- Email: [email protected]
Resting metabolic rate is reduced in patients treated with antidepressants
692
Brief Reports
BIOL PSYCHIATRY 1985;20:688--692
Liebowitz MR, Quitkin FM, Stewart JW, McCaath PJ, Harrison W, Rabkin J, Tricamo E, Markowitz JS, Klein DF (1984): Phenelzine vs. imipramine in atypical depression. Arch Gen Psychiatry 41:669-677. Perry JCH, Klerman GL (1980): Clinical features of the borderline personality disorder. Am J Psychiatry 137:167-173. Pope HG, Jonas JM, Hudson H, Cohen BM, Gunderson JG (1983): The validity of DSM-III borderline personality disorder. Arch Gen Psychiatry 40:23-30.
Spitzer RL, Endicott J (1975): Schedule for Affective Disorders and Schizophrenia. New York: Biometrics Research Division, New York State Psychiatric Institute. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria. New York: Biometrics Research. Stone MH (1981): Borderline conditions: Or consideration of subtypes and an overview. Directions for research. Psychiatr Clin North Am 4:3-24. Van Valkenburg CH, Akiskal HS, Puzantian V, Rosenthal T ( 1984): Anxiety depressions. J Affective Disord 6:67-82.
Resting Metabolic Rate is Reduced in Patients Treated with Antidepressants Madelyn H. Fernstrom, Leonard H. Epstein, Duane G. Spiker, and David J. Kupfer Introduction Eating disturbances, most notably a decrease in appetite and weight loss, are associated with major depression (Robinson et al. 1975; Paykel 1977; Mezzich and Raab 1980). During antidepressant treatment, many symptoms of depression disappear (including appetite loss), and patients begin to gain weight. Several studies have shown that certain antidepressants, particularly tricyclic compounds, are associated with excessive weight gain (Paykel et al 1974; Kupfer et al. 1979; Berken et al. 1984). However, few
From the Department of Psychiatry and Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA. Supported in part by Mental Health Clinical Research Center Grant MH 30915. Address reprint requests to Dr. M. H. Fernstrom, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Room E-1228, Pittsburgh, PA 15213. Received November 17, 1984; revised December 26, 1984.
© 1985 Society of Biological Psychiatry
comprehensive data exist that focus on factors influencing weight change upon recovery from a depressive episode. Weight fluctuations reflect both caloric intake and caloric expenditure. Thus, weight gain is due to positive energy balance, which may be explained by an increase in total calories consumed and/or a reduction in calories used by the body. Resting metabolic rate (RMR), which reflects the number of calories utilized by an individual in a resting state, represents at least 70% of the total caloric utilization by an individual (Garrow 1978); RMR probably accounts for an even greater proportion of calories in hospitalized patients due to their greater inactivity. Therefore, if a reduction in metabolic rate occurs, an individual would gain weight without increasing caloric intake. Thus, we wanted to determine whether or not alterations in resting metabolic rate might occur in drug-treated depressed patients; such changes might ultimately contribute to potential weight changes.
0006-3223/85/$03.30
Brief Reports
Methods
Subjects Three female inpatients on the Clinical Research Unit at Western Psychiatric Institute and Clinic served as subjects. At the time of admission, a psychiatric interview and physical examination were conducted in which height and weight were carefully recorded. Patient 1 (age 51 years) weighed 131 pounds and was 64 inches tall; Patient 2 (age 53) weighed 149 pounds and was 62 inches tall; Patient 3 (age 34) weighed 133 pounds and was 65 inches tall. During a 2-week drug-free period, routine laboratory tests (including thyroid function tests) were performed. Resting metabolic rate determinations were carded out on three different mornings during the drug-free period. Following this drug-free period, the patients were interviewed by their psychiatrist using the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et at. 1978) and were diagnosed using the Research Diagnostic Criteria. With a diagnosis of major depression and a minimum of 30 on the Hamilton Rating Scale (using the sum of two raters for the first 17 items), the patients entered the protocol. Patient 1 received imipran~e in graded doses, reaching 150 mg/day during the second week and 200 mg/day during the fourth week of testing. Patient 2, who completed the first 2 weeks of drug therapy, was treated with imipramine in increasing amounts, reaching 200 mg/day during testing. Patient 3 received tranylcypromine in graded doses, reaching 40 mg/day during the second week; she then received a combination of 50 mg/day tranylcypromine plus 100 mg/day amitriptyline for the next 2 weeks (during the fourth week of testing).
Resting Metabolic Rate Determinations Following a 12-hr fast, and prior to arising from bed, subjects were fitted with a mask (connected with flexible tubing to a Douglas bag) for collection of expired air. Each patient breathed through the mask for 15 min; during the final 2.5 min, expired air was collected and sealed
BIOLPSYCHIATRY 1985;20:692-695
693
in the bag. The air was then immediately analyzed for total volume expired and oxygen and carbon dioxide content using Beckman OM-11 and LB-2 analyzers. Oxygen consumption in the sample was calculated by the method of Consolazio et al. (1963), and kilocalories per minute were then determined based on respiratory quotients (CO2 volume/O2 volume) (McArdle et al. 1981).
Results We first obtained resting metabolic rate levels in the subjects during their drug-free period. Three separate measurements were taken during the drug-free period and during the second and fourth weeks of antidepressant treatment. These determinations were very consistent within each testing period, and thus reflect a stable caloric intake and activity level. The drug-free determinations (Figure 1) in all subjects were quite reproducible, and resting metabolic rate values (expressed as kcal/min) were within the normal range for each individual's height and weight (Table 1). During drug treatment, all three subjects showed a reduction in metabolic rate, at both 2 and 4 weeks into treatment (Figure 1). Patient 1, who was treated with imipramine, showed a steady decline in RMR during the treatment period, with the largest reduction (24%) occuring 4 weeks into treatment. At the end of 4 weeks, she had gained 4 lb (1 lb/week). The second imipramine-treated subject, Patient 2, had a 17% reduction in RMR 2 weeks after the drug, and had gained 1 lb. Patient 3, treated with tranylcypromine only for 2 weeks, showed a variable RMR, but produced a clear reduction (18%) in RMR during the fourth treatment week (during which time she also received amitriptyline). She gained 1 lb after 2 weeks of treatment, which was maintained through the fourth week. The respiratory quotient (the ratio of carbon dioxide production to oxygen consumption) for all three subjects showed a monotonic increase during the treatment period, when compared to drug-free values (Table 1).
694
BIOLPSYCHIATRY
Brief Reports
1985;20:692-695
DRUG FREE
4TH
2ND WEEK
WEEK
1.2 o--e...._e
RESTING METABOLIC RATE (kcal/min)
t.o
7
,,--r----
0.8
0.6
I 1
i 3
I 5
I
I
15
17
I
19
a
a
n
29
31
33
DAYS
Figure 1. Effect of antidepressant treatment on resting metabolic rate in depressed patients. Data represent three separate measurements taken during each time period. Measurementswere performed during the drug-free period (within the second of two drug-free weeks) and during the second and fourth weeks of drug treatment. (o---o) Patient l; (A--A) Patient 2; ( i - - - i ) Patient 3.
Discussion We have observed major reductions in resting metabolic rate in individuals treated with antidepressants. All three subjects treated with antidepressants showed a decrease in RMR, ranging between 17% and 24%. Such reductions are remarkably large and far exceed any other stimuli known to produce changes in RMR. For example, exercise produces a 5%-10% change in RMR (McArdle et al. 1981), an effect that is considered robust. Our results demonstrate that particular antidepressants can elicit a change in RMR that is 2-3 times greater than other reported values, a finding that may have important
ramifications in overall metabolic function. These kinds of changes, expressed in kcal/min, reflect a reduction in daily caloric need of about 300-400 kcal. Thus, an individual might be expected to gain a pound every 9-12 days, independent of any change in caloric intake. Our results support the idea that weight increases occurring during antidepressant treatment may be contributed to, at least in part, by changes in caloric expenditure. An increase in weight would be expected to increase, n o t reduce, resting metabolic rate (Garrow 1978), suggesting further that the effect on the RMR is drug-related. Only Patient 1 showed a steady weight gain of 1 lb each week
Table I. Respiratory Quotients of Depressed Subjects before and during Antidepressant Treatment Respiratory quotient Patient
R M R ~ (kcal/min), drug-free
Drug-free
Week 2
Week 4
1 2 3
1.13 ± 0.01 0.92 ± 0.02 1.03 ± 0.02
0.74 -+ 0.01 0.69 ± 0.01 0.84 ± 0.02
0.78 ± 0.01 0.81 ± 0.02 0.90 ± 0.03
0.86 ± 0.03 0.87 ± 0.01 --
°Resting metabolic rate. Respiratory quotient and RMR represent the mean +- SEM of three determinations during each time period.
Brief Reports
BIOLPSYCHIATRY
695
1985;20:692-695
over 4 weeks; she also produced the greatest reduction in RMR. The reduction in RMR (400 kcal/day) alone can account for 80% of her weight gain during this period. Patients 2 and 3 each had a small weight gain during this period (1 lb), which could be attributed to a number of factors. However, subjects were tested for an acute period---only 2-4 weeks. The drop in RMR in these patients might contribute to long-term weight gain in these individuals (of course, increases in appetite and food intake, often reported upon recovery from a depressive episode, are also important factors to consider in evaluating chronic weight gain). That the respiratory quotient (RQ) (the ratio of carbon dioxide production to oxygen consumption) increased in all three patients during drug treatment indicates that a change in metabolic fuel (i.e., fats, carbohydrates, and proteins) utilization has occurred during drug treatment (Table 1); fat has an RQ of 0.72, protein of 0.82, and carbohydrate of 1.00. How might this change in RQ be explained? The most likely explanation is that the comparatively lower RQ in the drug-free state represents an increased mobilization of stored body fat during a period of time when the depressed patient is not likely to be eating adequate numbers of calories. The relative increase in RQ seen during antidepressant treatment may thus reflect an increase in overall food consumption, which would be composed of proteins and carbohydrates, as well as fats. However, based on the data, it is not possible to evaluate whether any particular nutrient is eaten preferentially. Our data demonstrate that during this short observation interval of 1 month, significant reductions in RMR occur. These results indicate that caloric expenditure is a factor to consider in understanding the potential side effect of excessive weight gain during chronic antidepres-
sant treatment. Whether or not these observations can be generalized to all depressed patients treated with the available antidepressants remains to be seen. Most importantly, however, these results demonstrate that certain antidepressants can produce substantial alterations in fundamental metabolic function.
We wish to thank Mr. Mehran Massoudi and Ms. Colleen McGowan for their excellent assistance.
References Berken G, Weinstein D, Stem W (1984): Weight gain. A side effect of tricyclic antidepressants. J Affective Disord 7:133-138. Consolazio C, Johnson R, Pecora L (1963): Physiological Measurements of Metabolic Functions in Man. New York: McGraw-Hill. Garrow JS (1978): Energy Balance and Obesity in Man (ed 2). Oxford: Elsevier-North Holland Press. Kupfer DJ, Coble PA, Rubenstein D (1979): Changes in weight during treatment for depression. Psychosom Med 41:535-543. Mezzich JE, Raab JS (1980): Depressive symptomology across the Americas. Arch Gen Psychiatry 37:818-823. McArdle W, Katch F, Katch V (1981): Exercise Physiology: Energy Nutrition and Human Performance. Philadelphia: Lea & Fibiger. Paykel ES (1977): Depression and appetite. J Psychosom Res 21:401-407. Paykel ES, Mueller PS, DeLaVergne PM (1973): Amitriptyline, weight gain, and carbohydrate craving: A side effect. Br J Psychiatry 123:501-507. Robinson RG, McHugh PR, Folstein MF (1975): Measurement of appetite disturbances in psychiatric disorders. J Psychiatr Res 12:59-68. Spitzer RL, Endicott J, Robins E (1978): Research diagnostic criteria: Rationality and reliability. Arch Gen Psychiatry 35:773-782.
Brief Reports
BIOL PSYCHIATRY 1985;20:688--692
Liebowitz MR, Quitkin FM, Stewart JW, McCaath PJ, Harrison W, Rabkin J, Tricamo E, Markowitz JS, Klein DF (1984): Phenelzine vs. imipramine in atypical depression. Arch Gen Psychiatry 41:669-677. Perry JCH, Klerman GL (1980): Clinical features of the borderline personality disorder. Am J Psychiatry 137:167-173. Pope HG, Jonas JM, Hudson H, Cohen BM, Gunderson JG (1983): The validity of DSM-III borderline personality disorder. Arch Gen Psychiatry 40:23-30.
Spitzer RL, Endicott J (1975): Schedule for Affective Disorders and Schizophrenia. New York: Biometrics Research Division, New York State Psychiatric Institute. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria. New York: Biometrics Research. Stone MH (1981): Borderline conditions: Or consideration of subtypes and an overview. Directions for research. Psychiatr Clin North Am 4:3-24. Van Valkenburg CH, Akiskal HS, Puzantian V, Rosenthal T ( 1984): Anxiety depressions. J Affective Disord 6:67-82.
Resting Metabolic Rate is Reduced in Patients Treated with Antidepressants Madelyn H. Fernstrom, Leonard H. Epstein, Duane G. Spiker, and David J. Kupfer Introduction Eating disturbances, most notably a decrease in appetite and weight loss, are associated with major depression (Robinson et al. 1975; Paykel 1977; Mezzich and Raab 1980). During antidepressant treatment, many symptoms of depression disappear (including appetite loss), and patients begin to gain weight. Several studies have shown that certain antidepressants, particularly tricyclic compounds, are associated with excessive weight gain (Paykel et al 1974; Kupfer et al. 1979; Berken et al. 1984). However, few
From the Department of Psychiatry and Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA. Supported in part by Mental Health Clinical Research Center Grant MH 30915. Address reprint requests to Dr. M. H. Fernstrom, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Room E-1228, Pittsburgh, PA 15213. Received November 17, 1984; revised December 26, 1984.
© 1985 Society of Biological Psychiatry
comprehensive data exist that focus on factors influencing weight change upon recovery from a depressive episode. Weight fluctuations reflect both caloric intake and caloric expenditure. Thus, weight gain is due to positive energy balance, which may be explained by an increase in total calories consumed and/or a reduction in calories used by the body. Resting metabolic rate (RMR), which reflects the number of calories utilized by an individual in a resting state, represents at least 70% of the total caloric utilization by an individual (Garrow 1978); RMR probably accounts for an even greater proportion of calories in hospitalized patients due to their greater inactivity. Therefore, if a reduction in metabolic rate occurs, an individual would gain weight without increasing caloric intake. Thus, we wanted to determine whether or not alterations in resting metabolic rate might occur in drug-treated depressed patients; such changes might ultimately contribute to potential weight changes.
0006-3223/85/$03.30
Brief Reports
Methods
Subjects Three female inpatients on the Clinical Research Unit at Western Psychiatric Institute and Clinic served as subjects. At the time of admission, a psychiatric interview and physical examination were conducted in which height and weight were carefully recorded. Patient 1 (age 51 years) weighed 131 pounds and was 64 inches tall; Patient 2 (age 53) weighed 149 pounds and was 62 inches tall; Patient 3 (age 34) weighed 133 pounds and was 65 inches tall. During a 2-week drug-free period, routine laboratory tests (including thyroid function tests) were performed. Resting metabolic rate determinations were carded out on three different mornings during the drug-free period. Following this drug-free period, the patients were interviewed by their psychiatrist using the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et at. 1978) and were diagnosed using the Research Diagnostic Criteria. With a diagnosis of major depression and a minimum of 30 on the Hamilton Rating Scale (using the sum of two raters for the first 17 items), the patients entered the protocol. Patient 1 received imipran~e in graded doses, reaching 150 mg/day during the second week and 200 mg/day during the fourth week of testing. Patient 2, who completed the first 2 weeks of drug therapy, was treated with imipramine in increasing amounts, reaching 200 mg/day during testing. Patient 3 received tranylcypromine in graded doses, reaching 40 mg/day during the second week; she then received a combination of 50 mg/day tranylcypromine plus 100 mg/day amitriptyline for the next 2 weeks (during the fourth week of testing).
Resting Metabolic Rate Determinations Following a 12-hr fast, and prior to arising from bed, subjects were fitted with a mask (connected with flexible tubing to a Douglas bag) for collection of expired air. Each patient breathed through the mask for 15 min; during the final 2.5 min, expired air was collected and sealed
BIOLPSYCHIATRY 1985;20:692-695
693
in the bag. The air was then immediately analyzed for total volume expired and oxygen and carbon dioxide content using Beckman OM-11 and LB-2 analyzers. Oxygen consumption in the sample was calculated by the method of Consolazio et al. (1963), and kilocalories per minute were then determined based on respiratory quotients (CO2 volume/O2 volume) (McArdle et al. 1981).
Results We first obtained resting metabolic rate levels in the subjects during their drug-free period. Three separate measurements were taken during the drug-free period and during the second and fourth weeks of antidepressant treatment. These determinations were very consistent within each testing period, and thus reflect a stable caloric intake and activity level. The drug-free determinations (Figure 1) in all subjects were quite reproducible, and resting metabolic rate values (expressed as kcal/min) were within the normal range for each individual's height and weight (Table 1). During drug treatment, all three subjects showed a reduction in metabolic rate, at both 2 and 4 weeks into treatment (Figure 1). Patient 1, who was treated with imipramine, showed a steady decline in RMR during the treatment period, with the largest reduction (24%) occuring 4 weeks into treatment. At the end of 4 weeks, she had gained 4 lb (1 lb/week). The second imipramine-treated subject, Patient 2, had a 17% reduction in RMR 2 weeks after the drug, and had gained 1 lb. Patient 3, treated with tranylcypromine only for 2 weeks, showed a variable RMR, but produced a clear reduction (18%) in RMR during the fourth treatment week (during which time she also received amitriptyline). She gained 1 lb after 2 weeks of treatment, which was maintained through the fourth week. The respiratory quotient (the ratio of carbon dioxide production to oxygen consumption) for all three subjects showed a monotonic increase during the treatment period, when compared to drug-free values (Table 1).
694
BIOLPSYCHIATRY
Brief Reports
1985;20:692-695
DRUG FREE
4TH
2ND WEEK
WEEK
1.2 o--e...._e
RESTING METABOLIC RATE (kcal/min)
t.o
7
,,--r----
0.8
0.6
I 1
i 3
I 5
I
I
15
17
I
19
a
a
n
29
31
33
DAYS
Figure 1. Effect of antidepressant treatment on resting metabolic rate in depressed patients. Data represent three separate measurements taken during each time period. Measurementswere performed during the drug-free period (within the second of two drug-free weeks) and during the second and fourth weeks of drug treatment. (o---o) Patient l; (A--A) Patient 2; ( i - - - i ) Patient 3.
Discussion We have observed major reductions in resting metabolic rate in individuals treated with antidepressants. All three subjects treated with antidepressants showed a decrease in RMR, ranging between 17% and 24%. Such reductions are remarkably large and far exceed any other stimuli known to produce changes in RMR. For example, exercise produces a 5%-10% change in RMR (McArdle et al. 1981), an effect that is considered robust. Our results demonstrate that particular antidepressants can elicit a change in RMR that is 2-3 times greater than other reported values, a finding that may have important
ramifications in overall metabolic function. These kinds of changes, expressed in kcal/min, reflect a reduction in daily caloric need of about 300-400 kcal. Thus, an individual might be expected to gain a pound every 9-12 days, independent of any change in caloric intake. Our results support the idea that weight increases occurring during antidepressant treatment may be contributed to, at least in part, by changes in caloric expenditure. An increase in weight would be expected to increase, n o t reduce, resting metabolic rate (Garrow 1978), suggesting further that the effect on the RMR is drug-related. Only Patient 1 showed a steady weight gain of 1 lb each week
Table I. Respiratory Quotients of Depressed Subjects before and during Antidepressant Treatment Respiratory quotient Patient
R M R ~ (kcal/min), drug-free
Drug-free
Week 2
Week 4
1 2 3
1.13 ± 0.01 0.92 ± 0.02 1.03 ± 0.02
0.74 -+ 0.01 0.69 ± 0.01 0.84 ± 0.02
0.78 ± 0.01 0.81 ± 0.02 0.90 ± 0.03
0.86 ± 0.03 0.87 ± 0.01 --
°Resting metabolic rate. Respiratory quotient and RMR represent the mean +- SEM of three determinations during each time period.
Brief Reports
BIOLPSYCHIATRY
695
1985;20:692-695
over 4 weeks; she also produced the greatest reduction in RMR. The reduction in RMR (400 kcal/day) alone can account for 80% of her weight gain during this period. Patients 2 and 3 each had a small weight gain during this period (1 lb), which could be attributed to a number of factors. However, subjects were tested for an acute period---only 2-4 weeks. The drop in RMR in these patients might contribute to long-term weight gain in these individuals (of course, increases in appetite and food intake, often reported upon recovery from a depressive episode, are also important factors to consider in evaluating chronic weight gain). That the respiratory quotient (RQ) (the ratio of carbon dioxide production to oxygen consumption) increased in all three patients during drug treatment indicates that a change in metabolic fuel (i.e., fats, carbohydrates, and proteins) utilization has occurred during drug treatment (Table 1); fat has an RQ of 0.72, protein of 0.82, and carbohydrate of 1.00. How might this change in RQ be explained? The most likely explanation is that the comparatively lower RQ in the drug-free state represents an increased mobilization of stored body fat during a period of time when the depressed patient is not likely to be eating adequate numbers of calories. The relative increase in RQ seen during antidepressant treatment may thus reflect an increase in overall food consumption, which would be composed of proteins and carbohydrates, as well as fats. However, based on the data, it is not possible to evaluate whether any particular nutrient is eaten preferentially. Our data demonstrate that during this short observation interval of 1 month, significant reductions in RMR occur. These results indicate that caloric expenditure is a factor to consider in understanding the potential side effect of excessive weight gain during chronic antidepres-
sant treatment. Whether or not these observations can be generalized to all depressed patients treated with the available antidepressants remains to be seen. Most importantly, however, these results demonstrate that certain antidepressants can produce substantial alterations in fundamental metabolic function.
We wish to thank Mr. Mehran Massoudi and Ms. Colleen McGowan for their excellent assistance.
References Berken G, Weinstein D, Stem W (1984): Weight gain. A side effect of tricyclic antidepressants. J Affective Disord 7:133-138. Consolazio C, Johnson R, Pecora L (1963): Physiological Measurements of Metabolic Functions in Man. New York: McGraw-Hill. Garrow JS (1978): Energy Balance and Obesity in Man (ed 2). Oxford: Elsevier-North Holland Press. Kupfer DJ, Coble PA, Rubenstein D (1979): Changes in weight during treatment for depression. Psychosom Med 41:535-543. Mezzich JE, Raab JS (1980): Depressive symptomology across the Americas. Arch Gen Psychiatry 37:818-823. McArdle W, Katch F, Katch V (1981): Exercise Physiology: Energy Nutrition and Human Performance. Philadelphia: Lea & Fibiger. Paykel ES (1977): Depression and appetite. J Psychosom Res 21:401-407. Paykel ES, Mueller PS, DeLaVergne PM (1973): Amitriptyline, weight gain, and carbohydrate craving: A side effect. Br J Psychiatry 123:501-507. Robinson RG, McHugh PR, Folstein MF (1975): Measurement of appetite disturbances in psychiatric disorders. J Psychiatr Res 12:59-68. Spitzer RL, Endicott J, Robins E (1978): Research diagnostic criteria: Rationality and reliability. Arch Gen Psychiatry 35:773-782.