Tardive dyskinesia (TD) is a clinical subtype of tardive syndrome (TS). It is characterized by delayed onset of abnormal and purposeless involuntary movements induced by dopamine blocking agents, primarily first-generation antipsychotics (FGAs). In contrast to tardive dystonia, which causes slow, painful, twisting, and spasmodic muscular contractions, most commonly of the face and neck, TD presents with rapid jerky movements, usually a choreiform athetoid or rhythmic type. Although TD commonly involves orobuccolingual muscles, it can also involve other parts of the body.1 TD can be debilitating, both socially and physically, and lead to medication nonadherence that can ultimately result in a relapse of underlying psychotic symptoms.2 It affects about 20% to 30% of patients receiving long-term antipsychotic treatment, with elderly patients at higher risk.3 Different research studies have proved that TD is less common with second-generation antipsychotics (SGAs) than FGAs.4,5 The most common strategy for treating FGA-induced TD is discontinuation of the medication and switching to an SGA. However, the treatment of SGA-induced TD is more difficult, especially when psychotic symptoms recur with the discontinuation of antipsychotic medication.
Although various medications have been proposed for the treatment of TS, including noradrenergic antagonists (propranolol and clonidine), dopamine agonists and antagonists, catecholamine depleting agents (reserpine and tetrabenazine), cholinomimetic agents, gamma-aminobutyric acid receptor potentiators (clonazepam), vitamin E, baclofen, and others,1 no randomized controlled trials have demonstrated their efficacy. Nevertheless, these treatment modalities may be useful in treating 50% to 60% of TS.6 Olanzapine, a widely used SGA, is commonly prescribed for FGA-induced TD in clinical settings, and its beneficial effect has been reported in various research studies.7–9 However, cases have also been reported (Table 1) that indicate the potential risk that olanzapine may induce TD. This report adds another case history to those findings.5
Clozapine, a dibenzodiazepine derivative, is an atypical antipsychotic medication with a unique profile of low affinity for striatal dopamine-2 (D2) receptors, which probably accounts for its low incidence of TD. It also has high affinity for D1 receptors, along with antiserotonergic (5HT-2, 5HT-1C), anticholinergic, and antihistaminergic effects.16 Despite being the most efficacious drug for the treatment of psychosis, it is only prescribed as a final option for treatment-resistant schizophrenia because of its serious side effect of agranulocytosis.
We reviewed the literature in various databases including PubMed, PsycINFO, and Google Scholar on the effectiveness of clozapine for treating TD induced by antipsychotic medications. Of 3 double-blind controlled trials, 2 studies16,17 demonstrated beneficial effects of clozapine for patients with TD, and 1 study18 showed no improvement in symptoms. Similarly, in 4 single-blind studies, 2 studies19,20 found >50% improvement in TD symptoms, 1 study21 showed mild benefit, and 1 study22 found no benefit. Among open-label studies that involved >20 subjects, 2 studies23,24 found mild to moderate benefit, 2 studies25,26 showed 43% to >75% improvement in symptoms, and 1 study27 demonstrated a 20% improvement (Table 2). Similarly, a review article2 suggested that clozapine had been effective in treating 34 different patients in 28 case reports. An analysis of 8 published articles concerning 30 patients with TD treated with clozapine showed 43% improvement in TD symptoms.25 In contrast, clozapine has also been reported not only to worsen the symptoms but also to induce TD in some patients.28–30
In this report, we describe the case of a patient with paranoid schizophrenia who developed severe TD after 12 years of treatment with olanzapine. Tremendous improvement was noted in both the patient’s psychotic and TD symptoms within a few weeks of clozapine treatment. Our case differed from the studies listed in Table 2, in that the TD was induced by an SGA rather than an FGA.
The case involved a 66-year-old Hispanic male, domiciled at an adult home care facility, who had a diagnosis of paranoid schizophrenia for 25 years. He had taken olanzapine 30 to 40 mg/d for at least 15 years for psychotic symptoms, and citalopram 30 mg/d for 10 years for some negative symptoms. During this period, his symptoms had been stable except for a single psychiatric hospitalization 8 years earlier for anxiety and agitation. In December 2014, when the patient was brought to our service, he had severe, involuntary, orobuccolingual movements with constant opening and closing of the jaw, and frequent protruding movements of his tongue which affected his speech. He also displayed severe truncal dyskinesia with continuous rhythmic movements of both arms and trunk. According to the staff of the adult home, the symptoms had started insidiously about 3 years earlier and had gradually worsened since October 2014. The patient did not report any active psychotic symptoms, and his mood was euthymic. No other associated physical, neurological, or psychiatric symptoms were reported.
On examination, constant alternate opening and closing of the jaw, protruding movement of the tongue, and involuntary rhythmic movements of the arms and trunk were noted. The patient’s speech was unintelligible and unarticulated. The patient’s vital signs were normal, and no other systemic or neurological abnormalities were evident. On mental status examination, the patient was cognitively impaired with poor judgment and limited insight due to chronic schizophrenia. Results of routine laboratory investigations were within normal limits. Results of a work-up for renal and liver function, a thyroid function test, a chest x-ray, and computed tomography of the head were unremarkable.
After ruling out possible psychiatric, general medical, and other neurological causes of the patient’s symptoms, we considered a diagnosis of olanzapine-induced TD. We began to taper the dose of olanzapine in February 2015 over a period of a few weeks and finally discontinued the olanzapine in March 2015. The patient was subsequently started on clonazepam 0.5 mg 3 times daily but with no response. Instead, 2 weeks after the discontinuation of olanzapine, the patient’s psychotic symptoms began to recur, and the patient eventually became extremely paranoid and agitated, displaying aggressive behavior toward the staff and other residents of the facility where he lived. As a result, he was admitted to the psychiatry inpatient unit in April 2015, where he was started on clozapine 75 mg/d (25 mg in the morning and 50 mg at bed time) and continued on clonazepam 0.5 mg 3 times daily; the citalopram was discontinued. In the following few weeks of inpatient treatment, the patient’s psychotic symptoms and aggressive behavior subsided and, notably, his overall TD symptoms improved by 75%, including the orobuccolingual movements and the dancing movements of the arms. His speech became more comprehensible and intelligible. After the patient returned to his baseline, he was discharged from the hospital on the same dose of medications. Since that time, the effect of the clozapine has been sustained for 10 months, with the improvement in the patient’s TD symptoms maintained without any side effects from the clozapine. The patient is being closely monitored for any adverse effects of clozapine with the recommended frequency of white blood cell and absolute neutrophil counts.
We described a unique case of TD presenting after very long-term treatment with olanzapine. The diagnosis of TD was made based on the criteria of Schooler and Kane31 which comprise (i) at least 3 months of antipsychotic use, (ii) involuntary movement of moderate severity in at least 1 region or of mild severity in at least 2 regions, and (iii) exclusion of other medical and neurological causes. Although a randomized controlled trial has shown olanzapine to be associated with a very low risk of developing TD,5 on the basis of our literature search, we identified 8 patients with olanzapine-induced TD reported in 7 different case reports (Table 1). Of the 8 subjects, 5 had TD,3,13–15 2 had both TD and tardive dystonia,10,12 and 1 had Pisa syndrome.11 (Pisa syndrome, as the name implies from the “Leaning tower of Pisa,” is characterized by the lateral flexion of the trunk when sitting or standing,32 usually associated with the use of neuroleptics, antiemetics, and/or cholinesterase inhibitors.) In these cases, the duration of olanzapine use before onset of symptoms ranged from 12 days14 to 5 years.10,15 In contrast to our 66-year-old patient, these 8 patients ranged in age from 22 to 65 years. Our patient was also being treated with a higher dose of olanzapine (30 to 40 mg/d) compared with the doses used in the majority of the 8 reported cases (20 to 30 mg/d). In 4 of the 8 patients, the TD was treated by discontinuing the olanzapine and adding clozapine (as was done in our case), which resulted in improvement in 3 patients11,12,14 and no change in 1 patient.13 Among the 3 patients who improved with clozapine, 1 patient had tardive dystonia rather than TD,11 1 had mild TD symptoms in the hands and feet which responded after 1 month of treatment,14 and the third patient improved after 4 months12 (Table 1). However, in our case, the patient had been taking olanzapine for 12 years before he experienced the symptoms of TD and rapid improvement (after 2 to 3 wk) occurred in both the tardive and psychotic symptoms with clozapine treatment.
Risk factors associated with the development of TD in patients treated with antipsychotics are older age, female sex, African American ethnicity, high dose, and long duration of antipsychotic medication treatment, preexisting mood disorders and substance use, cognitive impairment, presence of negative symptoms, use of antiparkinsonian agents and lithium, early extrapyramidal symptoms, and medical conditions such as diabetes and human immunodeficiency virus infection.2 Potential risk factors for developing TD in the patient in our case were his age (66 y), long-term exposure to an antipsychotic, and cognitive impairment and negative symptoms. Despite such recognized risk factors, it is practically impossible to predict which medications will cause TD and what treatments will be potentially effective in its treatment. Moreover, no fixed guidelines exist for the treatment of TD. Some commonly used interventions are discontinuing or reducing the dose of the antipsychotic drug, switching to clozapine or another atypical antipsychotic, adding an adjunctive agent, or using deep brain stimulation.33
When our patient had first developed TD, his medication was not changed because the symptoms were mild and the patient was not bothered by them because of his limited insight and impaired cognition. There was also a potential risk of psychotic relapse occurring if the olanzapine was stopped, given the fact that the patient had been stable on olanzapine for a long period. However, when the TD symptoms later became severe enough to affect the patient’s functioning, including his speech, we finally decided to stop the olanzapine and monitor the symptoms, which continued to worsen. This finding was consistent with a previous study in which 49 patients with TD were kept off antipsychotic drugs and monitored and only 1 patient completely remitted.34 Thus, for our patient, clozapine was one of the best alternatives to benefit both his psychotic and tardive symptoms.
This case report has 2 unique findings. First, it presents a rare case of olanzapine-induced TD associated with the longest duration reported in the literature. Second, it reports rapid improvement of both TD and psychotic symptoms with clozapine treatment. To the best of our knowledge, this is the first case report of clozapine treament of TD caused by 12 years of continuous olanzapine use. On the basis of our report, we suggest that, in treating patients with TD, clinicians should always use their clinical judgment and assess the risk-benefit ratio before discontinuing the antipsychotic medication, switching to a new drug, or adding an adjunctive medication. In addition, we recommend that every patient treated with an FGA or an SGA be periodically assessed for the risk factors and symptoms of TD, regardless of the duration of treatment, and that, if indicated, clozapine be considered as a good therapeutic option in selected cases of antipsychotic-induced TD. However, future research is needed to evaluate the effectiveness of clozapine in reversing the symptoms of TD and the mechanism of action involved.
COMMENTARY by David A. Kahn, MD
This important case report describes TD induced by long-term treatment with olanzapine, which improved significantly when clozapine was substituted. The duration of olanzapine treatment and the speed of response to clozapine are unique aspects of the report, adding new information to the handful of previously reported cases of this scenario. It is noteworthy that the dose of clozapine, only 75 mg, was comparatively low, compared with the ongoing dose of olanzapine the patient had been receiving of 30 to 50 mg/d, which is at the very upper end of the usual range. This leads me to speculate that the patient may have received an excessive long-term dose of olanzapine following resolution of acute symptoms, perhaps elevating the risk of TD unnecessarily, before his encounter with the clinicians who wrote this report.
A key issue in the use of SGAs is that we do not know the true, long-term rate at which TD can be expected to occur with theses agents in comparison with FGAs. The era in which FGAs were the only antipsychotics available taught us that the risk of TD is cumulative with years of exposure and total lifetime dosage. This perspective was derived from observations made over many decades. It has been estimated that, with FGAs, the risk of persistent TD is 32% after 5 years of exposure, 57% after 15 years of exposure, and 68% after 25 years of exposure.35 This translates into roughly 4% to 6% risk per year of exposure, with higher rates earlier in treatment but an enormous cumulative likelihood averaging about 5% per year of exposure. Moreover, the risk appears to be related to cumulative lifetime amount of antipsychotic medication received,36 meaning that low doses for a very long time may postpone but not eliminate the risk.
We have no comparable data on the epidemiology of TD with SGAs over such long periods of time. However, estimates using shorter time frames and limited comparison data between the classes of medication still indicate annual incident rates of 2.98% with SGAs versus 7.7% with FGAs in nongeriatric adults, and 5.2% with both SGAs and FGAs in the elderly.37 In schizophrenia, one recent estimate is that TD point prevalence rates are 13.1% for patients taking SGAs and 32.4% for those taking FGAs,37 although correcting for total time of exposure and prior exposure to FGAs before taking SGAs is still a problem in interpreting these data. Thus, although less of a problem than with FGAs, TD is still a substantial risk associated with treatment with SGAs.
Estimating the risk of TD with clozapine poses a problem because it is generally used after prolonged exposure to SGAs or FGAs, sometimes precisely because of neurological side effects. However, observations in China, where it is used as a first-line medication, provide valuable information about this question. Recent findings demonstrated a prevalence of only 3.96% over an average exposure of 12 years, far lower than the rates seen with other antipsychotics.29
The best way to minimize the risk of TD is to use SGAs, as is now the standard of care, and to limit the dosage to the minimum needed to prevent relapse. However, we must not forget that SGAs are not risk-free for this problem, so that it is still important to monitor patients taking these agents regularly for TD. Clozapine is an important option in both prevention and treatment. We should also note that, at the time of this case’s activity, the authors were practicing at Zucker Hillside Hospital, one of the research centers that has contributed enormously to our knowledge of antipsychotic medications in schizophrenia and of TD in particular.
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