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Neuroleptic malignant syndrome and catatonia: One entity or two?
EDITORIAL
Neuroleptic Malignant Syndrome and Catatonia: One Entity or Two? The neuroleptic malignant syndrome [NMS] and catatonia have much in common. The sudden appearance of mental changes, motor rigidity, fever, and autonomic dysregulation with a history of ingestion of neuroleptic drugs is sufficient to define NMS. Motor rigidity, mutism, negativism, and altered consciousness define catatonia; the lethal or malignant varieties are also associated with autonomic instability and fever. Are NMS and catatonia separate syndromes or is NMS a type of catatonia? The question assumes clinical importance since both syndromes may be lethal, practitioners differ in their treatment approaches, and treatments do affect outcome. The question also assumes theoretic importance, directing our attention to pathophysiology.
NMS A syndrome of altered consciousness, motor rigidity, fever, and autonomic instability following the administration of neuroleptic drugs may be fatal when it is not recognized. Most patients recover with discontinuation of the offending neuroleptic agent and systemic supportive measures alone. Dopamine receptor down-regulation is hypothesized and dopamine agonists are recommended treatments (Lazarus et al 1989). The same authors also ascribe importance to fever in the syndrome, and suggest a pathophysiological connection with malignant hyperthermia, for which the antispasticity drug dantrolene is recommended (Lazarus et al 1989). The merit of dopamine agonists and dantrolene remains controversial, with some authors finding support in the case literature (Rosenberg and Green 1989), and others questioning their efficacy (Rosebush and Stewart 1989). Some reports also find relief with diazepam (Kumar 1987; Kontaxakis et al 1988; O'Brien 1988; White 1992) and lorazepam (Woodbury and Woodbury 1992), but these cases are inconclusive. © 1996 Society of Biological Psychiatry
Catatonia A syndrome characterized by mutism, negativism, rigidity, and stupor, often accompanied by autonomic instability and fever, occurs in a wide range of illnesses--in patients with systemic disorders such as lupus erythematosus and typhoid fever, in persons with severe mood disorders, especially manic states, as a toxic response to psychoactive drugs, and in schizophrenia (Abrams and Taylor 1976; Gelenberg 1976, 1977; Taylor and Abrams, 1977; Taylor 1990; Fink and Taylor 1991; Rogers 1992). A variety dominated by excitement is recognized. It is seen as a state phenomenon resulting from dysfunction of the brain's motor regulation centers, does not result from structural brain changes, and, regardless of comorbid symptoms or mental or physical disorder, resolves quickly with adequate treatment (Taylor 1990). Diagnostic classifications [DSM-III, DSM-IIIR, ICD-9] defined catatonia only as a type of schizophrenia, neglecting its association with other psychiatric disorders (APA 1980, 1987; WHO 1977). That catatonia is a feature of disorders other than schizophrenia is now acknowledged in DSM-IV in the diagnostic class 293.89: catatonia disorder due to...[a general medical condition] (APA 1994). The recognition of catatonia is not difficult. Taylor (1990), Rosebush et al (1990), Lund et al (1991), and Bush et al (in press, a) provide guides to examination and rating scales to identify and measure the severity of more than 20 signs considered characteristic of the syndrome. The persistence of 2 or more motor signs for more than 24 hours is sufficient for the diagnosis (Fink and Taylor, 1991; Taylor, 1991; Bush et al in press, a). Between 5% and 9% of psychiatric in-patient admissions to academic services exhibit two or more signs of catatonia (Rosebush et al 1990; Ungvari et al 1994 a,b; Bush et al in press a). As neuroleptic drugs may precipitate NMS, neuroleptic treatment also worsens catatonia (Fricchione et al 1983). Amobarbital, however, relieves about half the cases (Mc0006-3223/96/515.00 SSDI 0006-3223(95)00552-8
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Call et al 1992). It has been replaced in recent practice by lorazepam (Fricchione et al 1983; Wetzel et al 1985; Menza and Harris 1989; Rosebush et al 1990; Bush et al in press b) and diazepam (White and Robins 1991; White, 1992; Ungvari et al 1994b). When these treatments fail, clinicians turn to electroconvulsive therapy [ECT], which is described as "lifesaving," particularly in patients with malignant catatonia (Hermle and Oepen 1986; Mann et al 1986; Rummans and Bassingthwaighte 1991; Philbrick and Rummans 1994). Failure to administer ECT within five days of the onset of catatonia is associated with a high mortality rate (Philbrick and Rummans 1994). Patients with NMS also respond to ECT, although the same hesitancy can be read in the literature as seen with dopaminergic agonists and dantrolene (Davis et al 1991). Descriptive case material argues that NMS is a form of catatonia. White and Robins (1991) describe five consecutive patients diagnosed with NMS where a syndrome of alternating episodes of catatonic excitement and mutism preceded the administration of a neuroleptic. The diagnosis of NMS was given when muscular rigidity developed and the syndrome assumed a fulminating, malignant course following exposure to a neuroleptic agent. The clinical features of these cases were consistent with the diagnosis of malignant catatonia. That NMS is a neuroleptic intensified form of an antecedent catatonic state is also well demonstrated by a case where separate episodes of both catatonia and NMS occurred within the same patient (White 1992). Two retrospective reviews of NMS case material assessing scores on catatonia scales find that 24/27 and 21/22 cases of NMS meet catatonia criteria (Goforth and Carroll 1995; Koch et al 1995). Biochemical studies are sparse and not distinguishing. Elevated serum creatinine kinases has been considered a characteristic of NMS, but many case reports define NMS in its absence. More important, elevated kinases result from elevated temperature alone or changes in muscle activity as in restraint, intramuscular injections, and increased motor activity, and their elevation is a nonspecific laboratory finding. Cerebrospinal measures of homovanillic acid [HVA] and 5-hydroxyindole acetic acid [5-HIAA] fail to find any consistent patterns in patients with NMS (Lazarus et al 1989; Nisijama and Ishiguro 1990). For NMS, a deficiency in serum iron has been associated with active forms of the disorder (Rosebush and Mazurek 1991). In another examination of 12 episodes of catatonia in 11 patients, 3 patients exhibited markedly decreased serum iron levels; 2 of the 3 had received neuroleptic drugs and were considered instances of NMS (Carroll and Goforth 1995). Fever is nonspecific, occurring in up to 80% of cases of
NMS. Fever is also characteristic of catatonia, especially the malignant varieties. The pathophysiology of NMS is viewed as central blockage of dopamine receptors, particularly D 2 receptors, and their down-regulation (Caroff et al 1991; Lazarus et al 1989). Evidence for dopaminergic dysfunction are the correlations between the potency of neuroleptic drugs as D 2 receptor antagonists and their association with NMS, the apparent success of dopamine agonists in reversing NMS, and NMS following reduced dopaminergic activity as in the depletion of dopamine storage pools by alphamethyltyrosine and treatment with nonneuroleptic dopamine blocking agents as metoclopramide (Mann et al 1991). The pathophysiology of catatonia is poorly defined. Taylor (1990) cites the characteristics of catatonia as consistent with defined functions of the frontal lobes and with the behavioral effects of localized abnormal dopaminergic transmission. That benzodiazepines, barbiturates, and ECT effectively relieve catatonia implicates the gamma-amino-butyric acid [GABA] system, the principal agent of central inhibition, rather than dopamine. Each of these interventions increases brain seizure thresholds, and each is an effective anticonvulsant. A principal characteristic of catatonia is increased "tension," an expression of heightened vigilance. Neuropharmacologists describe GABA as a primary inhibitor of brain excitatory activity, reducing excitatory transmitter release through presynaptic action and the excitability of postsynaptic cells. Two forms of GABA receptors are defined. The more prevalent GABA n receptors are activated by barbiturates and benzodiazepines, augmenting the inhibitory actions of GABAergic receptors (Krnjevic 1991). Supporting a specific role for benzodiazepine receptors is the report that catatonia relieved by benzodiazepines recurs with the administration of the benzodiazepine antagonist flumazenil (Wetzel et al 1987). The effects of ECT on brain GABAergic activity is seen in the rise in seizure thresholds during a course of ECT, the abrupt turn-off of ECT-induced seizures, the isoelectric EEG after a successful seizure, and the efficacy of ECT to abort status epilepticus (Kalinowsky and Kennedy 1943; Caplan 1946). The motor abnormalities of catatonia may result from decreased GABAergic activity in specific brain nuclei, and the downregulation of GABA receptors that subserve these motor functions. Direct stimulation of receptors by benzodiazepines or by seizures increase functional GABA levels and reverse these deficiencies (Krnjevic 1991). Although reviewers of the pathophysiology of NMS emphasize the relation to dopaminergic receptor physiology, and reviewers of catatonia emphasize the relation to GABAergic systems, neither view is supported by corn-
Editorial
BIOLPSYCHIATRY
3
1996;39:1-4
pelling laboratory or clinical evidence. In clinical practice, removal of neuroleptic drugs and systemic supportive measures are clearly the first interventions in both NMS and catatonia. For severe cases of NMS, the evidence for the use of dopamine agonists and dantrolene is insufficient to compel their use, and the clinical evidence for high dose benzodiazepines in NMS is also weak. Nevertheless, the efficacy of benzodiazepines in catatonia argue for their consideration in both syndromes, especially when assessing their more malignant forms. Applying high doses of benzodiazepines and/or ECT favors clinical resolution and reduces illness and fatality. The similarities in NMS and catatonia argue that these conditions are variants of the same disorder. Similar views
have previously been expressed by Fricchione (1985), Kellam (1990), Chandler (1991), and Rogers (1992). Approaching these syndromes as a single entity assures adequate treatment for those afflicted by the use of high doses of BZD and when these fail, a course of ECT. This view also encourages tests of GABA-ergic functions, with opportunities to assess the pathophysiology and psychopathology in cases of both NMS and of catatonia. M a x Fink Department of Psychiatry and Behavioral Sciences School of Medicine State University of New York at Stony Brook St. James, NY 11780-0457
References Abrams R, Taylor MA (1976): Catatonia, a prospective clinical study. Arch Gen Psychiatry 33:579-581. American Psychiatric Association (1980): Diagnostic and Statistical Manual of Mental Disorders (Third Edition). Washington, DC. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revised). Washington, DC. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Washington, DC. Bush G, Fink M, Petrides G, Dowling F, Francis A: Catatonia: I: Rating scale and standardized examination. Acta Psychiatr Scand (in press, a). Bush G, Fink M, Petrides G, Dowling F, Francis A: Catatonia: II. Treatment with lorazepam and electroconvulsive therapy. Acta Psychiatr Scand (in press, b). Caplan G. (1946): Electrical convulsion therapy in the treatment of epilepsy. J Ment Sci 92:784-786. Caroff SN, Mann SC, Lazarus A, Sullivan K, Macfadden W (1991): Neuroleptic malignant syndrome: Diagnostic issues. Psychiatr Ann 21:130-147. Carroll BT, Goforth HW (1995): Serum iron in catatonia. Biol Psychiatry 38:776-777. Chandler JD (1991): Psychogenic catatonia with elevated creatine kinase and autonomic hyperativity. Can J Psychiatry 36:530-532. Davis JM, Janicak PG, Sakkas P, Gilmore C, Wang Z (1991): Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convulsive Ther 7:111-120. Fink M, Taylor MA (1991): Catatonia: A separate category for DSM-IV? Integrative Psychiatry 7:2-10. Fricchione GL (1985): Neuroleptic catatonia and its relationship to psychogenic catatonia Biol Psychiatry 20:304-313. Fricchione GL, Cassem NH, Hooberman D et al (1983): Intravenous lorazepam in neuroleptic-induced catatonia. J Clin Psychopharm 3:338-342. Gelenberg AJ (1976): The catatonic syndrome. Lancet 2:13391341.
Gelenberg AJ (1977): Catatonic reactions to high-potency neuroleptic drugs. Arch Gen Psychiatry 34:947-950. Gelenberg AJ, Mandel MR (1977): Catatonic reactions to high potency neuroleptic drugs. Arch Gen Psychiatry 34:947-950. Goforth HW, Carroll BT (1995): The overlap of neuroleptic malignant syndrome (NMS) and catatonic diagnoses. J Neuropsychiatry Clin Neurosci 7:402 [abstract]. Hermle L, Oepen G (1986): Zur differentialdiagnose der akut lebensbedrohlichen Katatonie und des malignen Neuroleptikasyndroms--ein kasuister Beitrag. Fortschr Neurol Psychiatr 54:189-195. Kalinowsky L, Kennedy F (1943): Observations in electric shock therapy applied to problems of epilepsy. J Nerv Ment Dis 98:56-60. Kellam AMP (1990): The (frequently) neuroleptic (potentially) malignant syndrome. Br J Psychiatry 157:169-173. Koch MA, Petrides G, Francis AJ (1995): Catatonia from neuroleptics and NMS: Two entities? APA New Res Abstr NR 227:117. Kontaxakis VP, Christodoulou GN, Markidis MP, Havaki-Kontaxaki BJ (1988): Treatment of a mild form of neuroleptic malignant syndrome with oral diazepam. Acta Psychiatr Scand 78:396-398. Krnjevic K (1991): Significance of GABA in brain function. In: G. Tunnicliff B.U. Raess (Eds.) GABA Mechanisms in Epilepsy. New York: Wiley-Liss, 3:47-88. Kumar V (1987): A case of neuroleptic malignant syndrome treated with diazepam (letter). Can J Psychiatry 32:815-816. Lazarus A, Mann SC, Caroff SN (1989): The Neuroleptic Malignant Syndrome and Related Conditions. Washington DC: American Psychiatric Press. Lund CE, Mortimer AM, Rogers D, McKenna PJ (1991): Motor, volitional and behavioural disorders in schizophrenia 1: Assessment using the modified Rogers scale. Br J Psychiatry 158:323-327. Mann SC, Caroff SN, Bleier JR, Welz WKR, Kling MA, Hayashida M (1986): Lethal catatonia. Am J Psychiatry 143:1374-1381.
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Mann SC, Caroff SN, Lazarus A (1991): Pathogenesis of neuroleptic malignant syndrome. Psychiatr Ann 21:175-180. McCall WV, Shelp FE, McDonald WM (1992): Controlled investigation of the amobarbital interview for catatonic mutism. Am J Psychiatry 149:202-206. Menza MA, Harris D (1989): Benzodiazepines and catatonia: An overview. Biol Psychiatry 26:842-846. Nisijama K, Ishiguro T (1990): Neuroleptic malignant syndrome: A study of CSF monoamine metabolism. Biol Psychiatry 27:280-288. O'Brien P (1988). Neuroleptic malignant syndrome treated with diazepam (letter). Can J Psychiatry 33:780. Petrides G, Bush G, Francis AJ (1995): Combined lorazepam and ECT to treat catatonia. APA New Res Abstr NR490:186-187. Philbrick KL, Rummans TA (1994): Malignant catatonia. J Neuropsychiatry Clin Neurosci 6:1-13. Rogers D (1992): Motor Disorders in Psychiatry: Towards a Neurological Psychiatry. Chichester: Wiley. Rosebush PI, Hildebrand AM, Furlong BG, Mazurek MF (1990): Catatonic syndrome in a general psychiatric population: Frequency, clinical presentation, and response to lorazepam, J Clin Psychiatry 51:357-362. Rosebush PI, Mazurek MF (1991): Serum iron and neuroleptic malignant syndrome. Lancet 338:149-151. Rosebush P, Stewart T (1989): A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 146:717-725. Rosenberg MR, Green M (1989): Neuroleptic malignant syndrome: Review of response to therapy. Arch Int Med 149: 1927-1931.
Editorial
Rummans T, Bassingthwaighte ME (199l): Severe medical and neurologic complications associated with near-lethal catatonia treated with electroconvulsive therapy. Convulsive Ther 7:121-124. Taylor MA (1990): Catatonia. A review of the behavioral neurologic syndrome. Neuropsychiat Neuropsychol Behav Neurol 3:48-72. Taylor MA, Abrams R (1977): Catatonia: Prevalence and importance in the manic phase of manic-depressive illness. Arch Gen Psychiatry 34:1223-1225. Ungvari GS, Leung HCM, Lee TS (1994a): Benzodiazepines and the psychopathology of catatonia. Pharmacopsychiatry 27: 242-245. Ungvari GS, Leung CM, Wong MK, Lau J (1994b): Benzodiazepines in the treatment of catatonic syndrome. Acta Psychiatr Scand 89:285-888. Wetzel H, Heuser I, Benkert O (1987): Stupor and affective state: Alleviation of psychomotor disturbances by lorazepam and recurrence of symptoms after Ro 15-1788. J Nerv Mental Dis 175:240-242. White DAC (1992): Catatonia and the neuroleptic malignant syndrome--A single entity? Br J Psychiatry 161:558-560. White DAC, Robins AH (1991): Catatonia: Harbinger of the neuroleptic malignant syndrome. Br J Psychiatry 158:419421. Woodbury MM, Woodbury MA (1992): Neuroleptic-induced catatonia as a stage in the progression toward neuroleptic malignant syndrome. J Am Acad Child Adolesc Psychiatry 31:1161-1164. World Health Organization (1977): International Classification of Diseases., rev IX. Geneva: World Health Organization.
Neuroleptic Malignant Syndrome and Catatonia: One Entity or Two? The neuroleptic malignant syndrome [NMS] and catatonia have much in common. The sudden appearance of mental changes, motor rigidity, fever, and autonomic dysregulation with a history of ingestion of neuroleptic drugs is sufficient to define NMS. Motor rigidity, mutism, negativism, and altered consciousness define catatonia; the lethal or malignant varieties are also associated with autonomic instability and fever. Are NMS and catatonia separate syndromes or is NMS a type of catatonia? The question assumes clinical importance since both syndromes may be lethal, practitioners differ in their treatment approaches, and treatments do affect outcome. The question also assumes theoretic importance, directing our attention to pathophysiology.
NMS A syndrome of altered consciousness, motor rigidity, fever, and autonomic instability following the administration of neuroleptic drugs may be fatal when it is not recognized. Most patients recover with discontinuation of the offending neuroleptic agent and systemic supportive measures alone. Dopamine receptor down-regulation is hypothesized and dopamine agonists are recommended treatments (Lazarus et al 1989). The same authors also ascribe importance to fever in the syndrome, and suggest a pathophysiological connection with malignant hyperthermia, for which the antispasticity drug dantrolene is recommended (Lazarus et al 1989). The merit of dopamine agonists and dantrolene remains controversial, with some authors finding support in the case literature (Rosenberg and Green 1989), and others questioning their efficacy (Rosebush and Stewart 1989). Some reports also find relief with diazepam (Kumar 1987; Kontaxakis et al 1988; O'Brien 1988; White 1992) and lorazepam (Woodbury and Woodbury 1992), but these cases are inconclusive. © 1996 Society of Biological Psychiatry
Catatonia A syndrome characterized by mutism, negativism, rigidity, and stupor, often accompanied by autonomic instability and fever, occurs in a wide range of illnesses--in patients with systemic disorders such as lupus erythematosus and typhoid fever, in persons with severe mood disorders, especially manic states, as a toxic response to psychoactive drugs, and in schizophrenia (Abrams and Taylor 1976; Gelenberg 1976, 1977; Taylor and Abrams, 1977; Taylor 1990; Fink and Taylor 1991; Rogers 1992). A variety dominated by excitement is recognized. It is seen as a state phenomenon resulting from dysfunction of the brain's motor regulation centers, does not result from structural brain changes, and, regardless of comorbid symptoms or mental or physical disorder, resolves quickly with adequate treatment (Taylor 1990). Diagnostic classifications [DSM-III, DSM-IIIR, ICD-9] defined catatonia only as a type of schizophrenia, neglecting its association with other psychiatric disorders (APA 1980, 1987; WHO 1977). That catatonia is a feature of disorders other than schizophrenia is now acknowledged in DSM-IV in the diagnostic class 293.89: catatonia disorder due to...[a general medical condition] (APA 1994). The recognition of catatonia is not difficult. Taylor (1990), Rosebush et al (1990), Lund et al (1991), and Bush et al (in press, a) provide guides to examination and rating scales to identify and measure the severity of more than 20 signs considered characteristic of the syndrome. The persistence of 2 or more motor signs for more than 24 hours is sufficient for the diagnosis (Fink and Taylor, 1991; Taylor, 1991; Bush et al in press, a). Between 5% and 9% of psychiatric in-patient admissions to academic services exhibit two or more signs of catatonia (Rosebush et al 1990; Ungvari et al 1994 a,b; Bush et al in press a). As neuroleptic drugs may precipitate NMS, neuroleptic treatment also worsens catatonia (Fricchione et al 1983). Amobarbital, however, relieves about half the cases (Mc0006-3223/96/515.00 SSDI 0006-3223(95)00552-8
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1996;39:l-4
Call et al 1992). It has been replaced in recent practice by lorazepam (Fricchione et al 1983; Wetzel et al 1985; Menza and Harris 1989; Rosebush et al 1990; Bush et al in press b) and diazepam (White and Robins 1991; White, 1992; Ungvari et al 1994b). When these treatments fail, clinicians turn to electroconvulsive therapy [ECT], which is described as "lifesaving," particularly in patients with malignant catatonia (Hermle and Oepen 1986; Mann et al 1986; Rummans and Bassingthwaighte 1991; Philbrick and Rummans 1994). Failure to administer ECT within five days of the onset of catatonia is associated with a high mortality rate (Philbrick and Rummans 1994). Patients with NMS also respond to ECT, although the same hesitancy can be read in the literature as seen with dopaminergic agonists and dantrolene (Davis et al 1991). Descriptive case material argues that NMS is a form of catatonia. White and Robins (1991) describe five consecutive patients diagnosed with NMS where a syndrome of alternating episodes of catatonic excitement and mutism preceded the administration of a neuroleptic. The diagnosis of NMS was given when muscular rigidity developed and the syndrome assumed a fulminating, malignant course following exposure to a neuroleptic agent. The clinical features of these cases were consistent with the diagnosis of malignant catatonia. That NMS is a neuroleptic intensified form of an antecedent catatonic state is also well demonstrated by a case where separate episodes of both catatonia and NMS occurred within the same patient (White 1992). Two retrospective reviews of NMS case material assessing scores on catatonia scales find that 24/27 and 21/22 cases of NMS meet catatonia criteria (Goforth and Carroll 1995; Koch et al 1995). Biochemical studies are sparse and not distinguishing. Elevated serum creatinine kinases has been considered a characteristic of NMS, but many case reports define NMS in its absence. More important, elevated kinases result from elevated temperature alone or changes in muscle activity as in restraint, intramuscular injections, and increased motor activity, and their elevation is a nonspecific laboratory finding. Cerebrospinal measures of homovanillic acid [HVA] and 5-hydroxyindole acetic acid [5-HIAA] fail to find any consistent patterns in patients with NMS (Lazarus et al 1989; Nisijama and Ishiguro 1990). For NMS, a deficiency in serum iron has been associated with active forms of the disorder (Rosebush and Mazurek 1991). In another examination of 12 episodes of catatonia in 11 patients, 3 patients exhibited markedly decreased serum iron levels; 2 of the 3 had received neuroleptic drugs and were considered instances of NMS (Carroll and Goforth 1995). Fever is nonspecific, occurring in up to 80% of cases of
NMS. Fever is also characteristic of catatonia, especially the malignant varieties. The pathophysiology of NMS is viewed as central blockage of dopamine receptors, particularly D 2 receptors, and their down-regulation (Caroff et al 1991; Lazarus et al 1989). Evidence for dopaminergic dysfunction are the correlations between the potency of neuroleptic drugs as D 2 receptor antagonists and their association with NMS, the apparent success of dopamine agonists in reversing NMS, and NMS following reduced dopaminergic activity as in the depletion of dopamine storage pools by alphamethyltyrosine and treatment with nonneuroleptic dopamine blocking agents as metoclopramide (Mann et al 1991). The pathophysiology of catatonia is poorly defined. Taylor (1990) cites the characteristics of catatonia as consistent with defined functions of the frontal lobes and with the behavioral effects of localized abnormal dopaminergic transmission. That benzodiazepines, barbiturates, and ECT effectively relieve catatonia implicates the gamma-amino-butyric acid [GABA] system, the principal agent of central inhibition, rather than dopamine. Each of these interventions increases brain seizure thresholds, and each is an effective anticonvulsant. A principal characteristic of catatonia is increased "tension," an expression of heightened vigilance. Neuropharmacologists describe GABA as a primary inhibitor of brain excitatory activity, reducing excitatory transmitter release through presynaptic action and the excitability of postsynaptic cells. Two forms of GABA receptors are defined. The more prevalent GABA n receptors are activated by barbiturates and benzodiazepines, augmenting the inhibitory actions of GABAergic receptors (Krnjevic 1991). Supporting a specific role for benzodiazepine receptors is the report that catatonia relieved by benzodiazepines recurs with the administration of the benzodiazepine antagonist flumazenil (Wetzel et al 1987). The effects of ECT on brain GABAergic activity is seen in the rise in seizure thresholds during a course of ECT, the abrupt turn-off of ECT-induced seizures, the isoelectric EEG after a successful seizure, and the efficacy of ECT to abort status epilepticus (Kalinowsky and Kennedy 1943; Caplan 1946). The motor abnormalities of catatonia may result from decreased GABAergic activity in specific brain nuclei, and the downregulation of GABA receptors that subserve these motor functions. Direct stimulation of receptors by benzodiazepines or by seizures increase functional GABA levels and reverse these deficiencies (Krnjevic 1991). Although reviewers of the pathophysiology of NMS emphasize the relation to dopaminergic receptor physiology, and reviewers of catatonia emphasize the relation to GABAergic systems, neither view is supported by corn-
Editorial
BIOLPSYCHIATRY
3
1996;39:1-4
pelling laboratory or clinical evidence. In clinical practice, removal of neuroleptic drugs and systemic supportive measures are clearly the first interventions in both NMS and catatonia. For severe cases of NMS, the evidence for the use of dopamine agonists and dantrolene is insufficient to compel their use, and the clinical evidence for high dose benzodiazepines in NMS is also weak. Nevertheless, the efficacy of benzodiazepines in catatonia argue for their consideration in both syndromes, especially when assessing their more malignant forms. Applying high doses of benzodiazepines and/or ECT favors clinical resolution and reduces illness and fatality. The similarities in NMS and catatonia argue that these conditions are variants of the same disorder. Similar views
have previously been expressed by Fricchione (1985), Kellam (1990), Chandler (1991), and Rogers (1992). Approaching these syndromes as a single entity assures adequate treatment for those afflicted by the use of high doses of BZD and when these fail, a course of ECT. This view also encourages tests of GABA-ergic functions, with opportunities to assess the pathophysiology and psychopathology in cases of both NMS and of catatonia. M a x Fink Department of Psychiatry and Behavioral Sciences School of Medicine State University of New York at Stony Brook St. James, NY 11780-0457
References Abrams R, Taylor MA (1976): Catatonia, a prospective clinical study. Arch Gen Psychiatry 33:579-581. American Psychiatric Association (1980): Diagnostic and Statistical Manual of Mental Disorders (Third Edition). Washington, DC. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revised). Washington, DC. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Washington, DC. Bush G, Fink M, Petrides G, Dowling F, Francis A: Catatonia: I: Rating scale and standardized examination. Acta Psychiatr Scand (in press, a). Bush G, Fink M, Petrides G, Dowling F, Francis A: Catatonia: II. Treatment with lorazepam and electroconvulsive therapy. Acta Psychiatr Scand (in press, b). Caplan G. (1946): Electrical convulsion therapy in the treatment of epilepsy. J Ment Sci 92:784-786. Caroff SN, Mann SC, Lazarus A, Sullivan K, Macfadden W (1991): Neuroleptic malignant syndrome: Diagnostic issues. Psychiatr Ann 21:130-147. Carroll BT, Goforth HW (1995): Serum iron in catatonia. Biol Psychiatry 38:776-777. Chandler JD (1991): Psychogenic catatonia with elevated creatine kinase and autonomic hyperativity. Can J Psychiatry 36:530-532. Davis JM, Janicak PG, Sakkas P, Gilmore C, Wang Z (1991): Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convulsive Ther 7:111-120. Fink M, Taylor MA (1991): Catatonia: A separate category for DSM-IV? Integrative Psychiatry 7:2-10. Fricchione GL (1985): Neuroleptic catatonia and its relationship to psychogenic catatonia Biol Psychiatry 20:304-313. Fricchione GL, Cassem NH, Hooberman D et al (1983): Intravenous lorazepam in neuroleptic-induced catatonia. J Clin Psychopharm 3:338-342. Gelenberg AJ (1976): The catatonic syndrome. Lancet 2:13391341.
Gelenberg AJ (1977): Catatonic reactions to high-potency neuroleptic drugs. Arch Gen Psychiatry 34:947-950. Gelenberg AJ, Mandel MR (1977): Catatonic reactions to high potency neuroleptic drugs. Arch Gen Psychiatry 34:947-950. Goforth HW, Carroll BT (1995): The overlap of neuroleptic malignant syndrome (NMS) and catatonic diagnoses. J Neuropsychiatry Clin Neurosci 7:402 [abstract]. Hermle L, Oepen G (1986): Zur differentialdiagnose der akut lebensbedrohlichen Katatonie und des malignen Neuroleptikasyndroms--ein kasuister Beitrag. Fortschr Neurol Psychiatr 54:189-195. Kalinowsky L, Kennedy F (1943): Observations in electric shock therapy applied to problems of epilepsy. J Nerv Ment Dis 98:56-60. Kellam AMP (1990): The (frequently) neuroleptic (potentially) malignant syndrome. Br J Psychiatry 157:169-173. Koch MA, Petrides G, Francis AJ (1995): Catatonia from neuroleptics and NMS: Two entities? APA New Res Abstr NR 227:117. Kontaxakis VP, Christodoulou GN, Markidis MP, Havaki-Kontaxaki BJ (1988): Treatment of a mild form of neuroleptic malignant syndrome with oral diazepam. Acta Psychiatr Scand 78:396-398. Krnjevic K (1991): Significance of GABA in brain function. In: G. Tunnicliff B.U. Raess (Eds.) GABA Mechanisms in Epilepsy. New York: Wiley-Liss, 3:47-88. Kumar V (1987): A case of neuroleptic malignant syndrome treated with diazepam (letter). Can J Psychiatry 32:815-816. Lazarus A, Mann SC, Caroff SN (1989): The Neuroleptic Malignant Syndrome and Related Conditions. Washington DC: American Psychiatric Press. Lund CE, Mortimer AM, Rogers D, McKenna PJ (1991): Motor, volitional and behavioural disorders in schizophrenia 1: Assessment using the modified Rogers scale. Br J Psychiatry 158:323-327. Mann SC, Caroff SN, Bleier JR, Welz WKR, Kling MA, Hayashida M (1986): Lethal catatonia. Am J Psychiatry 143:1374-1381.
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