Posted by linkadge on June 3, 2008, at 18:02:26
In reply to Re: The best Tricyclic for anxiety.... » johnj, posted by Phillipa on June 1, 2008, at 19:37:11
>Scott, I still don't understand how SSRI/NRI's >can be effective for anxiety as some are >indicated for anxiety use when, as you say, >serotonergic tracts can be anxiogenic. As I >understand these particular drugs, the increase >the action of serotonin by blocking reuptake. >Why is there this inconsistency between claims >made that increased serotonin activity >aggravates anxiety and the claim that serotonin >activating drugs improve anxiety?
I think SLS answered that well. I just wanted to add a few things. Both serotonin and norepinephrine can be highly anxiety provoking when released in certain areas of the brain.
Like SLS said, one theory suggests that it is the downregulation of serotonin and norepinephrine receptors that produces the clinical changes. Ie after prolonged administration certain circuts actually become less responsive to the neurotransmitter and in doing so less responsive to stress induced neurotransmitter release.
This theory does't answer many things though. For instance, if certain areas of the brain become less responsive to the neurotransmitter then doesn't the antidepressant effect stop (ie doesn't the AD effect depend on the neurotrophic actions of serotonin?)
There are other theories. There is the allopregnanalone theory. All of the SSRI's actually have a recently detected common mechanism. The appear to directly increase the synthesis of a powerful gabaergic neurosteroid called allopregnanalone. This effect is independant of their effect on serotonin uptake inhibition. It is not an effect shared by the TCA's.
It may infact be that the serotonin uptake effect is anxiogenic and the allopregnanalone effect is what is reducing anxiety.
A more comprehensive effect looks at the brain region that the drugs work at. Increasing serotonin in the hippocampus may confer the antianxiety effect and the antidepressant effect. Stimulation of 5-ht1a receptors in the hippocampus appears to reduce anxiety and depression. SSRI's however are not that selective. They increase serotonin transmission at every single site in the body and brain. increasing serotonin in the dorsal raphai neucleus can be very anxiety provoking. Certain agents actually reduce serotonin release there to reduce anxiety. Buspar and nicotine inhibit serotonin firing in the dorsal raphai neucleus to reduce anxiety. Serotonin release in the amygdala is also highly anxiogenic.
The differences in responce to SSRI's for anxiety may have a lot to do with which SERT gene you have. Individuals with the SS gene for the serotonin transporter have a lower uptake of serotonin and individuals with the LL gene have a higher uptake level. Indivdiuals with the SS gene do not seem to respond well to SSRI's, probably because their serotonin transporter levels are already low. LL individuals respond better and have fewer side effects.
So it could be that all the people who get super agitated and anxious on SSRI's nomatter how long they take them have the SS varient of the gene and that the SSRI is raising their serotonin levels even higher in anxiety provoking brain regions.
5-ht2 blockers can reduce the effect of serotonin acting on the amygdala. This may conver antianxiety effects and even antischizophrenic effects. It can also improve sleep by altering the serotonin/melatonin ratio in the penal gland.
My personal theory is that for SSRI's, the serotonin upake inhibition is not really critical. I personally think the alloprenanalone boost is what reduces dysphoria and anxiety. Individuals with the LL varient probably tollerate the serotonin uptake inhibition better than do indivudals with the LL varient.
I think there is a dysregulation of serotonin in depression but it has absolutely nothing to do with serotonin uptake or monoamine oxidase.
I think its got to do with the sensitivity of the presynaptic 5-ht1b serotonin autopreceptors. These receptors selectively control serotonin release in the hippocampus and do not affect serotonin release in the dorsal raphai neucleus or amygdala. Long term lithium, exercise, shock, rTMS or antidepressant seem to favorably alter the level of this autoreceptor. Even antidepressant drugs that do not directly affect serotonin neurotransmission alter the level of this autoreceptor. The expression of this autoreceptor is highly sensitive to stress hormones.
Drugs that selectivly desensitize or funcitonally inhibit the activity of the 5-ht1b autoreceptor would be able to rapidly increase serotonin neuotransmission in brain regions implicated in depression without causing distressing physical or emotional side effects.
Linkadge
poster:linkadge
thread:831465
URL: http://www.dr-bob.org/babble/20080528/msgs/832746.html