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Lurasidone Augmentation of Clozapine in Refractory Schizophrenia: A Case Report
Arienti V1, Bassetti N1, Civardi SC1, Brondino N1,2, Politi P1,2, Olivola M1,2
1Department of Brain and Behavioral Sciences, University of Pavia, Italy
2ASST Pavia, Pavia, Italy
Received Date: 11/09/2021; Published Date: 04/10/2021
*Corresponding author: Olivola Miriam, ASST Pavia, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
Introduction
Treatment resistant schizophrenia is characterized by persistent psychotic symptoms despite at least two trials of 6 or more weeks with 1st or 2nd generation antipsychotic drugs used in monotherapy [1]. However, it is of fundamental importance to distinguish “true” treatment resistant schizophrenia from an apparent resistance. This latter condition can be a consequence of poor adherence, inadequate dose schedule or treatment duration, side effects and medical comorbidities [2]. Approximately 30% of patients diagnosed with schizophrenia can be properly defined as “treatment resistant” [3]. Early identification of treatment resistant schizophrenia is crucial, as it allows early introduction of clozapine. This atypical antipsychotic drug has proven the only successful treatment option for these patients [4]. Unfortunately, a significant portion of them shows a sub-optimal response [5]. For these so called “ultra resistant” patients various augmentation strategies are available. For example, atypical antipsychotics have been used, even if results are still controversial [6].
Of notice, cognitive deficits still represent the most critical dimension in treatment of schizophrenia and are particularly impaired in TRS patients. In this regard, Lurasidone, a widely used atypical antipsychotic drug, has shown promising beneficial effects on cognition in preclinical studies. These properties are due to 5-HT1a partial agonism and 5HT7 antagonism [7].
This report is aimed at highlighting the incouraging results of Lurasidone augmentation of clozapine in two subjects admitted to our Acute Psychiatric Inpatient Unit at IRCCS Policlinico San Matteo Hospital in Pavia, Italy. General psychopathology was assessed by means of the PANSS (Positive and Negative Syndrome Scale) [8], both at baseline and at discharge. Adverse effects were evaluated using the UKU (the Udvalg for Kliniske Undersøgelser) side effects scale[9]. Data on blood tests and EKG features were collected from patients’ clinical records.
Case 1
V. is a 44 year-old unmarried man. The onset of symptoms seems to have happened in 1995 when, at the age of 22, he was hospitalized for behavioral anomalies. No history of substance abuse. He suffered from persecutory delusions and auditory hallucinations; the diagnosis of schizophrenia was then established. In the following years the symptoms were significant autistic withdrawal, without any work and social planning, abulia, affective flattening, anhedonia, unwillingness to adhere to any rehabilitation project. This psychopathological condition has remained unchanged over time despite treatments with appropriate dosage and duration with haloperidol, quetiapine, clotiapine and paliperidone. The psychopathological condition were never completely compensated and this led to some hospitalizations during the years; the last one dates back to January 2021 when the patient had a riacutization of the positive symptoms and an episode of psychomotor agitation. On that occasion, in consideration of the treatment resistance, it was introduced Clozapine with the dose gradually titrated up to 500 mg daily in monotherapy, with weekly monitoring of blood counts. Clozapine plasmatic levels were at therapeutic dosages with a good clinical response. No Clozapine-associated side effects were detected. After discharge, the patient was placed in a psychiatric therapeutic community.
In June 2021 the patient had a riacutization of psychotic simptoms with auditory hallucinations, paranoid delusions and thoughts of failure. clozapine levels were at therapeutic dosages (clozapine 435 ng/ml, norclozapine 200 ng/ml, clozapine/norclozapine ratio 2,17) consistent with an adequate assumption, as confirmed by mental health workers of he therapeutic community. When evaluated with PANSS scores were 28 for positive scale, 30 for negative scale and 57 for general psychopathology. Lurasidone was introduced as add-on to clozapine and titrated up to 74 mg daily. The patient encountered no significant side effects from the introduction of lurasidone. On discharge, there was a reduction of positive symptoms with a partial clinical response.
In August 2021 the patient was hospitalized again. In that occasion lurasidone was titrated up to 148 mg die, with no significant side effects and, finally, a good control on positive and negative symptoms (PANSS positive scale = 22, negative scale = 23, and general psychopathology = 45). After 5 weeks of augmentation therapy with Lurasidone, psychosis symptoms gradually decreased. PANSS scores were as follows: positive scale = 18, negative scale = 17, and general psychopathology = 41.
Case 2
F. is a 54 years old male patient diagnosed with Schizophrenia at the age of 20. The diagnosis of schizophrenia according to Diagnostica and Statistical Manual of Mental Disorders V edition was then established. In the past years he was treated with different antipsychotics (olanzapine, risperidone, quetiapine) at adequate dosage for congrous time reaching only partial or transient benefit on auditory hallucinations and persecutory delusions. He was therefore administered clozapine with good control on positive and negative symptoms. After 6 years, the patient showed a riacutization of hallucinatory symptoms and persecutory ideation, with worsening of negative symtomatology, too. He was than admitted to hospital in order to rearrange psychopharmacological treatment. At the beginning of the hospitalization haematic clozapine levels were tested in order to exclude absence of therapeutic compliance causing reacutization. Clozapine levels were at therapeutic dosages (clozapine 367 ng/ml, norclozapine 91 ng/ml, clozapine/norclozapine ratio 4.03) consistent with an adequate assumption, as confirmed by the patient himself and domiciliary assistance (with daily assumption of 300 mg). PANSS scores were as follows: positive scale = 25, negative scale = 26, and general psychopathology = 51. Lurasidone was introduced as add-on to clozapine and titrated up to 74 mg die. The patient encountered no significant side effects from the introduction of lurasidone. On discharge, after 7 days of augmentation therapy, the PANSS scores were: positive scale = 20, negative scale = 19, and general psychopathology = 46, with reduction of positive symptoms and an improvement of cognitive focus. In particular, the patient referred a significant reduction of the intrusiveness of hallucinations. He appeared less suspicious and more critical towards persecutory ideation, with positive impact on irritability and anxiety.
Discussion
Patients achieved a significant reduction of both positive and negative symptoms. As far as side effects are concerned, the routine medical workup showed no major alterations: blood tests were within normal limits, as well as QTc interval on the electrocardiogram. Extrapyramidal symptoms were never observed during hospitalization. These findings are consistent with previous literature [10,11]. Our observation suggests that lurasidone can lead to clinically significant improvements in psychopathology and shows a good tolerability profile. However, it is important to acknowledge the limited sample size for this preliminary report, from which no strong conclusion can be drawn. Further studies are thus needed, in order to shed new light on the mechanisms underlying Lurasidone’s effects on both psychopathology and cognition also on a clinical level.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Consent
Written informed consent was obtained from the patient for publication of this paper.
References
- Meltzer HY. Treatment-resistant schizophrenia--the role of clozapine. Curr Med Res Opin. 1997; 14(1): 1-20.
- Elkis H. Treatment-resistant schizophrenia. Psychiatr Clin North Am. 2007; 30(3): 511-515 doi: 10.1016/j.psc.2007.04.001. PMID: 17720034.
- Lally J, Ajnakina O, Di Forti M, et al. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med. 2016; 46: 3231.
- Kane JM, Agid O, Baldwin ML, et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry, 2019; 80(2): 18com12123.
- Siskind D, Siskind V, Kisely S. Clozapine Response Rates among People with Treatment-Resistant Schizophrenia: Data from a Systematic Review and Meta-Analysis. Can J Psychiatry. 2017; 62(11): 772-777. doi: 10.1177/0706743717718167. Epub 2017 Jun 28.
- Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence. JAMA Psychiatry. 2017; 74(7): 675-684.
- Huang M, Panos JJ, Kwon S, Oyamada Y, Rajagopal L, Meltzer HY. Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism. J Neurochem. 2014; 128(6): 938-939 doi: 10.1111/jnc.12512. Epub 2013 Nov 14.
- Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2): 261-262.
- Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987; 334: 1-100.
- Citrome L, Cucchiaro J, Sarma K, Phillips D, Silva R, Tsuchiya S, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol. 2012; 27(3):165-171
- Ogasa M, Kimura T, Nakamura M, Guarino J. Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study. Psychopharmacology (Berl). 2013; 225(3): 519-525
