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Is akathisia a forerunner of tardive dyskinesia?
IS AKATHISIA A FORERUNNER OF TARDIVE DYSKINESIA? A clinical report with brief review of literature UTPAL GOSWAMI*
and S.M. CHANNABASAVANNA*
INTRODUCTION SUMMARY Akathisia is a relatively early side effect of neuroleptic therapy characterized by a subjective sense of inner restlessness leading to an inability to sit still and a compulsion to move. It usually appears within the first 3 months after the first intake of neuroleptics in about 21.5% of the cases’, although higher incidence has also been reported2. A considerable amount of recent literature on akathisia was devoted to encourage the clinicians to entertain the diagnosis of akathisia in patients receiving neuroleptic medication in order to avoid underdiagnosing akathisia. The principal purpose was to distinguish akathisia from anxiety and hyperactivity frequently seen in psychotic patients and thereby to prevent worsening of this extrapyramidal symptom by unwarranted addition of increasing doses of neuroleptic9. This emphasis to avoid underdiagnosis of akathisia often recurred until recently when the need and importance of avoiding overdiagnosing akathisia was stressed by Munetz and Comes” who drew attention to the difficulties in distinguishing akathisia and tardive dyskinesia. The lower extremity component of tardive dyskinesia, being involuntary, late of onset and unresponsive to treatment, may not be clinically distinct from the subjectively distressful akathisia, which is theoretically of early onset, treatment responsive and has voluntary movements as a secondary phenomenon. The fact that so much literature on tardive dyskinesia and akathisia exists, suggests the likelihood of
* From the Depurtment
of Psvchiatry.
National
Institute
ofMen!al
A bipolar manic-depressive patient, developed while on lithium prophylaxis, akathisia at therapeutic serum lithium levels and subsequently bucco-lingua-masticatory dyskinesia. The authors propose that differential involvement of dopamine systems may account for the transition from akathisia to tardive dyskinesia. In the light of a brief review of literature, a prospective study of akathisia and tardive dyskinesia seems justified. Key words: akathisia, tardive dyskinesia.
side-effects,
dopamine.
some important relationship between these two disorders. Firstly, there may be a positive association between the occurrence of akathisia and tardive dyskinesia. Secondly, some akathisia may actually be tardive dyskinesia or some form ‘fruste’ of tardive dyskinesia (pseudoakathisia). Lastly, there may be a progression from true through pseudoakathisia and akathisia ultimately to true tardive dyskinesia. The authors here report a case developing akathisia during lithium prophylaxis and sebsequently manifesting central features of tardive dyskinesia. CASE REPORT A 55year-old man with a history of rapid cycling bipolar manic-depressive psychosis in the past 3 years, was first seen and admitted in the
Health
and Neuro-Sciences,
Bangalore-
029, India.
Clin Neural Neurosurg 1984.Vol. 86-2 (Accepted 2.1.84)
107
institute (National Institute of Mental Health and Neurosciences, Bangalore. India) in June, 1981 during a manic episode. A review of his past treatment revealed indiscriminate polypharmacy. When he was included in an ongoing lithium research project in the institute, all drugs were stopped and lithium started after relevant investigations. After remission. prophylactic lithium was started with a daily dose varying between 900 and 1350 mg’day depending on serum levels, ranging from 0.9 to 1.3 mEq/L. He remained euthymic for the next two years. Subsequently, he had a brief hypomanic swing when lithium was increased to 1500 mg/day. Three days later he developed severe restlessness, inability to sit still, or lie down even for a brief period and an irresistible urge to pace up and down. This was accompanied by a subjective dysphoria over the peculiar restlessness coming mainly from the lower limbs. The patient was unable to sleep properly or concentrate on any work. On the second day he received 200 mg of chlorpromazine orally from a general practitioner for ‘manic excitement’. This worsened his restlessness. In addition, he developed restriction of movements and rapid hand tremors. On the third day, when he was brought to the psychiatric out-patient department he was conscious, alert but dysphoric. He admitted to have a pecuiiar inner restlessness. He had a dysarthric speech and coarse tremors of the outstretched hands. Higher functions, cranial nerves, ocular fundi and tendon-reflexes were normal. He walked with short shuffling gait with minimal associated movements. There was moderate to severe cogwheel rigidity in all four limbs. All other systemic examinations were normal. The process of examination was difticult as the patient frequently got out of bed, paced up and down the corridor, rested for 5 to IO seconds and repeated the same. Serum lithium, estimated 12 hours after the previous night dose of 750 mg was 1.2 mEq/L. Erythrocytic lithium was 0.6 mEq/L. Complete haemogram, urinalysis, renal function tests and serum electrolytes were ail within normal limits. An injection of prometha~ine 50 mg was given immediately and repeated within an hour. Concomitantly. trihexiphenidyl was started at the dose of 4 mg/day. in two divided 108
doses; total dose of lithium was kept unchanged at 1500 mg/day. Akathisia resolved completely within 36 hours after starting anticholinergrcs whereas mild cogwheel rigidity and tine hand tremor continued for more than 3 weeks. All initial investigations were repeated twtoc a week during these three weeks and were found to be normal. Two weeks after the onset of akathisia, the patient became euthymic but developed involuntary sucking and chewing movements along with protrusion of the tongue. These oral, masticatory and lingual movements could not be controlled voluntarily for more than 30 to 45 seconds with carry over phenomenon confined to the lower limbs in the form of ~hore~fo~ movements of the toes and thumping of the feet. These movements slightly decreased when anticholinergics were stopped after three weeks. At follow-ups the patient still showed to have these movement and mild cogwheel rigidity but remained euthymic with 900 mg/day of lithium. DISCUSSION In this patient, euthymic on prophylactic lithium, for 2 years, an extrapyramidal syndrome developed at the therapeutic serum lithium levels, when the total daily dose was increased by 25% during a brief manic episode. The clinical profile was markedly dominated by akathisia initially and bucco-lingua-masticatory dyskinesia at the later stages. Lithium neurotoxicity at ‘therapeutic’ levels has been reported earlie@ and has been recently reviewed by Ghadirian and Lehmann6. More recently, Perenyi, et a1.,7 reported akathisia in a case with lithium-neuroleptic combination out of a total of thirty patients. They failed to find any symptom of akathisia in twenty-four patients treated with lithium alone. Nor did any of twenty-seven patients on ~ithium-antidepressant combination develop akathisia. However, akathisia developing after usage of only lithium has, to the best of our knowledge, not been reported in literature so far. The authors are inclined to consider this phenomenon as a dose-independent, idiosyncratic reaction to lithium, the exact mechanism of which remains unclear at present. Within the therapeutic
range, the most frequently reported extrapyramidal reactions are cogwheel rigidity and rapid hand tremorsa-lo. The onset of the extrapyramidal syndrome after administration of ~hlo~romazine indicates its synergy with lithium. Phenothiazines are proved to cause increased influx of lithium into erythrocytes, possibly by a passive leak diffusionll. The second important aspect of this case is the development of buc~o-linguo-masticator dyskinesia about two weeks after the onset of akathisia. The patient did not have any neuroleptics for a period of about two years. Worsening of akathisia (and precipitation of a neurotoxic syndrome) after addition of chforpromazine as well as improvement of the same with promethazine, would certainly favour the diagnosis of true akathisia rather than pseudoakathisia which is a form ‘fruste’ of tardive dyskinesia. This is, then, a case where tardive dyskinesia followed true akathisia in a close temporal sequence. This temporal association is significant. While it is known that parkinsonism and tardive dyskinesia can coexist’“. it is still unclear whether the first predisposes the second. In this connection, Chouinard’” suggested that akathisia and tremor (hyperkinetic parkinsonism) may be different from the typical hypokinetic parkinsonism. Having found a decreased association between hypokinetic parkinsonism and tardive dyskinesia, he suggested that hyperkinetic parkinsonian symptoms, like akathisia, could represent a transitional state between hypokinetic parkinsonism and tardive dyskinesia. The present case tends to support this “transitional hypothesis”. This is of considerable neurological value. It is not yet known whether akathisia is etiologically related to tardive dyskinesia or whether tardive dyskinesia is more frequent in patients with akathisia. In considering their concept of tardive dysphrenia, elsewhere described as supersensitivity or tardive psychosis 14,15,Forest and Fahn16 described the presence of subjective akathisia in six of seven patients being treated for tardive dyskinesia. They hypothesized that akathisia (the subjective feeling of restlessness) may be a form of tardive dysphrenia. Marsden and Jenner17 indeed suggested that akathisia results from
altered receptor sensitivity in the mesocortical dopamine system and not in the mesolimbic or nigrostriatal systems. This involvement of a cortical system helps to explain the predominant subjective nature of akathisia while nigrostriatal dopamine receptor supersensitivity could explain the motor components. In this particular case, it may be that mesocortical system was involved initially, followed by altered functioning of the nigro-striatal system. The likelihood of differential susceptibility of dopamine receptors in the behavioural (mesocortical and mesolimbic) and motor (nigrostriatal) dopamine systems has been earlier postulated by the authorG7. Whether or not akathisia is a forerunner of tardive dyskinesia is an important question that needs to be addressed by prospective studies in which akathisia and tardive dyskinesia are carefully defined, in a design that would include clinical characteristics as well as biochemical indices. REFERENCES FJ. A survey of drug-induced extrapyramidal reactions. Jama 1961; 175: 1054-1060. VAN PUTTEK T. Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 1974: 3 1: 67-7 I R.~SKINDE. Akathisia: a side effect to be remembered. Am J Psychatry 1972; 129: 345-347. MUNET% MR. CORNES CL. Akathisia. pseudoakathisia and tardive dyskinesia: clinical examples. Compr Psychiatry 1982: 23: 345-352. STRAYHORN JM. NASH JL. Severe neurotoxicity despite “therapeutic” serum Iithium levels. Dis Nerv Syst 1977: 38: 107-111. GHADIRIAN AM.I.EHMANN HE. Neurological side effects of hthium: Organic brain syndrome. seizures, extrapyramidal stde effects and EEG changes. Compr Psychiatry 1980; 21: 327-334. PERENYI A.RIHMER Z,EANKI CM. Parkinsonian symptoms with lithium. lithiunl-neuroIeptic. and lithium-ant~depressant treatment. J Aff disorders 1983; S: 171-177. SHOPSIN B. GERSHON s. Cogwheel rigidity with lithium maintenance. Am J Psychiatry 1975: 132: 536-538. BRANCHEY MH. CHARLES I, SIMPSON GM. Extrapyramidal side effects in lithium maintenance therapy. Am J Psychiatry 1976, 133: 444-445. to KAN& J. RIFKIN A. QUTKIN F et at. Extrapy~midal side effects in lithium treatment. Am J Psychiatry 1978: 135: 851-853. *I PANDEY GN. GOEL I,DAVIS JM. Effect of neuroleptic drugs on lithium uptake by the human erythrocytes. C’lin Pharmacol Ther 1979: 26: 96-102. If KESHAVAN MS GANGADHAR %N, CHATTERJEE SOMNATH. Co-existence of parkinsonism and tardive dyskinesia and CSF amine metabolites. NIMHANS Journal 1983: 1: AYD
11l-1 13. I3 CH~UINARD
G. ANN.~B~.E L, ROSS-CHOUINARD
Factors related to tardive 1979: 136: 79-83.
dyskinesia.
A et al.
Am J Psychiatry
109
” M<<‘ARrHY IJ.I‘ardive psychosis. Am J Phychlatr\i 1976: 135: 625-626. Ii CHOCINARD G, JONES BD. Neuroleptic-mduced supersensitivity. Psychosis: Clinical and Pharmacologic Characteristi& Am J Psychiatry 1980; 137: 16-21. “’ FOREST DV. FAHN s. Tardive dyskinesia and subjective akathisia. J Clin Psychiatry 1979: 40: 206.
110
I7 M.~RSIXN (‘II). JLNNER P. The pathophysioiog! it cxtr,rp>ramidal Gde effects of neuroleptlc druss, Pr\chol Meli 1980: IO: 55-72. ‘* ('H.4NNABASAVANNA SM. GOSWAMI UT1'41. L'L.NKAltSHH. PRADHAX x";.Idiopathic torsion dystonia with schizw phrenia in first degree relatives. Indian J Ps>chiatr> lQ611: ‘4: x-94.
and S.M. CHANNABASAVANNA*
INTRODUCTION SUMMARY Akathisia is a relatively early side effect of neuroleptic therapy characterized by a subjective sense of inner restlessness leading to an inability to sit still and a compulsion to move. It usually appears within the first 3 months after the first intake of neuroleptics in about 21.5% of the cases’, although higher incidence has also been reported2. A considerable amount of recent literature on akathisia was devoted to encourage the clinicians to entertain the diagnosis of akathisia in patients receiving neuroleptic medication in order to avoid underdiagnosing akathisia. The principal purpose was to distinguish akathisia from anxiety and hyperactivity frequently seen in psychotic patients and thereby to prevent worsening of this extrapyramidal symptom by unwarranted addition of increasing doses of neuroleptic9. This emphasis to avoid underdiagnosis of akathisia often recurred until recently when the need and importance of avoiding overdiagnosing akathisia was stressed by Munetz and Comes” who drew attention to the difficulties in distinguishing akathisia and tardive dyskinesia. The lower extremity component of tardive dyskinesia, being involuntary, late of onset and unresponsive to treatment, may not be clinically distinct from the subjectively distressful akathisia, which is theoretically of early onset, treatment responsive and has voluntary movements as a secondary phenomenon. The fact that so much literature on tardive dyskinesia and akathisia exists, suggests the likelihood of
* From the Depurtment
of Psvchiatry.
National
Institute
ofMen!al
A bipolar manic-depressive patient, developed while on lithium prophylaxis, akathisia at therapeutic serum lithium levels and subsequently bucco-lingua-masticatory dyskinesia. The authors propose that differential involvement of dopamine systems may account for the transition from akathisia to tardive dyskinesia. In the light of a brief review of literature, a prospective study of akathisia and tardive dyskinesia seems justified. Key words: akathisia, tardive dyskinesia.
side-effects,
dopamine.
some important relationship between these two disorders. Firstly, there may be a positive association between the occurrence of akathisia and tardive dyskinesia. Secondly, some akathisia may actually be tardive dyskinesia or some form ‘fruste’ of tardive dyskinesia (pseudoakathisia). Lastly, there may be a progression from true through pseudoakathisia and akathisia ultimately to true tardive dyskinesia. The authors here report a case developing akathisia during lithium prophylaxis and sebsequently manifesting central features of tardive dyskinesia. CASE REPORT A 55year-old man with a history of rapid cycling bipolar manic-depressive psychosis in the past 3 years, was first seen and admitted in the
Health
and Neuro-Sciences,
Bangalore-
029, India.
Clin Neural Neurosurg 1984.Vol. 86-2 (Accepted 2.1.84)
107
institute (National Institute of Mental Health and Neurosciences, Bangalore. India) in June, 1981 during a manic episode. A review of his past treatment revealed indiscriminate polypharmacy. When he was included in an ongoing lithium research project in the institute, all drugs were stopped and lithium started after relevant investigations. After remission. prophylactic lithium was started with a daily dose varying between 900 and 1350 mg’day depending on serum levels, ranging from 0.9 to 1.3 mEq/L. He remained euthymic for the next two years. Subsequently, he had a brief hypomanic swing when lithium was increased to 1500 mg/day. Three days later he developed severe restlessness, inability to sit still, or lie down even for a brief period and an irresistible urge to pace up and down. This was accompanied by a subjective dysphoria over the peculiar restlessness coming mainly from the lower limbs. The patient was unable to sleep properly or concentrate on any work. On the second day he received 200 mg of chlorpromazine orally from a general practitioner for ‘manic excitement’. This worsened his restlessness. In addition, he developed restriction of movements and rapid hand tremors. On the third day, when he was brought to the psychiatric out-patient department he was conscious, alert but dysphoric. He admitted to have a pecuiiar inner restlessness. He had a dysarthric speech and coarse tremors of the outstretched hands. Higher functions, cranial nerves, ocular fundi and tendon-reflexes were normal. He walked with short shuffling gait with minimal associated movements. There was moderate to severe cogwheel rigidity in all four limbs. All other systemic examinations were normal. The process of examination was difticult as the patient frequently got out of bed, paced up and down the corridor, rested for 5 to IO seconds and repeated the same. Serum lithium, estimated 12 hours after the previous night dose of 750 mg was 1.2 mEq/L. Erythrocytic lithium was 0.6 mEq/L. Complete haemogram, urinalysis, renal function tests and serum electrolytes were ail within normal limits. An injection of prometha~ine 50 mg was given immediately and repeated within an hour. Concomitantly. trihexiphenidyl was started at the dose of 4 mg/day. in two divided 108
doses; total dose of lithium was kept unchanged at 1500 mg/day. Akathisia resolved completely within 36 hours after starting anticholinergrcs whereas mild cogwheel rigidity and tine hand tremor continued for more than 3 weeks. All initial investigations were repeated twtoc a week during these three weeks and were found to be normal. Two weeks after the onset of akathisia, the patient became euthymic but developed involuntary sucking and chewing movements along with protrusion of the tongue. These oral, masticatory and lingual movements could not be controlled voluntarily for more than 30 to 45 seconds with carry over phenomenon confined to the lower limbs in the form of ~hore~fo~ movements of the toes and thumping of the feet. These movements slightly decreased when anticholinergics were stopped after three weeks. At follow-ups the patient still showed to have these movement and mild cogwheel rigidity but remained euthymic with 900 mg/day of lithium. DISCUSSION In this patient, euthymic on prophylactic lithium, for 2 years, an extrapyramidal syndrome developed at the therapeutic serum lithium levels, when the total daily dose was increased by 25% during a brief manic episode. The clinical profile was markedly dominated by akathisia initially and bucco-lingua-masticatory dyskinesia at the later stages. Lithium neurotoxicity at ‘therapeutic’ levels has been reported earlie@ and has been recently reviewed by Ghadirian and Lehmann6. More recently, Perenyi, et a1.,7 reported akathisia in a case with lithium-neuroleptic combination out of a total of thirty patients. They failed to find any symptom of akathisia in twenty-four patients treated with lithium alone. Nor did any of twenty-seven patients on ~ithium-antidepressant combination develop akathisia. However, akathisia developing after usage of only lithium has, to the best of our knowledge, not been reported in literature so far. The authors are inclined to consider this phenomenon as a dose-independent, idiosyncratic reaction to lithium, the exact mechanism of which remains unclear at present. Within the therapeutic
range, the most frequently reported extrapyramidal reactions are cogwheel rigidity and rapid hand tremorsa-lo. The onset of the extrapyramidal syndrome after administration of ~hlo~romazine indicates its synergy with lithium. Phenothiazines are proved to cause increased influx of lithium into erythrocytes, possibly by a passive leak diffusionll. The second important aspect of this case is the development of buc~o-linguo-masticator dyskinesia about two weeks after the onset of akathisia. The patient did not have any neuroleptics for a period of about two years. Worsening of akathisia (and precipitation of a neurotoxic syndrome) after addition of chforpromazine as well as improvement of the same with promethazine, would certainly favour the diagnosis of true akathisia rather than pseudoakathisia which is a form ‘fruste’ of tardive dyskinesia. This is, then, a case where tardive dyskinesia followed true akathisia in a close temporal sequence. This temporal association is significant. While it is known that parkinsonism and tardive dyskinesia can coexist’“. it is still unclear whether the first predisposes the second. In this connection, Chouinard’” suggested that akathisia and tremor (hyperkinetic parkinsonism) may be different from the typical hypokinetic parkinsonism. Having found a decreased association between hypokinetic parkinsonism and tardive dyskinesia, he suggested that hyperkinetic parkinsonian symptoms, like akathisia, could represent a transitional state between hypokinetic parkinsonism and tardive dyskinesia. The present case tends to support this “transitional hypothesis”. This is of considerable neurological value. It is not yet known whether akathisia is etiologically related to tardive dyskinesia or whether tardive dyskinesia is more frequent in patients with akathisia. In considering their concept of tardive dysphrenia, elsewhere described as supersensitivity or tardive psychosis 14,15,Forest and Fahn16 described the presence of subjective akathisia in six of seven patients being treated for tardive dyskinesia. They hypothesized that akathisia (the subjective feeling of restlessness) may be a form of tardive dysphrenia. Marsden and Jenner17 indeed suggested that akathisia results from
altered receptor sensitivity in the mesocortical dopamine system and not in the mesolimbic or nigrostriatal systems. This involvement of a cortical system helps to explain the predominant subjective nature of akathisia while nigrostriatal dopamine receptor supersensitivity could explain the motor components. In this particular case, it may be that mesocortical system was involved initially, followed by altered functioning of the nigro-striatal system. The likelihood of differential susceptibility of dopamine receptors in the behavioural (mesocortical and mesolimbic) and motor (nigrostriatal) dopamine systems has been earlier postulated by the authorG7. Whether or not akathisia is a forerunner of tardive dyskinesia is an important question that needs to be addressed by prospective studies in which akathisia and tardive dyskinesia are carefully defined, in a design that would include clinical characteristics as well as biochemical indices. REFERENCES FJ. A survey of drug-induced extrapyramidal reactions. Jama 1961; 175: 1054-1060. VAN PUTTEK T. Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 1974: 3 1: 67-7 I R.~SKINDE. Akathisia: a side effect to be remembered. Am J Psychatry 1972; 129: 345-347. MUNET% MR. CORNES CL. Akathisia. pseudoakathisia and tardive dyskinesia: clinical examples. Compr Psychiatry 1982: 23: 345-352. STRAYHORN JM. NASH JL. Severe neurotoxicity despite “therapeutic” serum Iithium levels. Dis Nerv Syst 1977: 38: 107-111. GHADIRIAN AM.I.EHMANN HE. Neurological side effects of hthium: Organic brain syndrome. seizures, extrapyramidal stde effects and EEG changes. Compr Psychiatry 1980; 21: 327-334. PERENYI A.RIHMER Z,EANKI CM. Parkinsonian symptoms with lithium. lithiunl-neuroIeptic. and lithium-ant~depressant treatment. J Aff disorders 1983; S: 171-177. SHOPSIN B. GERSHON s. Cogwheel rigidity with lithium maintenance. Am J Psychiatry 1975: 132: 536-538. BRANCHEY MH. CHARLES I, SIMPSON GM. Extrapyramidal side effects in lithium maintenance therapy. Am J Psychiatry 1976, 133: 444-445. to KAN& J. RIFKIN A. QUTKIN F et at. Extrapy~midal side effects in lithium treatment. Am J Psychiatry 1978: 135: 851-853. *I PANDEY GN. GOEL I,DAVIS JM. Effect of neuroleptic drugs on lithium uptake by the human erythrocytes. C’lin Pharmacol Ther 1979: 26: 96-102. If KESHAVAN MS GANGADHAR %N, CHATTERJEE SOMNATH. Co-existence of parkinsonism and tardive dyskinesia and CSF amine metabolites. NIMHANS Journal 1983: 1: AYD
11l-1 13. I3 CH~UINARD
G. ANN.~B~.E L, ROSS-CHOUINARD
Factors related to tardive 1979: 136: 79-83.
dyskinesia.
A et al.
Am J Psychiatry
109
” M<<‘ARrHY IJ.I‘ardive psychosis. Am J Phychlatr\i 1976: 135: 625-626. Ii CHOCINARD G, JONES BD. Neuroleptic-mduced supersensitivity. Psychosis: Clinical and Pharmacologic Characteristi& Am J Psychiatry 1980; 137: 16-21. “’ FOREST DV. FAHN s. Tardive dyskinesia and subjective akathisia. J Clin Psychiatry 1979: 40: 206.
110
I7 M.~RSIXN (‘II). JLNNER P. The pathophysioiog! it cxtr,rp>ramidal Gde effects of neuroleptlc druss, Pr\chol Meli 1980: IO: 55-72. ‘* ('H.4NNABASAVANNA SM. GOSWAMI UT1'41. L'L.NKAltSHH. PRADHAX x";.Idiopathic torsion dystonia with schizw phrenia in first degree relatives. Indian J Ps>chiatr> lQ611: ‘4: x-94.