mirtazapine and weight gain


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(Updated 5/25/04)

Nutt DJ.
Tolerability and safety aspects of mirtazapine.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S37-41
"The tolerability and safety profile of the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine reflects its unique pharmacological profile. The 5-HT(2) blocking effect contributes towards its anxiolytic effects and benefits on sleep, as well as preventing the sexual dysfunction that may occur with non-specific stimulation of the serotonin system by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting. Weight gain is the most commonly reported side-effect of mirtazapine, although there is evidence to suggest that this is not a significant problem during long-term treatment. In conclusion, mirtazapine has a good tolerability and safety profile that demonstrates several benefits over other antidepressants." [Abstract] [Mirtazapine is an antagonist at both 5-HT2A and 5-HT2C receptors.]

Roose SP.
Tolerability and patient compliance.
J Clin Psychiatry 1999;60 Suppl 17:14-7; discussion 46-8
"Because of interactions with the histamine (H1) receptor, mirtazapine may be related to transient initial somnolence and weight gain in some patients." [Abstract]

Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F.
Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram.
Eur J Neurosci 2000 Mar;12(3):1079-95
"In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors." [Abstract]

Bray GA.
Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications.
Int J Obes Relat Metab Disord 2000 Jun;24 Suppl 2:S8-17
"The neuropeptides, monoamines and many drugs involved with modulating food intake and fat stores have reciprocal effects on sympathetic activity and thermogenesis. Both serotonin, acting through 5HT1B/2C receptors, and norepinephrine acting through beta2 and/or beta3 receptors reduce food intake and augment sympathetic activity. Neuropeptide Y, beta-endorphin, orexin, galanin and melanin concentrating hormone all increase food intake and, where tested, reduce sympathetic activity. In contrast, a larger number of peptides including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, leptin, CART and alpha-MSH reduce food intake and increase sympathetic activity. Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity. Chronic administration of neuropeptide Y (NPY) can produce chronically increased food intake and obesity. This syndrome is similar to the ventromedial hypothalamus (VMH) syndrome and suggests that NPY must be acting as an inhibitory signal to stimulate a feeding system and inhibit sympathetic activity. The melanocortin receptor system may be particularly important in modulating food intake, because a transgenic mouse which does not express melanocortin-4 receptors is massively overweight. Adrenal glucocorticoids are important in obesity since adrenalectomy will reverse or prevent the development of all forms of obesity. The clinical importance of the sympathetic nervous system and food intake is emphasized by the inverse relation of sympathetic activity and body fat. The inhibition of food intake, lower body fat stores and higher energy expenditure in smokers also support this hypothesis. The reciprocal relationship between food intake and sympathetic activity is robust, suggesting that beta receptors in the periphery and brain may be involved in the control of feeding and a reduction in food intake in humans accounts for most of the weight loss with ephedrine and caffeine. We conclude that the inhibition of feeding by activating the SNS is an important satiety system which helps regulate body fat stores." [Abstract]

OMIM - Online Mendelian Inheritance in Man: 5-HT2C Receptor
[5-HT2C has been located at Xq24]
"Heisler et al. (2002) hypothesized that 5-HT receptors are expressed in POMC (176830) neurons and that action at these receptors mediates a component of the anorexic effect of d-FEN (D-fenfluramine). Heisler et al. (2002) found that up to 80% of alpha-MSH neurons express HTR2C mRNA and that the pattern of coexpression was greatest in the caudal arcuate nucleus of the hypothalamus. Heisler et al. (2002) demonstrated that direct activation of HTR2C by agonist in rats decreased their food intake and showed increased induction of FOS-like immunoreactivity in a pattern persistent with d-FEN-induced FOS-like immunoreactivity expression in the arcuate nucleus and paraventricular nucleus of the hypothalamus. Heisler et al. (2002) demonstrated that d-FEN directly activates POMC neurons, indicating that central 5-HT systems directly activate POMC neurons." -Ada Hamosh (2002)

Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK.
Activation of central melanocortin pathways by fenfluramine.
Science 2002 Jul 26;297(5581):609-11
"D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN's anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective anti-obesity treatments.
...
On the basis of these findings, we hypothesized that d-FEN stimulates the release of 5-HT in the ARC and that the neurotransmitter then binds to 5-HT2CRs expressed in POMC neurons. This in turn could stimulate the release of alpha-MSH, which acts on effector neurons expressing melanocortin 4 receptors (MC4-R) and melanocortin 3 receptors (MC3-R)." [Full Text]

Bickerdike MJ.
5-HT2C receptor agonists as potential drugs for the treatment of obesity.
Curr Top Med Chem. 2003;3(8):885-97.
"Importantly, ethological studies of animal behaviour have shown that the hypophagia resulting from 5-HT(2C) receptor activation is likely to be a consequence of increased satiety and this is in contrast to hypophagia following 5-HT(2C) receptor activation. Furthermore, recent studies have also shown that 5-HT(2C) receptor agonists not only reduce feeding when acutely administered to rats or mice, they can also reduce body weight without inducing tolerance when administered chronically to obese animals. These observations have led researchers to conclude that selective 5-HT(2C) receptor agonists have the potential to be effective anti-obesity agents. Encouragingly, this suggestion is supported by both direct and indirect evidence from clinical studies. Indirect evidence stems from recent observations that the clinically effective anorectic agent d-fenfluramine exerts its hypophagic and weight-loss effects via 5-HT(2C) receptor activation. More direct clinical evidence derives from the use of the prototypical 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP), with which both acute hypophagia and body-weight loss have been observed." [Abstract]

Sharon L. Wardlaw
Obesity as a Neuroendocrine Disease: Lessons to Be Learned from Proopiomelanocortin and Melanocortin Receptor Mutations in Mice and Men
J. Clin. Endocrinol. Metab. 86: 1442-1446
"The central melanocortin system, which consists of POMC, AGRP, and the brain MC-Rs, plays a key role in regulating feeding behavior and energy homeostasis. A growing number of studies in both the mouse and the human with genetic defects in the synthesis or processing of POMC, or with defects in MC-R signaling, clearly indicate the importance of this system. A genetic POMC deficiency syndrome characterized by adrenal insufficiency, red hair pigmentation, and early-onset obesity has recently been described in the human. It is particularly striking that obesity occurs in patients with generalized POMC deficiency and in Pomc knockout mice despite the presence of adrenal insufficiency. The contrast between these patients with generalized POMC deficiency and with the more typical patients who have POMC deficiency limited to the pituitary underscores the critical role that hypothalamic POMC plays in regulating energy balance. The importance of the MC4-R in this process is demonstrated by the Mc4-r knockout mouse and by the growing number of obese patients reported with MC4-R mutations, making this the most common known monogenic cause of human obesity. The melanocortin regulatory system seems to be sensitive to variations in MC4-R expression, as indicated by the fact that heterozygous mutations produce obesity in both mice and in humans. Thus, there is considerable evidence that the hypothalamic melanocortin pathway regulates human feeding behavior and energy homeostasis and that abnormalities in this pathway can lead to obesity. A more detailed understanding of the control of this pathway and its integration with a growing number of other hypothalamic signaling pathways involved in maintaining energy balance will hopefully lead to effective new therapies for human obesity." [Full Text]

Berrettini WH, Nurnberger JI Jr, Chan JS, Chrousos GP, Gaspar L, Gold PW, Seidah NG, Simmons-Alling S, Goldin LR, Chretien M, et al.
Pro-opiomelanocortin-related peptides in cerebrospinal fluid: a study of manic-depressive disorder.
Psychiatry Res 1985 Dec;16(4):287-302
"With the exception of alpha-melanocyte-stimulating hormone, in the normal volunteers' CSF, levels of these peptides were highly correlated with one another, suggesting that: (1) some common regulatory factor may control the levels of these four peptides in CSF; and (2) CSF alpha-melanocyte-stimulating hormone is independently regulated from the other pro-opiomelanocortin products." [Abstract]

Schule C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G.
The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects.
Psychopharmacology (Berl) 2002 Aug;163(1):95-101
"The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of application of placebo or mirtazapine) up to 8:00 a.m. the day after. RESULTS. Multivariate analyses of variance revealed significantly lower COR AUC, ACTH AUC, and UFC values after 15 mg mirtazapine compared to placebo, whereas no differences were found with respect to GH and PRL stimulation, MAP, and heart rate." [Abstract]

Jorgensen H, Knigge U, Kjaer A, Moller M, Warberg J.
Serotonergic Stimulation of Corticotropin-Releasing Hormone and Pro-Opiomelanocortin Gene Expression.
J Neuroendocrinol 2002 Oct;14(10):788-795
"The neurotransmitter serotonin (5-HT) stimulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland via activation of central 5-HT1 and 5-HT2 receptors. The effect of 5-HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin-releasing hormone (CRH). We therefore investigated the possible involvement of CRH in the serotonergic stimulation of ACTH secretion in male rats. Increased neuronal 5-HT content induced by systemic administration of the precursor 5-hydroxytryptophan (5-HTP) in combination with the 5-HT reuptake inhibitor fluoxetine raised CRH mRNA expression in the paraventricular nucleus (PVN) by 64%, increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary lobe by 17% and stimulated ACTH secretion five-fold. Central administration of 5-HT agonists specific to 5-HT1A, 5-HT1B, 5-HT2A or 5-HT2C receptors increased CRH mRNA in the PVN by 15-50%, POMC mRNA in the anterior pituitary by 15-27% and ACTH secretion three- to five-fold, whereas a specific 5-HT3 agonist had no effect. Systemic administration of a specific anti-CRH antiserum inhibited the ACTH response to 5-HTP and fluoxetine and prevented the 5-HTP and fluoxetine-induced POMC mRNA response in the anterior pituitary lobe. Central or systemic infusion of 5-HT increased ACTH secretion seven- and eight-fold, respectively. Systemic pretreatment with the anti-CRH antiserum reduced the ACTH responses to 5-HT by 80% and 64%, respectively. It is concluded that 5-HT via activation of 5-HT1A, 5-HT2A, 5-HT2C and possibly also 5-HT1B receptors increases the synthesis of CRH in the PVN and POMC in the anterior pituitary lobe, which results in increased ACTH secretion. Furthermore, the results indicate that CRH is an important mediator of the ACTH response to 5-HT." [Abstract]

Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH.
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.
Nat Genet 2000 Sep;26(1):97-102
"Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis." [Abstract]

Yeo, G.S.H., Farooqi, I.S., Challis, B.G., Jackson, R.S., O'Rahilly, S.
The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models
QJM 2000 93: 7-14
"The peptide products of the pro-opiomelanocortin (POMC) gene have established roles in the control of physiological processes as diverse as adrenal steroidogenesis, skin pigmentation, analgesia and inflammation. In the last 5 years, evidence accumulated from murine and human genetic models of disrupted melanocortin signalling has firmly established a central role for a population of hypothalamic neurons expressing POMC in the control of appetite and body weight. Of the five known melanocortin receptors, the MC4R has been most closely linked to body weight regulation. While a-MSH is active at this receptor and suppresses appetite after central injection, important roles for other POMC-derived products have not been excluded. The development of pharmacological agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may provide exciting opportunities for the therapy of human obesity." [Full Text]

Harrold JA, Widdowson PS, Williams G.
beta-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?
Peptides. 2003 Mar;24(3):397-405.
"alpha-Melanocyte stimulating hormone (MSH) has generally been assumed to be the endogenous ligand acting at the melanocortin-4 receptor (MC4-R), activation of which in the hypothalamus leads to reduced feeding. However, beta-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that beta-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. We found that beta-MSH had significantly higher affinities than alpha-MSH at both human MC4-R transfected into CHO cells (K(i): beta-MSH, 11.4+/-0.4 nmol/l versus alpha-MSH, 324+/-16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates (K(i): beta-MSH, 5.0+/-0.4 nmol/l versus alpha-MSH, 22.5+/-2.3 nmol/l, P<0.001). Incubation of brain slices with 5 microM beta-MSH significantly increased [35S]GTPgammaS binding by 140-160% (P<0.001), indicating activation of G-protein-coupled receptors (GPCRs), in the hypothalamic ventromedial (VMH), dorsomedial (DMH), arcuate (ARC) and paraventricular (PVN) nuclei. These sites match the distribution of beta-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased beta-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst alpha-MSH concentrations were unchanged. We propose that increased beta-MSH concentrations reflect blockade of the peptide's release in these sites, consistent with the increased hunger and the known up-regulation of MC4-R in the same nuclei. Thus, we conclude that (1). beta-MSH has higher affinity at MC4-R than alpha-MSH; (2). beta-MSH activates GPCR in these sites, which are rich in MC4-R; and (3). beta-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that beta-MSH rather than alpha-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of beta-MSH is one mechanism contributing to hunger in under-feeding." [Abstract]

Adage, Tiziana, Scheurink, Anton J. W., de Boer, Sietse F., de Vries, Koert, Konsman, Jan Pieter, Kuipers, Folkert, Adan, Roger A. H., Baskin, Denis G., Schwartz, Michael W., van Dijk, Gertjan
Hypothalamic, Metabolic, and Behavioral Responses to Pharmacological Inhibition of CNS Melanocortin Signaling in Rats
J. Neurosci. 2001 21: 3639-3645
"The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake-independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i.e., corticotropin-releasing hormone (CRH), cocaine-amphetamine-related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle-treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight ( approximately 14%) and fat content ( approximately 90%), hepatic glycogen content ( approximately 40%), and plasma levels of cholesterol ( approximately 48%), insulin ( approximately 259%), glucagon ( approximately 80%), and leptin ( approximately 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair-feeding of i3vt SHU9119-treated animals to i3vt vehicle-treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol ( approximately 31%) and leptin ( approximately 104%) and body fat content ( approximately 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i.e., CART, POMC, and NPY) and paraventricular (i.e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake-dependent and -independent mechanisms." [Full Text]

Nicholas LM, Ford AL, Esposito SM, Ekstrom RD, Golden RN.
The effects of mirtazapine on plasma lipid profiles in healthy subjects.
J Clin Psychiatry. 2003 Aug;64(8):883-9.
"BACKGROUND: The novel antidepressant mirtazapine has been linked to elevated random plasma total cholesterol (TC) levels. The purpose of this study was to evaluate in a more controlled and precise approach the putative effects of mirtazapine on plasma lipids. METHOD: In a double-blind design, 50 healthy subjects (30 women and 20 men) were randomized to receive either mirtazapine (N = 28) or placebo (N = 22) for a 4-week period. The study was conducted from June 1997 to September 1998. The initial dose for the mirtazapine group was 15 mg daily, which was increased to 30 mg daily at the beginning of the second week. Body weight and plasma lipoprotein profiles, including TC, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides, were determined at baseline and at weekly intervals throughout the study period. RESULTS: At baseline, there were no group differences in any of the measures. There was a statistically significant increase of 2.5% in mean body weight over the course of the study in the mirtazapine group that appeared to reach a plateau at 3 weeks, while no increase was observed in the placebo group. Mirtazapine subjects also showed significantly increased TC at week 4 (p =.016) and a transient rise in triglycerides that normalized by week 4. No significant changes in any of the other lipid parameters, including HDL, LDL, and TC/HDL ratios, were observed within either group. Changes in TC were significantly and positively correlated with changes in weight (p <.01). CONCLUSION: These results suggest that while mirtazapine may be associated with increased TC, it does not increase LDL levels or affect the ratio of TC to HDL." [Abstract]

Skuladottir, Gudrun V., Jonsson, Logi, Skarphedinsson, Jon O., Mutulis, Felikss, Muceniece, Ruta, Raine, Amanda, Mutule, Ilze, Helgason, Johannes, Prusis, Peteris, Wikberg, Jarl E.S., Schioth, Helgi B.
Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist
Br. J. Pharmacol. 1999 126: 27-34
"1. We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2. One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH2(22)]-beta-MSH11-22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3. HS028 antagonised a alpha-MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4. Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5. This is the first report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis." [Abstract]

JA Harrold, PS Widdowson, and G Williams
Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding
Diabetes 48: 267-271, 1999.
"We have examined the effects of underfeeding and obesity on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding." [Abstract/Full Text]

Birt J.
Management of weight gain associated with antipsychotics.
Ann Clin Psychiatry. 2003 Mar;15(1):49-58.
"The prevalence of overweight and obesity in untreated patients with severe mental illness mimicks the trends seen in the general population. Furthermore, weight gain is likely to occur with the addition of pharmacotherapy with an antipsychotic. The literature does indicate that despite fundamental cognitive and psychosocial deficits seen in patients with severe and persistent mental disorders such as schizophrenia and bipolar disorder, it is possible to effectively manage weight gain in this population. In particular, behavioral interventions have been shown to be effective in the prevention and treatment of weight gain associated with antipsychotic therapy. Some success has also been seen with the use of adjunctive medication such as amantadine, histamine (H2) antagonists, metformin, topiramate, and orlistat. Additional, prospective, controlled studies of long-term antipsychotic drug associated weight gain and its clinical consequences are needed in order to identify the most effective therapy for the reduction and maintenance of body weight in patients taking antipsychotic therapy." [Abstract]

Kraus T, Haack M, Schuld A, Hinze-Selch D, Koethe D, Pollmacher T.
Body Weight, the Tumor Necrosis Factor System, and Leptin Production during Treatment with Mirtazapine or Venlafaxine.
Pharmacopsychiatry 2002 Nov;35(6):220-5
"Weight gain is a frequent and important side effect of psychopharmacotherapy. Recent studies suggest that the fat-cell-derived hormone leptin and the tumor necrosis factor-alpha (TNF-alpha) cytokine system are pathophysiologically involved. No information is available concerning the influence of the antidepressants mirtazapine and venlafaxine on these immunoendocrine variables. An open-labeled study was performed in 20 patients suffering from major depression treated with either mirtazapine (N = 11) or venlafaxine (N = 9). During 4 weeks, the patients' weight, body mass index (BMI), and plasma levels of leptin, TNF-alpha, sTNF-R p55, and sTNF-R p75 were assessed. Mirtazapine induced a significant increase in weight (mean weight gain: 2.4 kg) that was evident after the first week of treatment. In parallel, the plasma levels of TNF-alpha and both soluble TNF receptors increased. In addition, a slight rise in leptin levels, which occurred slowly and was significant only at the end of the 4 th week of treatment, was observed. Weight decreased slightly but significantly in patients treated with venlafaxine (mean weight loss: 0.4 kg), whereas plasma levels of leptin, TNF-alpha, or soluble TNF receptors did not change significantly. The present results further support the notion that the activation of the TNF-alpha cytokine system is an early, sensitive, and specific marker of weight gain induced by psychotropic agents. In contrast, the effects of such drugs on leptin production seem to be less sensitive with respect to weight gain and more variable." [Abstract]

Rajora, Nilum, Boccoli, Giovanni, Burns, Dennis, Sharma, Sarita, Catania, Anna P., Lipton, James M.
alpha -MSH Modulates Local and Circulating Tumor Necrosis Factor-alpha in Experimental Brain Inflammation
J. Neurosci. 1997 17: 2181-2186
"The neuroimmunomodulatory peptide alpha-MSH modulates actions and production of proinflammatory cytokines including TNF-alpha, but there is no prior evidence that it alters TNF-alpha induced within the brain. To test for this potential influence of the peptide, TNF-alpha was induced centrally by local injection of bacterial lipopolysaccharide (LPS). alpha-MSH given once i.c.v. with LPS challenge, twice daily intraperitoneally (i.p.) for 5 d between central LPS injections, or both i.p. and centrally, inhibited production of TNF-alpha within brain tissue. Inhibition of TNF-alpha protein formation by alpha-MSH was confirmed by inhibition of TNF-alpha mRNA. Plasma TNF-alpha concentration was elevated markedly after central LPS, indicative of an augmented peripheral host response induced by the CNS signal. The increase was inhibited by alpha-MSH treatments, in relation to inhibition of central TNF-alpha. Presence within normal mouse brain of mRNA for the alpha-MSH receptor MC-1 suggests that the inhibitory effects of alpha-MSH on brain and plasma TNF-alpha might be mediated by this receptor subtype. The inhibitory effect of alpha-MSH on brain TNF-alpha did not depend on circulating factors because the effect also occurred in brain tissue in vitro." [Full Text]

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 pharmacogenetic puzzle.
J Clin Psychiatry 2001;62 Suppl 23:45-66
"Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing." [Abstract]

Wetterling T.
Bodyweight gain with atypical antipsychotics. A comparative review.
Drug Saf 2001 Jan;24(1):59-73
"The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity." [Abstract]

Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, Mintz J, Marder SR.
Novel antipsychotics: comparison of weight gain liabilities.
J Clin Psychiatry 1999 Jun;60(6):358-63
"BACKGROUND: We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain. METHOD: Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated. RESULTS: Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04). CONCLUSION: Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings." [Abstract] [Examine the reliability of the last statement made given the evidence shown below that olanzapine is a more potent drug at histamine H1 receptors than clozapine is.]

Richelson E, Souder T.
Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds.
Life Sci 2000 Nov 24;68(1):29-39
"Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (K(d)s) for nine new antipsychotic drugs (iloperidone, melperone, olanzapine, ORG 5222, quetiapine, risperidone, sertindole, ziprasidone, and zotepine), one metabolite of a new drug (9-OH-risperidone), and three older antipsychotics (clozapine, haloperidol, and pimozide) at nine different receptors (alpha1-adrenergic, alpha2-adrenergic, dopamine D2, histamine H1, muscarinic, and serotonin 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C receptors). Iloperidone was the most potent drug at the two adrenergic receptors. ORG 5222 was the most potent drug at dopamine D2 and 5-HT2c receptors, while ziprasidone was the most potent compound at three serotonergic receptors (5-HT1A, 5-HT1D, and 5-HT2A). At the remaining two receptors, olanzapine was the most potent drug at the histamine H1 receptor (Kd=0.087 nM); clozapine at the muscarinic receptor (Kd=9 nM). Certain therapeutic and adverse effects, as well as certain drug interactions can be predicted from a drug's potency for blocking a specific receptor. These data can provide guidelines for the clinician in the choice of antipsychotic drug."
[Abstract]

Sanchez C, Arnt J.
In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics.
Behav Pharmacol 2000 Jun;11(3-4):291-8
"The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature." [Abstract]

Reynolds GP, Zhang Z, Zhang X.
Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain.
Am J Psychiatry. 2003 Apr;160(4):677-9.
"OBJECTIVE: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. A recent study showed that a polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene is associated with antipsychotic-induced weight gain. The authors determined whether this association held true for weight gain after clozapine treatment. METHOD: Thirty-two Chinese Han patients with first-episode schizophrenia were genotyped for the -759C/T polymorphism and had weight changes monitored after 6 weeks of clozapine treatment. RESULTS: The authors found that the 10 patients with the -759T variant allele showed significantly less weight gain than those without this allele. The effect was strongest in the male patients and not apparent in the female patients. CONCLUSIONS: These findings identify an important genetic factor associated with clozapine-induced weight increases in schizophrenia." [Abstract]

Reynolds GP, Zhang ZJ, Zhang XB.
Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism.
Lancet 2002 Jun 15;359(9323):2086-7
"A side-effect of treatment with antipsychotic drugs for schizophrenia is increased body fat, which leads to further morbidity and poor adherence to treatment. The 5-hydroxytryptamine 2C receptor (5-HT2C) has been associated with this effect; we aimed to establish whether a genetic polymorphism of the promoter region of this receptor affects weight gain after drug treatment in first-episode patients with schizophrenia. We noted significantly less weight gain in patients with the -759T variant allele (p=0.0003) than in those without this allele, who were more likely to have substantial (>7%) weight gain (p=0.002). We have identified a genetic factor that is associated with antipsychotic drug-induced weight gain." [Abstract]

Zhang Z, Zhang X, Yao Z, Chen J, Sun J, Yao H, Hou G, Zhang X, Reynolds GP.
[Association of antipsychotic agent-induced weight gain with a polymorphism of the promotor region of the 5-HT2C receptor gene]
Zhonghua Yi Xue Za Zhi 2002 Aug 25;82(16):1097-101
"OBJECTIVE: To determine whether 5-hydroxytryptamine 2C (5-HT2C) receptor gene 759C/T polymorphism influences the weight gain following antipsychotic agents (APS) treatment in patient with schizophrenia. METHODS: DNA was extracted from the peripheral blood of 117 Chinese first-episode patients of Han nationality with schizophrenia diagnosed according to CCMD-II-R criteria. PCR-RELP technique was used to analyse the frequencies of 5-HTR2C receptor gene 759C/T hemizygote (male) and genotype (female). Monotherapy with APS (chlorpromazine or rispperidone) was given for 10 weeks. The body weight was taken and body mass index (BMI) was calculated on admission and every week subsequently for each patient. The correlation of hemizygote or genotype and the BMI was analyzed. RESULTS: Ten weeks after treatment, there was an average increase in body weight of (3.2 +/- 3.5) kg or (5.7 +/- 6.2)% of the baseline weight with a range of -7 kg approximately 12 kg or -7.8% approximately 32%. The frequency of mutant hemizygote was 58% among the 58 male subjects; the frequency of mutant homozygote was 0%, and the frequency of mutant heterozygote was 27.0% among the 59 female subjects. The body weight gain > 7% occurred in 53% of wild type hemizygote males and 47% of wild type homozygote females; and only 18% of mutant hemizygote males and 13% of mutant heterozygote females. The proportions of 759T hemizygote males or heterozygote females in those with body weight gain > 7% and those with body weight < 7% were significantly different (chi(2) = 22.35, v1, P = 0.000 1; chi(2) = 12.36, v1, P = 0.000 1). Patients without mutant allele were five to six times more likely to develop substantial weight gain (OR = 5.11, 6.68). CONCLUSION: The 5-HT2C-receptor gene -759C/T polymorphism is associated with APS-induced weight gain. 759C-->T may be a protective factor for the development of weight gain in Chinese schizophrenic patients of Han nationality." [Abstract]

Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM.
RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist.
Neuropharmacology 1997 Apr-May;36(4-5):621-9
"Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats." [Abstract]

Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D.
Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.
Nature 1995 Apr 6;374(6522):542-6
"Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite." [Abstract]

Nonogaki K, Strack AM, Dallman MF, Tecott LH.
Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene.
Nat Med 1998 Oct;4(10):1152-6
"Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes." [Abstract]

Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K.
Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes.
Diabetologia 2000 Mar;43(3):373-6
"AIMS/HYPOTHESIS: Polymorphisms in the upstream region of the 5-HT2C receptor gene could play a part in the development of obesity. METHODS: We screened the upstream region from 27 men by the single strand conformational polymorphism analysis and PCR-direct sequencing and then genotyped 466 non-obese (body mass index < 28 kg/m2) and 123 obese (> or = 28 kg/m2) men including 138 patients with Type II (non-insulin-dependent) diabetes mellitus. RESULTS: Three loci of single nucleotide substitution (G-->A at -995, C-->T at -759, G-->C at -697) and a (GT)n dinucleotide repeat polymorphism at -1,027 were identified. The frequency of -995/-759 and -697 variants was higher in non-obese subjects and that of -995/-759 variants in non-diabetic subjects. In the dinucleotide repeat locus, five alleles were detected including Z containing 17 repeats. The Z - 6 allele was more common in non-obese subjects and the Z + 2 allele in obese subjects. Haplotype 3 (Z - 6, -995A, -759T, -697C) was associated with leanness (p = 0.02) and the absence of diabetes (p = 0.033) and haplotype 9 (Z + 2, -995G, -759C, -697G) with obesity (p = 0.007). Haplotype 2 (Z - 6, -995G, -759C, -697C) tended to be more common in non-obese subjects. A luciferase reporter assay showed that haplotype 2 and haplotype 3 had 1.44- or 2.58-fold higher promoter activities than the most common haplotype 6 (Z, -995G, -759C, -697G). CONCLUSION/INTERPRETATION: The haplotypes containing the nucleotide substitutions could be associated with higher transcription levels of the gene and thereby with resistance to obesity and Type II diabetes. Promoter polymorphisms of the 5-HT2C receptor gene may play an important part in genetic predisposition to the disorders." [Abstract]

Sakata T, Yoshimatsu H, Kurokawa M.
Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism.
Nutrition 1997 May;13(5):403-11
"In a series of studies on histaminergic functions in the hypothalamus, probes to manipulate activities of histaminergic neuron systems were applied to assess its physiologic and pathophysiologic implications using non-obese normal and Zucker obese rats, an animal model of genetic obesity. Food intake is suppressed by either activation of H1-receptor or inhibition of the H3-receptor in the ventromedial hypothalamus (VMH) or the paraventricular nucleus, each of which is involved in satiety regulation. Histamine neurons in the mesencephalic trigeminal sensory nucleus modulate masticatory functions, particularly eating speed through the mesencephalic trigeminal motor nucleus, and activation of the histamine neurons in the VMH suppress intake volume of feeding at meals. Energy deficiency in the brain, i.e., intraneuronal glucoprivation, activates neuronal histamine in the hypothalamus. Such low energy intake in turn accelerates glycogenolysis in the astrocytes to prevent the brain from energy deficit. Thus, both mastication and low energy intake act as afferent signals for activation of histaminergic nerve systems in the hypothalamus and result in enhancement of satiation. There is a rationale for efficacy of a very-low-calorie conventional Japanese diet as a therapeutic tool for weight reduction. Feeding circadian rhythm is modulated by manipulation of hypothalamic histamine neurons. Hypothalamic histamine neurons are activated by an increase in ambient temperature. Hypothalamic neuronal histamine controls adaptive behavior including a decrease in food intake and ambulation, and an increase in water intake to maintain body temperature to be normally constant. In addition, interleukin-1 beta, an endogenous pyrogen, enhanced turnover of neuronal histamine through prostaglandin E2 in the brain. Taken together, the histamine neuron system in the hypothalamus is essential for maintenance of thermoregulation through the direct and indirect control of adaptive behavior. Behavioral and metabolic abnormalities of obese Zucker rats including hyperphagia, disruption of feeding circadian rhythm, hyperlipidemia, hyperinsulinemia, and disturbance of thermoregulation are essentially derived from a defect in hypothalamic neuronal histamine. Abnormalities produced by depletion of neuronal histamine from the hypothalamus in normal rats mimic those of obese Zuckers. Grafting the lean Zucker fetal hypothalamus into the obese Zucker pups attenuates those abnormalities. These findings indicate that histamine nerve systems in the brain play a crucial role in maintaining homeostatic energy balance." [Abstract]

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Recent Mirtazapine & Weight Gain Research

1) Segers K, Surquin M
Can Mirtazapine Counteract the Weight Loss Associated With Alzheimer Disease? A Retrospective Open-label Study.
Alzheimer Dis Assoc Disord. 2012 Jul 2;
Weight loss is a frequent complication of Alzheimer disease (AD), associated with increased morbidity and mortality. Increased appetite and weight gain are known side effects of the antidepressant mirtazapine. This analysis was undertaken to assess the safety and potential utility of mirtazapine to counteract weight loss in patients with AD or mixed AD (AD with cerebrovascular lesions). We performed a retrospective analysis of the clinical records of all outpatients attending our memory clinic for AD or mixed AD, who had received mirtazapine (30 mg daily) with the specific purpose of inducing weight or appetite gain. Data were available for a total of 22 patients (mean age, 80.9 y, 86.4% female). The mean weight at baseline was 52.4 kg and the mean BMI was 20.5 kg/m. 77.3% of the patients had gained weight after 3 months (mean gain, 1.93 kg or 3.9% of initial body weight) and 82.3% after 6 months (2.11 kg or 4.6%). One patient had to discontinue mirtazapine because of daytime sleepiness. Mirtazapine seems to be a safe and useful approach to counteract weight loss in AD, if possible in combination with nonpharmacological interventions. Body weight should be monitored during treatment to avoid excessive weight gain. [PubMed Citation] [Order full text from Infotrieve]


2) Jiang SM, Wu JH, Jia L
Intervention of Mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts.
World J Gastroenterol. 2012 Jun 14;18(22):2867-71.
[PubMed Citation] [Order full text from Infotrieve]


3) Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, Furukawa TA
Mirtazapine versus other antidepressive agents for depression.
Cochrane Database Syst Rev. 2011 12;(12):CD006528.
[PubMed Citation] [Order full text from Infotrieve]


4) Coskun M, Alyanak B
Psychiatric Co-morbidity and Efficacy of Mirtazapine Treatment in Young Subjects With Chronic or Cyclic Vomiting Syndromes: A Case Series.
J Neurogastroenterol Motil. 2011;17(3):305-11.
The aim of this case report was to evaluate the psychiatric co-morbidity and efficacy of mirtazapine treatment in young subjects with chronic or cyclic vomiting syndromes. This is a case series of 8 young subjects (age range of 6-16 years, 11.12 ▒ 3.52 years) who were referred or consulted to child psychiatry department. They were referred or consulted by pediatric gastroenterology or surgery departments for the presence of non-remitting and medically unexplained vomiting. They were investigated for co-morbid psychiatric disorders using a structured psychiatric interview. An open trial of mirtazapine was conducted for the treatment and/or prevention of vomiting. Primary outcome measure was Clinical Global Impression-Improvement scale. Subjects were diagnosed with chronic (n = 5) or cyclic (n = 3) vomiting syndromes. Duration of vomiting ranged from 6 months to 10 years (3.5 ▒ 3.2 years). All subjects received multiple psychiatric diagnoses with anxiety disorders being the most frequent. Maximum mirtazapine dosage was 7.5-30 mg/day (16.00 ▒ 6.16 mg/day). Three subjects showed complete remission and 5 subjects showed much to very much improvement in vomiting. Most frequent side effects were increased appetite, weight gain and sedation. Young subjects with chronic or cyclic vomiting may frequently suffer anxiety and/or depressive symptoms or disorders. Mirtazapine could be an effective treatment option for the treatment of vomiting and co-morbid anxiety or depressive disorders in these subjects. More systematic research are needed on this topic. [PubMed Citation] [Order full text from Infotrieve]


5) McGuire JL, Fridman V, WŘthrich C, Koralnik IJ, Jacobs D
Progressive multifocal leukoencephalopathy associated with isolated CD8+ T-lymphocyte deficiency mimicking tumefactive MS.
J Neurovirol. 2011 Jul;17(5):500-3.
[PubMed Citation] [Order full text from Infotrieve]


6) Dolev Z
Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin add-on and monotherapy.
Arch Womens Ment Health. 2011 Oct;14(3):269-73.
[PubMed Citation] [Order full text from Infotrieve]


7) Chiu HW, Li TC
Rapid weight gain during mirtazapine treatment.
J Neuropsychiatry Clin Neurosci. 2011 Jun;23(1):E7.
[PubMed Citation] [Order full text from Infotrieve]


8) Sahoo J, Pattnaik AK, Mishra N
Behavioral and developmental changes in rats with prenatal exposure of mirtazapine.
Sci Pharm. 2011;78(3):451-63.
Mirtazapine is an often used antidepressant drug; however insufficient information is available regarding its safety during pregnancy. Therefore, this work was initiated to study the effect of prenatal exposure of mirtazapine on postnatal developments of rats. The study was conducted on pregnant rats to observe the safety profile of mirtazapine in comparison to control. The percentage weight gain, gestation period and litter size of the rats treated with double therapeutic dose (DTD) was significantly lower than the rats treated with therapeutic dose (TD) and rats of control group. However the litter size of the TD treated rats was also found smaller than the control. The offspring were examined through battery of test in order to evaluate their developmental neurotoxicity. The test includes the assessment of postnatal growth, reflex ontogeny, neuromotor abilities, activity level, emotional reactivity and learning ability. The DTD exposure negatively affected on overall growth of pups in comparison to TD exposed pups and control group. Further, the amine concentration in brain was also found significantly lower in DTD exposed pups. Therefore, this study reveals that the treatment of pregnant rats with TD and DTD decreases their litter size. In addition the prenatal exposure of DTD of mirtazapine negatively affects on neurodevelopment of rats. [PubMed Citation] [Order full text from Infotrieve]


9) Cho SJ, Yook K, Kim B, Choi TK, Lee KS, Kim YW, Lee JE, Suh S, Yook KH, Lee SH
Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial.
Prog Neuropsychopharmacol Biol Psychiatry. 2010;35(1):208-11.
This preliminary study aimed to determine if adding mirtazapine to risperidone might improve negative and cognitive symptoms in schizophrenia. In an 8-week, double-blind clinical trial, we randomly assigned 21 stabilized outpatients with schizophrenia undergoing risperidone treatment to adjunctive treatment with either mirtazapine or a placebo. The mirtazapine group exhibited a statistically significant improvement in cognitive function, including vocabulary and immediate memory, and negative symptoms (as measured by negative symptom scales) and showed an adverse effect of 5.83 kg mean weight gain. This study suggests augmenting risperidone with mirtazapine can effectively improve both negative and some cognitive symptoms of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]


10) Serretti A, Mandelli L
Antidepressants and body weight: a comprehensive review and meta-analysis.
J Clin Psychiatry. 2011 Jan 15;71(10):1259-72.
[PubMed Citation] [Order full text from Infotrieve]


11) Kast RE
Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct.
Turk Neurosurg. 2010 Oct;20(4):425-9.
CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma's use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population's homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+-activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment. [PubMed Citation] [Order full text from Infotrieve]


12) Laino CH, Fonseca C, Sterin-Speziale N, Slobodianik N, ReinÚs A
Potentiation of omega-3 fatty acid antidepressant-like effects with low non-antidepressant doses of fluoxetine and mirtazapine.
Eur J Pharmacol. 2010 Oct;648(1-3):117-26.
Despite the advances in psychopharmacology, the treatment of depressive disorders is still not satisfactory. Side effects and resistance to antidepressant drugs are the greatest complications during treatment. Based on recent evidence, omega-3 fatty acids may influence vulnerability and outcome in depressive disorders. The aim of this study was to further characterize the omega-3 antidepressant-like effect in rats in terms of its behavioral features in the depression model forced swimming test either alone or in combination with antidepressants fluoxetine or mirtazapine. Ultimately, we prompted to determine the lowest dose at which omega-3 fatty acids and antidepressant drugs may still represent a pharmacological advantage when employed in combined treatments. Chronic diet supplementation with omega-3 fatty acids produced concentration-dependent antidepressant-like effects in the forced swimming test displaying a behavioral profile similar to fluoxetine but different from mirtazapine. Fluoxetine or mirtazapine at antidepressant doses (10 and 20 mg/kg/day, respectively) rendered additive effects in combination with omega-3 fatty acid supplementation (720 mg/kg/day). Beneficial effects of combined treatment were also observed at sub-effective doses (1 mg/kg/day) of fluoxetine or mirtazapine, since in combination with omega-3 fatty acids (720 mg/kg/day), antidepressants potentiated omega-3 antidepressant-like effects. The antidepressant-like effects occurred in the absence of changes in brain phospholipid classes. The therapeutic approach of combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression, especially in patients with depression resistant to conventional treatments and even may contribute to patient compliance by decreasing the magnitude of some antidepressant dose-dependent side effects. [PubMed Citation] [Order full text from Infotrieve]


13) Risselada AJ, Mulder H, Heerdink ER, Grube AM, Wilmink FW, Egberts TC
The association between serotonin 2C receptor polymorphisms and weight gain and eating behavior in patients using mirtazapine: a prospective follow-up study.
J Clin Psychopharmacol. 2010 Dec 1;30(2):207-9.
[PubMed Citation] [Order full text from Infotrieve]


14) Padala KP, Padala PR, Malloy T, Burke WJ
New onset multimodal hallucinations associated with mirtazapine: a case report.
Int Psychogeriatr. 2010 Apr;22(5):837-9.
Mirtazapine, a commonly used antidepressant, has a relatively safe side effect profile and is commonly used in the elderly for treatment of depression. It has been proposed as being particularly suitable for patients with depression associated with insomnia and weight loss. Although mental status changes and perceptual abnormalities secondary to its use are rare, special care needs to be taken, especially while starting treatment or while increasing the dose. We report three cases of auditory, musical and visual hallucinations associated with the use of mirtazapine. [PubMed Citation] [Order full text from Infotrieve]


15) Safer DL, Darcy AM, Lock J
Use of mirtazapine in an adult with refractory anorexia nervosa and comorbid depression: a case report.
Int J Eat Disord. 2010 Aug;44(2):178-81.
The objective of this report was to describe an efficacious treatment of an adult with long-standing anorexia nervosa (AN). A 50-year-old woman with an over 7-year history of AN and comorbid major depression had been treated unsuccessfully with numerous psychotropic medications, manualized cognitive behavior therapy, and an intensive outpatient treatment program before referral. After treatment with mirtazapine, she gained weight and her depression improved. A 9-month follow-up revealed a maintenance of these benefits. Mirtazapine may be useful for older, chronically ill patients presenting with AN and comorbid depression. [PubMed Citation] [Order full text from Infotrieve]


16) Markoula S, Konitsiotis S, Chatzistefanidis D, Lagos G, Kyritsis AP
Akathisia induced by mirtazapine after 20 years of continuous treatment.
Clin Neuropharmacol. 2011 Mar;33(1):50-1.
[PubMed Citation] [Order full text from Infotrieve]


17) Hay PJ, Claudino AM
Bulimia nervosa.
Clin Evid (Online). 2010 Jan-Feb;2010
[PubMed Citation] [Order full text from Infotrieve]


18) Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, McGuire H, Churchill R, Furukawa TA
Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis.
CNS Drugs. 2010;24(1):35-53.
[PubMed Citation] [Order full text from Infotrieve]


19) Danileviciūte V, Sveikata A, Adomaitiene V, Gumbrevicius G, Fokas V, Sveikatiene R
Efficacy, tolerability, and preference of mirtazapine orally disintegrating tablets in depressed patients: a 17-week naturalistic study in Lithuania.
Medicina (Kaunas). 2010 Jan;45(10):778-84.
Mirtazapine is an established antidepressant with well-documented efficacy demonstrated in controlled clinical trials. However, the gap between the results obtained in controlled clinical trials and everyday clinical practice exists. Therefore, the importance of naturalistic studies in psychiatry is becoming recognized. The aim of present naturalistic study was to acquire data on efficacy, safety, and preference of mirtazapine orally disintegrating tablets during a 17-week treatment of depression. This prospective, open-label, multicenter study in patients with mild to severe depression was conducted at 47 mental health centers of Lithuania by 78 psychiatrists. Patients were initially given 15 mg or 30 mg of mirtazapine orally disintegrating tablets; the maximum allowed dose was 45 mg per day. The primary efficacy measure was the total score on the Hamilton Depression Rating Scale-17 (HAMD-17), the Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scales. Tolerability was primarily measured by assessing the incidence of treatment-emergent adverse events. Patients were evaluated at baseline, at weeks 1, 5, 9, 13, and 17. A total of 779 patients (595 women [76.4%] with a mean [SD] age of 50.2 [13.65] and 184 men [23.6%] with a mean [SD] age of 52.4 [14.6] years) were enrolled into the study; 687 (88.2%) patients completed the study. The mean (SD) daily dose of mirtazapine orally disintegrating tablets was 29.0 (3.8) mg. The mean total (SD) HAMD-17 score improved significantly from 25.7 (4.6) to 7.3 (4.3) (P<0.005). At each visit, the mean HAMD-17 score was significantly lower than that at the preceding visit. At week 17, remission (HAMD-17 score < or =7) was observed in 436 (56%) patients. The mean (SD) CGI-S score improved significantly from 4.9 (1.0) at baseline to 1.5 (0.6) at endpoint (P<0.001). According to the CGI-I assessments, 621 patients (89.4%) improved and improved very much. The vast majority of patients (80%) preferred the new formulation of mirtazapine - mirtazapine orally disintegrating tablet. Treatment-emergent adverse events occurred in 106 patients (13.6%). The most frequent adverse events were weight gain, sedation, dizziness, and dry mouth. In this study conducted in Lithuania with depressed patients, a significant improvement was shown in all efficacy measures. In addition, mirtazapine orally disintegrating tablet was a well-tolerated and preferable formulation for the treatment of depressed patients. [PubMed Citation] [Order full text from Infotrieve]