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Dr. Bob is Robert Hsiung, MD,
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Posted by phidippus on September 10, 2012, at 13:26:08
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 9, 2012, at 22:58:38
Fluazenil made me feel kind of up and racy. It wasn't unpleasant.
Lyrica is nothing like benzodiazapines. It has no affinity for GABA. It works by binding to the alpha delta subunit of voltage gated calcium channels.
Eric
Posted by linkadge on September 10, 2012, at 20:10:29
In reply to Re: is a GABA antagonist what i need? » poser938, posted by phidippus on September 10, 2012, at 13:26:08
you're not going to get a Flumazenil prescription for depression.
even if you did....there is zero clinical evidence that ity has any effect in anhedonia.
But, alas, as I remember from my last conversation with you a few years back...you seem to get some strange abstract theory in your mind about why some drug might help you and there is little I can do to convince you otherwise.
Posted by poser938 on September 10, 2012, at 21:20:55
In reply to Re: is a GABA antagonist what i need?, posted by linkadge on September 10, 2012, at 20:10:29
i believe you're referring to cyproheptadine when talking about my "strange idea"? i think you'd have to be since that is the only medicine that has ever helped me. you know it does share 5ht2c antagonism with prozac, right?
maybe you are right, maybe we should ignore anything that isn't labeled by the FDA as a medication that can be used to treat mood disorders, no matter how much sense it makes that it could have a benefit on someone. i'm just doing what everyone does and trying to follow a lead. when someone finds out one kind of medication helps somewhat, they try another medicine that might have the same end effect. it is weird how this is strange to some people.
i've been told by a few "medical professionals" that i am strange for thinking cyproheptadine helped me. and for thinking i have longterm effects from medication. but my doctor i see now listens to me. and she finally said something that makes sense. when someone has had a brain infection (encephalitis) that resulted in a coma, this can change the brain and make it very upredictable as to how their brain is going to respond to medication. for this same reason i am not allowed in many clinical trials.
why dont you keep your strange thoughts to yourself.
> you're not going to get a Flumazenil
prescription for depression.
>
> even if you did....there is zero clinical evidence that ity has any effect in anhedonia.
>
> But, alas, as I remember from my last conversation with you a few years back...you seem to get some strange abstract theory in your mind about why some drug might help you and there is little I can do to convince you otherwise.
>
>
Posted by poser938 on September 11, 2012, at 0:16:40
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 10, 2012, at 21:20:55
i never had to go through life with anyone telling me that i have "strange ideas" about anything until i decided that those Cymbalta commercials looked so neat and went to a psychiatrist to try antidepressants. after this, my life went to hell. to these "medical professionals" i have no say in what kind of person i am. i apparently am not even able to understand what kind of mood i am in. i lack the ability to know how a medicine effects me. if i say it made me feel bad, they tell me i'm wrong.. when the real problem is their medicine sucks and they dont know what to do anymore. their last resort is to tell me i have no idea how i feel.
i used to be just a simple guy with mild depression until i started dealing with some of the shadiest doctors on Earth. now i'm just crazy.
Posted by SLS on September 11, 2012, at 1:39:34
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 0:16:40
You are not crazy - just different.
Linkadge has an annoying habit of being right most of the time. However, I have learned that there is a surprising degree of interindividual differences in the way our brains are wired and controlled chemically. Two people can react in opposite ways to the same drug. This is both fascinating and frustrating.
It occurs to me that Geodon (ziprasidone) possesses a few properties that you might be interested in, as it is a potent 5-HT2c antagonist along with being a mild-to-moderate 5-HT and NE reuptake inhibitor:
DA2 antagonist
DA3 antagonist
5-HT1a agonist
5-HT1c antagonist
5-HT2a antagonist
NE reuptake inhibition
5-HT reuptake inhibition
Also, its sister drug, Latuda (lurasidone). It doesn't block 5-HT2c receptors or inhibit the reuptake of NE and 5-HT, but adds 5-HT7 receptor antagonism - something that is now being looked at for depression.DA2 antagonist
5-HT1a agonist
5-HT1d antagonist
5-HT2a antagonist
5-HT7 antagonist
- Scott
Posted by iforgotmypassword on September 11, 2012, at 2:38:31
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 8, 2012, at 22:52:56
when given off-label it seems it's usually given with anticonvulsants to temper this. since it is used to reverse addiction, bafflingly with a number of substances (in private clinics it seems, probably for a lot of $$$), it may reverse tolerance, hence it may reverse anhedonia, fatigue and the like, if they are to be conceptualised in certain cases as being tolerant to one's own dopaminergic output, via too much glutamatergic feedback back to the system (usually from pfc i think, to the basal ganglia or vta, i forget which, i get these mixed up; in any case this mechanism in whichever way it's properly articulated is why people have experimented with memantine.)
sorry this became one unbreakable sentence somehow, my attention and effort is hard to steer and going back just makes me run into obstacles in my head and makes posting harder, less likely.
Posted by phidippus on September 11, 2012, at 4:46:00
In reply to Re: is a GABA antagonist what i need?, posted by linkadge on September 10, 2012, at 20:10:29
Linkadge is right.
Eric
Posted by poser938 on September 11, 2012, at 5:05:07
In reply to Re: is a GABA antagonist what i need? » linkadge, posted by phidippus on September 11, 2012, at 4:46:00
he probably is right about me not getting flumazenil.
Posted by SLS on September 11, 2012, at 6:36:18
In reply to flumazenil is probably acutely neurotoxic, posted by iforgotmypassword on September 11, 2012, at 2:38:31
> when given off-label it seems it's usually given with anticonvulsants to temper this. since it is used to reverse addiction, bafflingly with a number of substances (in private clinics it seems, probably for a lot of $$$), it may reverse tolerance, hence it may reverse anhedonia, fatigue and the like, if they are to be conceptualised in certain cases as being tolerant to one's own dopaminergic output, via too much glutamatergic feedback back to the system (usually from pfc i think, to the basal ganglia or vta, i forget which, i get these mixed up; in any case this mechanism in whichever way it's properly articulated is why people have experimented with memantine.)
>
> sorry this became one unbreakable sentence somehow, my attention and effort is hard to steer and going back just makes me run into obstacles in my head and makes posting harder, less likely.All things considered, that's not a bad sentence.
:-)
I appreciate the effort it takes for you to post.
You are probably right about flumazenil being neurotoxic. If it reverses the effects of BZDs, which it does, it would allow for rebound glutamatergic hyperactivity, which is generally thought to be toxic via its ability to flood the neuron with calcium ion.
Is there any evidence that dopaminergic function is affected by flumazenil?
Have a good day.
- Scott
Posted by phidippus on September 11, 2012, at 17:28:06
In reply to Re: flumazenil is probably acutely neurotoxic » iforgotmypassword, posted by SLS on September 11, 2012, at 6:36:18
"administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens"
That's a huge increase in dopamine.
Eric
Posted by phidippus on September 11, 2012, at 17:44:33
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 5:05:07
My understanding is that it is given as an injection and designed for one time use, not therapeutically, day too day.
Bottom line is the drug is designed to reverse the effects of benzodiazapines, period. The only off-label use this drug has had is in the treatment of Parkinson's.
Flumazenil will not treat your anhedonia. In fact, its likely the drug will do nothing for you.
There are many other ways to treat anhedonia that tried and true. Focus on those therapies.
Eric
Posted by phidippus on September 11, 2012, at 17:49:44
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 10, 2012, at 21:20:55
What did cyproheptadine do for you? Its an antihistamine and seratonin antagonist
"i'm just doing what everyone does and trying to follow a lead."
The GABA antagonist lead is bad. Pick another one.
What normal therapies have you tried, antidepressant-wise?
Eric
Posted by phidippus on September 11, 2012, at 17:51:40
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 0:16:40
Paranoia really suits you well.
Eric
Posted by poser938 on September 11, 2012, at 18:33:56
In reply to Re: is a GABA antagonist what i need? » poser938, posted by phidippus on September 11, 2012, at 17:51:40
thanks man.
my doc prescribed Gabapentin today and she said to only get a 3 day fill of this. if it doesnt work we will be trying a GABA antagonist. she said it makes a lot of sense to try this next.
Posted by poser938 on September 11, 2012, at 18:51:21
In reply to Re: is a GABA antagonist what i need? » poser938, posted by phidippus on September 11, 2012, at 17:51:40
> Paranoia really suits you well.
>
> Ericand i do think i'm going to go with her idea. she knows my situation and what medications i have tried in the past better than you guys.
Posted by SLS on September 11, 2012, at 19:54:48
In reply to Re: flumazenil is probably acutely neurotoxic » SLS, posted by phidippus on September 11, 2012, at 17:28:06
> "administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens"
>
> That's a huge increase in dopamine.
>
> EricThat might be supportive of what Linkadge often says about too much dopamine activity in certain regions of the brain causing rather than relieving depressive symptoms. I guess it depends on the circuitry.
- Scott
Posted by SLS on September 11, 2012, at 20:16:29
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 18:33:56
> thanks man.
>
> my doc prescribed Gabapentin today and she said to only get a 3 day fill of this. if it doesnt work we will be trying a GABA antagonist. she said it makes a lot of sense to try this next.I'll be interested to follow your progress. It will be an opportunity to learn something. If you fail to respond to gabapentin and feel worse with flumazenil, you might need to look at glutamate. Have you tried Lamictal? (I apologize if you have already addressed this question). If Lamictal is at all helpful, you might find that combining it with minocycline will produce a more robust antidepressant response. You might even consider adding to these two drugs a tricyclic like desipramine.
Your brain will make for an interesting proving ground. I hope your hunch regarding flumazenil is correct. However, if it isn't, perhaps doing some brainstorming will help discover a treatment that works for you.
It is true that you and your doctor know better your treatment history than we do. I hope you don't mind answering the same questions repeatedly from different people. It can only work in your favor. I still don't have the mental energy to read entire threads.
- Scott
Posted by poser938 on September 11, 2012, at 20:40:08
In reply to Re: is a GABA antagonist what i need? » poser938, posted by SLS on September 11, 2012, at 20:16:29
well yes i tried lamictal about a month ago and felt no effects from it. well.. except for a slight dizzy feeling lasting 5 minutes when i first started and when my dose was raised.
if neither of these meds work i am going to try finding a Magnetic Seizure Stimulation clinical trial i can join. i had looked on clinicaltrialls.gov already and couldnt find anything in america, but i think there are trials going on for things that arent listed on that site sometimes. i dont think i will ever decide to do ECT, though.
Posted by SLS on September 11, 2012, at 21:34:12
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 20:40:08
> well yes i tried lamictal about a month ago and felt no effects from it. well.. except for a slight dizzy feeling lasting 5 minutes when i first started and when my dose was raised.
>
> if neither of these meds work i am going to try finding a Magnetic Seizure Stimulation clinical trial i can join. i had looked on clinicaltrialls.gov already and couldnt find anything in america, but i think there are trials going on for things that arent listed on that site sometimes. i dont think i will ever decide to do ECT, though.Try contacting Columbia / New York Presbyterian and ask for Sarah Lisanby. She can probably tell you where to look for MST if it is not already being studied there.
http://asp.cumc.columbia.edu/facdb/profile_list.asp?uni=shl24&DepAffil=Psychiatry
http://www.brainstimulation.columbia.edu/staff/bio_lisanby.html
- Scott
Posted by phidippus on September 11, 2012, at 21:46:32
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 18:51:21
What medications haave you tried in the past. Based on your list, I can probably make some good suggestions.
Eric
Posted by phidippus on September 11, 2012, at 21:52:27
In reply to Re: flumazenil is probably acutely neurotoxic » phidippus, posted by SLS on September 11, 2012, at 19:54:48
Dopamine May Play New Role in Depression
High Level of the Feel-Good Brain Chemical May Cause DepressionShare this:
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AAAWebMD Health News
July 28, 2005 -- A chemical in the brain normally associated with feelings of happiness and pleasure may also raise the risk of depression.
Researchers say they've found a new way in which prolonged exposure to the chemical messenger dopamine may play a role in depression as well as drug addiction. If confirmed by further studies, they say the discovery could lead to a new understanding of these complex disorders as well as better treatments.
Current antidepression treatments are mostly based on the deficiency or imbalance of the brain chemicals serotonin and norepinephrine, says researcher Li-Huei Tsai, a professor of pathology at Harvard Medical School, in a news release.
"This new study highlights the importance of the dopamine system, a less appreciated target in the current antidepression therapies," he says.
Short-term surges of dopamine are normally associated with feelings of pleasure. But abnormally high concentrations of the chemical messenger are linked to schizophrenia, attention deficit disorder, and other psychiatric disorders.
Two new studies looking at the association of dopamine, depression, and other psychiatric conditions appear in the current issue of Cell.
Dopamine and Depression
The studies show that certain receptors in the brain respond to dopamine in a previously unknown way that occurs over a period of hours rather than minutes or seconds. In this manner, researchers say the chemical may affect the brain indefinitely.
Receptors are proteins found on the surface of nerve cells that recognize and translate the signals from a chemical messenger to trigger a response by the cell.
In laboratory tests with mice, researchers found prolonged exposure to dopamine through this pathway inactivated a regulatory protein in the brain known as Akt and caused the mice to behave like they were depressed in response to stress.
In addition, inactivation of this protein caused a molecular chain of events that caused the mice to become desensitized to certain drugs.
Researchers say this type of prolonged exposure to dopamine may also help explain the impact of drug abuse on the brain. Most addictive drugs, such as cocaine and amphetamines, directly or indirectly raise dopamine levels, and the chemical plays a major role in drug-induced highs.
"This mechanism appears to be more important than those earlier described for prolonged stimulation by dopamine, as would be the case in those with psychiatric conditions," says researcher Marc Caron, PhD, professor of cell biology at Duke University, in a news release.
"The new pathway can now be evaluated for potential new inhibitors that might be better at controlling particular psychotic behaviors."
Eric
Posted by phidippus on September 11, 2012, at 21:54:07
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 11, 2012, at 18:33:56
Gabapentin can cause some initial euphoria and be on the look out for 'abnormal' thinking.
How will you go about dosing a GABA antagonist-most are delivered intraveneously?
Eric
Posted by linkadge on September 12, 2012, at 8:25:49
In reply to flumazenil is probably acutely neurotoxic, posted by iforgotmypassword on September 11, 2012, at 2:38:31
flumazenil will reverse tolerance to benzodiazapines, (or at least reduce the acute effects of benzodiazapine overdose).
The problem is that flumazenil is not selective for the nucleus acumbens - it is going to antagonize benzodiazapine receptors in all brain regions.
flumazenil treatment would be about as pleasurable as benzodazapine withdrawl.
iirc, you were convinced that you hand some sort of dopamine depletion or something. Well, cyprohepdadine has many actions. Yes it is a 5-ht2c angagonist, but (believe it or not) also shows some antipsychotic like effects. It is also an antihistamine, 5-ht7 antagonist, calcium channel blocker etc.
Lets just say your problem was different. Lets suppose you have genetic dysfunction with your calcium channel receptor - gene which has been linked to anhedonia. So, cyproheptadine is really working because it is a calcium channel blocker.
Now, you decide your problem will be solved with a benzodazapine antagonist. If your problem was due to overactive calcium channels, flumazenil will send you into a tailspin.
I agree completely with you that doctors fall way too short in understanding depression in many patients, but that being said....a little knowledge can be a very dangerous thing.
I certainly have only caused myself more damage through years of feeling around in the dark with this or that theory.
But.....be as you will.
Linkadge
Posted by AlexCanada on September 12, 2012, at 11:41:46
In reply to Re: is a GABA antagonist what i need? » poser938, posted by phidippus on September 11, 2012, at 17:44:33
> Flumazenil will not treat your anhedonia. In fact, its likely the drug will do nothing for you.
>
> There are many other ways to treat anhedonia that tried and true. Focus on those therapies.
>
>
> EricCan you mention which treatments these may be? I constantly have strong anhedonia with my melancholic depression...
Posted by phidippus on September 12, 2012, at 17:13:11
In reply to Re: is a GABA antagonist what i need? » phidippus, posted by AlexCanada on September 12, 2012, at 11:41:46
Researchers theorize that anhedonia may result from the breakdown in the brain's reward system, involving the neurotransmitter dopamine.
Keeping that in mind, the drugs I'm going to recommend to you are mostly dopiminergic in nature or affect dopamine in the CNS.
Mirapex and Requip are both dopamine enhancing drugs. Pramipexole(Mirapex) acts as a partial/full agonist at the following receptors: D2S receptor (Ki = 3.9 nM; IA = 130%)
D2L receptor (Ki = 2.2 nM; IA = 70%)
D3 receptor (Ki = 0.5 nM; IA = 70%)
D4 receptor (Ki = 5.1 nM; IA = 42%)
Ropinirole (Requip) acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D2Nuvigil - Orexin neurons are activated by Nuvigil. Orexinergic neurons are found exclusively in the lateral hypothalamic area. Their activation is associated with enhanced pleasure-seeking and motivation as well as arousal. Orexinergic fibers project to the entire central nervous system. Its dopamine-releasing action in the nucleus accumbens is weak and dose-dependent.
Rotigotine (Neupro) - has been shown effective in the treatment of anhedonia and depression. It is a dopamine agonist.
Abilify is a partial dopamine agonist of the third generation class of atypical antipsychotics with additional antidepressant properties that is used in the treatment of schizophrenia, bipolar disorder, and clinical depression. Abilify is also a 5ht1a partial agonist.
Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats.
http://www.ncbi.nlm.nih.gov/pubmed/22327556
Dextroamphetamine increases dopamine in the brain and can reverse anhedonia
Ritalin (methylphenidate hcl) presumably activates the brain stem arousal system
Buprenorphine can help with anhedonia
Eric
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