Posted by Bill L on August 4, 2003, at 9:17:47
Docguide.com is a great website for medical information. Free registration is required to subscribe. I thought that the abstracts of these 2 papers were interesting.
1) Escitalopram (Lexapro in the US) is studied in rats using some kind of a swimming test. The author explains how the R and S isomers compete with each other (the R "counteracts the capacity" of the S) which might imply that Lexapro could be more than 2x as effective as Celexa.
2) For antidepressant related weight gain, the author recommends exercise, restricting calories, and a small amount of buproprion (Wellbutrin in the US). The author mentions that paroxetine (Paxil in the US) might cause more weight gain than other SSRI's.
Here are the abstracts:
1: Encephale. 2003 May-Jun;29(3 Pt 1):259-65. Related Articles, Links
[Mechanisms of action of antidepressants: new data from Escitalopram]
[Article in French]Fabre V, Hamon M.
INSERM U288, Neuropsychopharmacologie, CHU Pitie-Salpetriere, 91, boulevard de l'Hopital, 75634 Paris cedex 13.
A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, weight gain, dry mouth, etc, mainly caused by their capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approximately 30% of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 weeks of treatment, like that observed with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addition, the potency of Escitalopram to inhibit serotonin reuptake (K(i)=2,1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is especially relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such as fluoxetine) to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 weeks of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 weeks with any other antidepressant drug. These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is) > or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.
PMID: 12876551 [PubMed - in process]
Managing Weight Gain as a Side Effect of Some Antidepressants
A DGReview of :"Managing weight gain as a side effect of antidepressant therapy"
Cleveland Clinic Journal of Medicine07/25/2003
By Emma Hitt, PhDWeight gain associated with antidepressant use can lead to patient non-compliance with therapy. Understanding which antidepressants can result in weight gain is, therefore, important for practitioners.
In their recent article, Rashmi Deshmukh, MD, and Kathleen Franco, MD, Department of Psychiatry and Psychology, Cleveland Clinic, Ohio, United States, reviewed the various classes of antidepressants and their effects on weight gain.
Irreversible monoamine oxidase inhibitors (MAOIs), such as phenelzine, isocarboxazid, and tranylcypromine typically cause weight gain when used for less than 6 months or on a long-term basis, the authors write, while reversible MAOIs are less likely to cause weight gain, although they are not currently available in the United States.
Tricyclic antidepressants are likely to cause weight gain with both short-term and long-term use, the researchers continue, primarily because they increase appetite. Furthermore, the tertiary tricyclic drugs -- such as amitriptyline, imipramine, and doxepin -- are more likely to cause weight gain than secondary tricyclics because they are stronger histamine blockers.
In contrast, selective serotonin reuptake inhibitors (SSRIs) are not likely to cause weight gain if used for 6 months or less, although paroxetine may be more likely than other SSRIs to cause weight gain. Whether SSRIs cause weight gain when used for 1 year or longer is still under debate.
"Weight change induced by SSRIs is probably related to alteration in serotonin 2C receptor activity, appetite increase, carbohydrate craving, or recovery from clinical depression," the researchers note.
For long-term therapy, nefazodone, a phenylpiperazine with selective serotonin and norepinephrine reuptake inhibition, is less likely than SSRIs and tricyclic compounds to cause weight gain, whereas bupropion "is essentially devoid of antihistaminic effects and is commonly associated with weight loss," the authors note. "For long-term therapy, [bupropion] is less likely than SSRIs to cause weight gain," they add.
To help manage weight gain, the researchers recommend educating patients about this possible side effect, and preventing weight gain by recommending exercise and caloric restriction. Clinicians can also consider switching patients to another antidepressant drug or adding another agent, such as a stimulant or an H2 receptor agonist to therapy.
"In our practice, we have found that adding low-dose bupropion (100 to 150 mg/day) or topiramate (25 to 50 mg/day) may help weight loss when used in addition to diet control and exercise," the authors write.
Cleveland Clin J 2003;70:614-623.
poster:Bill L
thread:247996
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