron from peripheral tissuesinto the brain, or decrease iron turnover in the brain leading to its accumulation (Ben-Shachar and Youdim, 1987). Long-term administration of chlorpromazine to the pig has been shown to increase the iron content of the caudate nucleus(Weiner et al, 1977). The metal chelating activities of the phenothiazines have significance for their action on the catecholaminergic systems (Rajan et al, 1974). DA receptor supersensitivity, which is considered one possible mechanism for the development of TD, may involve neuroleptic-related altered iron metabo: lism, as direct injection of FeC13 into the brain leads to D receptor Further, t&e ligation of supersensitivity (Ben-Shachar and Youdim, 1987). phenothiazines with transaction metal ions can produce free radical species (Rajan et al, 1974) with the potential to cause cell damage. Recent reports of the association of TD with negative symptoms and cognitive impairment in schizophrenia have resulted in speculation on the role of oxidative damage in the pathogenesis of TD (Casey, 1991). and neuroleptic-iron interaction is of interest in this regard. The irreversibility of TD in a proportion of patients is also better explained by brain damage than supersensitivity which is a reversible phenomenon, at least in animals (Jenner and Marsden, 1986). If the role of increased brain iron is indeed established in TD, it would suggest the following potential treatment strategies: reduction of iron using iron chelators (Gutteridge et al, 1979). prevention of iron-catalyzed free radical damage with free radical scavengers (Lohr et al, 1988). or preventing oxidation by using MAO inhibitors such as deprenyl used in Parkinson's diseaOne study (Lohr et al, 1988) did report that se (Tetrud and Langston, 1989). scavenger, improved TD in some alpha-tocopherol (vitamin E), a free radical especially those with a shorter history. patients,
2.2 Drug-induced Parkinsonism This results from DA blockade, producing the equivalent of DA deficiency responsible for symptoms in Parkinson's disease.(tiornykiewicz,'1975). Since ID leads to a sibsensitivity of D2 receptors, it should arguably worsen drug-induced parkinsonism. O'Loughlin et al, 1991, while examining akathisia primarily, found no differences in the iron status between Parkinsonian and non-Parkinsonian patients. The hypothesis, however, has not been adequately examined empirically. 2.3. Akathisia The role of ID in the pathogenesis of drug-induced akathisia has, on the These studies were prompted by in some studies. other hand, been examined the observations that ID can cause motor restlessness in rats (Weinberg et to hyperactivity in children (Webb and Oski, al. 1980) and may contribute The symptoms of akathisia resemble those of restless legs syndrome. 1974).
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a disorder that is more common in individuals with ID (Ekbom, 1960). A study that examined the association of serum iron status with the propensity to develope acute neuroleptic-induced akathisia reported negative results (Sachdev and Loneragan, 1991). Two studies using chronic (tardive) akathisia patients (Brown et al, 1987; Barnes et al, 1990) reported conflicting results. The pathophysiology of tardive akathisia may, however, be distinct from that of acute akathisia and be more akin to TD (Sachdev and Chee, 1990). The. issue, therefore, needs further examination. 2.4.Neuroleptic Malignant Syndrome Rosg&sh and Stewart (1989) reported a low serum iron level in 18 (95%) of their 19 neuroleptic malignant-syndrome (NMS) patients in whom it was determined, with a level of 20 mg/dl or less (normal range 52-180) in 7 This finding, though needing confirmation, is consistent with the patients. D2 receptor blockade hypothesis for the pathophysiology of NMS (Henderson and Wooten, 1981). The authors (Rosebush and Mazurek, 1991) reported, however, that serum iron levels fell precipitously in the first week after the onset of the syndrome, an adequate explanation for which is lacking. 3.Conclusions The role of iron in the pathogenesis of NIMD,and indeed other neuropsychiatric Further studies are clearly disorders, is only beginning to be investigated. indicated as preliminary studies increase our interest in neuropsychiatry of trace metals. Acknowledgements The National Health and Medical Research Council of Australia, Ramaciotti and the Rebecca F Cooper Foundationsfor financial support. C. Loneragan for assistance with literature search. References ASHKENAZI, R., BEN-SHACHAR, D. and YOUDIM, M.B.H. (1982). Nutritional iron and dopamine binding sites in the rat brain. Pharmacol Behav. -17 (Suppl), 43-47. BARNES, T.R.E., HALSTEAD, S.M. and LITTLE, P. (1990). Akathisia variants: Prevalence and iron status in a inpatient population with chronic schizophrenia. Schiz. Res., 3, 79(Abs). BARTON, A., ROWIE, A., and ELIMEIER, K. (1990). Low plasma iron status and akathisia. J. Neurol. Neurosurg. Psychiatry, 53, 671-674. BARTZOKIS, G., GARBER, H.J., MARDER, S.R. and OLENDORF, W.H. (1990). MRI in tardive dyskinesia: Shortened left caudate T2. Biol. Psychiatry.28, 10271036. BEN-SHACHAR, D. and YOUDIM, M.B.H. (1987). Neuroleptic induced receptor supersenstivity and tardive dyskinesia may involve altered brain iron metabolism (Abstr). (1962). Interaction of trace metals with BORG, B.C. and COTZIAS, G.C. phenothiazine drug derivatives, Parst 1.11 and III. Proc. Natl. Acad. Sci. USA,.e, 617-652. BROWN, K.W., GLEN, S.E. and WHITHE, T. (1987). Low serum iron status and akathisia. Lancet, 1, 1234-1236. CAMPBELL, W.G., RAST(IND, M.A., GORDON, T. and SHAW, C.M. (1985). Iron pigment in the brain of a man with tardive dyskinesia. Am. J. Psychiatry, 142, 364-365. CASEY, D.E. (1991). Neuropsychiatry of involuntary movement disorders: tardive dyskinesia. Curr. Opin. Psychiatry, 4, 86-89. CHEN, J.C., HARDY, P.A., CLAUBERG, M., JOSHI, J.G., PARRAVANO, J., DECK, J.H.N., HENKELMAN, R.M.. BECKER, L.E. and KUCHARCZYK, W-(1989). T2 values in the human brain: Comparison with quantitive assays of iron and ferritin. Radiology, 173, 521-526. CZERNANSKY, J.G., HOLMAN, C.A., BONNETT. K.A.. GRABOWSKY. K. KING, R. and HOLLISTER, L. (1983). Dopaminergic suoersensitivity at distant sites following induced epileptic foci. Life Sci.,z, 385-390. DALLMAN, P.R., SIIMES, M.A. and MANIES, E.C. (1975). Brain iron: persistant
P.Sachdev deficiency following short-term iron deprivation in the young rat. Brit. J. Haematol., 2. 209-215. DRAYER, B., BURGER, P.. DARWIN, R., RIEDERER. S., HERFKENS, R. and JOHNSON, G.A. (1986). Magnetic resonance imaging of brain iron. AJNR.;?, 373-380. EKBOM, K.A. (1960). Restless legs syndrome. Neurology, lo, 868-873. GUTTERIDGE, J.M.C., RICHMOND, R. and HALLIWELL, B. (1979). Inhibition of the iron-catalysed formation of hydroxyl radicals and of lipid peroxidation by desferrioxamine. Biochem. .I., 184, 469-472. HALLBERG, L., BENGTSSON, B., GARBEY, L., LENNATSSON, .I., ROSSANDER, L. and TIBBLIN. E. (1979). An analysis of factors leading to a reduction in iron deficiency in Swedish women. Bull. WHO, 57, 947-954. HALLGREN. B. and SOURANDER, P. (1958). The effect of age on the non-haemin iron in the human brain. J. Neurochem., 3_, 41-51. HENDERSON, V.W. and WOOTEN, G.F. (1981). Neuroleptic malignant syndrome: a pathogenic role for dopamine receptor blockade. Neurology, 31, 132-137. HILL, J.M. (1988). The distribution of iron in the brain. In: Brain Iron: neurochemistry and behavioural aspects, M.B.H. Youdim. (Ed) pp. l-24. London: Taylor and Francis. HOECK, A., DENMEL, U., SCHICHA. S.. KASPEREK, K. and FEINENDEGEN, L.E. (1975). Trace element concentration in human brain. Brain, E, 49-64. HORNYKIEWICZ, 0. (1975). Parkinsonism induced by dopaminergic antagonists. In: Advances in Neurology. Volume 9, D.B. Caine, T.N. Chase and A. Barbeau (Bds). PP. 155-164. New York:Raven Press. HUNTER. R., BLACKWOOD, W., SMITH, M.C. and CUMMINGS, J.N. (1968). Neuropathological findings in three cases of persistent dyskinesia following phenthiamine medication. J. Neurol.Sci., 1, 263-273. JENNER, P. (1989). Clues to the mechanism underlying dopamine cell death in Parkinson's disease. 3. Neurol. Neurosurg. Psychiatry., Special Suppl, 22-28. JENNER, P. and MARSDEN, C.D. (1986). Is the dopaminergic hypothesis of tardive dyskinesia completely wrong? (letter). Trends Neurosci.. 2, 259. LOHR, J.B., CADET, J.L., LOHR, M-A., LARSON, L.. WASLL, E., WADE, L., HYLTON. R.,VIDONI,C., JESTE, D.V. and WYATT, R.J. (1988). Vitamine E in the treatment of tardive dyskinesia: The possible involvement of free radical mechanisms. Bull., 14, 291-296. MACKLER. 8. and FINCH, C. (1982). Iron in central nervous system oxidative metabolism, In: Iron deficiency:brain biochemistry and behaviour, E. Pollitt and R.L. Leibel (Eds).pp. 31-38. New York: Raven Press. NEMES, Z.C.. ROTROSEN, J., ANGRIST,B., PESELOW, E., and SCHIENTAG, R. (1991). Serum iron levels and akathasia Biol. Psychiatry, _29_,411-413. O'LOUGHLIN, v., DICKIE, A.C. and ELIMEIER, K.P. (1991). Serum iron and transferrin in acute neuroleptic induced akathisia: J. Neurol. Neurosurg. Psychiatry. 54, 363-364. ORELAND, L. (1971). Purification and properties of pig liver mitochrondrial monamine oxidase. Arch. Biochem. Biophys., 146, 410-421, POLLITT, E. and LEIBEL, R. (Eds) (1982). Iron deficiency: Brain biochemistry and behaviour. New York: Raven Press. R.L. (1974). Studies on RAJAN, K.S., MANIAN, A.A., DAVIS, J.M. and NIXON, metal chelation of chlorpromazine and its hydroxylated metabolites. Adv. Biochem. Psychopharmacol., 2. 571-591. ROSEBUSH, P.I. and MAZUREK, M.F. (1991). Low serum iron levels and neuroleptic malignant syndrome: a reply (letter). Am. J. Psychiatry, 148. 148-149. ROSEBUSH, P. and STEWART, T. (1989). A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am. J. Psychiatry, 146, 717-725. SACHDEV, P.S. and CHEE, K-Y. (1990). Pharmacological characterization of tardive akathisia. Biol. Psychiatry, 2, 809-818. SACHDEV, P.S. and LONERAGAN. C. (1991). Acute drug-induced akathisia is not associated with low serum iron status. Psychpharmacology, 103, 138-139. TANEJA, V., MISHRA, K. and AGARWAL, K.N. (1986). Effect of early iron deficiency in rate on the gala-aminobutyric acid shunt in brain. J. Neurochem., 46, 1670-1674. TETRUD, J.W. and LANGSTON, J.W. (1989). The effect of Deprenyl (Selegiline) on the natural history of Parkinson's disease. Science, 245, 519-522. WEBB, T.E. and OSKI, F.A. (1974). Behavioural status of young adolescents with iron deficiency anemia. .I. Spec. Educ., 8, 153-156. WEINBERG, J., DALLMAN, P.R. and LEVINE, S. (1980). Iron deficiency during early development in the rat: Behavioural and physiological consequences.
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Pharmacol. Biochem. Behav., 12, 493-502. WEINER, J.W., NAUSIEDA, P.A. and KLAWANS, H.L. (1977). Effect of chlorpromazine on central nervous system concentrations of manganese, iron and copper. Life Sci., g, 1181-1186. YOUDIM, M.B.H., BEN-SHACHAR, D. and YEHUDA, S. (1989). putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behaviour. Am-J. Clin. Nutr.. 50, (Suppl), 607-617. YOUDIM, M.B.H., BEN-SHACHAR, D., ASHKENAZI, R. and YEHUDA, S. (1983). Modulation of brain receptor.in stratum by iron: behavioural and biochemical correlates. In: Advances in Neurology. Vol 40. A. Hassler and C.J. Christ (Bds), PP. 159-173. New York: Raven Press. YOUDIM, W.B.H., SILLS, M-A., HEYDORN, W.E., CREED, G.J. and JACOBOWITZ, D.H. (1986). Iron deficiency alters discrete protein in rate caudate nucleus and nucleus accumbens. J. Neurochem., 47, 794-799. Inquiries and reprint requests should be addressed Dr. Perminder Sachdev Neuropsychiatric Institute The Prince Henry Hospital P-0. Box 233 Matraville 2036 New South Wales Australia
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