So what's it to be today? Would you care for our Unique Triple-Action model, or perhaps our new ultra-selective SSRI is more to your taste?
Trouble is of course that nobody knows. SSRI's, although they primarily effect serotonin, typically also increase dopamine levels after you give them for a while. It's all a big, messy feedback loop that may well be different for different individuals. Bottom line is that you have to give them to patients and see what happens.
Here's a sibutramine abstract and a sampling of others that give the general idea:
Int J Obes Relat Metab Disord 1998 Aug;22 Suppl 1:S18-28; discussion S29
Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine.
Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC
Knoll Pharmaceuticals Research & Development, Nottingham, UK.
Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.
J Clin Psychopharmacol 1998 Dec;18(6):447-54
Involvement of serotonin and dopamine in the mechanism of action of novel antidepressant drugs: a review.
Bonhomme N, Esposito E
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.
Several hypotheses regarding the physiopathology of major depression exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of depressive symptomatology. There is extensive literature describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of antidepressant drugs. However, a unitary analysis of the data in terms of interaction between different monoaminergic systems is still lacking. In this article, studies reporting the biochemical, behavioral, and clinical effects of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), selective blockers of presynaptic dopamine (DA) receptors, and antagonists of serotonin-2 (5-hydroxytryptamine-2 [5-HT2]) receptors were reviewed. Analysis of the current literature indicates that long-term treatment with antidepressants causes adaptive changes of the serotonergic and dopaminergic systems. In particular, long-term administration of TCAs enhances the responsiveness of postsynaptic serotonin receptors to iontophoretically applied serotonin and potentiates the behavioral responses to both direct and indirect dopaminergic agonists. Repeated administration of SSRIs and MAOIs increases serotonergic transmission by desensitizing the inhibitory 5-HT1A somatodendritic and terminal 5-HT1B/1D autoreceptors. Selective blockers of DA autoreceptors exert their antidepressant effect by enhancing DA release. A similar mechanism of action could be hypothesized for 5-HT2 receptor antagonists. There is general agreement that the clinical effect of antidepressant drugs, which becomes evident only after long-term treatment, is caused by their ability to induce adaptive changes of the monoaminergic systems. Increases in both serotonergic and dopaminergic function have been consistently found after long-term treatment with various classes of antidepressant drugs. Recent studies have focused on the functional interaction between the serotonergic and dopaminergic systems to explain the mechanism of the antidepressant action of SSRIs and 5-HT2 antagonists.
J Affect Disord 1998 Dec;51(3):237-54
Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion.
Horst WD, Preskorn SH
Psychiatric Research Institute, Wichita, KS 67214, USA.
[Medline record in process]
Tricyclic antidepressants have multiple sites of pharmacological actions which are responsible for their tolerability and toxicological problems as well as their efficacy. That fact has prompted the search for antidepressants with fewer sites of action. That search resulted in the serotonin selective reuptake inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs are safer and better tolerated than the TCAs, a significant percentage of patients do not benefit from SSRIs. A group of "atypical antidepressants" including bupropion, nefazodone, and venlafaxine are known to have multiple sites of antidepressant action but do not interact at sites associated with side effects or tolerance. Thus this group of antidepressants present an important alternative to the SSRIs in the pharmacological therapy of depression. The basic pharmacological properties of bupropion, nefazodone, and venlafaxine are presented along with clinical profiles and the role of these three antidepressants in the pharmacotherapy of depression is discussed
J Clin Psychopharmacol 1996 Jun;16(3 Suppl 2):1S-7S; discussion 7S-9S
Synaptic effects of antidepressants.
Richelson E
Department of Research, Mayo Clinic Jacksonville, Florida, USA.
Catecholamines, especially norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), have been implicated in the pathophysiology of depression. However, their exact roles and their interrelationship are not completely understood. Antidepressants have various effects on the body, including action at the neuronal synapses of the brain; the two most important of these effects are blockade of the reuptake of neurotransmitters, including NE, 5-HT, and dopamine, and blockade of certain neurotransmitter receptors. Currently available antidepressants may be classified as inhibitors of monoamine oxidase or as blockers of biogenic amine neurotransmitter reuptake, the latter best describing tricyclic antidepressants and selective 5-HT-reuptake inhibitors, because they block the reuptake of one or more neurotransmitters. However, recently introduced antidepressants, such as the 5-HT-NE-reuptake inhibitors, have synaptic effects that differ from those of older compounds. These synaptic effects are important in explaining certain side effects and drug-drug interactions associated with all classes of antidepresants. This article reviews the synaptic effects of marketed antidepressant agents to elucidate the anticipated side effects and drug-interaction potential of these agents.
Peter |
