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Dr. Bob is Robert Hsiung, MD,
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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
Posted by linkadge on September 12, 2012, at 18:42:27
In reply to Re: is a GABA antagonist what i need? » AlexCanada, posted by phidippus on September 12, 2012, at 17:13:11
Dopamine can actually cause anhedonia too.
Dopamine release in the NAA can cause feelings of pleasure (acutely, in the short term). However when the NAA recieves prolonged exposure to dopamine, it can result in behavioral depression.
This is associated with an elevation of BDNF in the neucleus accumbens (bad) - and decrease of BDNF in the hippocampus.Pleasure is meant to come only here and there (usually after the sucessful completion of a positive task). You don't want dopamine coming out of nowhere, for no reason, else you develop an addiction to the pleasure producing short cut, not the natural events in life that produce it.
People who use stimulants or opioids usually become antisocial. This is because the drug produces reward and the individual begins to focus more on the reward produced by the drug rather than natural social interaction (which can do the same thing).
The effect of dopamine on pleasure is inverse 'U' shaped. Why do you think that antipsychotics can reverse the severe behavioral withdrawl, apathy and other negative symptoms associated with schizophrenia?
Depression can be a side effects of ADD drugs like ritalin or dexedrine. According to my psychiatrist (who deals in ADD), its a fairly common side effect.
Posted by phidippus on September 12, 2012, at 19:57:06
In reply to Re: is a GABA antagonist what i need?, posted by linkadge on September 12, 2012, at 18:42:27
>People who use stimulants or opioids usually >become antisocial.
LOL, come on, man.
>Dopamine release in the NAA can cause feelings >of pleasure (acutely, in the short term).
What is the NAA?
Eric
Posted by poser938 on September 12, 2012, at 19:58:21
In reply to Re: is a GABA antagonist what i need?, posted by linkadge on September 12, 2012, at 18:42:27
my main problem was caused by medicines and the longterm effects they often have on me. before i ever tried any med i went through 17 years of my life being a pretty normal person that could relate well to others. then i decided to try antidepressants in the summer 0f 2005 and i have not been nearly the same since. my world is so different now than i ever could have imagined it to be.
it is a long story and might be a bit confusing if i really try to explain it but Adderall, Effexor and Mirapex are the meds that had the worst effects on me. Adderall was iincluded in my 1st set of meds prescribed by a psychiatrist and i didnt know it was the one that had the worst effect on me until later. i was on Geodon and Cymbalta. in the beginning of taking these meds i felt great (because of adderall) but the one day the Adderall had completely stopped working. i tried 40mgs of adderall to see if id get an effect and still nothing at all. then i noticed i was feeling very bad and couldnt stay in school a whole day anymore. i stopped all the meds and even a year later this very bad mood persisted.
i went back to the psychiatrist and tried a few meds. i tried Adderall again to see if it would work and still nothing from it. i also tried Zoloft, then Wellbutrin and then Effexor. on 75mgs of effexor it seemed to be effecting my mood on a deeper level than the other meds but wasnt sure if it was bad or good so the dose was raised to 150mgs. after a few days on this my hair started falling out, my mood started seeming like it was effected by foods i ate more and muscles in my face started tensing up on their own and it was painful.. but i still continued this med to see what would happen.
after 2 weeks i woke up one morning and my emotions were gone. i stopped taking it, read about cyproheptadine reversing effects of antidepressants and tried it. after being on it for a few weeks my emotions all the sudden turned on but were oonly about 75% there. i also noticed my hair was falling out even more and foods were still strongly effecting my emotions.
i once again stopped all meds and hoped my brain/emotions would go back to normal.
after 2 years i didnt make much progress. decided to try Mirapex. during the 1st few weeks it only made me more sensitive to "stimulation" with no effect on my mood and then after than my ability to feel pleasure was drastically decreased. i didnt know what happened but then i ordered Tianeptine and after 10 days my problem was made even worse. then i tried Ritalin, i felt a goood amount of stimulation for about 2 hours on my 1st dose but was then made worse after it wore off.
then i remembered the last med to have any good effect on me was Cyproheptadine. started taking it again and after 2 or 3 days i realized it was helping :) it was different this time though. it was helping but MUCH slower than the 1st time i was on it. i was on it for about 6 months and got to a very high dose on it because after about 3 days on a certain dose it would stop helping. but my emotions and pleasure feelings were getting better and better and better.
then i got to too high a dose and had to stop. that was about 2 years ago and have had the effects go away slowly. i am now almost back to how i was before i started it and i am sure had i taken it until my brain was back to how it was before i took Mirapex, it would have stayed like that.
since them i have tried a few antipsychotics. Low Dose Amisulpride, Saphris, Latuda, Seroquel and Fenapt and . i tried Buspar, rTMS and nasal Ketamine. and also Lamictal. then last month i tried Adderall with Fenapt to maybe block off my dopamine autoreceptors to try to keep any dopamiine release from being depleted while taking it with Adderall.. and i had a slight norepinephrine effect on the 1st day but nothing after that.
now, I'm going to take Gabapentin tonight at 800mgs.
Posted by poser938 on September 12, 2012, at 20:56:29
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 12, 2012, at 19:58:21
ya i wrote alot
Posted by poser938 on September 12, 2012, at 21:44:21
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 12, 2012, at 20:56:29
oh and she mentioned me getting which ever GABA antagonist we decide on at a compounding pharmacy
Posted by SLS on September 13, 2012, at 7:50:18
In reply to Re: is a GABA antagonist what i need?, posted by poser938 on September 12, 2012, at 21:44:21
> oh and she mentioned me getting which ever GABA antagonist we decide on at a compounding pharmacy
A GABA antagonist might be mimicked by using a pro-glutamatergic agent like modafinil (Provigil). This drug modulates the GLU/GABA ratio in favor of glutamate, a generally excitatory neurotransmitter.
Whether or not you need a GABA antagonist is unclear.
- Scott
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