Neuroguy,
In the conference call following the Prozac deal, they mentioned that Prozac II seemed to have increased 5HT2A effect compared with Prozac. My guess is that ultimately you will be able to individualize a cocktail for a particular individual, and that combinations of more specific agents will be the ultimate treatment for many depressions, anxieties etc. Lilly of course is ideally placed to do this, perhaps in combination with SNAP, who have cloned many of the 5HT receptor subtypes. (Incidentally, Lilly and SNAP are working on a 5HT1F agonist for migraine.)
Here's an abstract on the sexual dysfunction issue, and one on targeting different subtypes in anxiety:
Int Clin Psychopharmacol 1998 Jul;13 Suppl 6:S9-14
Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors
and sexual behaviour.
Olivier B, van Oorschot R, Waldinger MD
Department of Psychopharmacology, Rudolf Magnus Institute for Neurosciences,
Faculty of Pharmacy, Utrecht University, The Netherlands.
The serotonergic system in the brain modulates many types of behavioural and
physiological processes. An example of this modulatory function is seen with
the selective serotonin reuptake inhibitors (SSRIs) which enhance serotonin
transmission and influence mood, anxiety states, aggression, feeding and
sexual behaviour. At present, 14 different serotonin receptors have been
described and, although the function and localization of many of these
receptors is becoming increasingly clear, much remains unknown. The SSRIs
are intriguing drugs; by blocking presynaptic and somatodendritic serotonin
transporters, they enhance serotonergic neurotransmission and thereby
activate serotonin receptors. It is this effect which leads to the
characteristic effects of the SSRIs. Theoretically, however, it appears
possible that they may have differential effects on the various
subpopulations of serotonin receptors. Differences between the SSRIs have
recently been reported in males with rapid ejaculation; fluvoxamine, in
contrast to other SSRIs, did not affect rapid ejaculation. What difference
in the mechanism of action between the SSRIs is responsible for this
differential profile? A conditioned taste aversion procedure has been used
in mice to investigate the discriminatory stimuli (cues) of fluvoxamine and
fluoxetine. It appeared that the discriminatory stimulus of fluvoxamine is
primarily mediated via 5-hydroxytryptamine (HT)1A receptors, whilst that of
fluoxetine is primarily mediated via 5-HT2C receptors. Both types of
receptors have been implicated in depression and it is conceivable that
different SSRIs have intrinsic activity at these receptors. Investigations
are now ongoing to determine whether this differential mechanism of action
also applies to the other SSRIs and whether there are differences between
the SSRIs with respect to their effect on sexual behaviour in rodents.
Psychiatr Clin North Am 1995 Dec;18(4):895-909
Future directions in anxiolytic pharmacotherapy.
Kunovac JL, Stahl SM
Clinical Neuroscience Research Center, University of California, San Diego,
USA.
It seems that psychopharmacology may be well on its way toward the goal of
developing new anxiolytic drug(s) that are fast acting and free from the
unwanted effects associated with the traditional benzodiazepines. Several
specific candidates exist, based upon rational targeting of neurotransmitter
receptors shown to be linked to the neurobiology of anxiety. Thus, partial
agonists at the benzodiazepine receptor, such as alpidem, abecarnil, and
bretazenil, have highly promising preclinical profiles, and some useful
preliminary results in clinical testing of anxiety disorder subjects.
Neurosteroids are another interesting set of pharmacologic agents that
target the benzodiazepine receptor, have a preclinical anxiolytic profile,
and now need to be tested in clinical populations. Targeting of various
serotonin (5HT) receptor subtypes is a very active area of current research
for novel anxiolytic agents. 5HT3 antagonists may have an anxiolytic
profile, but clinical results are still preliminary and need more
validation. Of considerable interest is the idea of developing new drugs
that act at 5HT1A, 5HT2A, or 5HT2C receptors. It has even been proposed that
simultaneous targeting of both 5HT2A and 5HT1A receptors could result in
robust anxiolytic agents that will have more immediate onset of action than
currently available 5HT1A receptor acting drugs. Neuropeptide receptor
agonists and antagonists with anxiolytic properties may represent one of the
most striking new classes of potential anxiolytic drugs, but this is an
emerging field that still requires considerably more systematic clinical
testing. Nevertheless, preclinical studies as well as early clinical studies
suggest that at least three neuropeptide receptors are provocative targets
for novel anxiolytic agents: namely antagonists for CCK-B receptors,
antagonists for CRF receptors, and agonists for neuropeptide Y receptors.
Rational development of new pharmacologic agents based upon targeting
receptors for those neurotransmitters that regulate the neurobiology of
anxiety promises to bring forth a number of exciting therapeutic agents for
the treatment of anxiety disorders in the future.
---------------
Peter |
