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Home , Bornaprine, Oculogyric crisis

Isr J Psychiatry - Vol. 56 - No 3 (2019) Şengül Kocamer Şahin et al. Successful Treatment of Tardive Oculogyric Crisis with Bornaprine

Şengül Kocamer Şahin, MD,1 Ayşegül Şahin Ekici, MD,1 Gulcin Elboga, MD,1 Abdurrahman Altindag, MD,1 and Atil Bisgin, MD2

1 Department of Psychiatry, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey 2 Adana Genetics Diseases Diagnosis and Treatment Center and Medical Genetics Department of the Medical Faculty, Cukurova University, Adana, Turkey

The presentation is a specific dystonic reaction. Recurrent Abstract oculogyric crisis is different from the acute adverse drug event (4). It has been variously considered to be a form Tardive oculogyric crisis is one of the tardive syndromes of tardive (4). characterized by a spasmodic deviation of eyes typically discontinuation is still the primary turning upwards after long-term use of high- suggestion regarding the management of tardive syn- typical or rarely atypical . Antipsychotic dromes, although no definitive evidence is supported. discontinuation is suggested as a treatment option with If this is not possible, changing to an antipsychotic with changing to an antipsychotic with a lower tardive a lower tardive dystonia (TDt) risk is the next option risk. drugs such as may (5). Antidyskinetic agents may be added to treatment also improve the symptoms of tardive dystonia, but these in patients whose symptoms persist despite drug regula- drugs may trigger or aggravate tardive dyskinesia. We tion. Antioxidants that reduce free oxygen radicals such report on a case with tardive syndromes and treatment as Ginkgo biloba, vitamin E, vitamin B6, clonazepam, challenge. To our knowledge, this is the first presentation propranolol and may be used. However, the of tardive oculogyric crisis related to paliperidone treatment response rates are low (6, 7) Anticholinergic palmitate treatment in combination with aripiprazole drugs such as trihexyphenidyl may have a curative effect and treatment with bornaprine. on tardive dystonia, but these drugs may trigger or aggra- vate tardive dyskinesia (TDz) (1). We report on a case of a patient with tardive oculogyric crisis (TOC) that developed six weeks after initiating risperidone long-acting injection (LAI) every two weeks and aggravated with paliperidone palmitate (PP) treat- Introduction ment every three months and treatment with bornaprine. Tardive syndromes are delayed hyperkinetic and hypoki- In the literature review, we were not able to find any case netic movement disorders caused by antipsychotic treat- of treatment with bornaprine for TOC. ment and include dyskinesia, dystonia, akathisia, chorea, and ocular deviations. Oculogyric crisis is Case History a manifestation of dystonia as a tardive syndrome (1, 2). A 22-year-old woman was admitted to the psychiatry out- Oculogyric crisis is a recurrent dystonic adverse effect patient clinic in Gaziantep on the southeast coast of Turkey of antipsychotic drugs characterized by a spasmodic devi- due to spasmodic deviation of eyes turning upwards. ation of eyes typically turning upwards lasting minutes The medical history of the patient was acquired from her, to hours and can also be associated with other dystonic her mother and hospital data. The patient had been diag- symptoms (3). Acute oculogyric crisis in a patient on nosed with bipolar affective disorder in accordance with antipsychotic drug therapy is a familiar phenomenon. the DSM-5 criteria five years earlier. The first symptoms

Address for Correspondence: Şengül Kocamer Şahin, MD, Faculty of Medicine, Department of Psychiatry, Gaziantep University, Üniversite Avenue, 27310 Şehitkamil, Gaziantep, Turkey [email protected]

53 Successful Treatment of Tardive Oculogyric Crisis of the disorder were paranoid and persecutory delusions, year of treatment with PP, the PP monthly injection dose increase in irritability, engaging in unrestrained buying was changed to 175 mg in three-month formulations. sprees, talkativeness and decreased need for . These At the second injection of PP every three months, symptoms had required hospitalization in her first manic the patient developed recurrence of dystonic oculogyric period. symptoms every day. This time, she was admitted to our In the treatment process during the first two years, clinic. We increased the aripiprazole dosage from 15 to 20 the patient used 300 mg /day combined mg, added 3 × 2 mg/day and discontinued the with flupenthixol depot injection. However, due to three-month formulation of paliperidone treatment. The non-adherence to oral , she and her mother patient and her mother were given psychoeducation to had complained about every persecutory delusions and ensure compliance to oral treatment. After discontinuation unreasonable laughing, hallucinations and avolition of PP and adding biperiden 8 mg/day for three months, during some control visits. When she was using que- there was no improvement in the patients’ TOC symptoms. tiapine regularly combined with flupenthixol delusions One dosage elevation to 10 mg was attempted, but the decreased. During that period, she had no depressive patient could not tolerate it because of tachycardia. After episodes. However, she had been hospitalized twice for a literature review, trihexyphenidyl was considered for psychotic manic episodes. After a two-year period, the the treatment of TOC. However, since trihexyphenidyl patient was clinically stable without any depressive and therapy had not yet become available in Turkey, biperiden manic episodes, although she experienced a few adverse was discontinued and bornaprine 12 mg/day, which is effects. The disease in this patient exhibited a different another central anticholinergic drug, was added. progression pattern. Considering that the patient had After adding bornaprine treatment, the patients’ psychotic symptoms without affective episodes in the symptoms improved dramatically within a week. She first two years, a diagnosis of schizophrenia and also had no signs of dystonic symptoms with her eyes in manic episodes was made, indicating bipolar disorder. terms of oculogyric crisis and was clinically stable in Once mood stabilizers had been recommended, but the terms of her bipolar disorder at the follow-up visit after patient did not use them. Therefore, additional mood one month with bornaprine and aripiprazole treatment. stabilizers could not be added to the treatment. Unfortunately, this improvement persisted only for three The patient had been clinically stable when using months, after which she again had TOC episode lasting flupenthixol depot injection monthly for the past three five minutes. Moreover, there was recurrence of TOC years. Although she had used quetiapine regularly for a approximately once a week or once in two weeks for few months, she stopped using it for the past six months. three months. A prescription request was sent to the She had experienced adverse effects such as protrusion Ministry of Health with a letter of application to procure of the tongue, chewing and lateral jaw movements at the trihexyphenidyl from abroad. end of those three years. Because of tardive dyskinesia, her treatment was changed to risperidone LAI 37.5 mg every two weeks from the flupenthixol depot injection Discussion supplemented with aripiprazole 15 mg/day. Tardive dys- This case of TOC is an unusual and significant phe- kinesia was improved after changing to risperidone LAI nomenon in terms of diagnosis, treatment and follow- and adding aripiprazole within that same month. up. Therefore, the development of TOC, the persisting After the third risperidone LAI, she began complain- reasons and the treatment of this complication have to ing about spasmodic deviation of eyes turning upwards. be discussed separately. Because of noncompliance to treatment, the risperidone TDz was the first tardive syndrome developed in this LAI treatment was changed to PP 100 mg/month. The patient when she was using flupenthixol. The literature paliperidone dose was gradually decreased from 100 to reports that 6.7% of tardive dyskinesia cases are related to 50 mg because of ongoing oculogyric crisis findings. flupenthixol (8). In this patient, TDz was improved after The patient showed improvement and was clinically flupenthixol was changed to the less potent antipsychotic stabilized by decreasing the PP dose to 50 mg injection risperidone LAI supplemented with aripiprazole 15 mg/ per month and increasing the biperiden dosage to 6 mg/ day. Although cases of aripiprazole-induced TDz have been day with continuation of aripiprazole 15 mg/day. There reported in the literature, aripiprazole has also been used were no signs of oculogyric crisis findings. After one in the treatment of TDz (9). The addition of aripiprazole

54 Şengül Kocamer Şahin et al. during the first period of treatment in this case may be have been potentially associated with an increased risk of associated with the improvement of TDz, or changing to developing TD, namely the COMT, MAO, DRD2, DRD3, the less potent antipsychotic risperidone LAI may have CYP1A2 and MnSOD genes, but the clinical relevance of been adequate to achieve improvement. such associations has not yet been confirmed (13, 14). TOC was the second tardive syndrome developed in Hypersensitivity to the receptor system, this patient when she was using risperidone LAI plus dysfunction of GABAergic neurons, impaired balance aripiprazole 15 mg/day. At first, TOC improved after between and systems and changing to PP and adding biperiden 4 mg/, but with excitotoxicity have been implicated in the etiology of the continued use of PP, the TOC was aggravated after the TDz (15). In this case, the patient showed no response to three-month formulation PP treatment. In our literature treatment with biperiden, although her TOC condition review, we identified one case reported with probable improved with bornaprine treatment. Biperiden is an tardive dyskinesia (TDz), one case with tardive dyskinesia M1 muscarinic receptor antagonist and a weak inhibitor along with tardive dystonia (TDt) and one case with TDt of acetylcholinesterase. Bornaprine is a nonselective M1 related to PP (10-12).This may be another tardive syndrome and M2 antagonist (16). In fact, M1 antagonists have related to PP use. The duration of aripiprazole treatment been suggested to be more effective than M2, M3 or M4 was found to be shorter in aripiprazole-induced cases, antagonists in preventing EPS caused by antipsychotic whereas it was longer in aripiprazole-improved cases (9). drugs in an acute episode (17). However, if an impaired Therefore, long-term use of aripiprazole may be related to balance between the dopaminergic and cholinergic sys- this second tardive syndrome, while aripiprazole improved tems underlies the pathophysiologic mechanism of tardive TDz with short-term use in first developed tardive syn- dystonia, both the M1 and M2 antagonist bornaprine drome. Another explanation is that concomitant use of may have been more effective in this case. aripiprazole and PP in a three-month formulation may As a result, this patient developed tardive syndromes aggravate the occasion and the cessation of paliperidone twice during the follow-up with various LAI antipsychot- helped in the alleviation of symptoms. ics for approximately four years. At the first development Older age, female sex, African descent, mood disorder of the tardive syndrome TDz, aripiprazole was added diagnosis, cognitive symptoms in mood disorders, long that improved the symptoms. However, the second duration of schizophrenia illness, negative symptoms tardive syndrome TOC in this case was induced when in schizophrenia, intellectual disability, brain damage, the patient was using the PP three-month formulations intermittent non-adherence, Diabetes Mellitus with aripiprazole in the long term. TOC was improved substance abuse, parkinsonism, acute dystonia, antidopa- with bornaprine, a non-selective M1 and M2 antago- minergic treatment choice, high antidopaminergic drug nist, whereas the biperiden M1 receptor antagonist did dose or plasma level and anticholinergic co-treatment not work in the treatment of TOC. The improvement were found to be the risk factors for tardive syndromes was transient and the TOC relapsed after three months, (13). The patient in our case had tardive dyskinesia as although it was much less frequent than before. the tardive syndrome well before initiating PP treatment. She may already have been vulnerable to antipsychotics. Acknowledgements The risk factors in this patient are female sex, comorbid Authors would like to thank Enago (www.enago.com) for the English language mood disorder diagnosis and intermittent non-adherence. review. Furthermore, unknown genetic polymorphisms in genes All of the authors declare that there are no conflicts of interest in connection with this paper. involved in dopamine metabolism, packaging and receptor functioning may make the patient vulnerable. A significant relationship between TD risk and polymorphisms in genes References was found in the case of the VMAT2 gene, DRD2 gene and 1. Savitt D, Jankovic J. Tardive syndromes. J Neurol Sci 2018;389: 35-42. Val/Val COMT genotype (13). Thus in this study VMAT2 2. Lerner PP, Miodownik, C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry and DRD2 genes were sequenced by Sanger sequencing Clin Neurosci 334-321 :69 ;2015. (ABI 3130XL Genomic Analyzer). However, there was 3. Ayd FJ. A survey of drug-induced extrapyramidal reactions. JAMA neither polymorphism nor any mutation identified in our 1961; 175:1054-1060. 4. Schneider SA, Udani V, Sankhla CS, Bhatia KP. Recurrent acute dystonic patient. Genetic polymorphisms need further investiga- reaction and oculogyric crisis despite withdrawal of tion. Moreover, several gene polymorphism candidates blocking drugs. Mov Dis 2009;24:1226-1229.

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