|
Are Leptin and Cytokines Involved in Body Weight Gain During Treatment
With Antipsychotic Drugs?
General Conclusions
Primary obesity and AP-induced obesity are complex chronic diseases, and
few factors (except increased appetite and food consumption) have been
definitively shown to cause those conditions. Leptin and TNF-a are critically
involved in BW regulation. Most scientific evidence suggests that the high
serum levels of both hormones observed in obese people are consequences
rather than causes of the disease. However, they impair insulin sensitivity,
which in turn promotes glucose intolerance and cardiovascular diseases.
It is plausible that leptin and TNF-a further impair BW regulation and
indirectly perpetuate obesity. Currently, however, this assertion is only
a matter of speculation. More experimental studies exploring the effects
of leptin and cytokines on BW regulation during AP treatment are required.
Finally, clinical studies on this topic must carefully control for relevant
variables such as sex and BMI.
Implications of Elevated Leptin and TNF-a Serum Levels in Patients With
AP-Induced Obesity
At present, the most parsimonious conclusion is that the increased serum
levels in leptin and TNF-a in these patients is mainly a direct consequence
of BWG and not a specific phenomenon related to AP treatment. Interestingly,
however, the Melkerson and others study (7) offers the possibility that
some olanzapine-treated patients particularly sensitive to drug-induced
metabolic dysregulation may display high leptin and insulin levels despite
having normal BW. This may be related to insulin resistance, which prevents
BWG and promotes serum glucose increase. Hence, this leptin–BW dissociation
might be observed in patients receiving other APs.
Further studies should assess whether such hormone elevation further impairs
the mechanisms of weight regulation. Converging evidence points to the
role of these cytokines in the development and maintenance of myocardial
infarction (30), hypertension (31), insulin resistance (10), and prostatic
cancer (32). Therefore, excessive BWG and obesity must be prevented or
lessened in the general population and in AP-treated patients.
Funding and Support
This review was funded by a Pfizer fellowship and grant # M-718-01-03-B
from CDCH-T (ULA, Venezuela) to Trino Baptista.
References
1. Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms
and management. Acta Psychiatr Scand 1999;100:3–16.
2. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC,
and others. Antipsychotic-induced weight gain: a comprehensive research
synthesis. Am J Psychiatry 1999;156:1686–96.
3. Taylor DM, McAskill R. Atypical antipsychotics and weight gain a systematic
review. Acta Psychiatr Scand 2000;101:416–32.
4. Wetterling T. Bodyweight gain with atypical antipsychotics: A comparative
review. Drug Safety 2001;24:59–73.
5. Cassey DE, Zorn SH. The pharmacology of weight gain with antipsychotics.
J Clin Psychiatry 2001;62 (Suppl 7):4–10.
6. Pollmächer T, Haack M, Schuld A, Kraus T, Hinze-Selch D. Effects of
antipsychotic drugs on cytokine networks. J Psychiatr Res 2000;34:369–82.
7. Melkerson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin
and blood lipids in olanzapine-treated patients with schizophrenia or related
psychoses. J Clin Psychiatry 2000;61:742–9.
8. Melkerson KI, Hulting AL. Insulin and leptin levels in patients with
schizophrenia or related psychoses a comparison between different antipsychotic
agents. Psychopharmacology 2001;154:205–12.
9. Basile VS, Masellis M, McIntyre RS, Meltzer HY, Lieberman JA, Kennedy
JL. Genetic dissection of atypical antipsychotic-induced weight gain: novel
preliminary data on the pharmacological puzzle. J Clin Psychiatry 2001;62
(Suppl 23):45–66.
10. Harris RBS. Leptin-much more than a satiety signal. Annu Rev Nutr 2000;20:45
75.
11. Friedman JM, Halaas JL. Leptin and the regulation of body weight in
mammals. Nature 1998;22:763–70.
12. Woods SC, Seeley RJ, Porte D, Schwartz MW. Signals that regulate food
intake and energy homeostasis. Science 1998;280:1378–82.
13. Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL and
others. Leptin is a metabolic signal to the reproductive system. Endocrinology
1996;137:3144–7.
14. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D,
and others. Weight-reducing effects of the plasma protein encoded by the
obese gene. Science 1995;269:543–6.
15. Seeley RJ, van Dijk G, Campfield LA, Smith FJ, Burn P, Nelligan JA,
and others. Intraventricular leptin reduces food intake and body weight
of lean rats but not obese Zucker rats. Horm Metab Res 1996;28:679–84.
16. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kusher R, Hunt T,
and others. Recombinant leptin for wegiht loss in obese and lean adults:
a randomized, controlled, dose-escalation trial. JAMA 1999;282:1568–75.
17. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Sthephens TW. Serum
immunoreactive-leptin concentration in normal-weight and obese humans.
N Engl J Med 1996;334:292–5.
18. Haffner SM, Miettinen H, Mykkanen L, Stern MP. Leptin concentrations
are associated with higher proinsulin and insulin concentrations but a
lower proinsulin/insulin ratio in non-diabetic subjects. International
Journal of Obesity 1998;22:899–905.
19. Escobar L, Freire JM, Giron JA, Vazquez JM, Pajares M, Ortego J, and
others. Plasma levels of insulin and leptin in patients with morbid obesity
and anorexia nervosa after weight loss or gain, respectively. Rev Esp Med
Nucl 2000;19:199–206.
20. Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong ML, Bongiorno
PB, and others. Sex differences in circulating human leptin pulse amplitude:
clinical implications. J Clin Endocrinol Metab 1998;83:4140–7.
21. Argiles JM, Lopez-Soriano J, Busquets S, Lopez-Soriano FJ. Journey
from cachexia to obesity by TFN. FASEB J 1997;11:743–51.
22. Plata-Salamanca CR. Central nervous system mechanisms contribute to
the cachexia-anorexia syndrome. Nutrition 2000:16:1009–12.
23. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, and
others. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell
1987;50:555–63.
24. Tsukui S, Kanda T, Nara M, Nishino M, Kondo T, Kobayashi I. Moderate-intensity
regular exercise decreases serum tumor necrosis factor-alpha and HbA1c
levels in healthy women. Int J Obes Relat Metab Disord 2000;24:1207–11.
25. Iwata M, Haruta T, Usui I, Takata Y, Takano A, Uno T, and others. Pioglitazone
ameliorates tumor necrosis factor-alpha-induced insulin resistance by a
mechanism independent of adipogenic activity of peroxisome proliferator—
activated receptor-gamma. Diabetes 2001;50:1083–92.
26. Uysal T, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from
obesity- induced insulin resistance in mice lacking TNF- function. Nature
1997;389:610–4.
27. Ventre J, Doebber T, Wu M, MacNaul K, Stevens K, Pasparakis M, and
others. Targeted disruption of the tumor necrosis factor- gene: metabolic
consequences in obese and non-obese mice. Diabetes 1997;46: 526–31.
28. Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. Decreased serum leptin
in bulimia nervosa. J Clin Endocrinol Metab 2000;85:4511–4.
29. Pinkney JH, Goodrick SJ, Katz J, Johnson AB, Lightman SL, Coppack SW,
and others. Leptin and the pituitary-thyroid axis: a comparative study
in lean, obese, hypothyroid and hyperthyroid subjects. Clin Endocrinol
1998;49:583–8.
30. Söderberg S, Ahren B, Jansson JH, Johnson O, Hallmans G, Asplund K,
and others. Leptin is associated with increased risk of myocardial infarction.
J Intern Med 1992;246:409–18.
31. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, and
others. Pathophysiological role of leptin in obesity-related hypertension.
J Clin Invest 2000;105:1243–52.
32. Stattin P, Soderberg S, Hallmans G, Bylund A, Kaaks R, Stenman UH,
and others. Leptin is associated with increased prostate cancer risk: a
nested case-referent study. J Clin Endocrinol Metab 2001;86:1341–5.
33. Hill AB. The environment and disease: association or causality? Proceedings
of the Royal Society of Medicine 1965;58:295–300.
34. Weed DL. On the logic of causal inference. Am J Epidemiol 1986;123:965–79.
35. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol
Rev1994;74:761–811.
36. Ramirez I, Friedman MI. Metabolic concomitants of hypophagia during
recovery from insulin-induced obesity in rats. Am J Physiol 1983;245:E211–9.
37. Kahn BB. Lier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473–81.
38. Suga H, Hirano T, Kageyama H, Kashiba M, Oka J, Osaka T, and others.
Rapid increase in circulating leptin in ventromedial hypothalamus-induced
lesioned rats. Diabetes 1999;10:2034–8.
39. Ravussin E, Pratley RE, Maffei M, Wang H, Fiedman JH, Bennet PH, and
others. Relatively low plasma leptin concentrations precede weight gain
in Pima Indians. Nat Med 1997;3:238–40.
40. Hinze-Selch D, Deuschle M, Weber B, Heuser I, Pollmächer T. Effect
of coadministration of clozapine and fluvoxamine versus clozapine monotherapy
on blood cell counts, plasma levels of cytokines and body weight. Psychopharmacology
2000;149:163–9.
41. Ravusin E, Bouchard C. Human genomics and obesity: finding appropriate
drug targets. Eur J Pharmacol 2000;410:131–45.
42. Brömel T, Blum WF, Zeigler A, Schulz W, Bender M, Fleisbacher C, and
others. Serum leptin levels increase rapidily after initiation of clozapine
therapy. Mol Psychiatry 1998;3:76–80.
43. Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, and others.
Body weight and leptin plasma levels during treatment with antipsychotic
drugs. Am J Psychiatry 1999;156:321–4.
44. Baptista T, Lacruz A, Silvera R, Angeles F, Mendoza S, Mendoza JM,
and others. Body weight gain after administration of antipsychotic drugs:
correlation with leptin, insulin and reproductive hormones. Pharmacopsychiatry
2000;33:81–8.
45. Baptista T, Lacruz A, Angeles F, Silvera R, Mendoza MT, Mendoza S,
and others. Endocrine and metabolic profile in the obesity associated to
typical antipsychotic drug-administration. Pharmacopsychiatry 2001;34:223–31.
46. Herràn A, Garcia-Unzueta MT, Amado JA, de la Maza MT, Alvarez C, Vàzquez-
Barquero JL. Effects of long-term treatment with antipsychotics on serum
leptin levels. Br J Psychiatry 2001;9:59–62.
47. Eder U, Mangweth B, Ebenbichler C, Weiss E, Hofer A, Hummer M, and
others. Association of olanzapine-induced weight gain with an increase
in body fat. Am J Psychiatry 2001;158:1719–22.
48. Hagg S, Soderberg S, Ahren B, Olsson T, Mjorndal T. Leptin concentrations
are increased in subjects treated with clozapine or conventional antipsychotics.
J Clin Psychiatry 2001;62:843–8.
49. Baptista T, Lacruz A, Mendoza S, Hernández L. Endocrine effects of
lithium carbonate in healthy premenopausal women: relationship with body
weight regulation. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:1–16.
50. Lacruz A, Baptista T, de Mendoza S, Mendoza-Guillén JM, Hernández L.
Antipsychotic drug-induced obesity in rats: correlation between leptin,
insulin and body weight during sulpiride treatment. Mol Psychiatry 2000;5:70–6.
51. Baptista T, Beaulieu S. Bodyweight gain, insulin and leptin in olanzapine-treated
patients. J Clin Psychiatry 2001;62:902–3.
52. Baptista T, Beaulieu S. Leptin and antipsychotic drugs. Br J Psychiatry
2002;179:570–1.
53. Schuld A, Kraus T, Haack M, Hinza-Selch D, Kühn M, Pollmächer T. Plasma
levels of cytokines and soluble cytokine receptors during treatment with
olanzapine. Schiz Res 2000; 43: 164–6.
54. Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine
treatment: weight change and weight-related health factors in schizophrenia.
J Clin Psychiatry 2001;62: 92–100.
--------------------------------------------------------------------------------
Manuscript received November 2001, revised, and accepted June 2002.
1 Professor Los Andes University Medical School, Department of Physiology,
Mérida, Venezuela; Visiting scientist, Douglas Hospital Research Centre,
McGill University, Verdun, Québec.
2 Assistant Professor, Douglas Hospital Research Centre, McGill University, Verdun, Québec.
Address for correspondence: Dr T Baptista, PO Box 93, Mérida, 5101-A, Venezuela
e-mail: trinbap@yahoo.com
1 | 2 | 3 | 4
|
