Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review

Accepted Manuscript Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review Megan E. Harrison, Mark L. Norris, Amy Robinson, Wendy Spettigue, Morgan Morrissey, Leanna Isserlin PII:

S0195-6663(18)31508-3

DOI:

https://doi.org/10.1016/j.appet.2019.02.012

Reference:

APPET 4193

To appear in:

Appetite

Received Date: 19 October 2018 Revised Date:

11 February 2019

Accepted Date: 18 February 2019

Please cite this article as: Harrison M.E., Norris M.L., Robinson A., Spettigue W., Morrissey M. & Isserlin L., Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review, Appetite (2019), doi: https://doi.org/10.1016/j.appet.2019.02.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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1 2 3 4 Use of cyproheptadine to stimulate appetite and body weight gain: a systematic review

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Megan E. Harrison, MD1,2*, Mark L. Norris, MD1,2, Amy Robinson, MD1,2, Wendy

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Spettigue, MD2,3, Morgan Morrissey, BSc4, Leanna Isserlin, MD2,3

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Keywords: appetite stimulation; avoidant restrictive food intake disorder;

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cyproheptadine; eating disorder

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*Correspondence to: Dr Megan Harrison, MD, FRCPC, Division of Adolescent

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Medicine, Department of Pediatrics, Children’s Hospital of Eastern Ontario, 401 Smyth

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Road, Ottawa, Ontario, Canada, K1H 8L1. E-mail: [email protected]

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Ottawa, Ottawa, Ontario, Canada

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Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

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Department of Psychiatry, Children’s Hospital of Eastern Ontario, University of Ottawa,

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Ottawa, Ontario, Canada

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Department of Paediatrics, Children’s Hospital of Eastern Ontario, University of

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

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Abstract

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Objective: A systematic review identifying the use of cyproheptadine (CY) as an appetite stimulant was completed. Method: Studies of any design exploring the efficacy of CY as an appetite stimulant in all age groups and populations were included. Primary outcomes of studies included were weight gain, appetite stimulation, and/or caloric/nutritional intake increase. The review was completed in accordance with PRISMA standards. Results: A total of 46 articles across 21 different treatment populations met criteria for the review, including 32 randomized controlled trials, 4 prospective cohort studies, 4 retrospective cohort studies, 4 case reports and 2 case series. Of these, 39 demonstrated that CY resulted in significant weight gain in the sample under study. Studies exploring the use of CY in those with malignant/progressive disease states, such as HIV and cancer, showed minimal to no benefit of the medication. Transient mild to moderate sedation was the most commonly reported side effect. Studies included were heterogeneous in terms of methods as well as study patient demographics, characteristics and concurrent medical conditions. Few studies provided objective measures of appetite change. Discussion: CY appears to be a safe, generally well-tolerated medication that has utility in helping facilitate weight gain in patients drawn from a variety of underweight populations. Future prospective randomized controlled studies in low weight patients that include objective measures of appetite and intake are needed to better understand the mechanism by which CY augments weight gain.

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1. Introduction Cyproheptadine (CY) is a serotonin 5-HT2 and histamine H1 antagonist that was

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introduced for the treatment of allergic states. The medication was studied in 1959 in

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children with hay fever, with the authors noting a significant increase in appetite, body

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weight (BW) and linear growth as side effects (Lavenstein, Dacaney, & Metre, 1962). In

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the years that followed, these side effects were confirmed in those with and without

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allergies (Bergen, 1964; Drash, Elliott, Langs, Lavenstein, & Cooke, 1966; Francini,

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Santana, & Kitrosen, 1967). Over the last 50 years, numerous investigators have studied

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the medication’s utility as an appetite stimulant in malnourished and/or underweight

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patients with a variety of health conditions, such as cancer, metabolic disease, failure to

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thrive, malnutrition, HIV, anorexia nervosa (AN) and cystic fibrosis (CF) Although

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considered an ‘older’ drug, and one not typically used now in the treatment of eating

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disorders (EDs), it is worth reconsidering CY’s potential role in the treatment of under-

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nourished adults and children, including those with avoidant restrictive food intake

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disorder (ARFID).

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The primary objective of this study was to conduct a systematic review of CY’s use and

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ability to act as a stimulant of appetite and weight gain, using internationally accepted

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search criteria such as that outlined by PRISMA guidelines (Moher, Liberati, Tetzlaff, &

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Altman, 2009). Our secondary objectives were to: review the safety of CY and identify

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commonly noted side effects attributed to CY; and describe whether CY appears to be

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more effective in particular age groups or for particular diagnoses.

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In accordance with PRISMA guidelines, our systematic review protocol was registered

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with the International Prospective Register of Systematic Reviews (PROSPERO) on 19

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September 2016 (registration number CRD42016047875).

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91 2.0 Method

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2.1 Search Strategy

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The following databases were searched focusing on CY use as an appetite stimulant:

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MEDLINE including Epub Ahead of Print, In-Process & Other Non-Indexed Citations

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(1946- June 22, 2018) and Embase (1980- June 22, 2018) and the CENTRAL Trials

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Registry of the Cochrane Collaboration (May 2018 Issue) using the Ovid interface.

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Searches were designed and conducted by a librarian experienced in systematic reviews,

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using a method designed to optimize term selection (Bramer, Giustini, & Kramer, 2016).

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Search strategies are presented in Appendix 1. Non-English articles were included

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assuming they could be translated sufficiently, using Google Translate, for evaluation.

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Bibliographies of manuscripts were also searched to ensure any relevant articles were

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included in the initial screen.

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2.2 Eligibility Criteria

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Studies of any design, including published case reports, that involved pediatric and adult

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patients with any medical or psychiatric condition and in any setting were included.

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Studies were included where CY was the exposure and where the primary outcomes for

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the studies were: 1) weight gain, and/or 2) appetite stimulation, and/or 3)

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caloric/nutritional intake increase. Studies that were reviews, commentaries or conference

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abstracts, or could not be translated during the review timeframe were excluded.

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2.3 Abstract and Article Selection

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After initial online duplicate removal, records retrieved by the electronic search were

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downloaded and imported into a Reference Manager database, where any remaining

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duplicate references were removed. Throughout the review, newly identified records

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were integrated into the set for screening. Records were uploaded to CrowdScreen (Nama

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et al., 2017) and appraised against the inclusion criteria. First, two reviewers

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independently reviewed the titles and abstracts of the papers identified from the search,

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using the inclusion criteria. In cases where reviewers did not agree on the study’s

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eligibility, a third reviewer helped determine suitability. The full text of eligible studies

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was assessed for suitability by two review team members, with input from a third

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provider when necessary. Results were uploaded into a secure RedCap electronic

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database (Harris et al., 2010). Reviewers were not blinded to study authors or institutions

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during the review.

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3. Results

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In total, 591 records were identified through the initial database search, resulting in 530

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records for screening after duplicates were removed. Reference lists identified 8

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additional reports that were assessed for eligibility. A total of 46 articles met criteria for

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the review (Figure 1); 32 randomized controlled trials (RCTs), 4 prospective cohort

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studies, 4 retrospective cohort studies, 4 case reports and 2 case series.

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3.1 Cyproheptadine use in healthy adults

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A total of 5 studies were identified that examined CY’s as a stimulant of appetite and

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weight gain in healthy, “normal weight” adults (Table 1). In each of these studies,

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investigators sought to better understand CY’s mechanism of action and effect on the

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biochemical and metabolic profile of patients. Small sample sizes and varying durations

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of treatment precluded formal comparisons of studies. Only one study (Comer et al.,

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1997) included an objective measure for appetite. In this 18 day residential trial of 7

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normal weight volunteers, the authors demonstrated that CY increased caloric intake as

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measured by the number of eating occasions but not as a result of increased meal size.

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3.2 Cyproheptadine use in underweight adults

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Seven studies, including 6 RCTs were identified that explored the use of CY in

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underweight but otherwise healthy adults (Table 2).

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The RCTs showed mainly positive results regarding CY’s efficacy in promoting weight

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gain (Noble, 1969; Pawlowski, 1975; Sardesai et al., 1970; Silbert, 1971; Silverstone &

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Schuyler, 1975) with only one RCT showing no significant weight gain in elderly

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patients treated with CY (Andronic & Di Mascio, 1971). Silbert examined the use of CY

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in children and adults with multifactorial loss of appetite over 4 weeks, using CY doses

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that ranged from 2 to 8 mg/day (Silbert, 1971). A statistically greater increase in weight

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in the CY group was reported at weeks 8 and 12 regardless of dose. Pawlowski et al

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demonstrated a greater increase in weight for patients chronically underweight at each 2

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week interval for their CY group (12 mg/day), with the CY group gaining 3 kg as

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compared to 1.3 kg for the placebo group at the conclusion of the 12 week trial.

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3.3 Cyproheptadine use in Anorexia Nervosa

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Five RCTs examined the use of CY in adults with AN, four of which were conducted on

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hospital inpatient units and one of which took place in a hospital outpatient setting (Table

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3). Additionally, Benady published a case report that described favourable weight gain

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effects of CY in a 12 year old female with AN (Benady, 1970). In the RCTs, patients

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received doses of CY ranging from 2mg/day to 32mg/day in divided doses (e.g. three or

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four times daily). The primary outcome in the RCTs was weight gain (Goldberg, Halmi,

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Eckert, Casper, & Davis, 1979; Halmi, Eckert, & Falk, 1982, 1983; Halmi, Eckert, LaDu,

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& Cohen, 1986; Vigersky & Loriaux, 1977). Secondary outcomes were included in 3

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studies and consisted of appetite, and mood symptoms as rated by the Hamilton Rating

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Scale and Beck Depression Inventory (Halmi et al., 1982, 1983, 1986). Four of the five

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RCTs (Goldberg et al., 1979; Halmi et al., 1982, 1983, 1986) demonstrated a statistically

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significant increase in weight in CY-treated patients. Two of the five RCTs (Halmi et al.,

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1983, 1986) appeared to be a continuation of an earlier reported RCT (Halmi et al.,

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1982). In the largest of these studies, Halmi et al. (1986) reported a differential drug

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effect attributed to CY in patients with and without symptoms of bulimia. The drug

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significantly increased the efficacy of treatment for those whose endorsed primary

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restrictive symptoms, whereas the CY impaired treatment efficacy in patients who

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endorsed symptoms of bulimia. In the single study that failed to demonstrate a difference

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in weight gain between CY and placebo(Vigersky & Loriaux, 1977), the maximum dose

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used was far lower than in the other studies (12mg/day vs 32mg/day); the study was

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small (n= 13 for the CY group); and the study took place in an outpatient setting as

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compared to an inpatient setting. Table 3 further describes these studies.

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179 3.4 Cyproheptadine use in adults with mixed disease states

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A total of 5 RCTs and one parallel, non-blinded, non-randomized trial was included

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(Table 4). Four of these studies reported significant increases in weight. All of these

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studies had significant limitations, including using heterogeneous sample populations in

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terms of medical diagnosis (ie. “psychiatric leanness,” dystonia, neurasthenia, duodenal

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ulcers, gastritis, hepatitis, chronic urticaria, etc) (Irsy & Szatloczky, 1977; Tiszai &

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Szasz, 1972), as well as failing to account for confounding factors (i.e. socioeconomic

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status) (Rahman, 1975), short study periods (Irsy & Szatloczky, 1977; Tiszai & Szasz,

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1972), and lack of objective measures of appetite stimulation. In disease states involving

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anorexia and cachexia as symptoms of disease progression, no observable effect of CY

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on weight gain was noted. Irsy et al reported stimulation of appetite and increased weight

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gain in healthy volunteers as well as the majority of individuals studied with varying

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chronic illnesses, although no appreciable effects on appetite or weight were

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demonstrated in a group of patients suffering from malignant diseases. It must be noted

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however that that authors failed to include the mechanism by which appetite change was

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measured. In a larger, multicenter trial involving patients with advanced malignant

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cancer, Kardinal et al found mildly enhanced appetites reported by patients on CY, but no

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halt in progressive weight loss (average weight loss of 2 kg/month in the treatment group

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versus 2.2 kg/month in the placebo group, p = 0.72), even when adjusted for potential

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prognostic factors (Kardinal et al., 1990).

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In a study comparing CY versus megestrol acetate in HIV outpatients, Summerbell et al

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showed an increase in mean daily energy intake in both treatment groups compared to

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pretreatment assessment; energy intake increased by 500 kcal/day in both groups (p <

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0.05), however decreased after treatment (Summerbell, Youle, McDonald, Catalan, &

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Gazzard, 1992). Despite this, variable weight gain was seen with CY-treated patients

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(weight gain in 3/7 patients, weight loss in 2/7, stable weight in 1/7, one patient death). In

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another double blind placebo controlled study of CY’s effect on patients with irritable

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colon syndrome, Mainguet et al. (1972) reported greater weight gain and appetite

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stimulation in those treated with CY. In this study, appetite stimulation was measured by

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appetite level in combination with caloric intake, although the specific details by which

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this data was collected were not specified.

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3.5 Cyproheptadine use in malnourished and underweight children

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Ten articles investigating the utility of CY for appetite stimulation in pediatric

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malnourished and underweight patients were included in this review (Table 5).

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Randomized controlled trials were most common study design identified (n=8). None of

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the studies included objective measures of appetite. Although a total of 509 patients were

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included across all of the RCTs, variation in study sample age (1.3 to 16 years), study

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design, drug dosing and active comparator descriptions, as well as length of trials,

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prevented the completion of a meta-analysis. All studies that investigated the effect of

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CY on weight in underweight children showed some degree of improvement on

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medication. Further, studies that sought to also investigate CY’s effect on growth also

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showed a positive effect when study designs were 3 months in length or more

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(Mahachoklertwattana, Wanasuwankul, Poomthavorn, Choubtum, & Sriphrapradang,

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2009; Penfold, 1971). Only one study examined growth effects with outcomes at less

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than 3 months, with no effect demonstrated (Najib, Moghtaderi, Karamizadeh,

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Fallahzadehm, & Najib, K.; Moghtaderi, M.; Karamizadeh, Z.; Fallahzadehm, 2014). CY

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was typically well tolerated in all studies in this category, with no significant adverse

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effects reported. The most common side effect noted was sedation, which was noted to

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typically improve a few days after starting medication. In addition to the factors listed

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above, other important limitations exist within these studies, including possible effects of

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concurrent medical issues amongst sample size (ie. high rate of parasitic infections noted

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in one study) (Sanzgiri, Mohamad, & Raja, 1969) and high sample attrition

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(Mahachoklertwattana et al., 2009; Najib et al., 2014; Penfold, 1971).

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3.6 Cyproheptadine use in malnourished and/or underweight children with concurrent

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chronic medical conditions

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Twelve studies, that examined the effects of CY on weight gain and/or appetite in various

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childhood conditions were included in the review (Table 6). As noted in other sections,

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these studies also varied significantly in design, size (n ranging from 1 – 70), patient

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population characteristics (ie. disease conditions) and length of study treatment (ranging

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from 7 weeks to 12 months).

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CY’s effectiveness has been studied in underweight children with CF by 2 research

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groups (Epifanio et al., 2012; Homnick et al., 2004; Homnick, Marks, Hare, & Bonnema,

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2005). Homnick et al. (2004) initially performed a well-designed 12 week randomized

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blinded placebo controlled study of 18 patients with CF and ideal body weight for height

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<100%. Weight increased significantly more in the treatment group as compared to the

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placebo group (3.45 kg vs 1.1 kg, P <0.0001), as did percent ideal body weight, skin fold

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measurements, and BMI (all P<0.0001). Following the RCT, an open-label design

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continued for an additional 9 months and all placebo patients were prescribed CY (total

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n=12; 7 from the original treatment group in the 2004 study and 5 from the placebo group

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from the original study) (Homnick et al., 2005). Patients who changed from placebo to

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CY gained weight over 3-6 months, with less weight gain near the end of the study.

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Authors cited variable adherence to medication dosing as a possible explanation for less

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weight gain in the second portion of the study, as well as possible decreased effect of the

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medication over time. In another well-designed 12 week double blind placebo controlled

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study, Epifanio found significant increases in weight and BMI in pediatric patients with

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CF (n=25) who were treated with CY as compared to those on placebo (Epifanio et al.,

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2012).

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There are 2 reports of CY’s use in pediatric patients with cancer (Couluris et al., 2008;

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Erdem, Emir, Demir, & Tunç, 2014). In an open label prospective cohort study, Couluris

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found that CY was effective in promoting weight gain in children with cancer and

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treatment related cachexia (Couluris et al., 2008). Fifty of the 66 patients in the study

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responded to CY treatment with significant weight gain (mean weight gain 2.6 kg CI

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1.93-3.27); interestingly, those with hematologic cancers responded more than those with

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non-hematologic cancers (p=0.04). In a retrospective patient chart review of children

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with cachexia related to cancer treatment (n=14), Erdem reported an increase in weight in

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11/14 patients and self-reported increase in appetite in 10 patients (71%) in those who

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were treated with CY (Erdem et al., 2014).

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CY has also been effective in increasing weight in those with anorexia and low weight

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due to other conditions, including asthma (Bergen, 1964; Lavenstein et al., 1962),

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metabolic disease (Lerman-Sagie & Mimouni, 1995), tuberculous meningitis (Muranjan

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et al., 1994), GH deficiency (Kaplowitz & Jennings, 1987), ADHD treatment-related

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weight loss (Daviss & Scott, 2004), and Silver-Russell syndrome (Lemoine et al., 2018)

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(Table 6). Although several studies noted improvements in appetite based upon self

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report or parental observation, objective measures of appetite were not included.

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276 3.7 Tolerability of Cyproheptadine

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In general, CY was well tolerated in all studies with no serious adverse effects reported.

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As noted throughout the tables, mild to moderate drowsiness was commonly reported

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across many studies but was rarely severe enough to lead to medication discontinuation.

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In one study, authors noted that sedation appeared to be dose dependent (Silbert, 1971).

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Irritability was also reported as a side effect in one study (Lemoine et al., 2018) and

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nausea and dizziness in another (Irsy & Szatloczky, 1977).

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Studies that explored possible biochemical and laboratory changes in those taking CY

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showed no significant alterations to results either pre- versus post- trial or in treatment

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versus placebo groups, including fasting glucose (Najjar & Khachadurian, 1969; Stiel,

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Liddle, & Lacy, 1970), plasma insulin (Najjar & Khachadurian, 1969; Stiel et al., 1970),

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plasma growth hormone (Stiel et al., 1970), plasma free fatty acids(Stiel et al., 1970),

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plasma free amino acids (Najjar & Khachadurian, 1969), glucose tolerance (Najjar &

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Khachadurian, 1969), or urea (Noble, 1969). One study found greater levels of IGF-1 in

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research participants taking CY (Mahachoklertwattana et al., 2009). A significant

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increase in urinary sodium and creatinine excretion was explained by an increase in

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overall food intake with cyproheptadine use by Stiel et al.(Stiel et al., 1970).

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294 4.0 Discussion

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A total of 46 studies across 21 different treatment populations were identified in this

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systematic review. Of these, 39 demonstrated that CY prescription resulted in significant

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weight gain in the sample under study, of which 27 were RCTS, and 12 case studies.

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Only a few studies included appetite as an outcome, and of these, only 6 included

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measures of appetite and/or caloric intake (Bergen, 1964; Comer, Haney, Fischman, &

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Foltin, 1997; Genazzani et al., 2001; Mainguet, 1972; Silverstone & Schuyler, 1975;

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Summerbell et al., 1992). Comer et al.’s study (1997) findings were interesting as their

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results indicated that CY affected postprandial satiety or hunger mechanisms, as opposed

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to food reward or meal-derived satiation. The small study sample and short

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administration cycle (2 days) limits any conclusions or observations regarding sustained

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changes in appetite and weight. Due to the heterogeneity of study methods as well as

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study patient demographics, characteristics and medical conditions included, we are

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unable to provide a specific level or grade of evidence for the use of CY as an appetite

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stimulant.

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While overall CY appears to improve weight gain in many diverse patient populations, it

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is important to note that studies that explored the use of CY in those with malignant or

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progressive disease states, such as HIV and certain types of cancer, showed minimal to

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no benefit of the medication (Erdem et al., 2014; Irsy & Szatloczky, 1977; Kardinal et al.,

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1990; Summerbell et al., 1992). It is also interesting to note that the studies with the

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eldest patient groups, Andronic (n=30; mean age 73 years) (Andronic & Di Mascio,

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1971) and Kardinal (n=295; mean age 65 years)(Kardinal et al., 1990), found no

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significant changes in weight in those taking CY as compared to placebo. The latter two

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studies, however, have significant differences that make them difficult to compare and

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draw conclusions, including the variability in patient diagnoses (advanced malignant

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diseases vs unspecified psychiatric conditions), definitions of “underweight”/ history of

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weight loss, CY dose (8 mg tid in Kardinal study vs 4 mg tid in Andronic study),

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concurrent medications being used by study participants as well as length of treatment

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(34 days Kardinal vs 56 days Andronic). Of interest, in Halmi et al.’s study (1986), CY

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negatively influenced the treatment efficacy of those with bulimia subset. Although the

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authors could not definitively account for the reasons that contribute to this occurrence,

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they speculated that differences in appetite regulation between those with and without

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concomitant bulimia may have accounted for the differences. Given the propensity for

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CY to increase treatment efficacy and decrease days required to reach treatment goal

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weight in patients with AN, further study is required to better understand the mechanisms

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that might account for differences between subgroups. Each of the remaining studies that

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failed to show any benefit of CY as an appetite stimulant had many limitations as

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discussed in sections above (Fantino, Brondel, Swiergiel, & Lebec, 1990; Genazzani et

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al., 2001; Tiszai & Szasz, 1972; Vigersky & Loriaux, 1977).

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Despite the high number of studies with positive outcomes, many designs were limited,

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with small sample sizes, various dosing, short-term follow up, and other confounding

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factors that had the potential to affect findings. As an example, studies that involved

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subjects with mixed chronic diseases were typically fraught with a number of

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uncontrolled confounders (i.e. disease activity) with the potential to influence results, and

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thus limit their generalizability. Of further concern, not all studies controlled for, or

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referenced measures taken to limit, the extent to which factors such as poverty or

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admission to hospital might affect access to nutrition and thus also affect outcome. The

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issue of socioeconomic status has specific relevance given that results from one study

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that did control for access to nutrition/availability of nutrition suggested a faster but less

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robust treatment response in subjects treated with medication with uncompensated

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malnutrition (Burrows & Muzzo, 1981). As a result, weight gain was not greater

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compared to the placebo group at the 4-week mark (although weight gain was greater in

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those with compensated malnutrition at week 4). Outcomes between those with

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uncompensated and compensated nutrition at the 2 month mark were both significantly

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greater for those children taking CY than for those not treated with medication. Although

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not mentioned in other studies, Burrows & Muzzo speculate that the underlying reasons

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for the malnutrition also have the potential to affect outcome (Burrows & Muzzo, 1981).

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Similarly, there is little information available regarding activity levels, and whether some

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patients who did not respond may have been more active than others, or not had adequate

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nutrition to compensate for activity levels. In addition, more dated studies did not

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consistently report on whether there were randomization processes, blinding procedures

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(or in cases where blinding was reported, the method was not specified), research ethics

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board approval, details of how medications compliance was monitored, or how data

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regarding appetite increases were measured. Also, although most studies provided

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cursory descriptions as to how patients were investigated medically, it is possible that

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undiagnosed underlying medical issues may have impacted treatment responses. As an

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example, in Sanzgiri et al.’s study, most of the included children had co-occurring

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parasitic infections, which were considered endemic to that population in India (Sanzgiri

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et al., 1969). Many studies had only short-term follow up, despite the possibility that

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appetite stimulation and weight gain may only be short-lived, and few of the studies

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commented on whether the weight gain was considered clinically significant.

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In addition to the limitations outlined above, calculation of malnourishment and

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determinations of underweight status varied depending on the study. Many studies did

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not describe how they determined patients to be “low weight” or “lower than ideal”

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(Homnick et al., 2004; Irsy & Szatloczky, 1977; Mainguet, 1972; Penfold, 1971; Sanzgiri

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et al., 1969; Sardesai et al., 1970; Silbert, 1971). Burrows & Muzzo defined first degree

373

malnutrition as weight between the 10th and 25th percentiles, second degree between 10th

374

and 5th percentiles, and third degree malnutrition if under the 5th percentile (Burrows &

375

Muzzo, 1981). Malnutrition was considered compensated if the weight for height was

376

above the 25th percentile and decompensated if the ratio was below the 25th percentile.

377

Other examples that illustrate the diversity of malnourishment or “low weight”

378

determination include the arbitrary use of Metropolitan Life Insurance Tables to define

379

“underweight”(Andronic & Di Mascio, 1971; Noble, 1969; Pawlowski, 1975; Silverstone

380

& Schuyler, 1975), the use of the Gomez calculation to determine severity of

381

malnutrition (Najib et al., 2014), defining low weight as more than 2 standard deviations

382

below the mean (Mahachoklertwattana et al., 2009), or as <50th% on Stuart

383

anthropometric charts (Kibel, 1969; Lavenstein et al., 1962). The variation in definition

384

of underweight or malnourishment affects how results can be compared and generalized.

385

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Unfortunately, despite the number of studies identified through this review, very few

387

included objective measures of appetite. As such, our analysis does not provide much

388

insight into the manner by which CY acts as a stimulant of appetite. Comer et al.’s (1997)

389

study provided interesting results that suggested that CY contributed to increased number

390

of eating occasions, suggesting that the mechanism of action may be linked more to

391

satiety/ hunger signaling as compared to food reward pathways. This has relevance given

392

the medications effect at 5-HT2 and H1 receptors.

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386

Despite the observed limitations in published studies, there is certainly enough data to

395

suggest that further controlled studies that involve patients with conditions where appetite

396

is poor are warranted.

397

Although there were no serious side effects noted in the studies reviewed in this paper, it

398

is important to note that there are cases reported in the literature of anticholinergic

399

toxicity in pediatric patients in the context of CY overdose (ie. Accidental over-ingestion)

400

(Blaustein, Gaeta, Balentine, & Gindi, 1995; McGovern, McNamee, Marcus, & Kashani,

401

2017; Richmond & Seger, 1985).

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5.0 Conclusion

404

Based on this literature review and studies completed to date, CY appears to be a safe,

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generally well-tolerated medication that has utility in helping facilitate weight gain in

406

patients drawn from a variety of underweight populations. Moving forward, further

407

studies that examine CY should incorporate specific measures of appetite stimulation in

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order to better decipher how appetite signaling, satiety, and food reward pathways

409

influence the medications effect on nutritional intake.

410

These studies should also serve to increase knowledge relating to medication indication

411

and tolerance, optimal dosing, and side effect potential, in varying populations. Future

412

randomized controlled studies with more homogeneous populations would also allow for

413

meta-analyses that can better inform evidence-based guidelines.

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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

418 419

Declarations of interest: none.

420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444

Acknowledgements: We thank Jenna Pepper, MA and Katie O'Hearn, Msc, (Children’s Hospital of Eastern Ontario Research Institute) for methodological assistance and Margaret Sampson, MLIS, PhD, AHIP (Children’s Hospital of Eastern Ontario) for developing the electronic search strategies. We would also like to acknowledge the assistance of Mrs. Patricia Graziano for her help in article retrieval and table editing.

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References

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Andronic, A., & Di Mascio, A. (1971). Appetite-stimulating and weight-gain properties of cyproheptadine (Periactin) in geriatric subjects. Current Therapeutic Research, 13(1), 40–41. Benady, D. (1970). Cyproheptadine Hydrochloride (Periactin) and Anorexia Nervosa: A Case Report. Brit. J. Psychiat., 117, 681–682. Bergen, S. S. (1964). Appetite Stimulating Properties of Cyproheptadine. American Journal of Diseases of Children, 108(3), 270–273. https://doi.org/10.1001/archpedi.1964.02090010272008 Blaustein, B., Gaeta, T., Balentine, J., & Gindi, M. (1995). Cyproheptadine-induced central anticholinergic syndrome in a child: a case report. Pediatric Emergency Care, 11(4), 235–237. Bramer, W. M., Giustini, D., & Kramer, B. M. R. (2016). Comparing the coverage, recall, and precision of searches for 120 systematic reviews in Embase, MEDLINE, and Google Scholar: A prospective study. Systematic Reviews, 5(1), 1–7. https://doi.org/10.1186/s13643-016-0215-7 Burrows, R., & Muzzo, S. (1981). Effect of appetite stimulation on the rate of weight

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recovery in children with protein-calorie malnutrition (Spanish). Rev Chil Pediatr, 52(3), 187–193. Comer, S., Haney, M., Fischman, M., & Foltin, R. (1997). Cyproheptadine produced Modest Increases in Total Caloric Intake by Humans. Physiology & Behavior, 62(4), 831–839. Couluris, M., Mayer, J. L. R., Freyer, D. R., Sandler, E., Xu, P., & Krischer, J. P. (2008). The effect of cyproheptadine hydrochloride (Periactin) and megestrol acetate (Megace) on weight in children with cancer/treatment-related cachexia. Journal of Pediatric Hematology/Oncology, 30(11), 791–797. https://doi.org/10.1097/MPH.0b013e3181864a5e Daviss, W. B., & Scott, J. (2004). A Chart Review of Cyproheptadine for StimulantInduced Weight Loss. Journal of Child and Adolescent Psychopharmacology, 14(1), 65–73. https://doi.org/10.1089/104454604773840508 Drash, A., Elliott, J., Langs, H., Lavenstein, A., & Cooke, R. (1966). The Effect of Cyproheptadine on Carbohydrate Metabolism. Clinical Pharmacology and Therapeutics, 7(3), 340–346. Epifanio, M., Marostica, P. C., Mattiello, R., Feix, L., Nejedlo, R., Fischer, G. B., & Stein, R. T. (2012). A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis. Jornal de Pediatria, 88(2), 155–160. https://doi.org/10.2223/JPED.2174 Erdem, A. Y., Emir, S., Demir, H. A., & Tunç, B. (2014). Use of Cyproheptadine as an Appetite Stimulant in Children with Cancer. Güncel Pediatri, 12(2), 63–66. https://doi.org/10.4274/jcp.18189 Fantino, M., Brondel, L., Swiergiel, A. H., & Lebec, O. (1990). Reduction of negative alliesthesia for sweet gustatory stimuli by cyproheptadine, a serotonin antagonist. Life Sciences, 46(19), 1381–1387. https://doi.org/10.1016/0024-3205(90)90338-R Francini, D., Santana, J., & Kitrosen, J. (1967). Ciproheptadina Droga Antihistaminica y Antiserotonimica con Accion Sobre el Peso Coroporal Communicacion Previa. La Prensa Medica Argentina, 54(18), 826–828. Genazzani, A. D., Strucchi, C., Malavasi, B., Tortolani, F., Vecchi, F., Luisi, S., & Petraglia, F. (2001). Effects of cyproheptadine clorhydrate, a serotonin receptor antagonist, on endocrine parameters in weight-loss related amenorrhea. Gynecological Endocrinology, 15(4), 279–285. https://doi.org/10.1080/gye.15.4.279.285 Goldberg, S., Halmi, K., Eckert, E., Casper, R., & Davis, J. (1979). Cyproheptadine in Anorexia Nervosa. The British Journal of Psychiatry, 134(1), 67–70. Halmi, K., Eckert, E., & Falk, J. (1982). Cyproheptadine for Anorexia Nervosa. The Lancet, (1279), 1976–1977. Halmi, K., Eckert, E., & Falk, J. (1983). Cyproheptadine, an antidepressant and weightinducing drug for anorexia nervosa. Psychopharmacology Bulletin, 19(1), 103–105. Halmi, K., Eckert, E., LaDu, T., & Cohen, J. (1986). Anorexia Nervosa. Arch Gen Psychiatry, 43(4), 177–181. https://doi.org/10.1097/00006842-199907000-00019 Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2010). Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Information, 42(2), 377–381.

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https://doi.org/10.1016/j.jbi.2008.08.010.Research Homnick, D. N., Homnick, B. D., Reeves, A. J., Marks, J. H., Pimentel, R. S., & Bonnema, S. K. (2004). Cyproheptadine is an effective appetite stimulant in cystic fibrosis. Pediatric Pulmonology, 38(2), 129–134. https://doi.org/10.1002/ppul.20043 Homnick, D. N., Marks, J. H., Hare, K. L., & Bonnema, S. K. (2005). Long-term trial of cyproheptadine as an appetite stimulant in cystic fibrosis. Pediatric Pulmonology, 40(3), 251–256. https://doi.org/10.1002/ppul.20265 Irsy, G., & Szatloczky, E. (1977). Effect of Peritol in Stimulating Appetitie and Promoting Weight Gain. Ther. Hung., 25(3), 115–121. Kaplowitz, P. B., & Jennings, S. (1987). Enhancement of linear growth and weight gain by cyproheptadine in children with hypopituitarism receiving growth hormone therapy. The Journal of Pediatrics, 110(1), 140–143. https://doi.org/10.1016/S00223476(87)80310-4 Kardinal, C. G., Loprinizi, C. L., Schaid, D. J., Hass, A. C., Dose, A. M., Athmann, L. M., … Schray, M. F. (1990). A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. A Mayo Clinic/North Central Cancer Treatment Group trial [abstract]. Proceedings of the American Society of Clinical Oncology, 9, 325, Abstract 1258. Retrieved from http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/945/CN00715945/frame.html Kibel, M. (1969). Appetite and Weight Gain in Children: A Double-Blind Trial Using Cyproheptadine and Methandrostenolone. The Central Americn Journal of Medicine, 15(10), 229–232. Lavenstein, A. F., Dacaney, E. P., & Metre, T. E. Van. (1962). Effect of Cyproheptadine. JAMA, 180(11), 90–94. Lemoine, A., Harbison, M. D., Salem, J., Tounian, P., Netchine, I., & Dubern, B. (2018). Effect of Cyproheptadine on Weight and Growth Velocity in Children With SilverRussell Syndrome. Journal of Pediatric Gastroenterology and Nutrition, 66(2), 306–311. https://doi.org/10.1097/MPG.0000000000001708 Lerman-Sagie, T., & Mimouni, M. (1995). Reversal of anorexia in a child with partial ornithine transcarbamylase deficiency by cyproheptadine therapy. Clinical Pediatrics, 34(3), 163–165. https://doi.org/10.1177/000992289503400310 Mahachoklertwattana, P., Wanasuwankul, S., Poomthavorn, P., Choubtum, L., & Sriphrapradang, A. (2009). Short-term cyproheptadine therapy in underweight children: Effects on growth and serum insulin-like growth factor-I. Journal of Pediatric Endocrinology and Metabolism, 22(5), 425–432. https://doi.org/10.1515/JPEM.2009.22.5.425 Mainguet, P. (1972). Effect of Cyproheptadine on Anorexia and Loss of Weight in Adults. The Practitioner, 208(248), 797–800. McGovern, T., McNamee, J., Marcus, S., & Kashani, J. (2017). When Too Much Is Enough: Pediatric Cyproheptadine Overdose with Confirmatory Level. Clinical Practice and Cases in Emergency Medicine, 1(3), 205–207. https://doi.org/10.5811/cpcem.2017.2.33313 Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Annals of Internal Medicine, 151(4), 264–269.

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Muranjan, M. N., Mordekar, S. R., Bava, H. S., Alavi, S., Kher, A. S., Nadkarni, U. B., & Kamat, J. R. (1994). Cyproheptadine in severe anorexia. Indian Pediatr, 31, 1429– 1430. Najib, K., Moghtaderi, M., Karamizadeh, Z., Fallahzadehm, E., & Najib, K.; Moghtaderi, M.; Karamizadeh, Z.; Fallahzadehm, E. (2014). Beneficial Effect of Cyproheptadine on Body Mass Index in Undernourished Children: A Randomized Controlled Trial. Iran J Pediatr, 24(6), 753–758. Najjar, S., & Khachadurian, A. (1969). The Effect of Cyproheptadine on Body Weight Plasma Glucose and Insulin. Leb. Med. J., 22, 1–9. Nama, N., Iliriani, K., Xia, M. Y., Chen, B. P., Zhou, L. L., Kappel, C., McNally, J. (2017). A pilot validation study of crowdsourcing systematic reviews : update of a searchable database of pediatric clinical trials of high- dose vitamin D. Translational Pediatrics, 6(1), 18–26. https://doi.org/10.21037/tp.2016.12.01 Noble, R. (1969). Cyproheptadine on Appetite and Weight Gain Effect of in Adults. J Amer Med Assoc, 209(13), 1–2. Pawlowski, G. (1975). Cyproheptadine: Weight-Gain and Appetitie Stimulation in Essential Anorexic Adults. Current Therapeutic Research, 18(5), 673–678. Penfold, J. (1971). Effect of Cyproheptadine and a Multivitamin Preparation on Appetite Stimulation, Weight Gain, and Linear Growth. The Medical Journal of Australia, 307–310. Rahman, K. (1975). Appetite Stimulation and Weight Gain with Cyproheptadine (Periactin) in Tuberculosis Patients (Double-Blind Clinical Study). Med J Malaysia, 29(4), 270–274. Richmond, M., & Seger, D. (1985). Central anticholinergic syndrome in a child: A case report. The Journal of Emergency Medicine, 3(6), 453–456. https://doi.org/https://doi.org/10.1016/0736-4679(85)90004-6 Sanzgiri, R., Mohamad, H., & Raja, Z. (1969). Appetite Stimulation and Weight Gain with Cyproheptadine. Journal of Postgraduate Medicine, 16(1), 12–15. Sardesai, H., Sardesai, H., Melinkeri, R., Diwate, A., Karandikar, R., & Joshi, P. (1970). Weight gain with cyproheptadine hydrochloride ('Periactin’). A double blind trial in underweight medical students. Indian Journal of Medical Sciences, 24(11), 716– 721. Silbert, M. (1971). The Weight Gain Effect of periactin in anorexic Patients. S. A. Medical Journal, 374–377. Silverstone, T., & Schuyler, D. (1975). The Effect of Cyproheptadine on Hunger, Calorie Intake, and Body Weight in Man. Psychopharmacologia, 40, 335–340. Stiel, J. N., Liddle, G. W., & Lacy, W. W. (1970). Studies of mechanism of cyproheptadine induced weight gain in human subjects. Metabolism, 19(3), 192-. Retrieved from isi:A1970F660200002 Summerbell, C., Youle, M., McDonald, V., Catalan, J., & Gazzard, B. (1992). Megestrol acetate vs cyproheptadine in the treatment of weight loss associated with HIV infection. Int J STD AIDS, 3(4), 278–280. Tiszai, A., & Szasz, K. (1972). Peritol (cyproheptadine) in clinical practice. Therapia Hungarica, 20(1), 18–23. Vigersky, R., & Loriaux, D. (1977). The Effect of Cyproheptadine in Anorexia Nervosa: A Double-Blind Trial. Anorexia Nervosa, 349–356.

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Appendix 1 – Electronic search strategies

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Note: Searches were conducted as an Ovid multi-database search. Line 1 is optimized for MEDLINE. Lines 2-5 are optimized for Embase. Line 6 is optimized for CENTRAL. The next lines isolate the records to the database the search was designed for, combine those sets and then remove duplicate records and final isolate the records from each database again so each can be downloaded and imported into the citation manager using a database-specific import filter.

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1. ((Cyproheptadine/ or (adekin or Antergan or antisemin or Apeplus or apeton 4 or Apitup or Axoprol or Biohept or CHEMBL516 or Ciplactin or Cipractine or ciproeptadine or Ciproheptadina or ciproral or ciprotol or Ciprovit or ciprovit or Ciptadine or cryoheptidine or crypoheptadine or cycloheptadine or cyheptine or cylat or Cyllermin or cypraheptidine or cypro h or cyproatin or cyprogin or cyprohaptadine or cyproheptadiene or cyproheptadin or Cyproheptadine or Cyproheptadinum or cyproheptidine or Dihexazin or Dronactin or Eiproheptadine or Glutodina or Periactin or Periactine or Periactinol or Periactinreg or Periatin or Peritol or Peritolreg or Piperidine or Reactin or Viternum).ti,ab,kf.) and (exp Hunger/ or Appetite Stimulants/ or Appetite/ or (appetite or hunger or hungry or satiat* or feeding or body weight or weight gain or intake or calorie* or anorex* or dysorex*).ti,ab,kf. or (weight adj3 (body or increase* or gain* or loss)).ti,ab,kf.)) not (Animal/ not Human/) 2. (Cyproheptadine/ or (adekin or Antergan or antisemin or Apeplus or apeton 4 or Apitup or Axoprol or Biohept or CHEMBL516 or Ciplactin or Cipractine or ciproeptadine or Ciproheptadina or ciproral or ciprotol or Ciprovit or ciprovit or Ciptadine or cryoheptidine or crypoheptadine or cycloheptadine or cyheptine or cylat or Cyllermin or cypraheptidine or cypro h or cyproatin or cyprogin or cyprohaptadine or cyproheptadiene or cyproheptadin or Cyproheptadine or Cyproheptadinum or cyproheptidine or Dihexazin or Dronactin or Eiproheptadine or Glutodina or Periactin or Periactine or Periactinol or Periactinreg or Periatin or Peritol or Peritolreg or Piperidine or Reactin or Viternum).ti,ab,kw.) and (exp Appetite/ or exp Appetite Disorder/ or exp Appetite Stimulant/ or (appetite or hunger or hungry or satiat* or feeding or body weight or weight gain or intake or calorie* or anorex* or dysorex*).ti,ab,kw. or (weight adj3 (body or increase* or gain* or loss)).ti,ab,kw.) 3. limit 2 to animals 4. 2 not 3 5. limit 4 to embase 6. ((Cyproheptadine or adekin or Antergan or antisemin or Apeplus or apeton 4 or Apitup or Axoprol or Biohept or CHEMBL516 or Ciplactin or Cipractine or ciproeptadine or Ciproheptadina or ciproral or ciprotol or Ciprovit or ciprovit or Ciptadine or cryoheptidine or crypoheptadine or cycloheptadine or cyheptine or cylat or Cyllermin or cypraheptidine or cypro h or cyproatin or cyprogin or cyprohaptadine or cyproheptadiene or cyproheptadin or Cyproheptadine or Cyproheptadinum or cyproheptidine or Dihexazin or Dronactin or Eiproheptadine or Glutodina or Periactin or Periactine or Periactinol or Periactinreg or Periatin or Peritol or Peritolreg or Piperidine or Reactin or Viternum) and (appetite or hunger or hungry or satiat* or feeding or boy weight or weight gain or intake or calorie* or anorex* or dysorex* or (weight adj3 (body or increase* or gain* or loss)))).ti,ab,kf. 7. 1 use ppez 8. 5 use emez 9. 6 use cctr 10. or/7-9 11. remove duplicates from 10 12. 11 use ppez 13. 11 use emez 14. 11 use cctr

ACCEPTED MANUSCRIPT

Sex

Sample size

Setting+

Medication dose

17 M 4F

20 healthy adults, one adolescent

ND

CY 4 mg tid

Study duration 1-4 wks

RCT in study A; single blind in study B; case studies in study C

30.6 (22 – 48)

7F 5M

12 healthy adults

O

CY 4 mg tid

6 wks

Prospective case series

28 (25 – 31)

2M

2 healthy adults, one underweight

Prospective cohort

Stiel (1970)

Saleh (1979)

SC

Najjar (1969)

M AN U

Study design

RI PT

Age (mean yrs,range) 23.7 (13 – 39)

Author(s)

RCT 30.1 8M 14 healthy adults -cross-over study (19 - 48) 6F (mean BMI 22.26) -placebo vs CY -patients were own controls Comer RCT 26.3 4M 7 healthy adults (1997) -cross-over study (21 – 33) 3F (mean BMI 24.4 -placebo vs CY +/-2.7 kg/m2) -patients were own controls Table 1. Cyproheptadine use in Healthy “Normal Weight” Adults

AC C

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Fantino (1990)

HO

CY 4 mg tid

33 & 35 days

HL

CY 4 x 4 mg doses in prior 21 hours

24 hrs

CL

CY 4 mg tid daily; Regular, low- or high-carbohydrate diets

18 days

+ND=not documented;O=outpatient;HO=hospital outpatient;HL=hospital laboratory;CL=community laboratory *appetite measured via self-report

Outcomes Appetite stimulation in 17/20*; mean weight gain 1.2kg in 1 wk (n=20), 2.4kg in 4 wks (n=9) Higher mean weight gain on CY (mean 2.2kg in 2 wks) (P<0.001)and increased reported appetite* Increased weight gain with CY versus placebo (p<0.01), more apparent in underweight subject No effect on hunger/appetite sensation*

Total caloric intake increased by 500 kcal/d when taking CYP as compared to placebo (p<0.007)

ACCEPTED MANUSCRIPT

Samp le size

Setting^

Medication dose

Study duration

F& M+

20

O

CY 4 mg tid

56 d

16 – 23

27 M 13 F

40

O

CY 4 mg tid

RCT

16, 3-43

F& M+

65

HO

CY 2-8 mg/d

Andronic (1971)

RCT

63 –86

F&M+

30

HI

Pawlowski (1975)

RCT

32, 15-58

F&M+

26

HO

Silverstone (1975)

RCT crossover

21.6, 19-24

13 M 3F

16

Genazzani (2001)

Case Series

Not documente d

F

Silbert (1971)

O

8

CO

SC

RCT

Outcomes

Greater mean percentage weight-gain (CY 3.8 vs Control 1.3 kg) (p<0.05) and mean appetite increase* (p<0.01)

12 wks

Increased weight gain with CY (2.1 kg) versus placebo (0.4 kg) (p<0.05)

3 mos

Significantly greater appetite* and weight gain in CY groups, mean range 1.5 kg (CY 2mg) to 4.3 kg (CY 8 mg) vs placebo (0.2 kg)

CY 4 mg tid

56 d

No statistically significant increase in body weight or appetite ratings**

CY 12 mg/d

3 mos

Weight increase higher in CY group (3 kg) vs placebo (1.3 kg) Increase in appetite higher in CYP group*

CY 4 mg tid

8 wks

CY 4mg/d

120 d

Weight increase higher in CY group (2 kg) vs placebo (0.2 kg) (p<0.001) Increase in appetite higher in CYP group* Higher daily caloric increase in CY group (2905 kcal) vs placebo (2633 kcal) None of the patients resumed menstruation Non-significant increase in BMI was observed No significant changes in the quality of quantity of the food consumed

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Sardesai (1970)

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RCT

EP

Noble (1969)

Age (Mean, Range in yrs) 28; 18 - 48

AC C

Study design

RI PT

Sex

Author(s)

Table 2. Cyproheptadine use in underweight adults

*Appetite measured via self-report **nurses’ ratings of appetite +details not provided ^O=outpatient;HO=hospital outpatient;HI=hospital inpatient;CO=community outpatient

ACCEPTED MANUSCRIPT

Sex

Sampl e size

Settin g

Medication dose

Study duration

Benady (1970) Vigersky (1977) Goldberg (1979)

Case report RCT

F

1

CY 4 mg tid

6 months

F& M F

13

HI& HO* HO

8 weeks

41

HI

21, 1336

F

13

HI

CY 12 mg/day CY 12mg/day to 32mg/day CY 32 mg/day

RCT

Not reported

Halmi (1982)

RCT

Halmi (1983)

RCT

21, 1336

F

19

HI

CY 32 mg/day

3 weeks

Halmi (1986)

RCT

20.5, 1336

F

23

HI

CY 32 mg/day

3 months

Unclear

3 weeks

TE D

28.9

Outcomes

RI PT

Age in Years (Mean, Range) 12

Weight gain of 0.68kg/wk for 6 mos after starting treatment with CY. Patient achieved menarche. No difference in weight gain between CY and control groups. Non-significant weight gain in CY group (5.1kg) va placebo (4.3kg). Greatest benefit seen in patients with largest % weight loss at initiation of the study. Significant CY effect on HAM-D^ and on weight gain (increase from 75% of “normal” weight to 98% in CY group). Significant CY effect on weight gain (increase from 76.8% of “normal” weight to 98.8% in CY group) and HAM-D scores, no effect on BDI# scores. CY significantly increased treatment efficiency for restricting subtype patients and significantly impaired treatment efficiency for the binge-purge subtype patients when compared with the amitriptyline- and placebo-treated groups. CY group experienced a significant decrease in the HAM-D ratings.

SC

Study design

M AN U

Author(s)

EP

Table 3. Cyproheptadine use in Adults with Anorexia Nervosa

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*HI=hospital inpatient;HO=hospital outpatient ^= Hamilton Rating Scale

#

=Beck Depression Index

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Study design RCT

Age (mean yrs,range) 43, 15-79

Sex

Tiszai (1972)

Prospective Cohort study

55.2 (16 – 78)

Rahman (1975)

RCT

Irsy (1977)

RCT -cross-over study

Setting

Targeted disease

O*

Irritable colon syndrome

26 F 10 M

36

O

30.5 (16 – 50)

15 M 8F

23

I*

43.3

Group I: 16 F 9M

25

Group II: 3F 7M

10

Group III: 1F 4M 164 M

5

48 F 49 M

Medication dose CY 12 mg/day

Study duration 12 wks

Group A (n=16): mixed diseases++ Group B (n=13): mixed diseases+++ & DM
Group C (n=7): mixed diseases+++ and T2DM
Chronic pulmonary tuberculosis

CY 5 x 4 mg daily

14 days

CY 4 mg TID

12 -16 wks

Group I: mixed chronic diseases**; Group II: neoplastic diseases*** Group III: controls

CY 4 mg TID - QID

3 – 10 wks

Advanced malignant

CY 8 mg

Variable,

TE D

M AN U

SC

Mainguet (1972)

Sample size 97

RI PT

Author(s)

AC C

EP

I&O

Kardinal

RCT

65

293

O

Outcomes Weight gain significantly higher in CY group at each 4 week interval (p<0.001); at 12 weeks, CY group gained 5.5 kg vs 1.1 kg in placebo. Only patients consuming <1800 cal/d experienced a significant improvement in appetite throughout study.~ Increased average weight gain (2.5 kg) in patient group with mixed diseases+++ (p < 0.01); no effect on average body weight of DM or T2DM patients Increase in mean weight gain versus placebo (4.8 kg vs 1.9 kg) Significant weight gain in CY weeks in placebo-controlled patients (0.7 kg vs 0.2 kg; p values <0.05 to <0.001)+ ^; CY more effective than placebo in 70% of cases. No effect on weight of patients suffering from malignant disease. ^

Mildly enhanced appetites (p =

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RCT

129 F

Not specified

Not specified

cancer++

14

O

HIV

TID

M AN U

SC

Summerbell (1992)

(19 – 86)

RI PT

(1990)

CY 12 mg daily (vs up to 160 mg daily megestrol acetate)

median 36 daysdays 2 mos

0.01)$, but no halt in progressive weight loss (p = 0.78) Increase in mean daily energy intake in both groups compared to pretreatment assessment (increase of 500 kcal/day; p < 0.05); variable effect on weight gain, no difference between CY or megestrol acetate

Table 4. Cyproheptadine use in Adults with mixed disease states

AC C

EP

TE D

*O=outpatients;I=inpatients **examples include psychiatric leanness, dystonia, neurasthenia, duodenal ulcers, gastritis, hepatitis ***examples include Hodgkin Lymphoma, breast cancer, multiple myeloma, colon cancer
DM=subclinical diabetes mellitus; T2DM=type2 diabetes mellitus +stats analyzed per week of treatment for 21 (13 in treatment group, 8 in control group) patients of total sample of 40 ++primary tumor sites included were lung, GI, other +++ examples include chronic uticaria, neurasthenia, gastritis, bronchial asthma, depressive neurosis, angina pectoris, chronic enteritis, bronchopneumonia, cardiac insufficiency #dropped to 55 patients by week 16 of the trial ~appetite increase measured via increase in caloric intake ^no data provided on how increase in appetite was measured $appetite increase measured via self-report

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Sample size

Setting+

Medication dose

Study duration

Outcomes

26 F 14 M 49 F 49 M 62 F 67 M

40

CO

CY 2 mg tid

3 mos

96

HO

CY 4 mg bid

12 wks

129

HO

CY 8 mg daily

8 yrs

Not provided

36

HO

3 mos

RCT

1-4 yrs

Not provided

70

HO

Canani (1988)

RCT

2-11 yrs

20 F 20 M

40

HO

Mahachoklertwattana (2009) Benjasuwantep (2009)

RCT

2-10 yrs

11 F 10 M

21

HO

CY 2mg tid titrated to 4 mg tid > 2years: CY 10 mL bid; < 2 years: CY 5 mL bid CY 0.4 mg/kg/day divided tid before meals CY 0.1 mg/kg/day hs

Superior weight gain in CY group vs placebo (2.3 kg vs 0.3 kg) Superior weight gain and appetite improvement* in CY treated sample vs placebo group Greater weight gain in CY group vs placebo (5.9% increase vs 3.4% increase, p<0.01); increase in appetite in CY group at week 2 and 4* Greater weight gain in CY group vs vit B treated group (2.1 kg vs 1 kg)

Case Report

3 yrs

1M

1

8 wks

Najib (2014)

RCT

2-5 yrs

25 F 52 M

77

CY 0.25mg/kg/day divided tid CY 0.25 mg/kg/day divided bid 0.25 mg/kg/day divided BID

RCT

3-16 yrs

Penfold (1971)

RCT

Burrows (1981)

HO

HO

Sant’Anna Retrospec 34 +/70 M 127 HO et al. tive 4.8 57 F (2014) Cohort months Table 5. Cyproheptadine use in underweight and/or malnourished children +

CO=community outpatients;HO=hospital outpatients *appetite increase/improvement measured via self-report **measured by weight for age Z-scores

6 wks

SC

1-13 yrs

M AN U

RCT

TE D

RCT

EP

Sanzgiri (1969) Kibel (1969) Juillard (1971)

Age (mean, range) 4-8 yrs

AC C

Study design

RI PT

Sex

Author(s)

8 wks

Greater weight gain in CY group (293% increase in weight vs 155% increase in weight, p<0.0025)

4 wks

Improvement in weight in both groups (absolute change higher in the supplement + CY group); growth higher in the supplement + CY group

4 mos

Greater weight gain (0.7 kg/2mos vs 0.1 kg/2mos), growth (1.7 cm/2 mos vs 0.8 cm/2 mos), appetite* and IGF-1 scores in CY group vs placebo Weight gain (1 kg) noted by 4 weeks

1 mos

6 mos

Higher weight in CY group vs placebo at 1 month (0.6 kg vs 0.1 kg); no difference in weight or height at 2 months Improvement in weight**, mealtime and feeding behaviors; CY well tolerated overall

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Study design RCT

Age(mean Sex yr,range) 1-11 23 M 5F

Sample size 28

Diagnoses

Setting+

CYP dose

Asthma

HO

CY 4 mg qid

Bergen (1964)

RCT

6-13

16

Asthma

HI

CY 4 mg qid Vs placebo

15 wks

Kaplowitz (1986)

RCT cross over study

2–11

6

GH deficiency

Unclear

CY 0.25-0.4 mg/kg/d


16 wks

Muranjan (1994)

Case report

4

F

1

HI&HO

CY starting at 0.5 mg/kg/day

unclear

LermanSagie (1995) Daviss (2004) Homnick (2004) Homnick (2005)

Case report

11

F

1

HI

CY 0.2 mg/kg/day

7 wks

Retrospectiv e cohort RCT

8

21

PO

16

4-8 mg CY nightly 104.7 (mean dose 4.9) ** days CY 4 mg qid 12 wks

Open label, prospective cohort Prospective cohort study

15

18 M 3F 6M 10 F 8 Fe 4M

TB meningitis Anorexia Undernutrition Partial OTC deficiency ADHD and comorbidities^ CF

12

CF

HO

As above

9 mos

40 M 30 F

70

Various forms of Cancer

HI

CY 0.25 mg/kg/day div bid If no response by 4 weeks, changed to megestrol acetate for remaining 4 wks

8 wks

RCT

5-18

HI

CY 4 mg tid

12 wks

Retrospectiv e cohort

4.5 (2-16)

unclear

8 wks

Epifanio (2012) Erdem (2014)

12

9M 5F

25

CF

14

Various forms of Cancer

Study duration 20-28 wks

RI PT

SC

M AN U HO

TE D

Couluris (2008)

17

9M 7F

EP

Lavenstein (1962)

AC C

Author(s)

Outcomes (mean weight gain, appetite) Weight gain: 254% of normal/expected weight gain in CY group vs 120% in chlorpheniramine grp(4mg qid) Appetite increase in CY group* Weight gain: CY group had a 16.4% increase in weight as compared to 4.6% in the placebo control group Appetite* and food intake increase: Moderate to marked increase in CY gr. Weight gain: weight velocity increased from 1.3+/-1.3 to 7.8+/-3.6 kg/y Appetite increase noted in 5/6 patients* Weight gain: 4.4 kg over 12 weeks; 6 kg over 6 months Appetite increase noted* Weight gain: 3.5 kg in 7 weeks Appetite increase noted* Weight gain: 2.2 kg ;mean weight velocity 32.3 g/day Weight gain: 3.45 kg CY vs 1.1 kg Weight gain: Placebo patients gained weight (3.8 kg) in 3-6 months when switched to CY Weight gain: 50 patients (76%) responded to CY, weight gain 2.6 kg (95% CI: 64-85%) Hematologic CA had higher response (21/23 patients) vs nonhematologic CA (29/43) (p=0.04) Weight gain: 0.7 kg vs 1.6 kg BMI: Increased 0.02 kg/m2 vs 0.5 Weight gain: 11 patients (78.5%) had increased weights (1.4 kg) Appetite increase noted in 71% (10 patients)*

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Retrospectiv e cohort

2

23

Silver- Russell syndrome

Table 6. Cyproheptadine use in underweight children with mixed disease states +

CY 0.25 mg/kg/day div bid (max dose 0.4 mg/kg/day)

12 mos

RI PT

Lemoine (2018)

91% of patients responded to treatment with a gain of at least 0.5 SDS of weight during 1 year. Weight gain þ 0.1 SDS/mos of treatment and length/height gain þ 0.05 SDS/mos of treatment

HO=hospital outpatient;HI=hospital inpatient;PO=psychiatry outpatient ADHD=attention deficit hyperactivity disorder (n=21);ODD=oppositional defiant disorder (n=14);CD=conduct disorder (n=2);GAD=generalized anxiety disorder (n=1); PDD=pervasive developmental disorder (n=2); SU=substance use (n=1) *appetite increase measured via self-report or parent report  Leukemia (19);Sarcoma (15);Brain tumour (13);Lymphoma (6);Other (16)
All patients also taking GH 0.08 U/kg 3 times/wk ** All patients also on stimulant medication -11 on Adderall, 5 on Concerta, 2 on Adderall XR, 2 on dextroamphetamine tablets, 1 on methylphenidate  Neuroblastoma (4);Lymphoma (2);Germinoma (3);Other (5)

AC C

EP

TE D

M AN U

SC

^

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PRISMA 2009 Flow Diagram

RI PT

Records identified through database searching (n = 591)

Additional records identified through other sources (n = 8)

SC

Identification

Study: The use of cyproheptadine as an appetite stimulant: a systematic review

TE D

Records screened (n = 538)

AC C

Included

Records excluded (n = 359)

Full-text articles assessed for eligibility (n = 179)

EP

Eligibility

Screening

M AN U

Records after duplicates removed (n = 538)

Full-text articles excluded, with reasons (n = 133) • • • •

Study Design (n=51) Intervention/Exposure (n=26) No mention of primary outcome (n=10) Other (n=46)

Studies included in qualitative synthesis (n = 46)

Note: “Conference Abstract”, “Narrative Review”, “Systematic Review”, “Case Report/Case Series”, “Not an RCT”, “Ineligible study design” were grouped under “Study Design”. “Ineligible population age” and “Ineligible population setting” were grouped under “Population”. “Other” includes “cannot be translated”, “cannot be obtained”, “insufficient reporting of methods and/or results”