INFLUENCE OF ANTIDEPRESSANT THERAPIES ON WEIGHT AND APPETITE IN THE ELDERLY

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1 INFLUENCE OF ANTIDEPRESSANT THERAPIES ON WEIGHT AND APPETITE IN THE ELDERLY P. THOMAS*, C. HAZIF-THOMAS*, J.-P. CLEMENT** * Hôpital de Jour Gériatrique Louis Pasteur, Poitiers, France. ** Service Hospitalo-Universitaire de Psychiatrie, Centre Hospitalier Esquirol, Limoges, France. Correspondence: Dr Ph Thomas, Hôpital de Jour Gériatrique Louis Pasteur, Poitiers, France, tel : (0) ; fax (0) : ; p.thomas@chu-poitiers.fr Abstract: OBJECTIVE: Determine the nutritional impact of antidepressant drugs in elderly. METHODS: The study included 139 independently mobile out-patients managed by the Poitiers geriatric day hospital for problems of loss of home support, rehabilitation and medical or psychological care, with a stable treatment for 3 months at the time of inclusion and over the 3 months of the study. The study addressed the time course of nutritional parameters from baseline to 3 months post-inclusion. The physical examination included monthly weighing of the patients, 3-monthly evaluation of nutritional status using the Mini Nutritional Assessment (MNA) instrument and serum albumin. RESULTS: 52 men (76.3 ± 6.7 years [62-87]) and 87 women (81.0 ± 7.2 years [65-100]) were included. Seventy-nine patients presented with dementia. Seventy-four patients were receiving an antidepressant, of which 54 serotonin reuptake inhibitors. The patients free from dementia and not receiving antidepressants had nutritional indices that did not vary over the study period. The dementia-free patients receiving antidepressants gained weight (1.44 kg) kg on serotonin reuptake inhibitors - showed an improvement in MNA of 0.76/30 and showed a significant improvement in serum albumin of 1.78 g/l. The demented patients not receiving antidepressants lost weight (-1.01 kg), MNA score fell and serum albumin significantly decreased. On antidepressants, the demented patients significantly gained weight (0.73 kg) while no deterioration in the other parameters reflecting undernutrition was observed. Conclusions. In the middle term, in elderly subjects, antidepressants do not induce undernutrition or weight loss. Irrespective of antidepressant type, those agents seem to prevent weight loss in elderly subjects presenting with dementia. Key words: Undernutrition, depression, elderly, dementia, aging, nutrition, antidepressants, serotonin reuptake inhibitor antidepressants. Introduction Undernutrition is frequent in settings of dementia and its causes are complex (1). Undernutrition is pejorative to life expectancy and generates an additional work load for caregivers (2). Apathy and depression are frequent, often concomitant and difficult to diagnose in demented subjects (3). While the nutritional consequences of apathy are not known, depression has a marked impact on nutritional status in the elderly (4). Currently a consensus is emerging for the promotion of treatment, by general practitioners, of late-onset depressions that are readily masked and thus go undiagnosed. Among the reasons for the physicians' reluctance to initiate treatment, the adverse effects of serotonin reuptake inhibitors are paramount. One of those adverse effects is weight loss and the undernutrition that may result. The aim of the study was to determine the impact of antidepressant treatment on undernutrition in an elderly population after 3 months of stable treatment. Methods The study included independently mobile out-patients managed in the Poitiers geriatric day hospital for problems of loss of home support, rehabilitation, and medical or psychological care, who agreed to take part in the study. For the demented patients, the immediate families' written agreement was also requested. The vast majority of the patients attended the day hospital once a week, more rarely twice per week. All the patients lived at home and had conserved physical mobility. 168 patients intended the day care hospital during this period. The following were excluded from the study: 22 patients presenting with a progressive inflammatory or cancer or diabetes mellitus; 7 patients without a stable treatment. During the study period, no patient was lost to follow-up. The study was implemented from March 1999 to March patients intending regularly the day care hospital and whose treatment remained stable for 6 months were included. From 3 months to the inclusion date, which in the majority of cases was the date of the start of hospital management, were assessed by a psychiatrist and a geriatrician. Survey was performed over the 3-month study following inclusion, constituting the nutritional follow-up period. The study was designed to monitor nutritional parameters from baseline to 3 months post-inclusion. Various physical, psychometric and nutritional investigations included in the systematic assessment of incoming patients, and used for regular monitoring, were conducted. The clinical assessment consisted in monthly weighing of the patients and quarterly assessment of nutritional 166

2 status using the Mini Nutritional Assessment (MNA) instrument (5). The MNA generates a score out of 30 and the undernutrition cutoff is 24. The severe undernutrition cutoff is 17. The MNA includes biometric, psychological, therapeutic and nutritional items. Appetite was scored: 2 = good, 1 = weak, 0 = anorexia. Assay of serum albumin, another marker of undernutrition in the elderly, was conducted at baseline and 3 months. The baseline psychometric assessment consisted in cognitive assessment using the Mini Mental State (MMS) instrument (6) and evaluation of depression using Cornell's scale (7). The statistical analysis was conducted using the Systat9 software package. Student's paired t-test was used to determine the statistical significance of nutritional changes over the 3 months of the study and Student's t-test or ANOVA to compare the quantitative results for the different populations. The Chi2 test was used to compare the sub-populations. For anorexia, Wilcoxon test was used to compare variations during the period of the study, and the Mann Whitney test to compare subpopulations. Results One hundred and thirty-nine patients were recruited during the study. None of the day hospital patients or patients' families refused consent to participate. The population consisted in 52 men (76.3 ± 6.7 years [62-87]) and 87 women (81.0 ± 7.2 years [65-100]). The female population was significantly older (t = 3.85, p < 0.001). Table 1 shows no difference in gender or age between the groups. Seventy-nine patients presented with dementia, 62 of the Alzheimer type, 17 of another type. Forty-nine of the patients presenting with Alzheimer's disease were taking an cholinesterase inhibitor. Three non-demented patients were receiving a low dose antipsychotic versus 21 of the demented patients. Seventy-four patients were receiving an antidepressant: 34 non-demented and 40 demented patients. Fifty-four patients were taking a serotonin reuptake inhibitor antidepressant: 23 non-demented and 31 demented patients. Fifteen patients were on paroxetine, 15 on fluoxetine, 17 on citalopram and 7 on sertraline. Twenty patients were taking another antidepressant: 14 mianserin and 6 venlafaxine. Table 2 shows the characteristics of the scores for the patient categories on different scales used at inclusion in the study. For the non-demented patients, there was a significant difference in Cornell scale score between the groups taking and not taking antidepressants (p < 0.05). The scores were higher for patients receiving antidepressants. The latter patients had lower weights than the previous patients, although the difference was nonsignificant, and a lower MNA ( p = 0.001). There was no difference between the other parameters or sex ratio. For the demented patient categories, pairwise comparisons show no significant differences between the non-demented patients receiving and the non-demented patients not receiving antidepressant treatment. The non-demented and demented patient scores were obviously significantly different for the MMS instrument and Cornell scale, but not for age or sex ratio. Table 1 Presentation of the population Non-demented Demented Statistics (n = 60) (n = 79) Age 79.2 ± ± 7.2 t = 0.09, ns Gender (M/F) 21/39 31/48 Chi2 test, ns Antidepressant 26/34 39/40 Chi2 test, ns (N/Y)* ns = non significant Table 3 shows the time course of the nutritional parameters over the 3 months of follow-up in a given sub-population. Irrespective of the sub-population compared, demented versus non-demented, Student's t-test showed a significant difference (p < 0.01) for patient body weight, which was in all cases markedly lower in the demented population. Evaluated by the Mann Whitney test, appetite was weaker at baseline for the patient with antidepressant, non demented (z = ; p=0.03) or demented (z = ; p=0.002). At 3 months, patients with antidepressant have a best appetite than non treated patients (z = ; p = 0.02). Pairwise comparisons show no significant differences for the other parameters. The non-demented patients not receiving antidepressants had nutritional indices that did not vary over the study period. Non-demented patients receiving antidepressants gained weight (1.44 kg), improved their MNA by 0.76/30 and their appetite. They showed a significant improvement in serum albumin of 1.78 g/l. In the 23 non-demented patients receiving a serotonin reuptake inhibitor, the change in body weight and MNA remained significant. The demented patients not receiving antidepressant treatment lost weight (-1.01 kg), their appetite and MNA scores declined (-0.70), while a significant reduction in serum albumin was also observed. When the demented patients were receiving antidepressants, they showed a significant increase in body weight (0.73 kg) while the other parameters improved, but not always significantly. The change in body weight on serotonin reuptake inhibitor treatment was not significant. Cornell scale scores at D90 for the non demented population was for the subpopulation without antidepressant (n=26), for the subpopulation treated with antidepressant (n=34). Results for demented subpopulation was respectively (n=39) and Subpopulations under antidepressant treatment significantly (p<0.05) improved the Cornell scores. 167

3 ANTIDEPRESSANT DRUGS AND NUTRITION IN ELDERLY Table 2 Subulations characteristics Non demented Demented (n=60) (n=79) Patients without Patients with Statistics Demented patients Demented patients antidepressants antidepressants without antidepressants with antidepressants (n = 26) (n = 34) (n = 39) (n = 40) M/F 10/16 11/23 Chi2 test, ns 19/30 12/28 Age 80.8 ± ± 7.2 ns 79.0 ± ± 7.1 Cornell* 4.9 ± ± 5.1 t = ± ± 5.6 MMS 29.0 ± ± 2.7 ns 17.7 ± ± 7.1 * = p < 0.05, t = Student's t-test. None of the between-population changes in the parameters studied was significant for the demented patients. Table 3 Time course of nutritional parameters over the 3 months of follow-up Non-demented (n=60) Demented (n=79) Without With With serotoninergic Demented without With With serotoninergic antidepressant antidepressant antidepressant antidepressant antidepressant antidepressant n = 26 n = 34 n = 23 n = 39 n = 40 n = 31 WEIGHT D ± ± ± ± ± ± 12.3 WEIGHT D ± ± ± ± ± ± 12.5 WEIGHT D90-D * 1.87* -1.01* 0.73* 0.68 t = 4.45 t = 5.56 t = 2.07 t = 2.05 MNA D ± ± ± ± ± ± 3.9 MNA D ± ± ± ± ± ± 3.8 MNA D90-D * 1.15* -0.70* t = 3.13 t = 3.50 t = 3.10 APPETITE D ± ± ± ± ± 0.40 APPETITE D ± ± ± ± ± 0.50 APPETITE D90-D * 0.74* -0.24* 0.28* 0.58* z = z = z = z = z = z = ALB D ± ± ± ± ± ± 3.6 ALB D ± ± ± ± ± ± 3.9 ALB D90-D * 2.23* -1.89* t = 3.68 t = 3.37 t = 5.43 Body weight is expressed in kg, MNA score out of 30 and serum albumin in g/l, appetite score varies between 0 and 2. Paired t-test or Wilcoxon (Appetite change): * = p < Body weight is expressed in kg, MNA score out of 30. We investigated whether a given serotonin reuptake inhibitor could have a specific impact on weight, appetite, MNA score or serum albumin. The ANOVA test did not evidence a significant difference in these parameters when comparing serotonin reuptake inhibitors (Results not shown). No significant difference in the time course of nutritional parameters was observed when patients receiving and those not receiving cholinesterase inhibitors were compared. No significant difference between the presence or absence of antipsychotics was observed. As population was too small, specific study on no serotoninergic antidepressant was not performed. Discussion Different antidepressants drugs can both increase and decrease body weight as a side effect. This study was initiated in elderly subjects who had received stable treatment for 3 months. It is a pragmatic descriptive middle term follow-up of a population under the process of institutionalisation. Population is heterogeneous with large interaction between different characteristics and parameters, which render statistical consideration cautious. Weight and nutritional parameters variations can have many causes than the parameters tested in 168

4 this survey. Antidepressants frequently require a lag time of several weeks before achieving full efficacy, reason of the choice of the steady state period for the survey. The duration selected for patient inclusion and for the follow-up prior to the second assessment was also conditioned by the fact that nutritional status takes several weeks to become stable. Women were in the majority and the female population was older than the male population. This is a conventional observation in geriatric populations. The population studied was associated with several biases: the population had accepted follow-up in the day hospital and no change in treatment had taken place. The nutritional status of the elderly subject cannot be evaluated on body weight only since it is too dependent on other factors, such as degree of hydration (8). Evaluation of undernutrition is problematic in the elderly. For that reason, 4 parameters were combined to monitor nutritional status: body weight, MNA, appetite and serum albumin. In the present study, body weight, MNA, appetite and serum albumin generally changed in the same direction (Table 3). In both demented and non-demented patients, antidepressant treatment was accompanied by weight gain, appetite improvement and a decrease of Cornell s scale scores. The result was less significant for nutritional parameters when a serotonin reuptake inhibitor was prescribed for a demented patient. Non-demented patients receiving a serotoninergic or non-serotoninergic antidepressant showed improvement in all the nutritional parameters studied. The nutritional status of demented patients worsened when they did not receive antidepressant treatment. Anorexia is one of the characteristics of depression in the elderly and one of the sources of undernutrition in those subjects. Depression is the leading cause of anorexia in the elderly (4). It is therefore logical to improve body weight and nutritional parameters in the treatment of depression. In the non-demented population of the present study, the elderly depressed patients presented with more severe undernutrition than the non-depressed population. The improvement in parameters under antidepressant treatment thus constitutes a return to a nutritional equilibrium previously compromised by depression. The patients presenting with Alzheimer's disease had a lower body weight at inclusion than the non-demented patients and their nutritional parameters worsened in the absence of antidepressant treatment. In Alzheimer's disease, undernutrition has been reported related to the severity of the cognitive and behavioral disorders, particularly motor disorders. However, this study did not show an association between cognitive status and severity of depression as evaluated by the Cornell scale, on the one hand, and the variation in nutritional parameters (results not presented). The origin of weight loss in Alzheimer's disease is complex and multifactorial (2, 9). Marked and fast weight loss is correlated with a reduction in calorie intake and with the difficulties encountered in implementing everyday acts (1). Specific neurological impairment may also be involved such as atrophy of the temporal cortex, deglutition disorders, memory disorders and impaired taste and smell, which may contribute to decreasing food intake. The associated disturbances in laboratory parameters and hyperactivity may give rise to hypermetabolism. Anorexia and confusion may interfere with food intake. The behavioral disorders, particularly motor disorders, may induce excessive calorie consumption, although that cause of undernutrition has recently been questioned. However, for Poehlman and Dvorak (10), the weight loss in Alzheimer's disease does not appear to be related to physical hyperactivity. In the present study, the parameters of undernutrition were shown to worsen over the follow-up period in demented patients without antidepressant treatment. Undernutrition in the demented patient is an indicator of the familial burden. The more exhausted the family is, the more severe the patient's undernutrition. Familial exhaustion with particularly trying patients may make caregivers less available to satisfy the patient's dietary requirements (2). The familial burden has also been shown to constitute one of the causes of depression in caregivers (11). There are links between patient depression and familial burden. It is surprising to observe in this study that demented patients receiving antidepressants gained weight while demented patients not taking them continued to lose weight. The cause of undernutrition in depressed demented patients is both dementia and depression. The action of antidepressants seems to slow the course of undernutrition, raising the issue of the role of depression in undernutrition in settings of dementia. The patient's depression perhaps constitutes a bridge between patient undernutrition and caregiver burden. If that factor is accepted, it raises the question of the origin of the increasing undernutrition in demented patients not treated with antidepressants and hence the question of the under-diagnosis of depression in dementia. The Cornell scale scores for non-depressed demented patients are low (table 2), but both the clinical and psychometric assessments may be defective in that population in which communication difficulties and withdrawal may frequently interfere (3). Serotonin reuptake inhibitor antidepressants have been accused of inducing weight loss. Serotonin reuptake inhibitors induce anorexia and hence undernutrition, in particular in the elderly. The patients in Brymer's study, which supports that point of view, were, overall, followed up for 3.8 months, i.e., a period comparable to that in the present study (12). The anorexia induced by serotonin perhaps preferentially concerns carbohydrates, through interactions of serotonin at hypothalamic level (13). Serotonin reuptake inhibitors have been accused of giving rise to anorexia mediated, in particular, by interactions with a digestive hormone CCKb (14). In consequence, serotonin reuptake inhibitors have been suggested for the treatment of bulimia (15, 16). They have also been suggested as a treatment for obesity (17). For instance, a study by Darga showed that the weight loss in obese patients treated with serotonin reuptake inhibitors and a diet was greater than that obtained with the diet alone, but partially reversible over 169

5 ANTIDEPRESSANT DRUGS AND NUTRITION IN ELDERLY time (18). However, the adverse effects of certain serotonin reuptake inhibitors - anxiety, panic, nausea - related to the mcpp agonist effect of the 5-HT2C receptor may restrict their use in that indication (14). Surprisingly, in the review of the adverse effects of that class of medication, Spigset paradoxically reports weight gain as an adverse effect of serotonin reuptake inhibitor antidepressants studied on a national scale (19). The anorexigenic effect of the class may therefore only be transient, disappearing after a few months (20, 21). In this study, appetite improves with any antidepressants. The study reported herein was conducted some time after treatment introduction. Antidepressant drugs do not give rise to weight loss or undernutrition in the elderly. The four serotonin reuptake inhibitors drugs used: paroxetine, fluoxetine, citalopram and sertraline, showed no particular difference with respect to their results on undernutrition. Conclusion Antidepressant drugs do not induce weight loss or do not affect appetite. They may could help to prevent undernutrition in demented patients. Antidepressant drugs seem to have a positive effect on nutrition perhaps by correcting the anorexia related to depression. References 1. Guyonnet S, Nourhashemi F, Ousset PJ, de Glisezinski I, Rivière D, Alabarède JL, Vellas B. Alzheimer s disease and nutrition. Rev Neurol (Paris) 1999; 155: Gillette-Guyonnet S, Nourhashemi F, Andrieu S, de Glisezinski I, Ousset PJ, Rivière D, Albarède JL, Vellas B. Weight loss in Alzheimer disease. Am J Clin Nutr 2000; 71:637S-642S. 3. Thomas P, Clément JP, Hazif-Thomas C, Léger JM. Family, Alzhzeimer s disease and negative symptoms. Int J Geriatr Psychiatry 2001; 16: Morley J, Glick Z, Rubinstein LZ. Geriatric Nutrition. A comprehensive Review. 2d Ed. Raven Press: New York Guigoz Y, Garry PJ. Mini Nutritional Assessment : A practical assessment toll for grading the nutritional state of elderly patients. Facts and Research in Gerontology 1994; Suppl 2 : Folstein MF, Folstein SE, Mc Hugh PR Mini Mental State: A practical method for grading the cognitive status of patients for the clinician. J Psychiatr Res 12: Alexopoulos GS, Abrams RC, Young RC, Shamoian CA. Cornell Scale for Depression in Dementia. Biol Psychiatry 1988; 23: Mitchell SL, Berkowitz RE, Lawson FM, Lipsitz LA. A cross-national survey of tube-feeding decisions in cognitively impaired older persons. J Am Geriatr Soc 2000; 48: Rivière S, Gillette-Guyonnet S, Nourhashemi F, Vellas B. Nutrition and Alzheimer s disease. Nutr Rev 1999; 57: Poehlman ET, Dvorak RV. Energy expenditure, energy intake, and weight loss in Alzheimer s disease. Am J Clin Nutr 2000; 71:650S-655S. 11. Pfeiffer E, Baxter D, Candelora E, Haag S, Nadiminti L, and Laverton P. Finding and treating depression in Alzheimer s patients ; a study of the effects on patients and caregivers. Psychopharmacol Bull 1997; 33: Brymer C, Winograd C. Fluoxetine in elderly patients : is there cause for concern? J Am Geriatr Soc 1992; 40: Rieg TS, Ahmed I, Lauterio TJ, Aravich PF. Fluoxetine induces thymus oxytocin abnormalities in activity-based anorexia. Ann NY Acad Sci 1993; 22;689: Dourish CT. Multiple serotonin receptors: opportunities for new treatments for obesity? 1995; Obes Res Nov 3, Suppl 4:449S-462S. 15. Goldstein DJ, Rampey AH Jr, Enas GG, Potvin JH, Fludzinski LA, Levine LR. Fluoxetine: a randomized clinical trial in the treatment of obesity. Int J Obes Relat Metab Disord 1994; 18: Walsh BT. Fluoxetine treatment of boulimia nervosa. J Psychosom Res 1991; 35: Yen TT, Fuller RW. Preclinical pharmacology of fluoxetine, a serotonergic drug for weight loss. Am J Clin Nutr1992; 55;Suppl1:177S-180S. 18. Darga LL, Carroll-Michals L, Botsford SJ, Lucas CP Fluoxetine s effect on weight loss in obese subjects. Am J Clin Nutr 54: Spigset O. Adverse reactions of selective serotonin reuptake inhibitors. Reports from a spontaneous reporting system. Drug Safety 1999; 20: Souche A, Duclaud L, Zekri JR, Yzombard G, Masquin L, Vallee D, Leibovici G, Magnan M, Rouzier G, Dufour H. Patients treated for one year with tianeptine. Presentation of the results obtained by one of the Centres of the South-East of France. Encéphale 1990; 16: Michelson D, Amsterdam JD, Quitkin FM, Reimherr FW, Rosenbaum JF, Zajecka J, Sundell KL, Kim Y, Beasley CM Jr. Changes in weight during a 1-year trial of fluoxetine. Am J Psychiatry 1999; 156: