A Retrospective Study of Body Weight Changes in Patients Receiving Cyproheptadine in A Hospital-Based Outpatient Setting in Thailand

ABSTRACT


INTRODUCTION
Nutritional requirements are diverse in patients with various clinical conditions including chronic and metabolic diseases.Patients with anorexia due to underlying diseases or drug treatments may experience loss of appetite and body weight.There were medicatons used to stimulate appetite; one of the common conventional appetite stimulants was cyproheptadine (Roeland et al., 2020).Cyproheptadine is a first-generation antihistamine which has both antihistamine and anti-serotonin properties.Activation of serotonin (5-HT) receptor plays an important role in the inhibition of food intake (Blundell, 1984).Cyproheptadine appears to stimulate appetite by interfering serotonin effect (5-HT antagonism) on a satiety control area located in the hypothalamus (Scholar, 2007).Inhibition of serotonin makes the subject necessary for more energy, which increases appetite (Hall, 2011;Voigt & Fink, 2015).According to the literatures, cyproheptadine was a well-tolerated appetite stimulant with favorable side effects in both normal and underweight populations (Harrison et al., 2019).It was suggested that the use of cyproheptadine could be a short-term strategy for patients who require nutritional support (Epifanio et al., 2012).
The effect of cyproheptadine was firstly recognized in the clinical study on asthmatic 492 Volume 34 Issue 3 (2023) children where participants showed a significant increase in appetite and body weight (Lavenstein et al., 1962).Later on, the weight enhancing effect of cyproheptadine was noted in patients with various clinical conditions (Epifanio et al., 2012;Najib et al., 2014;Summerbell et al., 1992).Over the past century, it was prone to be effective stimulant for appetite and weight gain in underweight population (Noble, 1969).In the study group, both appetite and body weight increased significantly after receiving cyproheptadine at day 14, 28, 42 and 56.Likewise, the weigh gaining property of cyproheptadine was noted in human immunodeficiency virus (HIV) infected people with wasting (Summerbell et al., 1992).However, the inconsistencies on the weigh gaining effect of cyproheptadine were noted in the previous literature reporting that cyproheptadine was not effective in increasing body weight of patients with anorexia (Vigersky, 1977).
There are still discrepancies among studies on weight enhancing effect of this "old" drug in different populations.The effects of this medication on weight changes in adults and elderly are also unclear.The National List of Essential Medications of Thailand currently specify the indications of cyproheptadine as drugs used in the prophylaxis of migraine and the management of acute serotonin syndrome; however, the use of cyproheptadine as an appetite stimulant is off label which depends on professional discretion.Over the past years, studies on the outcomes of cyproheptadine use in Asian population; including Thailand, are limited.Thus, this study aimed to determine whether cyproheptadine use influenced on body weight over a year, and potential associated factors of body weight in Thai patients.

Study design and participants
This retrospective longitudinal study collected data from the clinical and laboratory records of the adult patients receiving cyproheptadine at the outpatient medical department, the Police General Hospital, Bangkok, Thailand from January 2019 to December 2021.The Police General Hospital is currently a fullyfledged state-run tertiary-care hospital with approximately 900 beds.The study was approved by the Institutional Review Board of the Police General Hospital (the number of approval was 133/2564) in accordance with the Declaration of Helsinki ethical principles for medical research involving human subjects.A requirement for informed consent was exempted due to the retrospective nature of the study and anonymous reported data.

Inclusion and exclusion criteria
The study included Thai patients receiving cyproheptadine as an off-labelled use for appetite stimulant, aged 18 years and above, whose body weights were recorded at 2 time periods within a year follow-up at the medical outpatients.Patients with incomplete body weight records, pregnancy, or lactating women were excluded.Patients who were diagnosed with migraine or acute serotonin syndrome were also excluded.We calculated sample size using the G*Power (v 3.1.9.4) software.We selected the statistical test as the means: the difference between two dependent means (matched pairs) with the effect size 0.25, alpha criterion 0.05, and the desired power as 0.8.After assumed 15% missing data was applied, the estimated required sample size was equal to 120 participants.

Data collection
Body weight data of the participants were carefully collected at two-time periods: 1 st visit and 2 nd visit between 2019 and 2021.In addition to body weights, height (for BMI calculation), age, gender, reimbursement status and clinical conditions including underlying medical conditions at the 1 st visit were collected through the review of patients' medical records.Dosage regimen of cyproheptadine, and the number of concurrent medications were also recorded to assess the polypharmacy status (5 or more medications) (Junius-Walker et al., 2007).
Laboratory data including fasting blood glucose, hemoglobin A1C, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and serum creatinine (sCr) were collected to analyze the effect of cyproheptadine on their changes at hospital visits.

Statistical analysis
Data were analyzed by IBM SPSS (version 22.0, Chicago, IL, USA).Demographic characteristics were presented as descriptive statistics.Categorical data were presented as numbers and percentages.Continuous data were presented as mean and standard deviation (SD).Paired t-test and independent t-test were used to analyze the mean differences and between-group differences, respectively.Multiple logistic regression and multiple linear regression were used to evaluate the potential association of body weight with factors such as age, gender, medications.P-value of < 0.05 was set up as a significance.

RESULTS AND DISCUSSION
A total of 125 patients were included.Eightyseven participants were female, and mean age of the participants was 78.38 (SD + 11.68) years.Majority (92%) were aged  60 years.The mean BMI at 1 st visit was 21.16 (SD + 3.64) kg/m 2 (Table I).The common medical conditions of the participants were hypertension, dyslipidemia, and diabetes mellitus.The off-labelled indication of cyproheptadine was appetite stimulant for anticipated weight improvement.In this population, the mean number of medications use including cyproheptadine and other concurrent drugs was substantially high.Polypharmacy was found in 109 (87.2%) of the participants.The interval duration between the visits was 2 to 12 months with the mean as 6 months.
All participants in this study received cyproheptadine 4 mg per day: before bedtime or after dinner due to its sedative effect.The mean body weight of the participants were 52.46 (SD + 11.11) kg and 52.61 (SD+ kg at 1 st and 2 nd visits, respectively.There were no statistical differences in body weights between the two visits (p = 0.684).Likewise, BMI showed no significant differences between the two hospital visits (p=0.595)(Table II).Among 84 participants who had the 6 to 12-month visit time interval, the mean body weight were 51.46 (SD + 10.87) kg and 52.32 (SD+ 10.86) kg at 1 st and 2 nd visits, respectively.Again, no significant differences inbody weights and BMI between the two hospital visits.By dividing participants into three groups: underweight (< 18.5 kg/m 2 ), normal weight (18.5 -23 kg/m 2 ) and overweight (> 23 kg/m 2 ), the mean differences in body weight between hospital visits were analyzed.The mean BMI in the underweight participants significantly declined over time showing a mean difference of -1.47.However, no significant differences in body weight were found between two visits in normal and overweight patients.Compared to the 1 st visit, the prescribed medications in overweight patients became higher at the 2 nd visit (Table III).By stratifying age into two groups: aged < 60 years and  60 years, the mean values were compared between hospital visits.However, mean body weight changes were negligible in both group (Table IV).
The changes in laboratory parameters after the administration of cyproheptadine in our patients are also analyzed.Although there were no significant changes among the hospital visits, most laboratory values were lower at 2 nd visit compared to 1 st visit.Using the Pearson's correlation analysis, we observed some factors correlated with body weight variation in this population.Factors including age, HDL and serum creatinine levels had clinically significant negative correlation with the body weight (data not shown).Multiple linear regression showed the associated factors of body weight variation in patients with different clinical underlying conditions.The increased HDL levels and older age were significantly associated with low body weight (Table V).By adjusting age and gender, the potential factors in association with normal body weight and abnormal body weight groups were analyzed by binary logistic regression.It was observed that participants with normal body weight had low number of prescribed medications, low prevalence of hypertension and low LDL levels (Table VI).
This study did not find the clinically significant weight change in medical outpatients after the administration of 4 mg cyproheptadine during two hospital visits with the mean interval of 6 months.The common underlying medical conditions of the patients were hypertension, hyperlipidemia, and diabetes mellitus.Majority of participants were elderly (aged  60 years) with polypharmacy in more than 80% of population.It is interesting to document that cyproheptadine appears to have no significant effect on the body weight in advance aged population.The finding was in accordance with the clinical trial of Kardinal et al., (Kardinal et a l., 1990) in which the mean age of the population was 65 years.The administration of 8 mg cyproheptadine three times a day did not show any significant enhancement in the body weight of cancer patients with anorexia and/or cachexia despite its mild appetite stimulation.A recent systematic review on the use of cyproheptadine as an appetite stimulant by Harrison et al.,(Harrison et al., 2019) included 46 studies in 21 different populations.The overall effect of cyproheptadine seemed to increase body weight; however, there were only minimal effects or no benefit in patients with cancers or HIV infection.
We analyzed mean body weight changes over period in patients with different medical conditions such as hypertension, diabetes mellitus, dyslipidemia and cardiovascular disease by subgroup analysis.There were no significant weight changes in our patients between 1 st and 2 nd visits.However, we found that older age and high HDL levels were correlated with lower body weight.Moreover, interestingly, patients with abnormal body weight seemed to have a high number of medications, hypertension and high LDL levels in this study.
In the previous clinical study on the effect of cyproheptadine, young adults received 4 mg cyproheptadine three times per day for a month.Compared to the placebo group, participants receiving the study drug significantly gained body weight (Silverstone & Schuyler, 1975).Of interest, the weight gaining effect of cyproheptadine was likely due to its stimulation of hunger which suggested the central serotonergic mechanism of drug.The recent double-blind, placebo-controlled randomized trial by Kim et al.,(Kim et al., 2021) included healthy adults with poor appetite.The study reported that there were significant increases in body weight and BMI after the 8-week administration of 3 mg cyproheptadine.Our study, however, did not support the previous findings, perhaps due to variation in appetite status and underlying disease status.
There are some limitations in our study.A retrospective study limited the causal relation of cyproheptadine and body weight.The assessment of medication adherence was beyond our records.We were unable to record side effects from the medication, assessment of nutritional status, appetite measurement, lifestyle factors and socioeconomical factors.The use of cyproheptadine in older population should be aware of the possible side effects such as orthostatic hypotension, tremor, dry mouth, drowsiness, irregular heartbeat, or difficulty urinating; however, limited data were recorded in the medical charts.There were also variations in underlying medical conditions which might influence our results.Moreover, due to the spread of corona virus and nationwide lock-down in the first pandemic period, the number of participants recruited for this study was limited in the medical records.The study did not collect first weight data of participants who had used cyproheptadine earlier than our study confined 1 st visit.Thus, the use of medication over a long period may not effectively change the body weight.There was no control group to analyze the effects of cyproheptadine.Since the study was based on a previously recorded electronic database, there might have registry bias in retrieved data.
The results of this study might be influenced by several factors such as different medical conditions, physical activity, different types of diet and lifestyle behaviors of the participants.Of note, it is crucial to consider the drug interactions of cyproheptadine with other concurrent medications as most of our participants had polypharmacy.In this study, the majority of the participants were well-nourished, and we did not find any improvement in body weight in underweight patients as well.Overall, it could be assumed that cyproheptadine did not change the body weight of patients with normal nutritional status; possibly because the amount of food intake varies in relation to nutrient requirements or energy expenditure.Additionally, the nutritional counseling should be considered in certain malnourished individuals to achieve the clinical improvement.

CONCLUSION
The administration of 4 mg cyproheptadine did not result in significant weight gain in medical outpatients with various chronic diseases.Several factors such as age, HDL, LDL, concurrent medications, hypertension were necessary to note as they may potentially influence the body weight of participants receiving cyproheptadine.Overprescription of cyproheptadine should be aware that it may not produce any beneficial effect in patients normal body weight.The information of this study will be useful for health care practitioners for considering medications to patients with various chronic diseases.Further prospective studies on the effect of cyproheptadine in malnourished patients with chronic diseases are highly warranted.

Table I .
Characteristics of participants included in the study.

Table II .
Overall mean difference in body weight and body mass index (N=125).
a Paired t-test comparing the means between hospital visits.Volume 34 Issue 3 (2023)

Table III .
Mean differences in laboratory data classified by BMI criteria

Table IV .
Mean differences in laboratory data classified

Table V .
Factors associated with body weight by linear regression.

Table VI .
Association of variables with normal weight status (BMI 18.5 -23 kg/m 2 ).
a Multiple logistic regression