5-HT blockers

On August 11, 1990, an editorial in The Lancet (5-HT Blockers, 1990) included the promotion of suicidal thoughts and behaviour (p. 346) among the adverse effects of fluoxetine. The journal was ahead of its time in its cautions ... 

Early studies from the Pfizer laboratories had revealed that compounds from a series of mzn.s-l-amino-4-phenyl-tetralins possessed potent norepinephrine (NE) uptake blocking activity. The activity was highly specific for the (1/ , 4S)-enantiomer and was confined to the trans derivatives. The corresponding (IS, 4/ )-enantiomer was much less active and the diastereomeric cis racemates were inactive at blocking NE uptake. It was subsequently shown that many compounds from the diastereomeric cis senes were unexpectedly potent and selective inhibitors of serotonin (5-HT) uptake, thus differentiating these compounds from the trans compounds. One of these compounds, sertraline (5), was originally discovered as a racemic mixture. Resolution showed that the (+)-enantiomer was several times more selective for 5-HT uptake blocking activity than the (-)-isomer. The (+)-enantiomer was subsequently shown to possess the in vivo behavioral effects expected of a potent and selective 5-HT blocker. Thus, as opposed to... 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

Figure 7.3 Dose-response effects of MDMA on the release of preloaded [3H]5-HT (left panel) and [3H]DA (right panel) from synaptosomes in vitro. [3H]Transmitter release is expressed as percent of tritium retained in tissue. Various concentrations of MDMA were incubated with or without the 5-HT uptake blocker fluoxetine (10 n/W) in [3H]5-HT assays, whereas various concentrations of MDMA were incubated with or without the DA uptake blocker GBR12909 (10 n/W) in [3H]DA assays. Data are mean SD for three separate experiments, each performed in triplicate. See Baumann et al.39 for methods.

Subjective effects were attenuated by 5-HT uptake blockers, suggesting the involvement of transporter-mediated 5-HT release. 

Bourgoin, S., Artaud, F., Bockaert, J., Hery, F., Glowinski, J., and Hamon, M. (1978) Paradoxical decrease of brain 5-HT turnover by metergoline, a central 5-HT receptor blocker. Naunyn Schmiedebergs Arch. Pharmacol., 302 313-321. 

The SSRls as a class are now widely considered to be appropriate first-line anxiolytic drugs in particular paroxetine, the most potent 5-HT reuptake blocker, has been licensed in the UK for the treatment of each of the major anxiety disorders. Short-term efficacy has been clearly demonstrated in randomised controlled trials, but in common with other antidepressants, research evidence is lacking for long-term efficacy and necessary duration of treatment. 

Gottfries CG, Nyth AL Effect of citalopram—a selective 5-HT reuptake blocker in emotionally disturbed patients with dementia. Ann N Y Acad Sci 640 276-279, 1991... 

Rabiner, E.A., Gunn. R.N., Castro. M.E., et aL beta-blocker binding to human 5-HT(1A) receptors m vivo and in vitro implications for antidepressant therapy. Neuropsychopharmacology 23(3), 285-293, 2000. 

Triazolodione has only part of the pharmacological activity of nefazodone, being a relatively pure 5-HT 2a antagonist blocker. Thus, it would be expected to produce only part of the overall pharmacological effects of the parent drug. Nonetheless, this metabolite may be clinically important because it accumulates in concentrations 10 times that of nefazodone because of its considerably longer half-life (i.e., 18 to 33 hours). 

Aprepitant NKj-receptor blocker in CNS Interferes with vomiting reflex no effect on 5-HT, dopamine, or steroid receptors Effective in reducing both early and delayed emesis in cancer chemotherapy Given orally IV fosaprepitant available fatigue, dizziness, diarrhea CYP interactions... 

Fig 2 5-HT receptors depolarize thalamic neurons by facilitating Ih. (A) Administration of 5-HTdepolarizes a neuron of the anterodorsal thalamic nucleus. This effect is mediated by the activation of 5-HT7 receptors (see text). (B) In these same cells, 5-HT shifts the voltage dependence of Ih in the depolarizing direction. (C) The serotonin-induced inward current, which mediates the depolarization, is inhibited by the Ih blocker ZD 7288. 

Fluoxetine represents US know-how at its best and has been aired in the media at a time when biological psychiatry has become supreme in North America. However, we do not know whether the drug is better than earlier antidepressants, whether 5-HT is the main neurotransmitter in depression, and whether the 5-HT uptake blockers have acceptable side effects. 

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