Evidence of Neuroleptic Drug-Induced Brain Damage in Patients:
A partial, Annotated Bibliography
by Vera Hassner Sharav
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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. rjwyderski@mvh.org
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. Jauss@USA.net
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:http://ajp.psychiatryonline.org/cgi/content/full/155/12/1711#F1
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. ÊHere 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, Germany.dfbraus@as200.zi-mannheim.de
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. daniel.casey@med.VA.gov
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<.04) after controlling for the effects of years of illness,
duration of hospitalization, motor speed, severity of illness, and
medication." The authors conclude: "our findings suggest that TD may
represent both a motor and dementing disorder regardless of major
psychiatric diagnosis."
Famuyiwa, O.O., Eccleston,
D., Donaldson, A.A., & Garside, R.F. (1979). Tardive dyskinesia and
dementia. British Journal of Psychiatriy, 135 500-504.
Schizophrenics both with
and without tardive dyskinesia were compared with both EMI scans and
psychological tests of intellectual function. Those with TD did worse on
the tests, and it was suggested that the higher incidence of pathology in
that group might be related to chronic neuroleptic toxicity.
Edwards, H. (1970). The
significance of brain damage in persistant oral dyskinesia. British
Journal of Psychiatry, 116, 271-275.
The author sought to
discover whether brain damage could be an important contributory cause of
TD. To examine that possibility, he compared two samples matched for
phenothiazine intake and age, one sample with TD, the other without. Both
groups were checked for brain damage and dementia. 28 out of 34 in the
group with TD, versus 14 out of 34 controls, showed at least some brain
damage. Edwards mostly focused on brain damage putting patients at risk
for TD, but he also raised the possibility that the drugs themselves cause
permanent neurological damage.
Wade, J.B., Taylor, M.A.,
Kasprisin, A., Rosenberg, S., & Fiducia, D. (1987). Tardive dyskinesia
and cognitive impairment. Biological Psychiatry, 22 393-395.
Because not all studies
have found a relationship between tardive dyskinesia and cognitive
functioning, the authors conducted a study using tasks known to find
cognitive impairment in Parkinson's and Huntington's diseases. These tasks
were chosen because the authors believed these diseases might provide a
neuropsychological, as well as a biochemical, model for TD. The authors
found a modest but significant linear relationship between TD and reduced
cognitive functioning, where those with the most severe forms of the
disorder were most impaired cognitively. Neuroleptics increase cognitive
decline in elderly people with dementia:
Waddington JL, Youssef HA
(1986) Late onset involuntary movements in chronic schizophrenia:
relationship of 'tardive' dyskinesia to intellectual impairment and
negative symptoms. Br J Psychiatry 1986 Nov;149:616-20
Intellectual impairment,
negative symptoms, and medication history were assessed in chronic
schizophrenic patients with and without abnormal involuntary movements
(tardive dyskinesia). Patients with involuntary movements had received
neither longer nor more intensive treatment with neuroleptics or
anticholinergics. However, the presence or absence of involuntary
movements was prominently associated with the presence or absence of
intellectual impairment/negative symptoms; these features are
characteristic of the defect state/type II syndrome of schizophrenia, in
which structural abnormalities of the brain may be over-represented. The
role of subtle organic changes in conferring vulnerability to the
emergence of such involuntary movements should be re-evaluated. PMID:
2880630, UI: 87129840
Waddington JL, Youssef HA
(1986) An unusual cluster of tardive dyskinesia in schizophrenia:
association with cognitive dysfunction and negative symptoms. Am J
Psychiatry 1986 Sep;143(9):1162-5.
Factors associated with
the emergence or nonemergence of involuntary movements (tardive
dyskinesia) during long-term neuroleptic treatment were investigated in an
atypical, isolated population of 31 schizophrenic inpatients with an
unusually high prevalence of this syndrome. Patients with involuntary
movements could not be distinguished from those without such movements by
general characteristics or conventional indices of neuroleptic or
anticholinergic treatment. However, they were more likely to show either
marked cognitive dysfunction or muteness. These findings support the
proposal that, at least in schizophrenia, subtle organic changes may
contribute to vulnerability to the emergence of involuntary movements.
Friedman JH "Rubral"
tremor induced by a neuroleptic drug. Journal of Movement Disorders
1992; 7(3):281-2 Neuropsychiatry Research and Training Center, Institute
for Mental Health, Cranston, RI
"Rubral" tremor is a rare
movement disorder that occurs typically with midbrain damage. It is
defined by its presence at rest, with sustained posture, and with
movement. Whether it is a single-tremor disorder or a combination of two
distinct tremors is debated. This report chronicles a severe neuroleptic
induced "rubral" tremor in a patient who had had a stable posttraumatic
ataxia. The dramatic response to benztropine and bromocriptine is
illustrated in the videotape.
Owens DG (1985)
Involuntary disorders of movement in chronic schizophrenia--the role of
the illness and its treatment. Psychopharmacology Suppl 1985;2:79-87
The prevalence and
distribution of involuntary movements in age-matched chronic
schizophrenics treated and not treated with neuroleptics were compared.
While exposure to neuroleptic drugs in the past was important, high rates
of movement disorder were associated with the severe, untreated illness.
Ventricular enlargement correlated with severe movement disorder but not
with past neuroleptic exposure. It is suggested that in the context of
Schizophrenia neuroleptic drugs may act to promote what are features of
the illness for some, and that in the search for predisposing factors
illness, as well as treatment variables, is worthy of consideration.
Marsden CD (1985) Is
tardive dyskinesia a unique disorder? Psychopharmacology Suppl
1985;2:64-71
ABSTRACT: The role of
neuroleptics in causing the tardive dyskinesia syndrome is controversial.
To properly assess the contribution of drugs as the etiology of
dyskinesias, the effects of aging, the natural history of psychosis, and
characteristics of spontaneous dyskinesias must be considered. Though the
buccolinguo-masticatory triad is seen more often in tardive than in
spontaneous dyskinesias, these two disorders have many symptoms in common.
Other dyskinesias, such as idiopathic and tardive dystonia or tardive
Tourette's syndrome and dyskinesias in untreated schizophrenia, are poorly
understood. Chronic neuroleptic treatment may only precipitate TD in those
already predisposed to develop such movement disorders.
Tardive dyskinesia is not
a unique movement disorder, but rather spans several clinical and
epidemiological phenomena which must be considered in a balanced
evaluation of how much of the permanent dyskinesias should be attributed
to neuroleptic drugs.
VHS Comment: The article
is an example of an established psychopharmacologist's resistance to the
evidence of TD as a neuroleptic-drug induced phenomenon, and to reach for
straw men in a futile attempt to deflect the damaging evidence. Before the
introduction of neuroleptics there were no reports of tardive dyskinesia!
~~~~~~~~~~~~
Full Text:
Authors: Al Madsen, N
Keiding, A Karle, S Esbjerg, R Hemmingsen Source: The Lancet, Sept
5, 1998 v352 n9130 p784 (1). Title: Neuroleptics in progressive
structural brain abnormalities in psychiatric illness.
Subjects: Antipsychotic
drugs - Adverse and sideeffects Schizophrenia - Drug therapy Cerebral
cortex -Effect of drugs on Electronic Collection: A21132289 RN: A21132289
COPYRIGHT 1998 Lancet Ltd.
Progressive abnormalities have been reported in schizophrenic patients.1
We did a prospective,
longitudinal study of brain structure. 31 drug-naive psychotic patients
underwent computed tomography (CT)at first admission to hospital and after
5 years of illness. We obtained written informed consent from all
patients. A radiologist masked to the patients' identities and diagnoses,
date of scans, and the nature of the study compared the first and second
CT scans.
Brain atrophy was assessed
on a visual scale, on which 0-1 meant no changes or dubious atrophy and
2-3 mean to moderate or severe atrophic changes. After 5 years of illness,
we found significant progression of frontal atrophy in 21 schizophrenic
patients, compared with nine consecutively included healthy volunteers. We
saw progressive frontal atrophy in ten non-schizophrenic patients, but to
a lesser degree. During follow-up, schizophrenic patients received a
median of 172040 mg (range 19 540-928450) neuroleptic medication
(chlorpromazine equivalents). Seve nnon-schizophrenic patients received a
median of 20780 mg (range 678-141596). The only atypical neuroleptic used
was clozapine, administered to three patients, always in high doses and in
combination with traditional neuroleptics. Patients were thought to have a
chronic, non-remittent course of illness if all psychiatric records
described a state of permanent psychosis, and if they were psychotic at
the time of the reinvestigation. Some patients were described as remitted,
but if in long interviews they showed firm delusive systems that seemed to
be integrated but not necessarily overt parts of their lives, and if they
were judged to be permanently deluded, despite their records, they were
classified as non-remittent. This classification was made without
knowledge of the results of the CT scans.
Nine schizophrenic
patients (eight men and one woman) had been continuously psychotic during
follow-up. At reinvestigation, non-remittent patients had significantly
higher ratings for psychopathology (SANS and SAPS2) than remittent
patients. Because of the small sample, we did exact tests in a logistic
regression analysis with Log Xact, adjusted for sex, course of illness,
(remission/non-remission), diagnosis, and neuroleptic load. Course of
illness and diagnosis had no significant impact on the development of
frontal atrophy. Sex was significant (p=0.035) if course of illness was
not included into the model, but sex became non-significant (p=0.138) if
course of illness was included. Neuroleptic load was significant whether
sex was included or not (p=0.013 and 0.0003,respectively). The estimated
risk of atrophy increases by 6.4% for each additional 10 g neuroleptic
drug. Non-remittent patients received a higher neuroleptic dose than
remittent patients, but the model wascorrected for this
interaction.Association has been shown between frontal atrophy or aplasia
and non-respondence to antipsychotic drugs,3and neuroleptic side-effects
as tardive dyskinesia and akathisia have been associated with wider
sulci.4 These studies do not include neuroleptic load as a possible
explanatory factor for the abnormalities found.Traditional neuroleptics
have been shown to affect brain structure because they enhance the volume
of basal ganglia,5 but the potential impact of neuroleptics, on frontal
cortex, for example, is not known.
Factors causing
progression of brain atrophy have not yet been identified. Our study
showed an unexpected effect of neuroleptic medication on cerebral cortex,
but our analysis suggests that the results cannot betaken as accidental.
Future longitudinal studies of brain structure in schizophrenia are needed
to showwhether atypical antipsychotic drugs may be more beneficial.
1. DeLisi LE, Sakuma M,
Tew W, Kushner M, Hoff AL,Grimson R. Schizophrenia as a chronic active
brain process: a study of progressive brain structural change subsequent
to the onset of schizophrenia. Psychiatr Res 1997; 7: 129-40.
2. Andreasen NC, Black DW,
Introductory textbook of psychiatry. Washington DC: American Psychiatric
Press, 1991.
3. Friedman L, Knutson L,
Shurell M, et al, Prefrontal sulcal prominence is inversely related to
response to clozapine in schizophrenia. Biol Psychiatry 1991; 29: 865-77.
4. Sandyk R, Kay SR,
Sulcal size andneuroleptic-induced akathisia. Biol Psychiatry 1990: 27:
466-67.
5. Frazier JA, Giedd JN,
Kaysen D, et al.Childhood-onset schizophrenia: brain MRI rescan after 2
years of clozapine maintenance treatment. Am J Psychiatry 1996; 153:
Department of Psychiatry
E, Bispebjerh Hospital, DK2400 Copenhagen NV, Denmark (A Madsen)
~~~~~~~~~~~~~
A sample of 3 decades of
animal studies show neuroleptics caused brain changes:
Pakkenberg, H., Fog, R., &
Nilakantan, B. (1973) The long term effect of perphenazine enanthate on
the rat brain. Some metabolic and anatomical observations. This study
found a significant decrease in the number of nerve cells in the basal
ganglia of rats under long-term treatment.
Muller, P. & Seeman, P.
(1977). Brain Neurotransmitter receptors after long-term haloperidol:
dopamine, acetylcholine, serotonin, -Noradrenergic and naloxone receptors.
Life Sciences 21, 1751-1758.
This study looked at the
effect of chronic haloperidol on a variety on neurotransmitters in rats.
The authors concluded that "these results indicate that long-term
haloperidol treatment produces rather selective increases in
dopamine/neuroleptic receptors, without much change in 4 other types of
receptors." The dopamine receptor changes were very significant though,
ranging from 34 to 45%.
Burt, D.R., Creese, I., &
Snyder, S.H. (1977). Anti-schizophrenic drugs: Chronic treatment
elevates dopamine receptor binding in brain. Science, 196, 326-328.
Another study looking at
changes in dopamine receptors. "Chronic treatment of rats with the
neuroleptic drugs haloperidol, fluphenazine , and reserpine elicits a 20
to 25 percent increase in striatal dopamine receptor binding assayed with
Haloperidol."
Nielsen, E.B., & Lyon, M.
(1978). Evidence for cell loss in corpus striatum after long-term
treatment with a neuroleptic drug (flupenthixol) in rats.
Psychopharmacology, 59 85-89.
The authors found a 10%
cell loss in one region of the rat's brains, which they concluded "further
suggest that persistent irreversible anatomical changes can follow
long-term neuroleptic treatment."
Benes, F.M., Paskevich,
P.A., Davidson, J., & Domesick, V.B. (1985) The effects of haloperidol
on synaptic patterns in the rat striatum. Brain Research, 329,
265-274.
This study finds changes
in cell size and in number of vesicles in rats in a particular part of
their brain. The authors cite other studies which have also found changes
in rat brains caused by neuroleptics. In their conclusion the authors
state that "The results of this study provide further evidence that
haloperidol can induce synaptic alterations in the rat central nervous
system, an effect which we first noted in the rat substantia nigra."
Jeste, D.V., Lohr, J.B., &
Manley, M. (1992). Study of neuropathologic changes in the striatum
following 4, 8 and 12 months of treatment with fluphenazine in rats.
Psychopharmacology, 106, 154-160.
In the literature review
of research over 3 decades, most studies listed found brain changes. The
current study also found brain changes: a lower density of large neurons
in the striatum of middle aged rats. Older rats did not show significant
differences, which the authors felt was because the neuroleptics were
accelerating the loss of large neurons which naturally die later as a
result of aging.
