brain damage

Neuroleptic drug induced BRAIN DAMAGE

Wednesday, September 17, 2008
Evidence of Neuroleptic Drug-Induced Brain Damage in Patients:
A partial, Annotated Bibliography
by Vera Hassner Sharav
142 West End Ave. Suite 28P New York, NY 10023
212-595-8974 FAX: 212-595-9086

For distribution: January, 2000
Although patients, families and the public were not informed – some would argue they were deceived – clinical psychiatrists and researchers have long known about severe adverse drug reactions (ADR) and disabling changes in the central nervous system in a high percentage of patients taking standard neuroleptic drugs. Foremost among these is “tardive dyskinesia” (TD), an often irreversible, disfiguring disorder of the central nervous system resulting in a variety of involuntary movements, particularly of the tongue, lips, and jaw. muscle movements which affects 40% to 60% of patients taking neuroleptics. Recent research findings corroborate earlier reports (since 1970) linking TD to a deterioration of cognitive functions (see below).

Other severe ADRs include: “extrapyramidal symptoms” (EPS), Parkinson-like, impaired motor coordination; sedation; extreme restlessness (“akathesia”); reduced cognitive function;as well as cardiovascular effects, orthostatic hypotension, abnormal liver changes, anticholinergic side effects, sexual dysfunction, and weight gain. Psychotic relapse has been linked to long-term neuroleptic treatment –referred to as, “supersensitivity psychosis.” Additionally, there is a one percent risk of “neuroleptic malignant syndrome” (NMS), a potentially fatal side effect. These, and a host of other adverse side effects, cause most schizophrenia patients to stop taking these drugs.

In an article written in 1986, Tardive Dyskinesia: Barriers to the Professional Recognition of Iatrogenic Disease, [Journal of Health and Social Behavior,1986, 27: 116-132], Brown and Funk stated: “tardive dyskinesia (TD), once regarded by psychiatrists as a rare syndrome, is currently recognized as the second most pervasive side effect following sedation of antipsychotic drugs.” Although evidence linking TD to neuroleptic drugs had been shown since 1957, Brown and Funk point out that the recognition of TD as a side effect had been “a slow and uneven process, involving psychiatric resistance….Even when physicians believe that patients should be informed about the risks of TD, usually only incomplete information is given, not all patients at risk are informed….” And, they noted, “psychiatrists who are critical of the profession’s lax treatment of the problem argue that if doctors were really concerned, they would reduce their use of neuroleptics and reduce dosages when drugs are employed…” and they would fully disclose the risks of TD to their patients.

But a review of the history of TD demonstrates clearly that despite the evidence physicians’ disclosure and practice with respect to neuroleptic drugs has remained unchanged, and TD afflicts ever more patients, especially after long-term exposure-estimates range between 40% to 60%. The APA has opposed written informed consent from patients.

Van Putten T, Marder SR (1987) Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987 Sep;48 Suppl:13-9

Extrapyramidal symptoms cause much misery, often go undiagnosed, and can interfere with treatment and rehabilitation. Akinesia is a behavioral state of diminished motoric and psychic spontaneity that is difficult to distinguish from the negative symptoms of schizophrenia. The most useful clinical correlates of akinesia are a subjective sense of sedation and excessive sleeping. Akinesia interferes with social adjustment and may manifest as “postpsychotic depression.” The subjective restlessness of akathisia is usually accompanied by telltale foot movements: rocking from foot to foot while standing or walking on the spot. Akathisia is strongly associated with depression and dysphoric responses to neuroleptics and has even been linked to suicidal and homicidal behavior in extreme cases.

Recent Findings Corroborate high incidence of drug-induced movement disorders:
Miller LG, Jankovic J (1990) Neurologic approach to drug-induced movement disorders: a study of 125 patients.South Med J 1990 May;83(5):525-32. Department of Family Medicine, Baylor College of Medicine, Houston, Tex.

Of 125 patients with neuroleptic (dopamine blocking) drug-induced movement disorders who had been referred to a specialized clinic to differentiate the predominant movement disorder, 63% had tardive dyskinesia, 30% had parkinsonism, 24% had dystonia, 7% had akathisia, and 2% had isolated tremor. Two or more movement disorders coexisted in 31 patients (25%).

Functional disability was more severe in patients with akathisia than in other patients. Women outnumbered men at a ratio of 4:1, except for tardive dystonia which affected both sexes equally. The average at onset was 56 years (range, 13 to 87); 69 patients (55%) had onset of movement disorder in the sixth decade. While tardive dystonia was distributed relatively evenly in all age groups, almost a third of patients with parkinsonism had it in the eighth decade. Haloperidol was implicated in 47 patients (37%), followed by amitriptyline/perphenazine in 30%, thioridazine in 27%, and chlorpromazine in 20%. Metoclopramide-induced movement disorders were found in 10 (8%). Most patients (101 or 81%) had history of psychiatric illnesses, but of these only 44 had psychosis.

Neuroleptic drugs had been prescribed for 33 patients (26%) who had gastrointestinal problems. It is important to recognize and differentiate various drug-induced movement disorders because such differentiation has pathophysiologic and therapeutic implications. Many patients could have been treated with less potent drugs.

Muscettola G, Barbato G, Pampallona S, Casiello M, Bollini P (1999) Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. J Clin Psychopharmacol 1999 Jun;19(3):203-8

ABSTRACT: Prevalence and risk factors for extrapyramidal syndromes (EPS) were investigated in a sample of 1,559 patients. The overall prevalence of EPS was 29.4% (N = 458). Among the EPS-diagnosed patients, Parkinsonism as assessed by the presence of core Parkinsonian symptoms (rigidity, tremor, bradykinesia) was present in 65.9% of patients (N = 302), akathisia in 31.8% (N = 145), and acute dystonia in 2.1% (N = 10).

EPS was diagnosed in 50.2% of 285 patients with persistent tardive dyskinesia (TD). Distribution of EPS in patients with TD showed that tremor and akathisia were more frequent in peripheral TD cases than in orofacial TD cases. Furthermore, there was a stronger association of NL-induced parkinsonism with peripheral TD than with orofacial TD. This study suggests that the association between EPS and TD may be limited to specific subtypes of TD. Peripheral TD showed a higher association with parkinsonism and with akathisia, suggesting that these symptoms may share a common pathophysiology.

Bristow MF, Hirsch SR (1993) Pitfalls and problems of the long term use of neuroleptic drugs in schizophrenia. Drug Safety 1993 Feb;8(2):136-48. Academic Department of Psychiatry, Charing Cross and Westminster Medical School, London, England.

ABSTRACT: Although acute and immediate extrapyramidal syndromes are common and, in the case of neuroleptic malignant syndrome, may have serious sequelae, the most important problem with psychotropic medication in schizophrenia remains the tardive movement disorders. These are increasingly recognised as being aetiologically as well as symptomatically heterogeneous. Although risk factors are being identified with greater clarity, there is little in the way of effective treatment. This suggests that clinicians must embark on long term neuroleptic treatment with vigilance. Clozapine alone has few extrapyramidal effects, and has been described in isolated instances as improving established movement disorders. However, haematological idiosyncrasies will preclude its use in all where compliance is uncertain. Its superior efficacy will hopefully give impetus to research into safer analogues.

Hansen TE, Brown WL, Weigel RM, Casey DE (1992) Underrecognition of tardive dyskinesia and drug-induced parkinsonism by psychiatric residents. Gen Hosp Psychiatry 1992 Sept; 14(5):340-4. Portland Veterans Affairs Medical Center, Oregon Health Sciences University 97207.

Recognition of tardive dyskinesia (TD) and other neuroleptic, drug-induced, extrapyramidal side effects presents a major challenge in modern clinical psychopharmacology. Failure to recognize these disorders can lead to poor patient care and may contribute to societal pressure for external control of psychiatric practice. This study reports the occurrence of tardive dyskinesia and drug-induced parkinsonism (DIP) in 101 inpatients, and documents under recognition of both disorders by resident physicians.

Researchers noted TD in 28% of cases and residents only described TD (or symptoms ofTD) in 12%. The researcher determined DIP prevalence rate of 26% contrasted with an 11% rate found by residents. Patients with psychotic disorders were more likely than other patients to have researcher-identified TD, whereas DIP (researcher cases) occurred more often in patients with affective diagnoses. Residents tended to miss milder cases of TD, and to miss DIP in younger patients and in patients with affective disorders. Improved teaching and clinical exams are recommended to improve recognition.

Neuroleptic drug induced psychotic relapse (“supersensitivity psychosis”)
Chouinard G. Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 1991 Jul-Aug;5(1):21-33 Psychiatric Research Center, Louis-H. Lafontaine Hospital, University of Montreal, Quebec, Canada.

ABSTRACT: Tardive dyskinesia is thought to result from neostriatal dopaminergic receptor supersensitivity induced by chronic treatment with neuroleptics. Similarly, receptor supersensitivity occurring in other dopaminergic regions of the brain could result in the development of supersensitivity psychosis. As with tardive dyskinesia, severe forms of the disorder are rare. Ten such cases are described whose main characteristic is that psychotic symptoms can no longer be masked by increased dosages of neuroleptics. Diagnostic criteria for the disorder are proposed, and treatment with antiepileptic medication is described.

Kirkpatrick B, Alphs L, Buchanan RW (1992) The concept of supersensitivity psychosis. J Nerv Ment Dis 1992 Apr;180(4):265-70. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore 21228.

ABSTRACT: The hypothesis that chronic neuroleptic treatment may induce relapse in some schizophrenic patients has received considerable attention. This effect, usually called supersensitivity psychosis, has been attributed to neuroleptic-induced changes in mesolimbic or mesocortical dopaminergic receptors. However, research has not established that neuroleptics cause the proposed effect, and considerations of mechanism have not been separated from those of causation. The focus of research in this area should be the establishment or refutation of a causal relationship between chronic neuroleptic use and psychotic relapse.

Chouinard G, Sultan S. Treatment of supersensitivity psychosis withantiepileptic drugs: report of a series of 43 cases. Psychopharmacol Bull 1990;26(3):337-41. Allan Memorial Institute, Montreal, Quebec, Canada.

Supersensitivity psychosis has emerged as a potential side effect of long-term neuroleptic therapy that may be similar to tardive dyskinesia. Schizophrenic patients with supersensitivity psychosis and considered to be drug-resistant were treated with anti-epileptic medication. Forty-three separate trials were conducted on a total of 35 patients. Over half improved on clinical global impression, some of them considerably. We propose that antiepileptic drugs ameliorate supersensitivity psychosis and so-called “drug-resistant” schizophrenic patients by correcting a pharmacological kindling effect in the limbic system which results from chronic neuroleptic therapy. Publication Types: Clinical trial

Kahne GJ. Rebound psychoses following the discontinuation of a high potency neuroleptic. Can J Psychiatry 1989 Apr;34(3):227-9

Increased familiarity with the effects of psychotropic medications has led to modifications in both prescribing habits and length of treatment. The case of a 34 year old woman is presented, in whom the return of psychotic symptoms following the discontinuation of neuroleptic medications is attributed to a rebound phenomena as opposed to a relapse of an underlying chronic illness

The author cites parallel situations previously described in the medical literature and outlines a conceptual framework for the understanding of this phenomenon.

Bowers MB Jr, Swigar ME. Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol 1988 Dec;8(6):417-21. Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut

ABSTRACT: We describe a group of psychotic patients who became worse early in the course of neuroleptic treatment. Characteristics of this group were: predominantly female sex, relatively brief onset, family history of affective disorder, hypomotoric presentation, and severe neuroleptic side effects. We propose that some patients with affective psychoses are uniquely susceptible to profound blockade of the nigrostriatal dopaminergic system by neuroleptics.

During the 1990s, the “Decade of the Brain:”
Newer “atypical” neuroleptics have been developed-clozapine, risperdone, olanzapine and quitepane-these drugs have a lower risk of EPS and TD, but are associated in varying degrees with sedation, cardiovascular and liver enzyme abnormalities, anticholinergic effects, extreme weight gain (30lbs to 50lbs) which significantly increases the risk for diabetes, sexual dysfunction, NMS, seizures, mania, and (in the case of clozapine) agranulocytosis.

Additionally, mounting clinical evidence and findings -from non-industry sponsored research-point to additional, severe, adverse neurological changes in response to long-term exposure to neuroleptics. These drugs’ actions suppress certain brain receptors (e.g., dopamine, glutamate), and when such drugs are withdrawn (or a patient stops taking them) the drug-induced receptor changes are unmasked, causing an acute “discontinuation syndrome” (i.e., “rebound psychosis” ) that is often more severe than the original symptoms of the illness. Psychotic relapse can cause months of mental and emotional anguish and loss of functioning-rebound psychosis can cause violent and suicidal behavior in patients not previously violent. [Often, these drug-induced reactions are used to justify forcing the person back on the drugs.]

Collaborative Working Group on Clinical Trial Evaluations. Adverse effects of the atypical antipsychotics. J Clin Psychiatry 1998; 59 Suppl 12:17-22

ABSTRACT: Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients’ concerns about adverse effects and attempt to choose medications that will improve their patients’ quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain.

The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual’s dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Wyderski RJ, Starrett WG, Abou-Saif A. Fatal status epilepticus associated with olanzapine therapy. Ann Pharmacother 1999 Jul-Aug;33(7-8):787-9. Department of Internal Medicine, School of Medicine, Wright State University, Dayton, OH 45409, USA.

OBJECTIVE: To report a case of fatal status epilepticus in a patient using olanzapine with no known underlying cause or predisposing factor for seizure. CASE SUMMARY: A 41-year-old white woman developed witnessed seizures at home that progressed to status epilepticus. She subsequently died from secondary rhabdomyolysis and disseminated intravascular coagulation.She had been taking olanzapine for five months prior to the event. No other toxic, metabolic, or anatomic abnormalities were identified pre- or postmortem to explain the seizures. Her seizures were a probable adverse drug reaction based on the Naranjo scale.

DISCUSSION: This is the first case of fatal status epilepticus described that has been associated with the use of olanzapine. The pharmacodynamics of olanzapine are similar to those of clozapine, which has been described to induce seizures in 1-4% of patients. It is possible that this patient may have suffered seizures due to a similar effect. Alternate explanations include neuroleptic malignant syndrome and alcohol or benzodiazepine withdrawal seizures, although her clinical history does not suggest these etiologies.

CONCLUSIONS: Although olanzapine has infrequently been associated with seizures in premarketing studies, its potential to induce them exists. Postmarketing surveillance should continue to determine how significant this effect may be.

Drug induced “rebound psychosis” & Mania
Shore D. Clinical implications of clozapine discontinuation: report of an NIMH workshop. Schizophr Bull 1995;21(2):333-8. Division of Clinical and Treatment Research, NIMH, Rockville, MD 20857, USA.

ABSTRACT: In September 1994, the National Institute of Mental Health convened a group of scientists to discuss the clinical effects of rapid clozapine discontinuation, especially in light of the introduction of risperidone for the treatment of schizophrenia. Despite concern over recent reports of clinical deterioration (psychotic exacerbations, somatic withdrawal symptoms, and extrapyramidal side effects) in a few patients abruptly discontinued from clozapine, there is currently insufficient information to determine the magnitude of the problems associated with clozapine withdrawal.

However, clinicians are reminded that the withdrawal schedule for clozapine indicates a gradual tapering schedule (unless the patient is experiencing severe side effects); that switching patients from clozapine to risperidone does not mean that such tapering is unnecessary; and that the use of risperidone may not produce all of the same effects as clozapine in some treatment-refractory patients. PMID: 7543218, UI: 95357664

Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997 Jun;58(6):252-5. Department of Psychiatry, Allegheny University, Norristown State Hospital, Pa. 19401, USA.

BACKGROUND: Withdrawal symptoms for typical antipsychotics are generally mild, self-limited and do not include development of psychotic symptoms. In contrast, withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms. Different pathophysiologic etiologies have been suggested for these severe symptoms, including dopaminergic supersensitivity and rebound. METHOD: Three case reports of clozapine withdrawal symptoms are presented. A review of previous case reports and discussion of the etiology of withdrawal symptoms of typical antipsychotics and clozapine are provided.

RESULTS: These three patients developed delirium with psychotic symptoms that resolved rapidly and completely upon resumption of low doses of clozapine.

CONCLUSION: The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity, such as thioridazine.

Durst R, Teitelbaum A, Katz G, Knobler HY (1999) Withdrawal from clozapine: the “rebound phenomenon”. Isr J Psychiatry Relat Sci 1999;36(2):122-8. Jerusalem Mental Health Center, Kfar Shaul Hospital, Israel.

Clozapine is an “atypical” antipsychotic agent for treating previously resistant schizophrenic patients. Its main advantages over “typical” neuroleptics are low incidence of extrapyramidal side effects and its capacity to induce therapeutic response in previously treated refractory patients. However, withdrawal from clozapine has been observed to lead to “atypical” clinical characteristics or a “rebound phenomenon,” manifested in two interwoven clinical forms: (1) psychotic exacerbation, and (2) cholinergic rebound. The underlying pathophysiological mechanism of this phenomenon is postulated to be a result of cholinergic supersensitivity. In this paper, the “rebound phenomenon” will be discussed and exemplified by three case histories in which abrupt cessation of clozapine led to serious deterioration and psychotic exacerbation, and one case in which gradual titration from the drug was employed in order to preempt this hazardous occurrence. PMID: 10472746, UI: 99401971

Still DJ, Dorson PG, Crismon ML, Pousson C Effects of switching inpatients with treatment-resistant schizophrenia from clozapine to risperidone. Psychiatr Serv 1996 Dec;47(12):1382-4. Department of Psychiatry, Community Hospitals Indianapolis, IN 46219, USA.

A prospective, open-label study in a 400-bed state psychiatric hospital evaluated change in therapeutic response among ten patients with treatment-resistant schizophrenia who were switched from clozapine to risperidone. Drug effects were examined before discontinuation of clozapine and at three, six, nine, and 12 weeks of risperidone treatment. No patients improved, and five discontinued treatment due to exacerbation of psychosis or adverse effects. Changes in scores on the Positive and Negative Syndrome Scale, the Brief Psychiatric Rating Scale, and the Barnes Akathisia Scale indicated clinically significant worsening of symptoms. The findings do not support replacing clozapine with risperidone for patients with treatment-resistant schizophrenia.

Delassus-Guenault N, Jegouzo A, Odou P, Seguret T, Zangerlin H, Vignole E, Robert H. Clozapine-olanzapine: a potentially dangerous switch. A report of two cases. J Clin Pharm Ther 1999 Jun;24(3):191-5. Department of Pharmacy, EPSM Lille-Metropole, Armentieres, France.

BACKGROUND: Withdrawal symptoms associated with switch between two typical antipsychotics are generally rare and mild. In contrast, switching from clozapine to risperidone can be lead to severe withdrawal symptoms. Different pathophysiologic aetiologies have been suggested for explaining these severe symptoms, including cholinergic supersensitivity and rebound. Theoretically, the switch from clozapine to olanzapine should not lead to any problems because those two agents have the same affinity in vitro for muscarinic receptors. OBJECTIVE: This study reports two cases of switches from clozapine to olanzapine, in refractory schizophrenic patients, which were associated with severe withdrawal symptoms.

RESULTS: After the switch, the two patients developed diaphoresis, hypersialorrhea, bronchial obstruction, agitation, anxiety and enuresis. The symptoms were treated with anticholinergic medication and by an increase in dose of olanzapine to 20 mg/day. For one of the patients this treatment led to normalization of secretion. For the other patient, a superinfection leading to a bilateral pneumopathy which required emergency hospitalization in a general hospital was observed.

CONCLUSION: The symptomatology and the response to treatment lead to the hypothesis of a muscarinic from abrupt weaning. The withdrawal symptoms disappeared rapidly with an increase in olanzapine dosage and with anticholinergic started at the beginning of the switch. We recommend slow clozapine weaning over 3 weeks or more with concurrent anticholinergic treatment.

Ekblom B, Eriksson K, Lindstrom LH. Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology (Berl) 1984;83(3):293-4.

In two patients with chronic schizophrenia, who were on clozapine medication for more than 6 months, a sudden withdrawal of the drug resulted in a very pronounced deterioration of the psychosis within 24-48 h. The most prominent symptoms were auditory hallucinations and persecutory ideas and one patient tried to commit suicide. These observations are interpreted as supersensitivity psychoses induced by the very effective clozapine treatment.

Jauss M, Schroder J, Pantel J, Bachmann S, Gerdsen I, Mundt C. Severe akathisia during olanzapine treatment of acute schizophrenia. Pharmacopsychiatry 1998 Jul;31(4):146-8. Department of Psychiatry, University of Heidelberg, Germany.

Olanzapine is a newly developed atypical neuroleptic with a marked affinity to the 5-HT2, D2 and D4 dopamine receptors. Like other atypical neuroleptics olanzapine is considered to show a reduced prevalence of extrapyramidal side effects when compared to classical neuroleptic drugs.

We report on three patients with acute schizophrenia, who developed severe akathisia during treatment with olanzapine (20-25 mg/d). In two of these cases akathisia resolved after withdrawal of olanzapine and substitution by a classical or an atypical neuroleptic agent, respectively. In one of these patients olanzapine was well tolerated when reintroduced in combination with lorazepam after complete remission of akathisia.

In the third patient akathisia as sufficiently controlled by dose reduction. Akathisia is generally considered to result from D2 dopamine receptor antagonism. In the case of atypical neuroleptics such as olanzapine a low but still considerable D2 dopamine receptor occupancy may be compensated by the 5-HT2 antagonism. However, this mechanism may fail under certain circumstances, in particular if D2 dopamine antagonism exceeds a certain threshold. One should therefore be aware of possible extrapyramidal side effects with olanzapine that are reduced compared to classical neuroleptic drugs but not completely eliminated.

Molho ES, Factor SA (1999). Worsening of motor features of parkinsonism with olanzapine. Mov Disord 1999 Nov;14(6):1014-6. Department of Neurology, Albany Medical College, New York, USA.

Clozapine is the current treatment of choice for drug-induced psychosis (DIP) occurring in Parkinson’s disease. However, alternative medications have been sought because of the small but significant risk of agranulocytosis and the need for frequent blood testing. The new “atypical” antipsychotic olanzapine (OLZ) has recently been proposed as a safe and effective option for treating psychosis in this setting. To investigate this, we retrospectively evaluated all 12 of our patients treated with OLZ for DIP. Symptoms of psychosis were improved in nine of 12 patients, but nine of 12 patients also experienced worsening of motor functioning while on OLZ. The worsening was considered dramatic in six of these patients. Overall, there was no significant increase in levodopa doses on OLZ. Only one patient remained on OLZ at the time of the analysis. Nine patients were switched to alternative treatment for DIP.

“We conclude that although Olanzapine may improve symptoms of psychosis in parkinsonian patients, it can also worsen motor functioning. In some patients, the degree of motor worsening may be intolerable.”

Life-threatening neuroleptic malignant syndrome (NMS)
NMS is the result of dopamine receptor blockade in the brain, induced by ALL neuroleptic drugs [included is a sample of published NMS reports associated with the new, “atypical” drugs]

Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999 May;33(5):623-30. Memorial University of Newfoundland, St. John’s, Canada.

BACKGROUND: Clozapine has recently been found to be associated with neuroleptic malignant syndrome (NMS). Our objective is to determine if clozapine causes NMS, if the presentation of clozapine-induced NMS differs from that of traditional agents, and which set of diagnostic criteria will most readily allow diagnosis of NMS associated with clozapine.

METHODS: Two new cases of clozapine-associated NMS are presented, along with previously reported cases from the literature, identified by using a MEDLINE search (1966-August 1998). From all cases, concomitant medications and washout periods were examined (if available) to assess clozapine as the likely cause of NMS. Characteristics of clozapine and traditional antipsychotic-induced NMS were compared. Different diagnostic criteria for NMS were applied to the cases to determine which were more likely to diagnose the syndrome.

RESULTS: Clozapine was deemed a highly probable cause of NMS in 14 cases, a medium probability cause in five cases, and a low probability cause in eight cases. The most commonly reported clinical features were tachycardia, mental status changes, and diaphoresis. Fever, rigidity, and elevated creatine kinase were less prominent than in NMS associated with classical neuroleptics.

CONCLUSIONS: Clozapine appears to cause NMS, although the presentation may be different than that of traditional antipsychotics. Levenson’s original and Addonizio’s modified criteria were more likely to diagnose NMS than were other criteria. Clozapine-associated NMS may present with fewer clinical features. Limitations are the lack of detailed information provided by many of the case reports and the use of “modified” diagnostic criteria for retrospective diagnosis.

Amore M, Zazzeri N, Berardi D. Atypical neuroleptic malignant syndrome associated with clozapine treatment. Neuropsychobiology 1997;35(4):197-9. Institute of Psychiatry, University of Bologna, Italy.

Clozapine is an atypical neuroleptic drug that was initially thought not to cause neuroleptic malignant syndrome (NMS). The authors report a case of NMS associated with clozapine use, developed in a patient without previous history of NMS. Considering that 13 such cases (including ours) have been reported so far, NMS should be considered in the differential diagnosis of a febrile patient treated with clozapine.

Thornberg SA, Ereshefsky L. Neuroleptic malignant syndrome associated with clozapine monotherapy. Pharmacotherapy 1993 Sep-Oct;13(5):510-4. Clinical Psychiatric Pharmacy Program, University of Texas Health Science Center at San Antonio 78284-6220.

Abstract: Neuroleptic malignant syndrome is thought to be a result of dopamine receptor blockade in the striatum. Clozapine has only weak affinity for dopamine type 1 and 2 receptors, and therefore it was thought this drug would not precipitate the syndrome. However, six cases of the syndrome have been reported in patients receiving clozapine monotherapy. A review of the pathoetiology of symptoms occurring in the syndrome is included.

Sachdev P, Kruk J, Kneebone M, Kissane D. Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol 1995 Oct;15(5):365-71. Neuropsychiatric Institute, Prince Henry Hospital, Sydney, Australia.

The published case reports of clozapine-induced neuroleptic malignant syndrome (NMS) are reviewed, to which the authors add three, and possibly four, new cases seen in Australia, occurring in and estimated 1,250 patients exposed to the drug. The review suggests that typical NMS does occur with clozapine and that its incidence may be as common as with the classic neuroleptics. The features of clozapine-induced NMS may be somewhat different, with fewer extrapyramidal side effects and a lower rise in creatine kinase levels. The occurrence of NMS with clozapine raises important issues with regard to our understanding of the pathophysiology of the syndrome.

Margolese HC, et al. [See Related Articles] Olanzapine-induced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry. 1999 Jul;156(7):1115-6. No abstract available.

Hickey C, et al. [See Related Articles] Olanzapine and NMS. Psychiatr Serv. 1999 Jun;50(6):836-7. No abstract available. PMID: 10375159; UI: 99301695.

Filice GA, McDougall BC, Ercan-Fang N, Billington CJ. Neuroleptic malignant syndrome associated with olanzapine. Ann Pharmacother 1998 Nov;32(11):1158-9. Infectious Disease Section, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.

OBJECTIVE: To report a case of neuroleptic malignant syndrome (NMS) associated with the use of olanzapine. CASE SUMMARY: A 67-year-old white man with bipolar disorder developed nausea and vomiting. After 12 days, he became confused, delirious, and manic. His only medications were olanzapine 10 mg/d and divalproex sodium 500 mg bid. He was admitted to a hospital and treated for dehydration and mania. Olanzapine was given on 6 of the first 7 hospital days. On hospital day 6, typical NMS developed with the body temperature increasing to 39.9 degrees C, obtundation, rigidity, tremor, diaphoresis, fluctuating pupillary diameter, labile tachycardia and hypertension, hypernatremia, and elevated serum creatine kinase. Olanzapine was stopped after hospital day 7, and the syndrome resolved by hospital day 12.

DISCUSSION: The patient had all of the major manifestations of NMS. There was no other likely explanation for his illness and he received no other drug likely to be associated with the syndrome. This is the first case reported in which NMS was associated with olanzapine.

Apple JE, et al. [See Related Articles] Neuroleptic malignant syndrome associated with olanzapine therapy. Psychosomatics. 1999 May-Jun;40(3):267-8. No abstract available. PMID: 10341541; UI: 99273087.

Moltz DA, et al. [See Related Articles] Case report: possible neuroleptic malignant syndrome associated with olanzapine. J Clin Psychopharmacol. 1998 Dec;18(6):485-6. No abstract available. PMID: 9864084; UI: 99079788.

Burkhard PR, et al. [See Related Articles] Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry. 1999 Jan;56(1):101-2. No abstract available. PMID: 9892264; UI: 99107282.

Johnson V, et al. [See Related Articles] Neuroleptic malignant syndrome associated with olanzapine. Aust N Z J Psychiatry. 1998 Dec;32(6):884-6. PMID: 10084355; UI: 99181846.

Gheorghiu S, et al. [See Related Articles] Recurrence of neuroleptic malignant syndrome with olanzapine treatment. Am J Psychiatry. 1999 Nov;156(11):1836. No abstract available. PMID: 10553758; UI: 20019186.

Emborg C. [See Related Articles] [Neuroleptic malignant syndrome after treatment with olanzapine]. Ugeskr Laeger. 1999 Mar 8;161(10):1424-5. Danish. PMID: 10085753; UI: 99185672.

Levenson JL. [See Related Articles] Neuroleptic malignant syndrome after the initiation of olanzapine. J Clin Psychopharmacol. 1999 Oct;19(5):477-8. No abstract available. PMID: 10505593; UI: 99433412.

Margolese HC, et al. [See Related Articles] Olanzapine-induced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry. 1999 Jul;156(7):1115-6. No abstract available. PMID: 10401467; UI: 99329710.

Garcia Lopez MM, et al. [See Related Articles] [Neuroleptic malignant syndrome associated with olanzapine]. Med Clin (Barc). 1999 Sep 4;113(6):239. Review. Spanish. No abstract available. PMID: 10472615; UI: 99401840.

Haggarty JM, et al. [See Related Articles] Atypical neuroleptic malignant syndrome? Can J Psychiatry. 1999 Sep;44(7):711-2. No abstract available. PMID: 10500880; UI: 99430667.

Hickey C, et al. [See Related Articles] Olanzapine and NMS. Psychiatr Serv. 1999 Jun;50(6):836-7. No abstract available. PMID: 10375159; UI: 99301695.

Corrigan FM, et al. [See Related Articles] Neuroleptic malignant syndrome (NMS) on neuroleptic withdrawal. Acta Psychiatr Scand. 1990 Sep;82(3):268-9. No abstract available.

1998 MRI Studies demonstrate structural brain changes in schizophrenia patients treated with both standard and “atypical” neuroleptic drugs:
Non-industry sponsored researchers are coming to realize that this rebound reaction to antipsychotic drugs-both standard and the newer atypicals– may be so great, it could be causing structural brain changes such as swelling of the brain. Gur, et al., (abstract below) conducted an NIMH-funded MRI imaging study to monitor changes in the size of the basal ganglia and thalamic regions of the brain in schizophrenia patients treated with neuroleptic drugs. They compared them to a group of patients who were never exposed to neuroleptic drugs, and to a group of healthy comparison subjects: As they put it: “Differences between groups and correlations between subcortical volumes and dose of medication indicate that exposure to neuroleptics is associated with hypertrophy…it appears that patients treated with neuroleptics show hypertrophy relative to their neuroleptic-naive counterparts and to healthy comparison subjects.”

Neuroleptics increased the area of both regions of the brain: a higher dose of standard neuroleptics was associated with a size increase in multiple areas, while atypcal neuroleptics increased the volume only of the thalamic portion. The researchers also reported that increased size of these regions of the brain is associated with greater severity of symptoms: “For the neuroleptic-naive group, sub-cortical volumes were not correlated with severity of negative symptoms, but higher volumes of the thalamus and putamen were associated with more severe positive symptoms…This association was evident for hallucinations…and bizarre behavior….For previously treated patients, higher subcortical volumes were associated with greater severity of both negative and positive symptoms.”

VHS Comment: The researchers themselves say the brain changes visible in the MRI scan “seem to be medication-induced hypertrophy.”

In other words, the patient’s brains were being changed by the drugs in ways that would likely increase the severity of their disabling illness – and make it more difficult for them to ever withdraw from neuroleptic drugs.

The only ambiguity in these findings is the researchers reluctance to attribute all of the brain changes to neuroleptics. However, whether “hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment” does not lessen the damage caused to these patients.

Gur, R.E., Maany, V., Mozley, P.D., Swanson, C., Bilker, W., & Gur, R.C. (1998). Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. American Journal of Psychiatry, 155 (12), 1711-1717. [Study was funded by NIMH] For the full article online go to:

ABSTRACT: Objective: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. Method: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined.

Results: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with greater severity of both negative and positive symptoms

Conclusions: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.

Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M., Lerner, G., Bogerts, B., Wu, H., Kinon, B., & Ashtari, M. (1994). Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry 151 (10) 1430-1436.

Based on MRI measurements of patients who initially had under 12 weeks of lifetime exposure to neuroleptics, and comparison with data after 18 months of treatment, the authors concluded that “caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.” It was known prior to this study that chronically treated patients had increased volumes in this portion of their brains, but it had been thought this was due to the disease and not the treatment.

Madsen Al, Keiding N, Karle A, Esbjerg S, Hemmingsen R: (1998) Neuroleptics in progressive structural brain abnormalities in psychiatric illness. The Lancet, 352 (9130) 784.

This was a longitudinal study of patients, some schizophrenic, some not, from the beginning of their treatment with neuroleptics until 5 years later. Before and after scans of the brain were done using computed tomography (CT). The finding was that diagnosis had no significant impact on the development of frontal atrophy, but that “the estimated risk of atrophy increases by 6.4% for each additional 10 g neuroleptic drug.” [Complete text of article at the end of bibliog]

Gur, R.E, Cowell, P., Turetsky, B.I., Gallacher, F., Cannon, Bilker, W., & Gur, R.C. (1998) A follow-up magnetic resonance imaging study of schizophrenia. Archives of General Psychiatry, 55 145-152.

This study looked at changes in the frontal and temporal lobes of the brains of schizophrenics over a period of about 31months. They found that for first episode patients, “higher medication dose was associated with greater reduction in frontal and temporal volume r = -0.75 and -0.66 respectively; P<.001)." Volume reduction was associated with decline in some neurobehavioral functions.

Harrison P (1999) Review: the neuropathological effects of antipsychotic drugs, Schizophr Res 1999 Nov 30;40(2):87-99.

ABSTRACT: In addition to their neurochemical effects, antipsychotic (neuroleptic) drugs produce structural brain changes. This property is relevant not only for understanding the drugs' mode of action, but because it complicates morphological studies of schizophrenia. ʈere the histological neuropathological effects of antipsychotics are reviewed, together with brief mention of those produced by other treatments sometimes used in schizophrenia (electroconvulsive shock, lithium and antidepressants)….The main alteration associated with antipsychotic medication concerns the ultrastructure and proportion of synaptic subpopulations in the caudate nucleus… The changes are indicative of a drug-induced synaptic plasticity, although the underlying mechanisms are poorly understood. Similarly, it is unclear whether the neuropathological features relate primarily to the therapeutic action of antipsychotics or, more likely, to their predisposition to cause tardive dyskinesia and other motor side-effects. Clozapine seems to cause lesser and somewhat different alterations than do typical antipsychotics, albeit based on few data. There is no good evidence that antipsychotics cause neuronal loss or gliosis, nor that they promote neurofibrillary tangle formation or other features of Alzheimer's disease.

The changes may be secondary to the effects of the antipsychotic drug on dopamine or glutamate neurotransmitters. It is not yet clear what these changes mean? they may be related to the efficacy of the drug or may possibly be a marker for side effects?.such changes in living individuals could potentially provide an early marker for tardive dyskinesia and thus indicate which individuals should not take these drugs. Virtually all the studies used Haldol, so it is not yet known whether clozapine or other newer antipsychotics may also produce these changes.

Tsai G, Goff DC, Chang RW, Flood J, Baer L, Coyle JT (1998) Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry 1998 Sep;155(9):1207-13 Department of Psychiatry, Harvard Medical School, Belmont, MA 02178, USA.

OBJECTIVE: Tardive dyskinesia is a movement disorder affecting 20%-40% of patients treated chronically with neuroleptic drugs. The dopamine supersensitivity hypothesis cannot account for the time course of tardive dyskinesia or for the persistence of tardive dyskinesia and the associated structural changes after neuroleptics are discontinued. The authors hypothesized that neuroleptics enhance striatal glutamatergic neurotransmission by blocking presynaptic dopamine receptors, which causes neuronal damage as a consequence of oxidative stress.

METHOD: CSF was obtained from 20 patients with schizophrenia, 11 of whom had tardive dyskinesia. Markers for oxidative stress, including superoxide dismutase, lipid hydroperoxide, and protein carbonyl groups, and markers for excitatory neurotransmission, including N-acetylaspartate, N-acetylaspartylglutamate, aspartate, and glutamate, were measured in the CSF specimens. Patients were also rated for tardive dyskinesia symptoms with the Abnormal Involuntary Movement Scale.

RESULTS: Tardive dyskinesia patients had significantly higher concentrations of N-acetylaspartate, N-acetylaspartylglutamate, and aspartate in their CSF than patients without tardive dyskinesia when age and neuroleptic dose were controlled for. The significance of the higher levels of protein-oxidized products associated with tardive dyskinesia did not pass Bonferroni correction, however. Tardive dyskinesia symptoms correlated positively with markers of excitatory neurotransmission and protein carbonyl group and negatively with CSF superoxide dismutase activity.

CONCLUSIONS: These findings suggest that there are elevated levels of oxidative stress and glutamatergic neurotransmission in tardive dyskinesia, both of which may be relevant to the pathophysiology of tardive dyskinesia.

Braus DF, Ende G, Weber-Fahr W, Sartorius A, Krier A, Hubrich-Ungureanu P, Ruf M, Stuck S, Henn FA (1999) Antipsychotic drug effects on motor activation measured by functional magnetic resonance imaging in schizophrenic patients. Schizophr Res 1999 Aug 23;39(1):19-29. Central Institute of Mental Health (ZI), NMR-Research, Mannheim,

Brain function and laterality in schizophrenia were investigated by means of a simple motor task with a self-generated left-hand sequential finger opposition (SFO) using a whole-brain high-speed functional imaging technique. Neuroleptic-naive, acutely ill schizophrenic patients were compared to schizophrenic patients under stable neuroleptic medication and matched controls. The goal was to evaluate both the motor function in first-episode patients and possible effects of different neuroleptic treatments on functional MRI results.

Forty schizophrenia patients matched in sex- and age to healthy volunteers participated in this study. All subjects underwent fMRI examinations on a conventional 1.5 T MR unit. The primary sensorimotor cortex and the high-order supplementary motor area (SMA) were evaluated.

There was a close similarity in the activation of the primary and high-order (SMA) sensorimotor areas between first-episode schizophrenic patients and controls. In contrast, a significant reduction in the overall blood oxygen level dependent (BOLD) response was seen in sensorimotor cortices in schizophrenic patients under stable medication with typical neuroleptics. This effect was not present in patients treated with atypical antipsychotics. Both antipsychotic treatments, however, led to a significant reduction in activation of the SMA region compared to controls and neuroleptic-naive subjects.

Thus, the present study provides no evidence for the localized involvement of the primary motor cortex or the SMA as a relatively stable vulnerability marker in schizophrenia. There is, however, strong evidence that neuroleptics themselves influence fMRI activation patterns and that there are major differences between typical neuroleptics and atypical antipsychotics.

Benes FM (1999) Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry 1999 Sep 1;46(5):589-99. Laboratory for The Program in Structural Neuroscience, McLean Hospital, Massachusetts

Recent postmortem studies have demonstrated subtle alterations in the hippocampal formation (HIPP) of patients with schizophrenia (SZ). These changes include a decreased density of neuron receptors and a neuroleptic-dose-related increase of receptor terminals. The researchers hypothesize that the brain receptor changes identified "could potentially involve excitotoxic damage to interneurons." The researchers indicate that "the precise time frame for the induction of such an injury during pre- versus postnatal life cannot as yet be inferred from the available data." These researchers do not entertain the possibility that the "induction of such an injury" might be the result of neuroleptic drugs. However, nothing in the data precludes such suspicion.

"These findings are consistent with reports of abnormal oscillatory rhythms and increased basal metabolic activity in the HIPP of patients with schizophrenia. The fact that patients with manic depression also show a decrease of NPs in CA2 suggests that changes in the GABA system may not be related to a susceptibility gene for SZ. Rather, these alterations could be associated with a nonspecific factor, such as stress, experienced either early in life or much later during adolescence or adulthood. Presumably, there are also changes associated in other transmitter systems that may play a more specific role in establishing the SZ phenotype."

McCarley RW, Wible CG, Frumin M, Hirayasu Y, Levitt JJ, Fischer IA, Shenton ME (1999). MRI anatomy of schizophrenia. Biol Psychiatry 1999 May 1;45(9):1099-119. Harvard Medical School, Department of Psychiatry, VA Medical Center, Brockton,Massachusetts 02401, USA.

This meta-analysis of 118 peer-reviewed controlled studies from 1987 to 1998 by Harvard investigators found overwhelming evidence of altered brain structure in schizophrenia patients."Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission."

The temporal lobe was the brain region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures… Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a "two-hit" model of schizophrenia, for which a cellular hypothesis is discussed.

VHS Comment: Although almost all patients during the years under examination have been exposed to neuroleptic drugs during various periods of their illness, the authors do not examine the possibility that these drugs may be a precipitating cause of the "two-hit" model of schizophrenia…

Casey DE (1999). Tardive dyskinesia and atypical antipsychotic drugs. Schizophrenia Research 1999 Mar 1;35 Suppl:S61-6. Mental Health Division, Veterans Affairs Medical Center, Portland, OR 97207, USA.

Typical antipsychotic agents produce central nervous system effects, especially extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Nearly every patient who receives neuroleptic therapy has one or more identifiable risk factors for TD, among the most significant of which are older age, female gender, presence of EPS, diabetes mellitus, affective disorders, and certain parameters of neuroleptic exposure (i.e. dose and duration of therapy). The typical course of TD is a gradual onset after several years of drug therapy, followed by slow improvement or remission, but a large number of patients have persistent TD with irreversible symptoms. In the management of TD, the patient's mental status is of primary concern. Currently, no uniformly safe and effective therapies for TD exist, though a variety of therapeutic agents, including some of the atypical neuroleptics, have been reported to treat TD successfully in some patients. Because TD liability is so much lower with novel antipsychotic therapy, all patients who have TD or are at risk for TD, as well as EPS, should be considered candidates for switching to these new drugs.

Evidence that TD involves brain changes that impair cognitive functioning:
Paulsen, J. S., Heaton, R.K., & Jeste, D.V. (1994). Neuropsychological impairment in tardive dyskinesia. Neuropsychology, 8 (2), 227-241.

The authors reviewed 31 published studies of neuropsychological testing comparing schizophrenics with and without TD. 24 of these studies, or 77%, found TD patients did worse on such tests. In an attempt to improve on past studies, the authors did their own study which matched patients with and without TD on a variety of measures, including duration and severity of illness. Those with TD demonstrated greater neuropsychological impairment, and those with more severe TD manifested greater neuropsychological impairment. The authors go on to discuss brain changes which may be associated with both TD and neuropsychological impairment, and concludes that "it is likely that TD involves an alteration of brain function that affects both motor and cognitive control."

Waddington, J.L., & Youssef, H.A. (1996). Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years. and its longitudinal relationship to the emergence of tardive dyskinesia. Psychological Medicine, 26 681-688.

Often the relationship between cognitive dysfunction and TD has been explained by suggesting that those with underlying cognitive dysfunctions are more prone to TD. This study sharply contradicts that explanation.

The authors followed the cognitive functioning of a group of chronic schizophrenic patients over 10 years.Most were stable in regards to cognitive functioning: the exceptions were the individuals who developed TD during the course of the study. The authors write that "Those patients demonstrating prospectively the emergence of orofacial dyskinesia showed a marked deterioration in their cognitive function over the same time-frame within which their movement disorder emerged, but this decline did not progress thereafter." The authors conclude that the cognitive changes are related to the patho-physiological process which also results in TD.

Sachdev, P., Hume, F., Toohey, P., & Doutney, C. (1996). Negative symptoms, cognitive dysfunction, tardive akathisia and tardive dyskinesia. Acta Psychiatrica Scandinavica, 93 (6), 451-459.

The authors, in their literature review, point out that while there are some studies that do not find a relationship between TD and cognitive deficits, there are many that do show a positive relationship between TD and cognitive deficits and none that show the opposite relationship. In the current study, TD was shown to be related to cognitive deficits, while tardive akathisia was shown to be even more strongly related to cognitive deficits. While the authors do not see this as proving that neuroleptics cause cognitive deficits, they recommend considering the possibility, and they compare TD and TA with other movement disorders such as Parkinson's disease and Huntington's disease, in which neuropsychological deficits and even subcortical dementia are known to occur.

McShane, R., Keene, J., Gedling, K., Fairburn, C., Jacoby, R., & Hope, T.(1997). Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. British Medical Journal, 314 (7076), 266-271.

This study looked at the impact of long term use of neuroleptics on the cognitive function of elderly people with dementia. It found that cognitive function declined twice as fast in those taking neuroleptics as in those not on neuroleptics. Brain differences were not found at autopsy, which means either that the cognitive decline was functional only, or that the brain differences escaped detection by the methods these researchers used.

Wade, J.B., Lehmann, L., Hart, R., Linden, D., Novak, T., & Hamer, R. (1989). Cognitive changes associated with tardive dyskinesia. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 1 (3), 217-227.

"The results of multiple regression analysis revealed a modest linear relationship between TD and cognition (p

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What is Questia? :: Questia at a Glance
Three Potentially Fatal Adverse Effects of Psychotropic Medications
Journal article by Pamelia Wren, Laura A. Frizzell, Norman L. Keltner, Amy V. Wright; Perspectives in Psychiatric Care, Vol. 39, 2003

Journal Article Excerpt

Three potentially fatal adverse effects of psychotropic medications.

by Pamelia Wren , Laura A. Frizzell , Norman L. Keltner , Amy V. Wright

He’s gone country Everybody’s gone country Yeah we’ve gone country The whole world’s gone country

–Alan Jackson

Psychotropic drugs are in. Even psychiatric nurses who once considered psychotropic drugs a necessary evil or a treatment of last resort, now embrace the inevitability of the times–the fusion of public expectations, third-party considerations, and time constraints. As a result, psychotropic medications have become firstline options in treatment. However, several serious and potentially fatal side effects are related to these agents–for example, neuroleptic malignant syndrome, serotonin syndrome, and agranulocytosis.

All these adverse responses were discovered “after the fact”: that is, these effects were not anticipated but were described after patients had developed symptoms or had died. With careful assessments demanded by unacceptable levels of morbidity and mortality, both incidence and death rates have dropped significantly in recent years. Rather than risk allowing these catastrophic consequences to drift to the periphery of practice, we attempt in the following pages to bring the discussions up…

George M. Simpson1, Ervin Varga1, J. Hillary Lee1 and Boris Zoubok1

(1) Department of Psychiatry, University of Southern California, 1934 Hospital Place, 90033 Los Angeles, California, USA

Received: 26 September 1977 Accepted: 18 January 1978

Abstract The adult population of a large mental hospital was screened for tardive dyskinesia (TD). Approximately 11% of the hospital population showed signs of TD; females and the elderly were over-represented in the TD group. A representative sample of those with TD was selected and a control (non-TD) patient was chosen to match each of the TD subjects in age, sex, length of hospitalization, diagnosis, and race. The charts of these subjects were searched for any indices of brain damage and the complete psychotropic medication history was recorded. There was no difference between the TD and controls in the amount of psychotropics ingested, in the duration of administration, in the kinds of drugs, or in the organicity history. Women as a group, however, tended to have more polypharmacy than men. The role of neuroleptics in TD is discussed as well as other possible etiological factors.
Key words Tardive dyskinesia – Neuroleptics – Dosage – Sex – Age


American College of Neuropsychopharmacology-Food and Drug Administration Task Force. Neurological syndromes associated with antipsychotic drug use. 289, 20–23

Asnis, G. M., Leopold, M. A., Duvoisin, R. C., Schwartz, A.: A survey of tardive dyskinesia in psychiatric outpatients. Paper presented at the 130th annual meeting of the American Psychiatric Association, Toronto, Canada (1977)

Ayd, F. J., Jr.: Neuroleptic-induced extrapyramidal reactions: incidence, manifestations and management. In: The future of pharmacotherapy new drug delivery system, F. J. Ayd, Jr., ed., pp. 77–88 Baltimore: International Drug Therapy Newsletter 1973

Crane, G. E.: High doses of trifluoperazine and tardive dyskinesia. Arch. Neurol. 22, 176–180 (1970)

Crane, G. E.: Persistent dyskinesia. Br. J. Psychiatry 122, 395–403 (1973)

Crane, G. E., Smeets, R. A.: Tardive dyskinesia and drug therapy in geriatric patients. Arch. Gen. Psychiatry 30, 341–343 (1974)

Degkwitz, R., Wenzel, W.: Persistent extrapyramidal side effects after long-term application of neuroleptics. In: Neuropsychopharmacology, International Congress Series No. 129, H. Brill, ed. Amsterdam: Excerpta Medica 1967

Edwards, H.: The significance of brain damage in persistent oral dyskinesia. Br. J. Psychiatry 116, 271–275 (1970)

Ericksen, S., Haraszti, J., Dekirmenjiar, H., Chang, S., Casper, R., Davis, J.: Haloperidol dose, plasma level and response. Paper presented at NCDEU meeting, Key Biscayne, Florida (1977)

Fann, W. D., Davis, J. M., Janowski, D. S.: The prevalence of tardive dyskinesia in mental hospital patients. Dis. Nerv. Syst. 37, 182–186 (1972)

Faurbye, A., Rasch, P. J., Peterson, P. B., Brandborg, G., Pakkenberg, H.: Neurological symptoms in pharmacotherapie of psychose. Acta Psychiatr. Scand. 40, 10–27 (1964)

Gardos, G., Cole, J., La Brie, R. A.: Drug variables in the etiology of tardive dyskinesia application of discriminant function analysis. Neuropsychopharmacology 1, 147–154 (1977)

Granacher, R. P., Baldessarini, R. J., Cole, J. O.: Deanol for tardive dyskinesia [cont.] [Letter]. New Engl. J. Med. 292, 926–927 (1975)

Hunter, R., Earl, C. J., Thoenicroft, S.: An apparently irreversible syndrome of abnormal movements following phenothiozine medication. Proc. R. Soc. Med. 57, 24–28 (1964)

Jus, A., Pineau, R., Lachance, R., Pelchat, G., Jus, K., Pires, P., Villeneuve, R.: Epidemiology of tardive dyskinesia. Dis. Nerv. Syst. 37, 210–214 (1976)

Kane, J., Wegner, J., Strune, F., Quitkin, F., Rifkin, A., Kline, D. F.: The mitten pattern as a potential EEG predictor of tardive dyskinesia. Paper presented at the NCDEU meeting, Key Biscayne, Florida (1977)

Kennedy, P. F., Hershon, H. I., McGuire, R. J.: Extrapyramidal disorders after prolonged phenothiazine therapy. Br. J. Psychiatry 118, 509–518 (1971)

Kiloh, L. G., Smith, S. J., Williams, S. E.: Antiparkinson drugs as causal agents in tardive dyskinesia. Med. J. Aust. 2, 591–593 (1973)

Ogita, K., Yagi, G., Itoh, H.: Comparative analysis of persistent dyskinesia of long-term usage with neurolepties in France and in Japan. Folia Psychiatr. Neurol. Jpn. 29, 315–320 (1975)

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FindArticles > American Journal of Drug and Alcohol Abuse > March-June, 1990 > Article > Print friendly

Tardive dyskinesia in psychiatric patients with substance use disorders

Arturo A. Olivera

Tardive dyskinesia (TD), a neurological disorder characterized by choreoathetotic involuntary movements (IMs) that affect various areas of the musculoskeletal system of psychiatric patients [1], is the major long-term complication of neuroleptic treatment [2]. Reports on the incidence of this disorder vary widely, ranging from 10 to 70% [3]. It is recognized that organic brain disorders may predispose psychiatric patients toward the development of TD [4]; however, the literature contains very little on the influence of chronic psychoactive substance abuse on the incidence of this disorder. It is possible that the brain damage produced by chronic exposure to the toxic effects of illicit drugs could increase the vulnerability to TD when drug users are treated with neuroleptics. The development of IMs similar to TD has been reported in conjunction with the use of L-DOPA, antihistamines, anticholinergics, anticonvulsants, and central nervous system (CNS) stimulants [5, 6].

The purpose of the present study was to determine the incidence and the anatomical characteristics of TD in a sample of psychiatric patients, who abuse illicit drugs (dual psychiatric disorder), while undergoing treatment with neuroleptic medication. The study also examined the relationship between the development of TD and the nature of the psychoactive substance abused.


Two-hundred-eighty-four first admissions to an inpatient unit specializing in the treatment of major mental disorders complicated by substance abuse were screened for IMs. Except for two subjects, all patients were male. All subjects were chronic illicit drug users and had at least one major psychiatric diagnosis; 234 (82.4%) were treated with neuroleptics, while the remaining 50 (17.6%) had never received neuroleptics. Sixty-four percent of these patients carried the diagnosis of schizophrenia, 14% other psychosis, 10% affective disorders, and 12% other diagnoses. Patients treated with neuroleptics had received a mean [+ or -] SD chlorpromazine equivalent of 935 [+ or -] 710 mg/day. The control group (N = 100) included individuals randomly extracted among substance users admitted to an inpatient drug treatment program; this group was observed to determine the influence of drug usage on the incidence of TD. The exclusion criterion for this group was the current and/or past history of either mental disorder or neuroleptic intake.

Tardive dyskinesia was independently assessed and rated by two experienced raters (A.A.O. and M.W.K.) in those individuals with positive signs of IMs. The control group was also screened for IMs by two screeners (A.A.O. and N.K.M.). The Abnormal Involuntary Movement Scale (AIMS) was used for the assessment, diagnosis, and rating of TD severity. This instrument is widely accepted for its reliability and clinical usefulness [7]. The AIMS utilizes a 5-point rating scale (0 = absent to 4 = severe) to rate individual area or global severity, incapacitation, distress, and awareness. All seven areas of anatomical distribution of TD, i.e., facial, perioral, lingual, jaw, upper and lower limbs, and trunk, were assessed. Age-related distribution of TD was calculated using 10-year intervals.

The patients’ history of substance abuse was elicited by a self-report questionnaire and a structured interview which included age of onset, type and quantity of drugs used, frequency, and complications. When available, previous patient records were used to confirm the drug history. All patients in the study met the requirements for a DSM-III diagnosis of chronic psychoactive substance dependence, complicated in all or some of the health, personal, family, social, financial, occupational, and legal areas.

The pattern of psychoactive drug use was established in both the patient and the control samples. The incidence of TD was calculated according to drug groups. Analysis of variance was utilized to determine the significance of integroup differences. Significance was set at p < .05


Table 1 includes the demographic characteristics and the mental and substance abuse history data for the patients affected by TD compared to those without the dyskynetic disorder. Although patients having TD were significantly older, the length of their mental illness was not statistically different from patients free of TD. Patients with TD also had a significantly longer history of concomitant substance use disorder. The groups did not differ significantly in terms of age of onset for either mental illness or substance abuse problems. Table 2 presents the characteristics of substance abuse in both TD and control groups. TD patients abused mostly alcohol, with a lesser frequency of cannabis usage; concurrent abuse of other drugs was significantly lower than in the control group. While polydrug abuse was the dominant pattern in the control group, TD patients abused one or two drugs predominantly (Table 2, Section IF), i.e., alcohol alone or in combination with cannabis (Table 2, Section HI).

Table 1. Demographic Characteristics of the Sample of Dual
Psychiatric Disorder Patients Studied: A. Patients without TD
(N = 224); B. Patients Identified as Affected by TD (N = 37);
C. Control Group, Substance Abusers "Free" of Mental Disorders
(N = 100)


Mean S. D. Mean S.D. Mean S. D.

Age 32.4 7.4 37.2 8.9 36.7 6.9 (a)
Mental illness:
Age of onset 20.5 5.9 24.3 10.5 — —
Length (years) 11.9 7.0 13.4 6.2 — —
Substance abuse:
Age of onset 17.3 4.5 16.4 3.1 18.7 11.5
Length (years) 15.1 7.7 21.2 9.5 15.2 6.7 (b)
Racial distribution (%):
Whites 61.6 70.3 38.0
Blacks 38.4 29.7 62.0

(a) p value for intergroup difference was .002 for B-A and A-C.

(b) p value for intergroup difference was .002 for B-A and B-C.
Table 2. Characteristics of Psychoactive Substance Use in Patients
Simultaneously Affected by Mental and Substance Use Disorders: A.
Patients Free of Tardive Dyskinesia (N = 247); B. Tardive Dyskinesia
Patients (N = 37); C. Control Group: Substance Users Free of Mental
Disorders (N = 100) (a)

Occurrence (%)

I. Psychoactive drugs
1. Sedative-Stimulants
Alcohol 87.4 * 94.6 * 64.0
Cannabis 70.4 59.5 83.0
2. Narcotics
Opioids 32.0 8.1 87.0
3. Stimulants
Cocaine 27.1 8.0 70.0
Amphetamines + Ritalin + Preludin 45.8 18.9 83.0
4. Sedatives (Benzodiazepines, 45.3 11.0 64.0
5. Hallucinogens (PCP, LSD, MDA) 26.3 10.8 38.0
6. Others
Talwin-Pyribenzamine 11.3 * 2.7 * 31.0
Organic solvents 2.0 0.0 0.0
II. Number of drugs used
1 17.4 35.1 2.0
2-3 36.4 46.0 20.0
4-6 38.9 18.9 45.0
7 7.3 0.0 33.0
III. Alcohol and cannabis use, only
Alcohol, only 15.4 35.0 0.0
Alcohol-cannabis, only 14.2 35.0 0.0
Alcohol + Alcohol-cannabis 29.6 70.0 0.0

(a) p value for intergroup differences was < .05, except for values
followed by an asterisk.
The incidence of TD, influence of treatment, and racial distribution of the dyskinetic disorder are presented in Table 3-A. This disorder was found only in those patients treated with neuroleptic drugs; neither untreated patients nor control subjects exhibited signs of the disorder. Among the TD patients, 70.3 % were Whites and 29.7 % Blacks; the incidence of the disorder was somewhat higher in Whites. Table 3-B summarizes the differences in the incidence of TD in those patients using only alcohol and/or cannabis versus those patients who used other drugs. The differences between single substance users and polysubstance users are summarized in Table 3-C. A significantly higher percentage of alcohol and/or cannabis users and of single substance users were found to be affected by TD.

Table 3. Incidence of Tardive Dyskinesia in Patients Affected by
Dual Psychiatric Disorders (N = 284): A. Patients Treated with
Neuroleptics (N = 234), Not Treated with Neuroleptics (N = 50),
and in Control Group of Substance Users "Free" of Mental Disorders
(N = 100); B. Alcohol and/or Cannabis Versus Other Substance Users;
C. Single Versus Polysubstance Users


Patient group N % N %

A. Total group 284 100 37 13.0
Neuroleptic: Treated 234 82.4 37 15.9
Not treated 50 17.6 0 0.0
Whites 174 71.3 26 15.0
Blacks 110 38.7 11 10.0
Control Group 100 0 0.0

of inter-

[chi P

B. Alcohol and/or cannabis 106 37.0 28 26.4
Other substances (a) 178 63.0 9 5.1 27.49 .001
(1 df)
C. Single substance users 63 22.0 16 25.4
(b) Polysubstance users 221 78.0 21 9.5 9.94 .002
(1 df)
(a) Sedatives, opioids, stimulants.

(b) Alcohol 54 (TD = l5), cannabis 7 (TD = 1), others 2.
Table 4 presents the age-related distribution of the TD patients in this study sample as compared to findings by other authors. According to this study, the greater incidence occurred between the ages of 40 and 59 (Table 4-A). As presented in Table 5, the anatomical areas most frequently affected were those of the head and upper limbs; the lower limbs were affected less frequently. The mink was also affected in approximately 50% of cases. The severity of the disorder in head and upper limbs was mild (AIMS 2) and minimal in lower limbs and trunk (AIMS 1). The distribution of patients according to level of severity and distress shows a predominance of mild cases, with minimal to mild incapacitation. Only one-third of the patients acknowledged the presence of IMs.

Table 4. Incidence of Tardive Dyskinesia as a Function of Age in
Patients Affected by Dual Psychiatric Disorders: A. In the Present
Study, Age Group Interval in 10 Years; B. % of Incidence According
to Other Authors



Age group Bell- Perenyi- Rey et al.
(years) N N % Smith Arato [11]
[9] [10]

10-19 1 0 0.0 0.0
20-29 107 7 6.5 6.1 5.0 (30) 6.6 (30)
30-39 128 21 16.4 10.5 22.0 33.3 (30-44)
40-49 20 4 20.0 29.6 25.0
50-59 21 4 19.0 35.5 27.0 53.0 (45-59)
60 and over 7 1 14.0 35.6 30.0 6.6
Total: 284 37 13.0 Numbers in parenthesis express age
group in years.


Age group Smith et al. Faurbye et al.
(years) [12] [13]

20-29 31.4 (20-49)
40-49 28.0 (30-49)
50-59 48.1 (50-69) 42.0
60 and over 37.8 (70) 22.0 (70)
Total: Numbers in parenthesis express age
group in years.
Table 5. Characteristics of Tardive Dykinesia in 37 Dual
Psychiatric Disorder Patients: A. Anatomical Distribution, Expressed
as Percentage of Occurrence; B. Severity, Incapacitation and
Distress, as Mean [+ or -] SE Values; C. Distribution of Patients
by Levels of Severity, Distress, and Incapacitation (expressed as
percentage of occurrence) (a)

Facial Perioral Jaw Tongue

A. Anatomical No.34 32 35 37
distribution % 91.9 86.5 94.6 100.0

B. Severity: Mean [+ 1.9 [+ or 1.6 [+ or 1.9 [+ or 1.9 [+ or
or -] SE -] 0.15 -] 0.17 -] 0.14 -] 0.14

Global severity Incapaci-

B. Severity: Mean [+ 2.1 [+ or -] 0.13 0.47 [+ or
or -] SE -] 0.13


Upper Lower Trunk

A. Anatomical 36 27 20
distribution 97.3 73.0 54.1

B. Severity: Mean [+ 2.1 [+ or * 1.4 [+ o** 0.8 [+ or
or -] SE -] 0.13 -] 0.19 -] 0.14


B. Severity: Mean [+ 0.75 [+ or -] 0.14
or -] SE

C. Patients' distribution
(%) by levels of:

Minimal Mild Moderate Severe

Severity 10.8 54.1 27.0 8.1
Distress 50.0 41.7 8.3 0.0
Incapacitation 52.6 42.1 5.3 0.0

Awareness of IMS (%)
Yes No

Severity 30.4 69.6

(a) p values for the difference with upper bodily areas: * .01,
** .0004. Lower limbs vs trunk: .014.

The 15.9 % incidence of TD found in the present study represents a corrected [3] incidence of the disorder in the neuroleptic-treated patients. This value is in the lower range of incidence usually cited in the literature [3]. It is also within the 10-20% range of TD prevalence indicated by the APA task force [8]. The findings of the present study are comparatively lower than those reported by other authors for similar age groups [9-13]. Seventy-five percent of the TD patients were in the 20-39 year age bracket, with an incidence of 11.9%. The incidence presently reported for the Black population alone is slightly higher than that reported by Odejide [14] in a Black population (7% for male patients).

The most significant finding in this study is the higher incidence of TD among patients who chronically used alcohol (alone or together with cannabis). This is consistent with earlier reports by other authors. Among the patients with organic brain disorder studied by Yassa et al. [15], 19.6% were alcoholics and the incidence of TD was 41%. Rey [11] found 24 % incidence of alcoholism in his TD group as compared to 8.1% in patients free of TD. These findings would suggest that chronic abuse of alcohol might facilitate the development of TD in individuals treated with neuroleptics. This study also suggests that polysubstance abuse or the abuse of other classes of substances does not lead to a similar increased incidence of TD. Evidently, patients treated with neuroleptics appear to be at higher risk for the development of TD when they are also chronic alcohol abusers than those patients who do not use alcohol, or those who use other drugs alone or together with alcohol. These results reinforce the need for therapeutic measures to prevent or eliminate the long-term use of alcohol among psychiatric patients. Rehabilitation measures, i.e., counseling, peer support, and Alcoholics Anonymous, must be included in the overall clinical management of these patients.

In this particular group of TD patients, the dyskinetic disorder was found to affect areas of the head and upper limbs in a pattern similar to that reported by other authors in different psychiatric populations [9, 11, 16]. Similarly, the levels of severity were higher in areas of the upper body and decreased toward the lower limbs and trunk. The mild global severity and the predominance of mild cases of TD found in this study is not unusual; the APA task force on TD [8] indicated a higher prevalence of mild cases (68 % of 2.0 AIMS vs 4 % of 4.0 AIMS severity). Mild or lesser levels of distress and incapacitation were common. Moderate levels of distress and functional incapacitation (3.0 AIMS) were identified in only three cases. Although cases of severely distressing and physically incapacitating TD were seen by the authors during the 2 1/2-year study period, they did not involve patients included in this study. One-third of the patients were aware of having the disorder, a figure that is larger than that reported by Smith et al. (see Ref. 9).

In conclusion: 1) Chronic alcohol use by mental patients apparently increases the incidence of TD. 2) The pattern of anatomical distribution and the levels of severity of the dyskinetlc disorder did not differ fundamentally from the reports by other authors in different psychiatric samples. 3) Alcohol is apparently the drug of preference in this patient sample, followed by cannabis. Polydrug use was less frequent than in drug users free of mental disorders. 4) It is important to carefully screen mental patients for drug use, especially alcohol, before beginning treatment with neuroleptics; this will eliminate the additional risk to develop TD. Because the use of alcohol and other psychoactive substances in psychiatric patients is a growing and pervasive problem, further research on TD in populations of mental patients abusing psychoactive drugs is needed to corroborate and expand the findings reported here. Such research is also necessary to document the relationship between abused drugs, neuroleptics, and the CNS.


[1] Grancher, R. P., Jr., Differential diagnosis of tardive dyskinesia: An overview, Am. J. Psychiatry 138:1288-1297 (1981).

[2] Klawans, H. L., Recognition and diagnosis of tardive dyskinesia, J. Clin. Psychiatry 46(4, Sec.2):3-7 (1985).

[3] Baldessarini, R. J., Clinical and epidemiologic aspects of tardive dyskineisa, J. Clin. Psychiatry 46(4, Sec. 2):8-13 (1985).

[4] Wolf, M. D., Ryan, J. J., and Mosnaim, A. D., Organicity and tardive dyskinesia, Psychosomatics 23:475-480 (1982).

[5] Rylander, G., Psychosis and the punding and choreiform syndromes in addiction to central stimulant drugs, Psychiatr. Neurol. Neurochir. 75:203-212 (1972).

[6] Casei, D. E., The differential diagnosis of tardive dyskinesia, Acta Psychiatr. Scand. (Suppl.) 63(291):71-87 (1981).

[7] Munetz, M. R., and Schulz, S. C., Screening for tardive dyskinesia, J. Clin. Psychiatry 47:75-77 (1986).

[8] The task force on the late neurological effects of antipsychotic drugs: Tardive dyskinesia: Summary of the task force report of the American Psychiatric Association, Am. J. Psychiatry 136:1163-1171 (1980).

[9] Bell, R. C., and Smith, R. C., Tardive dyskinesia: Characterization and prevalence in a statewide system, J. Clin. Psychiatry 39:39-47 (1978).

[10] Perenyi, A., and Arato, M., Tardive dyskinesia on Hangarian psychiatric wards, Psychosomatics 21:904-909 (1980).

[11] Rey, J. M., Hunt, G. E., and Johnson, G. F. S., Assessment of tardive dyskinesia in psychiatric outpatients using a standardized rating scale, Aust. N. Z. J. Psychiatry 15:33-37 (1981).

[12] Smith, J. M., Kucarski, L. T., Eblen, C., Knutsen, E., and Lima, C., An assessment of tardive dyskinesia in schizophrenic outpatients, Psychopharmacology 64:99-104 (1979).

[13] Fanrbye, A., Rasch, P. J., Petersan, P. B., Brandborg, G., and Pakkenberg, H., Neurological symptoms in pharmacotherapy of psychosis, Acta Psychiatr. Scand. 40:10-27 (1964).

[14] Odejide, A. O., Prevalence of persistent abnormal involuntary movements among patients in the Nigerian long-stay psychiatric unit, Int. Pharmacopsychiatry 15:292-300 (1980).

[15] Yassa, R., Nalr, V., and Schwartz, G., Tardive dyskinesia and the primary psychiauic diagnosis, Psychosomatics 25:135-138 (1984).

[16] Smith, J. M., Kucharski, L. T., Oswald, W. T., and Waterman, L. J., Systematic investigation of tardive dyskinesia in inpatients, Am. J. Psychiatry 136:918-922 (1979).

Arturo A. Olivera, * MD

Veterans Addiction Recovery Center Cleveland Veterans Administration Medical Center Brecksville Division Brecksville, Ohio 44141;

Department of Psychiatry Case-Western Reserve University Cleveland, Ohio 44106

Mary W. Kiefer, RN, MS Norlee K. Manley, RN, BSN, CNA

Cleveland-Veterans Administration Medical Center Brecksville Division Brecksville, Ohio 44141

* To whom requests for reprints should be addressed at Western Reserve Psychiatric Hospital, P.O. Box 305, Northfield, Ohio 44141.

COPYRIGHT 1990 Taylor & Francis Ltd.
COPYRIGHT 2008 Gale, Cengage Learning

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