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2007, Vol. 27, No. 12 (pp. 861-864)

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Case Reports
Tardive Oculogyric Crisis during Clozapine Treatment

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 Clin Drug Invest 2007; 27 (12): 861-864
CASE REPORTS 1173-2563/07/0012-0861/$44.95/0

 2007 Adis Data Information BV. All rights reserved.

Tardive Oculogyric Crisis during

Treatment with Clozapine
Report of Three Cases
Özcan Uzun and Ali Doruk
Department of Psychiatry, Gulhane School of Medicine, Ankara, Turkey

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Abstract Tardive oculogyric crisis (OGC) is a dystonic syndrome that starts after long-
term use of dopamine receptor antagonists. Atypical antipsychotics have reduced
liability for inducing tardive dystonia and show antidystonic properties in patients
with pre-existing tardive dystonia. Clozapine is an atypical antipsychotic drug,
and there have been case reports that clozapine may be an effective treatment for

the copyright of the tardive dystonia. Surprisingly, we found that three patients appeared to develop
tardive OGC while taking clozapine. The relationship between tardive OGC and
clozapine is still unknown. However, it is possible that the previous antipsychotic
exposure could have created a sensitising or priming effect on the striatum. Also,

original publisher.
there are some suggestions of an underlying susceptibility and possibly a genetic
predisposition, at least in some patients.

Tardive dystonia is one of the extrapyramidal Oculogyric crisis (OGC) is one of the dystonic

Unauthorised copying
syndromes that may start after long-term use of
dopamine receptor antagonists. Tardive dystonia oc-
curs in about 3% of patients during long-term anti-
reactions. Initial symptoms include restlessness, agi-
tation, malaise or a fixed stare followed by the more
characteristically described maximal upward devia-
psychotic treatment.[1] The pathophysiology of dys- tion of the eyes in a sustained fashion. The eyes may

and distribution
tonia is not well understood since the term describes
a symptom that may arise from a variety of cerebral
structures, such as the basal ganglia, thalamus,
also deviate upward, laterally or downward. Back-
ward and lateral flexion of the neck, wide open
mouth, tongue protrusion and ocular pain are the
most frequently reported associated findings.[5]
brainstem or cortex, or may be caused by genetic
Clozapine is considered to be an atypical anti-

is prohibited.
alterations.[2] Some probable risk factors for tardive
dystonia include younger age, male sex and the
presence of tardive dyskinesia. The management of
tardive dystonia depends on whether there is a need
to continue the causative antipsychotic drug. If anti-
psychotics are needed, a switch to an atypical anti-
psychotic, particularly clozapine, may be a helpful
choice. If tardive dystonia is more extensive, either
dopamine-depleting drugs or high dosages of anti-
cholinergics can be tried.[3,4]
psychotic drug since it induces dose-related catalep-
sy in rodent models and is associated with a low
incidence of acute extrapyramidal syndromes in
humans.[6] Furthermore, it is generally considered to
have little or no potential to cause tardive syn-
dromes. In contrast to other atypical antipsychotics,
clozapine has also been used to treat tardive dys-
tonia.[7]
Clearly, cases of tardive OGC resulting from
clozapine treatment would be of great interest. We
862
report here three cases of tardive OGC possibly
associated with clozapine monotherapy.
Case Reports
Case 1
The first case was a 38-year-old single female,
who was unemployed and living with her family.
The patient had met DSM-IV criteria[8] for schizo-
phrenia since she was 15 years old. Since 1980, she
had been receiving intermittent typical antipsychotic
medications without significant improvement. She
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had also been given anticholinergic medication on
an irregular basis for extrapyramidal adverse effects.
She was referred to our unit because of break-
through psychosis in 1999, and her medication was
then switched to clozapine. Clozapine was effective
the copyright of the
in controlling her psychosis and remained her exclu-
sive antipsychotic treatment for two years. After
that, she began to develop OGC, possibly induced
by clozapine. She had reported feelings of fear and
original publisher.
restlessness before the onset of OGC.
Case 2
The second case was a 19-year-old single female
student living with her family. She had met the
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DSM-IV criteria[8] for schizophrenia since the age of
15 years. Since 1999, she had been receiving atypi-
cal antipsychotic treatment with olanzapine without
significant improvement. She had not experienced
and distribution
extrapyramidal adverse effects. She was referred to
our unit in 2000, and was switched to clozapine
because of resistance to olanzapine. After 6 months
of clozapine treatment, she began to experience
OGC, accompanied by reports of fear and restless-
ness.
is prohibited.
Case 3
The third case was a 45-year-old single unem-
ployed female living with her family. The patient
had met the DSM-IV criteria[8] for schizophrenia
since she was 25 years old. Since 1984, she had been
receiving antipsychotic treatment with haloperidol
and sulpiride, with limited improvement. This pa-
 2007 Adis Data Information BV. All rights reserved.
Uzun & Doruk
tient had previously experienced extrapyramidal ad-
verse effects while taking haloperidol, and had
therefore also been given anticholinergic medication
for these adverse effects. She was referred to our
unit in 2001, and was switched to clozapine because
of breakthrough psychosis. Clozapine was effective
in controlling her psychosis and remained her exclu-
sive antipsychotic treatment for a year. After that,
she began to experience OGC.
There were no other involuntary movements in
any of these patients. The OGC attacks were resis-
tant to intramuscular biperiden. However, oculo-
gyric symptoms spontaneously remitted after 3–5
hours and recurred within 3–7 days. None of these
patients had any sign of head trauma, history of
substance abuse or family history of dystonia or
other neurological problems. Chemistry profile tests
for the patients, including liver and kidney func-
tions, serum ceruloplasmin and thyroid functions,
were all normal. All three patients were willing to
take clozapine medication, and clozapine therapy
was continued in these patients.
Discussion
In this paper we report on three patients with
schizophrenia who developed tardive OGC while
taking clozapine treatment. In the literature, we
could find only four previous reports of tardive
dystonia possibly associated with clozapine use,[9-12]
including one case of OGC.[9] Dave[9] reported a
patient who experienced recurrent OGCs with clo-
zapine. This patient had previously experienced
similar symptoms while taking perphenazine. In ad-
dition, each episode responded dramatically to anti-
cholinergic medication. Thus, it is possible that this
was a case of recurrent acute dystonia rather than
true tardive dystonia. Peacock and colleagues[10]
reported the onset of mild finger dystonia in a pa-
tient treated long term (>5 years) with clozapine. In
1999, Molho and Factor[11] reported on a patient
with tardive dystonia who was receiving clozapine.
This patient experienced involuntary movements
while receiving typical antipsychotic medication
before clozapine treatment. Trihexyphenidyl med-
ication was unsuccessful in treating his dystonia.
Clin Drug Invest 2007; 27 (12)
Tardive Oculogyric Crisis during Clozapine Treatment
Recently, Duggal and Mendhekar[12] identified a
patient who developed blepharospasm (tardive dys-
tonia) with clozapine. Initially, this patient was
treated with trifluoperazine, which was replaced
with clozapine because of severe akathisia. She had
a complete resolution of the blepharospasm with
clonazepam treatment. In our three cases, the oculo-
gyric symptoms continued for 3–5 hours, which we
thought was inconsistent with epileptic phenomena
and we therefore did not administer antiseizure med-
ication.
There are case reports that clozapine may be an
effective treatment for tardive dystonia.[7,13] The
This material is
efficacy of clozapine in treating tardive dystonia
may be because of its anti-dopamine D1 action
rather than its built-in anticholinergic action.[7] Clo-
zapine differs from conventional antipsychotics in
the copyright of the
that it has higher affinity for D1 and lower affinity
for D2 receptors than do conventional antipsychot-
ics, which are relatively selective D2 antagonists.
Trugman and colleagues[7] proposed that it is prima-
rily the D1 antagonist action of clozapine that ac-
original publisher.
counts for the therapeutic effect in tardive dystonia.
However, this report describes three patients with
schizophrenia all of whom developed episodes of
ocular dystonia as a delayed adverse effect of cloza-
Unauthorised copying
pine. This discrepancy may be explained in two
ways. Firstly, dystonia developed in two of these
patients (cases 1 and 3) following long-term expo-
sure to numerous typical antipsychotic medications
prior to clozapine use. It is possible that the previous
and distribution
antipsychotic exposure resulted in long-term func-
tional dopamine receptor abnormalities because of
long-term dopamine receptor blockade. Therefore,
this could have created a sensitising or priming
is prohibited.
effect on these patients’ striatum.[4,7] However,
Tarsy and Baldessarini[14] reported 13 published
cases of tardive dyskinesia in patients who had
never previously been exposed to typical anti-
psychotics and were treated exclusively with atypi-
cal antipsychotics. The second explanation is that
some patients are more susceptible to extra-
pyramidal signs. Chatterjee and colleagues[2] found
that extrapyramidal signs were present in a propor-
tion of antipsychotic-naive schizophrenic patients,
 2007 Adis Data Information BV. All rights reserved.
863
which possibly reflects basal ganglia pathology. In
addition, in individual patients, tardive dystonia
may be an idiosyncratic reaction resulting from an
underlying genetic susceptibility or occult basal
ganglia injury.[15] Familial occurrence of dystonic
reactions has been reported by Guala and col-
leagues.[16]
On the other hand, it has been hypothesised by
Bumpass and Knoll[17] that the tendency for OGC is
drug induced. The OGC occurs when this is com-
bined with an increased state of emotional arousal
and/or a reduction in the ability of the neuromuscu-
lar system to compensate.[17] Sachdev and Tang[18]
reported that episodes of tardive OGC were asso-
ciated with agitation. Our two cases also expressed
fear and restlessness accompanying the crises. Thus,
drug-induced OGC may be a multifaceted disorder
that includes disturbances of emotion and other fac-
tors.
Conclusion
Given the rarity of these reports, it would be
reasonable to conclude that the incidence of tardive
dystonia in clozapine-treated patients will be low.
Reporting of similar cases will hopefully lead to a
more accurate understanding of the incidence of this
potential adverse effect of clozapine therapy.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this report. The authors have no conflicts of interest
that are directly relevant to the content of this report.
References
1. Burke RE, Fahn S, Jankovic J, et al. Tardive dystonia: late-onset
and persistent dystonia caused by antipsychotic drugs. Neuro-
logy 1982; 32: 1335-46
2. Chatterjee A, Chakos M, Koreen A, et al. Prevalence and
clinical correlates of extrapyramidal signs and spontaneous
dyskinesia in never-medicated schizophrenic patients. Am J
Psychiatry 1995; 152: 1724-9
3. Van Harten PN, Kampuis DJ, Matroos GE. Use of clozapine in
tardive dystonia. Prog Neuropsychopharmacol Biol Psychiatry
1996; 20: 263-74
4. van Harten PN, Kahn RS. Tardive dystonia. Schizophr Bull
1999; 25: 741-8
5. FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neuro-
logy 1989; 39: 1434-7
6. Baldessarini RJ, Frankenburg FR. Clozapine: a novel anti-
psychotic agent. N Engl J Med 1991; 324: 746-54
Clin Drug Invest 2007; 27 (12)
864 Uzun & Doruk

7. Trugman JM, Leadbetter R, Zalis ME, et al. Treatment of severe
axial tardive dystonia with clozapine: case report and hypo-
thesis. Mov Disord 1994; 9: 441-6
8. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC: Ameri-
can Psychiatric Association, 1994
9. Dave M. Tardive oculogyric crises with clozapine. J Clin Psy-
chiatry 1994; 55: 264-5
10. Peacock L, Solgaard T, Lublin H, et al. Clozapine versus typical
antipsychotics: a retro- and prospective study of extrapyra-
midal side effects. Psychopharmacology 1996; 124: 188-96
11. Molho ES, Factor SA. Possible tardive dystonia resulting from
clozapine therapy. Mov Disord 1999; 14: 873-4
12. Duggal HS, Mendhekar DN. Clozapine-induced tardive dys-
tonia (blepharospasm). J Neuropsychiatry Clin Neurosci 2007;
15. Mihara K, Kondo T, Higuchi H, et al. Tardive dystonia and
genetic polymorphisms of cytochrome P4502D6 and dop-
amine D2 and D3 receptors: a preliminary finding. Am J Med
Genet 2002; 114: 693-5
16. Guala A, Mittino D, Ghini T, et al. Are metoclopramide dys-
tonias familial? Pediatr Med Chir 1992; 14: 617-8
17. Bumpass ER, Knoll 3rd JL. Emotional factors in oculogyric
crisis. J Nerv Ment Dis 1982; 170: 366-70
18. Sachdev P, Tang WM. Psychotic symptoms preceding ocular
deviation in a patient with tardive oculogyric crises. Aust N Z J
Psychiatry 1992; 26: 666-70
Correspondence: Dr Özcan Uzun, Department of Psychia-
try, Gulhane School of Medicine, 06018 Etlik, Ankara,
Turkey.
E-mail: ouzun@gata.edu.tr

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19: 86-7
13. Friedman JH. Clozapine treatment of psychosis in patients with
tardive dystonia: report of three cases. Mov Disord 1994; 9:
321-4
14. Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia:
is risk declining with modern antipsychotics? Mov Disord

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2006; 21: 589-98

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Erratum

Vol. 25, No. 6, 2005, page 412: The third sentence in the Results section should read: “A total of 131 men aged 35–55
years (mean 47.3 ± 4.6), randomised to atenolol (n = 44), nebivolol (n = 43) or atenolol + chlorthalidone (n = 44),
completed treatment.”
[Boydak B, Nalbantgil S, Fici F, Nalbantgil I, Zoghi M, Ozerkan F, Tengiz I, Ercan E, Yilmaz H, Yoket U, Onder R. A
Randomised Comparison of the Effects of Nebivolol and Atenolol with and without Chlorthalidone on the Sexual
Function of Hypertensive Men. Clin Drug Invest 2005; 25 (6): 409-416]

 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (12)