Posted by Sunnely on November 28, 2000, at 23:57:56
In reply to survey/weight gain, posted by cs on November 28, 2000, at 19:21:38
> Just curious-I have been reading the boards and so many people mention a weight gain with anti-depressants. Does anyone know what causes that?
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Virtually all antidepressants, except probably nefazodone (Serzone) and bupropion (Wellbutrin), are capable of inducing weight gain early on or during the late stages of treatment.
The exact cause(s) of antidepressant-induced weight gain remain unclear. Some of the possible mechanisms proposed include: 1) recovery from depression or clinical improvement, 2) appetite increase/carbohydrate craving, and 3) a great variety of regulatory substances, operating alone or in concert, involved in the complex regulation of appetite behavior. These include neurotransmitters such as norepinephrine (NE), dopamine (DA), histamine (H1), serotonin (5HT), neuropeptides such as cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y and opioids and other hormone-like peptides such as enterostatin, bombesin, amylin, and leptin. In addition, there appears to be increasing evidence suggesting a role for nitric oxide (NO) in regulating food intake.
THE ROLE OF NOREPINEPHRINE (NE) RECEPTORS:
The appetite-suppressant effect of sibutramine (Meridia), a NE-5HT selective reuptake inhibitor, is fully reversed by alpha-1 adrenergic receptor blockade and partially inhibited by beta-1 adrenergic receptor or 5HT2 receptor blockade, suggesting that stimulation of alpha-1 receptors plays a prominent role in appetite regulation.
THE ROLE OF DOPAMINE (DA) RECEPTORS:
A role for DA was suggested by the early observations that traditional antipsychotics, which are potent dopamine (D2) receptor blockers, are associated with significant weight gain. Conversely, amphetamines, which are powerful dopamine agents, have long been recognized as appetite-suppressant agents through an increase in arousal and/or decreasing hunger and food intake.
THE ROLE OF HISTAMINE RECEPTORS:
Histamine receptors exert an inhibitory action on feeding via histamine 1 (H1) receptors located in the (ventromedial) hypothalamus. For many years, blockade of H1 receptors have been associated with weight gain observed with the tricyclic antidepressants (TCAs). In rats, the stimulating action on carbohydrate intake induced by H1 blockade is well documented. However, this direct relationship has been difficult to establish in humans.
THE ROLE OF SEROTONIN (5HT) RECEPTORS:
There is evidence supporting the involvement of various 5HT receptor subtypes in appetite regulation, especially 5HT2C receptor. The obesity phenotype (gene) has been found in 5HT2C receptor-null mutant mice, as has elevated body weight, adipose (fatty) tissue deposition, and a tendency to display a resistance to the appetite suppresant actions of 5HT agonists (enhancers).
THE ROLE OF NMDA GLUTAMATE (EXCITATORY) RECEPTORS:
The excitatory receptors, N-methyl-D-aspartate (NMDA) glutamate, have been implicated in appetite regulation at the level of (lateral) hypothalamus. NMDA receptor stimulation also leads to nitric oxide synthesis, which has been found to exercise significant effects on appetite. Other glutamate receptors may be operating too. Topiramate (Topamax), an anticonvulsant drug with selective binding for the kainate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of excitatory glutamate receptor, induces weight loss and dulling of appetite in 10%-20% of patients.
THE ROLE OF GABA (INHIBITORY) RECEPTORS:
The opposite (NMDA glutamate) appears to apply to the role of gamma-aminobutyric acid (GABA) in appetite regulation where stimulation of GABA-A receptors (in nucleus accubens) stimulates feeding. Moreover, anticonvulsants that exert their therapeutic effects by potentiating or increasing GABA transmission, such as vigabatrin (Sabril, Sabrilex) and valproic acid (Depakene, Depakote), have been associated with weight gain.
The above mechanisms involving glutamate, GABA, or nitric oxide (NO) may play a subtle role in selective serotonin reuptake inhibitor (SSRI)- and TCA-induced appetite changes.
THE ROLE OF LEPTINS (VERY INTERESTING):
The recent discovery of leptin (from the Greek word "leptos," meaning thin), has greatly advanced our understanding of body adiposity and energy balance regulation. This hormone, produced mainly by adipose (fatty) tissue, conveys to the brain information about the size of energy stores and activates the hypothalamus centers that regulate energy intake and expenditure. Moreover, leptin affects several neuroendocrine mechanisms and regulates multiple hypothalamic-pituitary axes. The realization that adipose tissue is not simply a storage depot but also an important endocrine gland has created new opportunities for investigating the mechanism of weight gain stimulated by some pharmacologic drugs including the antidepressants.
The causation viewpoint of the pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and leptin. In obese animals, an increase in leptin receptor activity leads to an increase in NPY concentrations with resultant hyperphagia (overeating). Therefore, a functional loop between NPY and leptin has been postulated. Elevated levels of nocturnal (nighttime) leptin secretion have been observed in depressed patients that may contribute to the variable eating patterns characteristic of the condition. The long-term effects of psychotropic medications on these systems remain to explored, yet it is now apparent that leptin can exert effects on serotonin function. Fluoxetine (Prozac) has been found to decrease leptin levels and has also been found to decrease release of NPY (from arcuo-paraventricular neurons), an area highly sensitive to the appetite-enhancing effects of NPY. Similarly, olanzapine (Zyprexa) and clozapine (Clozaril), both potent 5HT2 receptor blockers, are associated with an increase in body mass and leptin levels that appear not to be attributable to dietary factors. However, it is premature at this stage to postulate whether medication induced body mass increase is caused by raised blood leptin levels or leptin receptor resistance.
poster:Sunnely
thread:49573
URL: http://www.dr-bob.org/babble/20001115/msgs/49584.html