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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Original article / research
Year : 2024 | Month : June | Volume : 18 | Issue : 6 | Page : VR04 - VR07 Full Version

Cariprazine Augmentation in Inadequate Clozapine Response: A Case Series

Published: June 1, 2024 | DOI: https://doi.org/10.7860/JCDR/2024/69088.19525

SS Asha Charitha, Soumya S Sobhan, Jibi Achamma Jacob Rajesh Gopalakrishnan, Anju Kuruvilla

1. Assistant Professor, Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, India. ORCID-0000-0002-8114-7471 2. Assistant Professor, Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, India. ORCID-0009-0004-3212-0231 3. Associate Professor, Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, India. ORCID-0000-0003-0078-3730 4. Professor, Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, India. ORCID-0000-0002-9137-6219 5. Professor, Department of Psychiatry, Christian Medical College, Vellore, Tamil Nadu, India. ORCID-0000-0003-1708-1620

Correspondence Address :
Dr. Jibi Achamma Jacob,
Associate Professor, Department of Psychiatry, Christian Medical College, Vellore-632002, Tamil Nadu, India.
E-mail: jibiachamma@gmail.com

Abstract

Managing patients with treatment-resistant schizophrenia who do not respond adequately to Clozapine poses a challenge. Cariprazine, with its unique mechanism of action, may be an option for such patients. The additional benefits of using Cariprazine as an augmentation strategy include once-daily dosing, ease of titration, and a favourable side-effect profile. The report outlines the authors’ experience of six patients with treatment-resistant schizophrenia who did not respond to Clozapine. The addition of Cariprazine was tolerated by all the patients. The majority showed improvement with symptom reduction, and in some cases, the dose of Clozapine could be reduced, thereby decreasing the side-effects of Clozapine.

Keywords

Anti-psychotic agents, Clozapine related side-effects, Ultra-resistant schizophrenia

Introduction
Cariprazine is a novel third-generation antipsychotic with a unique receptor profile. It exhibits partial agonism at Dopamine (D2/D3) receptors, with preferential binding to the D3 receptor, as well as partial agonism at the Serotonin- 5HT1A receptor and antagonistic actions at 5HT2A and 5HT2B receptors. Its low affinity for histaminergic, cholinergic, and adrenergic receptors contributes to its favourable side-effect profile. The active metabolites of Cariprazine- desmethyl Cariprazine and didesmethyl Cariprazine- have long half-lives, enabling a once-daily dosing schedule (1).

The concept of treatment resistance has evolved over the years as it became evident that many patients did not respond to antipsychotic medications and psychosocial interventions. The modified Kane’s criteria is the most widely accepted among the various criteria used to describe this concept. It defines treatment resistance as a lack of significant improvement in positive symptoms after treatment with two or more different non-clozapine antipsychotic medications at adequate doses (at least 600 mg Chlorpromazine equivalents), duration (6-8 weeks), and ensured medication adherence (2). With a reported prevalence of 20-33%, it is one of the most challenging psychiatric diagnoses (3). Clozapine is considered to be the drug of choice for its treatment. However, about 60% of individuals with Treatment Resistant Schizopenia (TRS) do not respond adequately to Clozapine. While definitions of Clozapine Resistant Schizophrenia (CRS) have been formulated, these are excessively reliant on positive symptoms (4). The utilisation of these criteria in clinical practice is hindered by practical difficulties in determining the adequacy of dose, estimating blood levels, judging adherence, and conducting prospective observation of patients during treatment with Clozapine.

In patients with CRS, strategies that have been attempted to manage persistent symptoms include giving higher doses of Clozapine or augmenting Clozapine with an antipsychotic, mood stabiliser, electroconvulsive therapy, or antidepressant. However, evidence supporting these strategies is inadequate. Psychotherapeutic interventions have also been reported to be beneficial in Clozapine-refractory psychotic symptoms (5).

Cariprazine, with its unique mechanism of action and favourable side-effect profile, would be an ideal augmentation agent in patients who do not respond to or are unable to tolerate Clozapine. However, evidence for its use and safety is limited as the drug has only recently been approved for use by regulatory agencies (6). There are reports of Cariprazine being successfully used as a substitute for Clozapine in patients who did not respond adequately or developed intolerable side-effects with it (7). Some reports show encouraging outcomes with Cariprazine as an augmentation agent in patients with Clozapine resistance; however, there is a lack of data from Asia in this regard (1),(6),(8),(9),(10),(11),(12). This case series details the authors’ experience with six patients with treatment-resistant schizophrenia who were augmented with Cariprazine due to inadequate response to Clozapine.
Case Report
Case 1

A 31-year-old unmarried male presented to the Department of Psychiatry with an 18-month history of a continuous illness characterised by anger, irritability, auditory hallucinations, hallucinatory behaviour, delusions of persecution and reference, disorganised behaviour, and disturbed sleep and appetite. He was socially withdrawn, and his personal care and occupational functioning had declined. There was no history of any medical illness or substance use. A diagnosis of schizophrenia was made, and the patient was initially treated with Olanzapine (25 mg/day for 7 months), followed by Risperidone (8 mg/day for six months). Despite the addition of Fluphenazine Decanoate (50 mg/month), he continued to experience persistent persecutory delusions and disorganised behaviour. Therefore, treatment resistance was considered, and Clozapine was initiated up to a dose of 400 mg/day. Following an episode of viral hepatitis, Clozapine had to be discontinued, and Amisulpride was started (700 mg per day). However, due to an exacerbation of symptoms and the onset of tardive dyskinetic movements, Clozapine was restarted with serial monitoring of liver function tests as advised by the Department of Hepatology. During the Coronavirus Disease-2019 (COVID-19) pandemic, he was lost to follow-up but continued Clozapine in the post-COVID-19 period. After reviewing his case, persistent positive, negative, and cognitive symptoms were noted post-COVID-19. In light of resistance to Clozapine, Cariprazine was added, and the dose was increased to 3 mg/day. Within five weeks, there was a clinically significant reduction in positive symptoms. These improvements were maintained, along with a reduction in negative symptoms, at the one-year follow-up. No adverse effects were reported following the addition of Cariprazine.

Case 2

A 48-year-old unmarried male presented to the Psychiatry Department in 2004 with a 15-year history of auditory hallucinations, delusions of persecution and reference, and thought broadcasting. Negative symptoms of affective blunting, anhedonia, poor socialisation, and cognitive symptoms of impaired attention and forgetfulness were also present. A diagnosis of schizophrenia was made. He was found to have hypothyroidism and was on Thyroxine replacement with normal thyroid stimulating hormone levels. A Psychiatrist in his hometown had initiated Clozapine due to poor response to Olanzapine, Risperidone, and Loxapine. Upon his visit to this centre, he was on Clozapine 75 mg/day, which was gradually increased to 550 mg/day. Despite the dose escalation, he remained symptomatic with auditory hallucinations, delusions of reference and persecution, and thought broadcasting. Negative and cognitive symptoms persisted. The patient reported side-effects of giddiness, sialorrhoea and a pulling sensation in the lower limbs, especially at night. Given the poor response to Clozapine, sequential augmentations with Amisulpride (500 mg per day), Aripiprazole (30 mg per day), Risperidone (5 mg per day), and repetitive transcranial magnetic stimulation (7 sessions) were attempted with inadequate response. Therefore, Cariprazine augmentation was considered. Within four weeks of initiating Cariprazine, there was a significant improvement in symptoms, including a reduction in delusions, hallucinations, and thought broadcasting. The dose of Clozapine could also be gradually reduced, thereby alleviating the distressing side-effects (13). These improvements were sustained at his last review, and the patient had successfully returned to his job.

Case 3

A 36-year-old unmarried male presented to the outpatient clinic of the Department of Psychiatry in 2014 with a 10-year illness characterised by delusions of persecution and reference, auditory hallucinations, disinhibited behaviour, disturbed biological functions, and poor socialisation. A diagnosis of schizophrenia was confirmed. His previous psychiatrist had diagnosed treatment resistance, and he was on Clozapine at the initial visit to this centre. He continued to take Clozapine but did not follow-up at centre for the next six years. During the next review in 2020, psychotic symptoms persisted (auditory hallucinations, delusions of persecution, reference, and aggression). Therefore, the dose of Clozapine was increased from 300 mg to 600 mg per day, with the addition of Sodium Valproate at 1 gm/day. Despite being on this dose of Clozapine for the following two years, he continued to experience psychotic symptoms and also developed side-effects such as sedation, sialorrhoea and constipation. Therefore, augmentation with Cariprazine was initiated, and the dose was increased to 3 mg/day in December 2022. A clinically significant reduction in psychotic symptoms was observed within four weeks, leading to a 25 mg reduction in the dose of Clozapine.

Case 4

A 36-year-old male, who is an engineer, presented to outpaient clinic in 2011 with a one-year history of an insidious onset, gradually progressive illness initially characterised by disorganised behaviour and ambivalence, followed by delusions of persecution and reference, along with amotivation, avolition, flattening of affect, impaired attention, and executive dysfunction. He was socially withdrawn and unable to sustain a job. A diagnosis of schizophrenia was made. Sequential trials of Risperidone (8 mg/day for 11 months), Amisulpride (800 mg/day for 9 months), and depot Fluphenazine decanoate (50 mg/month for 7 months) did not show any benefit. There was minimal response to Olanzapine (25 mg/day for 13 months); however, it had to be discontinued due to poor glycaemic control necessitating insulin injections. In 2019, treatment resistance was considered, and he was started on Clozapine. He remained stable on 400 mg per day of Clozapine for two years with no positive symptoms and good work functioning, after which the dose was gradually reduced to 350 mg. However, following the dose reduction, the patient experienced a relapse of symptoms characterised by wandering behaviour, irritability, irrelevant speech, hallucinatory behaviour, and difficulty with work. Despite increasing the dose back to 400 mg per day, with adequate serum Clozapine levels, there was no improvement noted. Therefore, augmentation with Cariprazine was initiated in February 2023. Within six weeks of starting Cariprazine (upto 3 mg/day), he returned to his premorbid level of functioning and rejoined work, remaining stable at follow-up after nine months. He has not reported any emergent side-effects following the addition of Cariprazine.

Case 5

A 34-year-old unmarried male presented to the Psychiatry Outpatient Department in 2010 with a two-month history of poor sleep, irritability, hearing non existent voices, disorganised behaviour, poor socialisation, and decreased personal care. In the absence of organic causes and substance use, a diagnosis of schizophrenia was made. He later reported delusions of erotomania, persecution, and reference and made several attempts of self-harm secondary to the psychotic symptoms. Negative symptoms of poor socialisation, decreased motivation, and poor personal care were also present. He had medical co-morbidities of iron deficiency anaemia, hiatus hernia, haemorrhoids, and reactive airway disease for which he was treated with hematinics, prokinetic agents, and bronchodilators. He was lost to follow-up but continued to be symptomatic despite adequate trials of Risperidone (5 mg per day), Aripiprazole (30 mg/day), and Olanzapine (25 mg/day) from elsewhere. There is a history of laryngeal dystonia and tardive dyskinesia while on Risperidone. The diagnosis was revised to treatment-resistant schizophrenia, and he was started on Clozapine in September 2021. He continued to remain symptomatic on Clozapine (425 mg/day). The addition of Olanzapine (25 mg/day) did not benefit the patient; therefore, Cariprazine augmentation was initiated in 2023, and the dose was increased to 4.5 mg per day. Even three months after the initiation of Cariprazine, he continued to have positive symptoms of auditory hallucinations, delusions of persecution, reference, and erotomania, disorganised behaviour, and significant socio-occupational decline, along with gestures of intentional self-harm. Consequently, Cariprazine was discontinued, and Amisulpride was started. He continues to remain symptomatic and at risk of self-harm at follow-up.

Case 6

A 25-year-old unmarried female was diagnosed with schizophrenia during her initial presentation to the department in 2021 based on a five-year history of hallucinatory behaviour, delusions of persecution, reference, somatic passivity, irritability, and progressive decline in social and occupational functioning. Medical co-morbidities of hypothyroidism and anaemia were present, which were well controlled with medication. Treatment resistance was diagnosed elsewhere due to failed trials of Lurasidone (80 mg/day) and Amisulpride (800 mg/day), and she had been started on Clozapine (250 mg/day) in 2018. Given the persistence of symptoms, the dose of Clozapine was increased to 450 mg per day. However, she remained symptomatic. Augmentation with Risperidone (4 mg/day) and Amisulpride (700 mg/day) did not provide much benefit, so Cariprazine was added, and the dose was increased to 4.5 mg/day. After four weeks of Cariprazine with no reduction in symptoms, it was tapered and stopped. Haloperidol and Olanzapine were added to Clozapine; however, the patient continues to have poor functioning and persistent psychotic symptoms at follow-up.

The sociodemographic and clinical details of the patients are described in (Table/Fig 1).
Discussion
Managing patients with Clozapine-resistant schizophrenia is one of the most challenging situations faced by a psychiatrist. While augmentation is a common strategy used in this situation, new side-effects associated with the add-on antipsychotic or the drug combination may emerge. Evidence for augmentation strategies is limited to anecdotal studies and small uncontrolled trials. Literature on the augmentation of Clozapine with Cariprazine is sparse (Table/Fig 2) (1),(6),(8),(11),(12),(14).

The present case series documents naturalistic observations on a small group of patients with schizophrenia with inadequate response to treatment with Clozapine. Four out of the six patients showed clinical improvement with the addition of Cariprazine, which allowed for a reduction in the dose of Clozapine and its associated side-effects such as sedation, sialorrhoea and weight gain. As with any antipsychotic, it appears that some (n=4; 66.6%) patients respond to Cariprazine, while others do not. While the clinical response was mixed, Cariprazine was found to be safe in all patients as no significant side-effects emerged with the addition of this drug. The advantages of using Cariprazine as an augmenting agent are its unique pharmacokinetic and pharmacodynamic properties that contribute to its efficacy and tolerability. Once-daily dosing, ease of titration, and a safer side-effect profile are the added benefits. The likelihood of weight gain and sedation is less with Cariprazine compared to other antipsychotic drugs due to its lower affinity to adrenergic, histaminergic, and cholinergic receptors (13),(15),(16). Based on the mechanism of action, both Clozapine and Cariprazine are thought to be beneficial in treating negative and cognitive symptoms of schizophrenia (15),(16). The synergistic effect of this combination needs to be explored in well-designed studies in the future.

Another benefit of adding Cariprazine is its weak competitive inhibition of CYP1A2, which metabolises Clozapine; thus, unlike other antipsychotics, it may not increase the plasma Clozapine levels and accentuate the adverse effects (9). As Cariprazine has only been introduced recently, its long-term effectiveness and side-effects are not clearly understood.

One could argue that pseudo-resistance to Clozapine was present in some of the patients in this series. The common causes of pseudo-resistance to Clozapine include inaccurate diagnosis, inadequate dose or treatment duration, insufficient serum Clozapine levels, limited compliance, and/or medical or psychiatric comorbidities (3). These factors were excluded by reclarifying history, including adherence to treatment, serial mental state examinations, and appropriate blood tests.

Recent evidence has suggested that patients who do not respond to a trial of Clozapine monotherapy are among the most severely ill of all patients with schizophrenia (14),(15). Two patients did not respond to Cariprazine or other augmentation strategies. This is in keeping with some researchers who suggest that the addition of a second antipsychotic to Clozapine may not have a significant impact on clinical response or symptom severity. Neurobiological postulates to this phenomenon have also been described. PANSS scoring was not available in two patients who had been initiated on Cariprazine on an outpatient basis. For patients from geographically distant places, both within and outside India, follow-up visits were limited by the COVID-19 pandemic, financial constraints, and travel constraints. For some patients in this series, this led to long delays in introducing augmentation agents. Patient and caregiver reluctance to consider augmentation strategies earlier in the course of treatment also contributed to the delay. The present case series report adds to existing knowledge and suggests the need for further studies on Cariprazine as an augmenting agent for Clozapine in treatment-resistant schizophrenia.
Conclusion
Cariprazine can be a useful augmenting agent in some patients with Clozapine-resistant schizophrenia. No adverse effects were reported among the patients in this series. Further research and randomised controlled trials are necessary to ascertain the efficacy and tolerability of this combination.
Reference
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DOI and Others
DOI: 10.7860/JCDR/2024/69088.19525

Date of Submission: Dec 14, 2023
Date of Peer Review: Mar 02, 2024
Date of Acceptance: Apr 25, 2024
Date of Publishing: Jun 01, 2024

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Dec 15, 2023
• Manual Googling: Mar 14, 2024
• iThenticate Software: Apr 24, 2024 (12%)

ETYMOLOGY: Author Origin

EMENDATIONS: 6
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