Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

Users Online : 39234

AbstractMaterial and MethodsResultsDiscussionConclusionReferencesDOI and Others
Article in PDF How to Cite Citation Manager Readers' Comments (0) Audio Visual Article Statistics Link to PUBMED Print this Article Send to a Friend
Advertisers Access Statistics Resources

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 Dermatolgy,
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
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : October | Volume : 16 | Issue : 10 | Page : VC08 - VC12 Full Version

Relationship Between Lithium Dose, Serum Concentration and Duration of Lithium Therapy with Cutaneous Side-effects in Bipolar Affective Disorder Patients


Published: October 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/57573.16944
B Suganya Priyadharshini, Syed Ummar Ibrahim, Karthikeyan, Jeevithan

1. Assistant Professor, Department of Psychiatry, KMCH Institute of Health Sciences and Research, Coimbatore, Tamil Nadu. 2. Professor, Department of Psychiatry, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu. 3. Assistant Professor, Department of Community Medicine, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu. 4. Professor, Department of Community Medicine, KMCH Institute of Health Sciences and Research, Coimbatore, Tamil Nadu.

Correspondence Address :
Dr. B Suganya Priyadharshini,
Assistant Professor, Department of Psychiatry, KMCH Institute of Health Sciences and Research, Coimbatore, Tamil Nadu.
E-mail: suganyapriyadharshini@yahoo.com

Abstract

Introduction: Lithium has been used in the treatment of mood disorders for more than five decades. Despite a few studies focusing on the relationship between the dose of lithium, serum lithium levels, duration of therapy, and cutaneous side-effects, results remain inconclusive. Lithium is known to cause multiple cutaneous side-effects like acneiform eruptions, psoriasiform eruption, seborrhoeic dermatitis, and follicular keratitis.

Aim: To evaluate the relationship between cutaneous side-effects of lithium with the serum lithium levels, dosage and duration of lithium therapy in bipolar affective disorder patients.

Materials and Methods: An ambispective observational study was conducted among 52 bipolar affective disorder patients on lithium therapy recruited by convenient sampling methods from both Inpatient and Outpatient Psychiatry Units of PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India, between June 2014 to August 2014. The patients with bipolar affective disorder who were either newly started on lithium or already on lithium therapy were included in the study. They were followed-up to assess the effect of lithium dosage, duration of lithium and serum lithium level with skin lesions, once a month for six months and once in two months for one year. Kaplan-Meier survival analysis was done with varying lithium dosages and serum lithium levels. Association between the lithium dose and serum lithium levels with the cutaneous side-effects were calculated using the survival analysis, taking p<0.01 to be statistically significant.

Results: Out of the total, 59.6% of the participants were in the age group less than 40 years and 34.6% were in the age group 40-60 years. There was almost equal distribution of males and females, 51.9% and 48.1%, respectively. Overall, 38.46% participants had cutaneous lesions. Various lithium dosage and serum lithium levels did not correlate statistically with skin reactions up to one year. Survival analysis at the end of 10 years revealed that participants with higher dosage and serum levels had higher prevalence of skin lesions (40% vs 4%: 47.1% vs 6.6% respectively, p<0.001). The cumulative proportion of skin lesions at the end of three, five, seven and 10 years for higher dose (>800 mg/day) was 38%, 46.9%, 52.2%, and 59% and for higher lithium levels (>0.8 mEq/L) was 41%, 58.2%, 65.2%, and 73.9%.

Conclusion: The patients who were treated with lower dosage and who had lower serum lithium level had reduced risk for cutaneous lesions. Lithium continued to exert its mood stabilisation property even when the serum level was maintained less than 0.8 mEq/L. This resulted in better compliance.

Keywords

Adverse-effect, Management, Mood disorder, Mood stabiliser

Lithium remains the cheaper, effective, and gold standard treatment for bipolar affective disorder for more than five decades. Lithium has narrow therapeutic index that is a low ratio between dose (serum levels) and its associated toxicity (1). Lithium has adverse effects on kidneys, thyroid gland, and parathyroid glands, necessitating the monitoring of these organ functions through periodic blood tests. In most cases, lithium associated cutaneous side-effects are relatively mild but severe cutaneous involvement like psoriasis are observed in measurable percentage (1.8-6%) of lithium treated patients. Recognition of these cutaneous side-effects is necessary and neglect of which might result in non adherence to medication. Perlick et al, showed average of 40% non adherence due to sideeffects with lithium therapy (2).

The reported prevalence of the cutaneous side-effects with lithium varies from 3% to 45% in different studies. Lithium is known to cause multiple cutaneous side-effects like acneiform eruptions, psoriasiform eruption, seborrhoeic dermatitis, and follicular keratitis. Other cutaneous manifestations include mucosal and vaginal ulceration, oedema, purpura, lupus erythematosis like syndrome, urticaria, pre-tibial ulceration, dermatitis herpetiformis, eczema, exfoliative dermatitis, folliculitis, alopecia, allergic vasculitis, hidradenitis suppurativa, lichenoid stomatitis, exacerbation of Darrier’s disease, palmoplantar hyperkeratosis with icthyosiform features, increased growth of wart, mycosis fungoidosis, and hair loss (3),(4),(5),(6),(7),(8).

The side-effects of lithium are dose-dependent and it correlates with the serum lithium levels. The National Institute for Health and Care Excellence (NICE) guidelines and Delphi Survey recommends the therapeutic serum levels should be 0.60-0.80 mmol/L (9),(10). Whereas the serum lithium level below 0.6 mmol/L is found to be ineffective, studies have also reported that no therapeutic advantage was noted when the serum lithium level is above 1.2 mEq/L and it may result in more significant ide-effects which can lead to poor compliance (11),(12).

Heng MC, have observed acneiform eruptions in several patients with serum lithium levels in the range of 1.5-2.5 mEq/L (13). Rao AV et al., observed that lithium-induced cutaneous side-effects like acne and hair loss occurred mostly within the therapeutic range (14). Few observed that longer the duration of lithium therapy, more is the chance of developing side-effects (15).

Most of the literature available measured only the prevalence of lithium induced cutaneaous side-effects, so this prospective study was planned with the rationale to find out the association of cutaneous side-effects with the dose, duration, and serum lithium levels in bipolar affective disorder patients. Whether regular monitoring, early diagnosis and management of lithium induced skin lesions, will help in avoiding the issue of non compliance and further worsening of mood symptoms was also studied. Hence, the present study aimed to evaluate the relationship between cutaneous sideeffects of lithium and serum lithium levels, dosage and duration of lithium therapy in bipolar affective disorder patients.

Material and Methods

An ambispective observational study was conducted among 52 bipolar affective disorder patients on lithium therapy at the PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India. The study was conducted on the in- and out-patients attending the Psychiatry unit of the study institute, from June 2014 to August 2014. The study was approved by the Institutional Human Ethics Committee with the reference number 14/147.

Sample size calculation: Sample size was calculated by considering 45% as prevalence of the skin lesions. Thus, the sample size was found to be 177, based on the following formula (16):

N= 4PQ/d2, where
P= Prevalence
Q= 100-P
d= Allowable error (15-20% of P)

Participants were selected through convenient sampling from Outpatient and Inpatient setting of the hospital.

Inclusion criteria: Male and female aged 18-65 years with the primary diagnosis of bipolar affective disorder based on International Classification of Diseases-10 (ICD-10) Criteria (17), who were newly started on lithium and already on lithium therapy for a duration of 10 years were eligible for the study. Participants who were newly started on lithium were recruited for prospectively studying the occurrence of skin lesions in the first year of the lithium therapy and participants who were on long-term therapy were included to study the association between the duration of treatment and the occurrence of skin lesions. Patients treated with antipsychotic medications like olanzapine with mean dosage of 15 mg and quetiapine with mean dosage of 300 mg at therapeutic dosages along with lithium were also included in the study.

Exclusion criteria: Patients on other mood stabilisers, on medications already known to cause cutaneous reactions, patients with thyroid disorder and acute or chronic kidney disease were excluded from the study. Diuretics, Angiotensin-I Converting Enzyme (ACE) inhibitors and Non Steroidal Anti-inflammatory Drugs (NSAIDs) which reduces excretion of lithium leading to toxicity were excluded from the study.

Procedure

Patients with bipolar affective disorder diagnosed by a qualified psychiatrist based on the ICD-10 criteria were included in the study after subjecting them to selection criteria (17). The study protocol was explained to the participants, and a written informed consent was obtained from the patient. If the patient could not consent, it was obtained from the family member and later from the patient when he/she could consent.

Initial assessment was done using semi-structured proforma by the principal investigator. It included details on dosage of lithium, serum lithium levels, duration of lithium therapy, details of skin lesions and its relationship to treatment. Based on a retrospective crosssectional study (17):

• The dose of lithium was divided arbitrarily into: <800 mg, 800- 1200 mg, and >1200 mg.
• Duration of lithium <6 months, 6 months to 1 year and >1 year.
• Serum lithium levels into subtherapeutic levels (<0.8 mEq/L), therapeutic levels (0.8 to 1.2 mEq/L) and supratherapeutic levels (>1.2 mEq/L).

Then participants were examined by the dermatologist at baseline for the diagnosis of pre-existing skin lesion and to determine if the lesion was related to the usage of lithium.

Follow-up assessments were done every month for the first six months from baseline and thereafter every two months for the next six months, based on the findings by Ummar S et al., who showed that cutaneous lesions emerge within the initial 6 months (15). During each follow-up, patients were examined for the presence of skin lesions and its relationship with the dose of lithium, duration of lithium and the serum lithium levels. A dermatologist's opinion was sought for all the patients who developed cutaneous lesions in the follow-up. If the patient had missed a follow-up, they were contacted over phone and enquired for the presence of any skin lesions and the current dose, duration, and serum lithium level both from the patient and the caregiver. Five patients were lost to followup (not reported the results of lithium levels).

Total 52 patients were recruited for the study. Ten patients dropped out till the end of the study. Five patients for poor compliance. One patient for lithium toxicity (immediately 1 week after initiating lithium). One patient due to persistent vomiting (at 4th month follow-up), one patient developed severe hair fall (at 4th month follow-up). One patient dropped out at the end of 5th month due to unaffordability to do routine serum lithium level and hence changed to other mood stabiliser. One patient’s diagnosis was changed to schizophrenia; hence the treating therapist had stopped her medication.

Statistical Analysis

Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 19.0 for Windows. Association of the cutaneous lesions with dosage, serum lithium level and duration in all follow-ups was calculated using the Chi-square test with statistical significance of p≤0.05. Association of the cutaneous lesion with lithium dose, serum lithium level, and duration was done using the independent Student’s t-test. Kaplan-Meier survival analysis was performed to estimate the proportion of skin lesions with lithium dosage and serum lithium levels. Survival analysis was planned for patients with long-term duration of treatment with lithium. Based on the survival function output table, percentage was calculated. Right censoring was done based on information available in case sheets, whereas left censoring was done based on periodic follow-up and attrition. Relapse and remission were not captured but the increase or decrease in dosing was considered in the statistical analysis as individual data points.

Results

In this study, 59.6% of the participants were in the age group less than 40 years and 34.6% were in the age group 40-60 years. There was almost equal distribution of males and females, 51.9% and 48.1% respectively. 94.2% of the participants belonged to upper middle socio-economic class and 5.8% belonged to the lower middle class as per modified Kuppuswamy classification of socioeconomic class (18) (Table/Fig 1).

Overall, 38.46% participants had cutaneous lesions out of which 19.2% had acneiform skin eruptions, 7.6% had hair fall and 1.9% had combined acne and hyperpigmentation, acne and hair fall and acne with seborrhoeic dermatitis. Prevalence of lithium induced skin lesions was 32.6% in the participants with >800 mg (n=41) of lithium therapy (Table/Fig 2). Prevalence of lithium induced skin lesion was 9.45% (2/11) in the participants with the dose <800 mg (n=11).

There was no significant association between occurrence of skin lesions and dose of lithium (Table/Fig 3) and serum lithium levels between the three groups during all the follow-ups at one year (Table/Fig 4). There was no association between prevalence of skin infection and duration of drug intake in all the visits except third follow-up (Table/Fig 5).

An event-based analysis is done to understand the lithium induced skin reaction with the dose of lithium. On analysing the association between the lithium dose and the skin reactions at 10 years showed 4% of the participants who were on <800 mg of lithium got skin reactions compared to 40% of those who took dose more than 800 mg. The results are statistically significant (Table/Fig 6).

An event-based analysis is done to understand the lithium induced skin reaction with the serum lithium level. On analysing the association between serum lithium levels and skin reaction at 10 years, the study population was divided into two groups <0.8 mEq/L and >0.8 mEq/L based on the serum lithium level since there were only two participants above the level >1.2 mEq/L of lithium. It showed 6.6% of the participants whose serum lithium levels were less than the recommended therapeutic range for the treatment of the bipolar disorder (0.8 mEq/L) got skin reactions compared to 47.1% of those whose serum lithium levels were more than the recommended therapeutic range (0.8 mEq/L). The results were statistically significant (Table/Fig 7).

The dose response relationship was studied using survival analysis. Patients newly started on lithium and already on lithium therapy for more than 10 years were subjected to survival analysis. Out of 52 participants, 16 patients were newly started on lithium and 36 patients were already on lithium therapy for more than 10 years. The drug dose response for 10 years was assessed using case records in addition to a follow-up of one year. Overall, 21.1% had lithium induced skin reactions in the study population. At the end of one year 12.2% of the study population had cutaneous skin lesion. The proportion of skin lesions at the end of three, five, seven and 10 years are 31.7%, 42.9%, 47.7% and 54.2% respectively from survival analysis (Table/Fig 8).

Kaplan-Meier survival analysis for varying lithium doses at 10 years showed that there is no lithium induced skin reaction up to one and a half years. The proportion of skin lesion at the end of three years is 20% and after five years is 40% for dose less than 800 mg of lithium. For those who were on lithium more than 800 mg, 19.7% of the study population had skin lesion at the end of one year. The proportion of skin lesions at the end of three, five, seven and 10 years are 38%, 46.9%, 52.2%, and 59% respectively. (Table/Fig 9) clearly shows that the proportion of skin reactions are higher in dose more than 800 mg compared to lower doses.

Kaplan-Meier survival analysis for varying serum lithium levels at 10 years follow-up determined the proportion of skin lesion at the end of three year is 9.6% and five years is 23.5% for serum lithium levels less than 0.8 mEq/L. For those who had serum lithium levels more than 0.8 mEq/L, 22.8% of the study population had cutaneous skin lesion at the end of one year. The proportion of skin lesions at the end of three, five, seven and 10 years are 41%, 58.2%, 65.2% and 73.9% respectively. The proportion of skin reactions are higher with serum lithium levels more than 0.8 mEq/L (Table/Fig 10). Relapse and remission were not captured but the increase or decrease in dosing was considered in statistical analysis as individual data points.

Discussion

The effectiveness of lithium for bipolar disorder was well established since the 1950’s. Concerns about toxicity and side-effects limited initial acceptance of lithium use but its use increased gradually over the last 50 years. Cutaneous side-effects are consistently found to be the most common side-effects associated with lithium with the prevalence rate of 38.46% in this study which is similar to the study done by Chann HH et al., and Sarantidis D and Waters B, which is 34% and 45% respectively (3),(19).

Skin reactions observed in this study are acneiform eruptions, hair fall, seborrhoeic dermatitis, lithium induced ulcers and hyperpigmentation. Acneiform eruption and hair fall were the most common cutaneous lesion seen in our study. In this study acneiform eruption and hair fall was found to commonly occur with the higher dosage of lithium which is in contrary with the case report done by Swetha P et al., where the lesion was reported to develop at the lower dose of lithium (20),(21).

In terms of the prevalence of skin lesions with the dose of lithium therapy, prevalence was high with therapeutic dosage during the one year of follow-up. This is consistent with the previous study by Ummar S et al., which revealed that as the dose of lithium increased, the frequency of skin lesions increased i.e., 50% of the participants in the dose group above 1200 mg developed skin lesions (15).

Several case reports published, had described cases developing skin lesions, within the therapeutic range of lithium levels (0.5- 1.5 mEq/L) (22). Other than case reports, no studies were found correlating the dose and the lithium levels with the cutaneous sideeffects. In the current study, it was observed that the proportion of skin lesions increased when measured at the end of five years compared to the 1 year follow-up in the participants with serum lithium level less than 0.8 mEq/L.

Observation regarding the cumulative prevalence of skin lesion with respect to the different doses and serum levels of lithium at the end of one year did not show any significant difference across the three groups, indicating no correlation between the dose and the serum levels of lithium to the occurrence of skin lesion. In the present study when the data was subjected to survival analysis, we found significant association between the dose and serum level of lithium to the prevalence of skin lesions, suggesting that patients on higher dose and high serum level for longer duration have increased risk for developing the cutaneous side-effects.

Kaplan-Meier survival analysis showed that significant proportion of lithium induced skin lesions (38%) developed within a period of three years (1000 days) in the above 800 mg dosage group compared to the 20% of the lesions in less than 800 mg dosage group. 59% of the skin lesions developed only when survival analysis was done for 10 years. This showed that maintaining less than 800 mg is beneficial in reducing the proportion of occurrence of skin lesions (Table/Fig 9).

Kaplan-Meier survival analysis showed that significant proportion of skin leisions (41%) developed within a period of 3 years (1000 days) in the serum level above 0.8 mEq/L group while 9.6% developed skin lesion in the <0.8 mEq/L group. This showed that maintaining therapeutic levels <0.8 mEq/L is beneficial in reducing the proportion of skin lesions (Table/Fig 10).

Previous study by Priyadharshini BS and Ummar IS also suggest that most skin reactions are reversible upon reduction or discontinuation of Lithium except for few serious skin lesions like psoriasis (22). In the present study, no such cases were reported, and one patient with systemic lupus erythematosus had severe hair fall, which improved after stopping Lithium.

Previous studies by Priyadharshini BS and Ummar IS have shown that increase in dosage of lithium resulted in deterioration of skin lesions which improved after reducing the lithium dosage (22). However, in this study, no reduction of the dosage of lithium was done and skin lesions subsided with subsequent dermatological treatment (topical applicant). Hence, continuing the same dosage of lithium with concomitant dermatological treatment after the onset of skin lesion may be advisable.

Limitation(s)

Since the study had small sample size, the results cannot be generalised. Sampling bias and interviewer bias was observed due to convenient sampling method. The dropout rate was high (19%). The compliance was analysed only with the patient’s own words.

Conclusion

The patients who were treated with lower dosage and who had lower serum lithium level had reduced risk for cutaneous lesions. Lithium continued to exert its mood stabilisation property even when the serum level was maintained less than 0.8 mEq/L. This resulted in better compliance.

References

1.
Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009:951- 75. Doi: https://doi.org/10.3727/096368909X471251. [crossref] [PubMed]
2.
Perlick DA, Rosen RA, Kaczynski R, Kozma L. Medication non-adherence in bipolar disorder: A patient centered review of research findings. Clin Approaches Bipolar Disord. 2004:3:56-64
3.
Chan HH, Wing YK, Su R, Krevel CV, Lee S. A control study of the cutaneous side effects of chronic lithium therapy. J Affect Disord. 200;57(1-3):107-13. Doi: https://doi.org/10.1016/S0165-0327(99)00064-6. [crossref] [PubMed]
4.
Albrecht G. Undesirable skin reactions to lithium. Hautarzt [Article in German]. 1985;36(2):77-82.
5.
Posey RE. Lithium carbonate and dermatitis. JAMA. 1972;25; 221(13):1517. Doi: https://doi.org/10.1001/jama.1972.03200260053026. PMID: 4262455. [crossref] [PubMed]
6.
Orwin A. Hair loss following lithium therapy. Br J Psychiatry. 1988;143:42-50.
7.
Aithal V, Appaih P. Lithium induced hidradenitis suppurativa and acne conglobata- Indian J Dermatol. 2004;70:307-09. PMID: 17642646.
8.
Rifkin A, Kurtin SB, Quitkin F, Klien DF. Lithium- induced folliculitis. Am J Psychiatry. 1973;130(9):1018-19. Doi: 10.1176/ajp.130.9.1018. PMID: 4727757. [crossref] [PubMed]
9.
National Institute for Health and Care Excellence. Bipolar disorder: Assessment and management. 2014.
10.
Shulman KI, Almeida OP, Herrmann N, Schaffer A, Strejilevich SA, Paternoster C, et al. Delphi survey of maintenance lithium treatment in older adults with bipolar disorder: An ISBD task force report. Bipolar Disord. 2019;21(2):117-23. Doi: 10.1111/bdi.12714. [crossref] [PubMed]
11.
Schou M, Baastrup PC, Grof P, Weis P, Angst J. Pharmacological and clinical problems of lithium prophylaxis: Myths and realities. Am J Psychiatry. 1989;146:573-76. Doi: 10.1192/bjp.116.535.615. PMID: 5452362. [crossref] [PubMed]
12.
Gelenberg AJ, Kane JM, Keller MB, Lavori P, Rosenbaum JF, Cole K, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321:1489-93. Doi: https://doi. org/10.1056/NEJM198911303212201. PMID: 2811970. [crossref] [PubMed]
13.
Heng MC. Cutaneous manifestations of lithium toxicity. Br J Dermatol. 1982;106(1):107-09. Doi: https://doi.org/10.1111/j.1365-2133.1982.tb00911.x. PMID: 6460518. [crossref] [PubMed]
14.
Rao AV, Hariharasubramanian N, Sugumar AA. Study of side effects of lithium. Indian J Psychiatry. 1983;25(2):87-93.
15.
Ummar S, Dorai BL, Ramanathan SA. Distressing cutaneous lesion among bipolar affective disorder patients on lithium therapy: A retrospective crosssectional study. Indian J Psychiatry. 2016;58(4):383-86. Doi: https://doi. org/10.4103/0019-5545.196708. PMID: 28196994. [crossref] [PubMed]
16.
Pourhoseingholi MA, Vahedi M, Rahimzadeh M. Sample size calculation in medical studies. Gastroenterol Hepatol Bed Bench. 2013;6(1):14-17. PMID: 24834239; PMCID: PMC4017493.
17.
World Health Organization (WHO). The ICD-10 classification of mental and behavioural disorders. World Health Organization, 1993.
18.
Kumar N, Shekhar C, Kumar P, Kundu AS. Kuppuswamy’s socioeconomic status scale- Updating for 2007. Indian J Pediatr. 2007;74:1131-32.
19.
Sarantidis D, Waters B. A review and controlled study of cutaneous conditions associated with lithium carbonate. Br J Psychiatry. 1983;143:42-50. Doi: https:// doi.org/10.1192/bjp.143.1.42. PMID: 6224526. [crossref] [PubMed]
20.
Swetha P, Rajeevi, Gupta PCB. Lithium induced rash: A case report. Indian J Psychiatry. 2022;64(Suppl 3):S691. Doi: 10.4103/0019-5545.342043.
21.
Aithal V, Appaih P. Lithium induced hidradenitis suppurativa and acne conglobata. Indian J Dermatol Venereol Leprol. 2004;70(5):307-09. PMID: 17642646.
22.
Priyadharshini BS, Ummar IS. Prevalence and sociodemographic profile of lithium-induced cutaneous side effects in bipolar affective disorder patients: A 1-year prospective observational study in South India. Indian J Psychol Med. 2017;39(5):648-52. Doi: https://doi.org/10.4103/IJPSYM.IJPSYM_87_17. PMID: 29200562. [crossref] [PubMed]

DOI and Others

DOI: 10.7860/JCDR/2022/57573.16944

Date of Submission: May 05, 2022
Date of Peer Review: Jun 22, 2022
Date of Acceptance: Sep 10, 2022
Date of Publishing: Oct 01, 2022

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

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: May 11, 2022
• Manual Googling: Sep 07, 2022
• iThenticate Software: Sep 14, 2022 (19%)

ETYMOLOGY: Author Origin

JCDR is now Monthly and more widely Indexed .
  • Emerging Sources Citation Index (Web of Science, thomsonreuters)
  • Index Copernicus ICV 2017: 134.54
  • Academic Search Complete Database
  • Directory of Open Access Journals (DOAJ)
  • Embase
  • EBSCOhost
  • Google Scholar
  • HINARI Access to Research in Health Programme
  • Indian Science Abstracts (ISA)
  • Journal seek Database
  • Google
  • Popline (reproductive health literature)
  • www.omnimedicalsearch.com