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    Sodium Valproate (Epilim) 
    #1
    Basically, what does this drug do exactly? My psychiatrist subscribed it to me today in addition to my regular Lexapro (15mg per day) and Valium (5m 4x per day). Apparently since the Valium wasn't fully curing my anxiety, he thinks this will stop me from getting frustrated/irritated (with bickering/arguing family), help me concentrate and calm down a bit.

    Any experiences and thought? P.S. Don't feel afraid to get technical, I can't find anything detailed about how this drug works besides "it does this"...
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    #2
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    From a quick wikipedia source, it looks like its an anti-seizure medication that can be an effective mood stabilizer. Strangely enough, there isn't very much information on its method of action, although I imagine it involves the GABA system..

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    #3
    Bluelight Crew amapola's Avatar
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    I skimmed this article and it seems quite detailed on its use in seizures, bi-polar, and migraines.
    After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of γ-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/β-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.
    http://www.springerlink.com/content/u689114448254644/
    edit:
    summary for those without access.
    NSFW:
    Overall interpretation
    A plethora of diverse data has been published over the
    past several years in an attempt to explain through a
    variety of mechanisms the efficacy of valproate in its
    different clinical indications. These data support the
    involvement of valproate in several pathways in which
    it had not been previously implicated. Yet, reviewing
    this information, it is remarkable that the number of
    cellular targets that have been proven to be directly
    affected by valproate is very small, and this number
    becomes even smaller when considering the relevance
    of some of these direct targets to epilepsy, bipolar
    disorder or migraine, at least as we understand their
    pathophysiology today.

    There is little doubt that valproate directly inter-
    feres with GABA metabolism to increase GABA
    brain levels, and that this effect likely plays a
    significant role in the immediate control valproate
    exerts over epileptic seizures [5] and possibly also
    mediates some early therapeutic effects of val-
    proate in bipolar disorder [8] and migraine [11] . The
    direct inhibition of GSK-3 by valproate, however, is
    at best controversial [70] , and the inhibition of
    microsomal long-chain fatty acyl-CoA synthase [42]
    still awaits further reproduction and substantiation
    of its relevance to human disease. Likewise, what
    underlies valproate inhibition of brain myo-inosi-
    tol-1-phosphate synthase activity, and whether this
    is at all relevant to bipolar disorder therapy, still
    needs elucidation [44] .

    In contrast to the latter cellular targets, valproate-
    induced changes in the expression of multiple genes,
    mediated at least partially through the direct inhib-
    ition of HDAC [18, 121, 122, 142] , have been
    repeatedly demonstrated and may very well be
    relevant to the therapeutic effects of this drug through
    interference with intracellular signalling, e.g. the
    inactivation of GSK-3 [73] , and neurotrophic and
    neuroprotective effects, e.g. through the promotion of
    BDNF expression [27] . Considering the large number
    of genes whose expression is altered by valproate [108,
    109] , it is reasonable to hypothesise that gene
    expression changes plays not an insignificant role in
    the long term effects of the drug. Future research
    should try and assess for every newly discovered
    valproate-induced cellular effect whether it is depend-
    ent or independent of HDAC inhibition or AP-1 DNA
    binding promotion by this drug. Nonetheless, many
    genomic effects of valproate cannot be explained with
    our current knowledge of its influences on AP-1 DNA
    binding and HDAC inhibition, and additional mech-
    anisms through which valproate, or its metabolites,
    can affect gene expression should be sought.

    In conclusion, influence of valproate at the genomic
    level may provide insights into therapeutic effects
    relevant to all three indications of epilepsy, migraine
    and bipolar mood disorder [12, 124, 138] . The ��unified
    field theory�� for the mechanism of action of valproate
    in neuropsychiatric disorders possibly comprises acute
    effects mediated essentially through the enhancement
    of GABAergic transmission followed by a variety of
    longer-term effects primarily resulting from gene
    expression changes.
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    #4
    Quote Originally Posted by NeighborhoodThreat View Post
    From a quick wikipedia source, it looks like its an anti-seizure medication that can be an effective mood stabilizer. Strangely enough, there isn't very much information on its method of action, although I imagine it involves the GABA system..
    Well, I am having the same experience. I even asked the head Psychiatrist what Sodium Valproate does, and although I pushed for specific in-dept neurological explanations, he basically said "it will stop you from having mood swings and getting irritable and in general calm you down.".... He assured me that although it was Bi-Polar and Anti-Epileptic medication, he has no doubt that I am NOT bi-polar. He just said that the medication does what he thinks I need, and that is to calm me down and help me focus. Essentially replacing my old Ritalin prescription with a non-stimulant, as I get stimulant-anxiety these days. And I need Benzo's to counteract the anxiety (but still get the positive effects from both).

    Anyway... Looking forward for some veteran pharmacologists to blow my mind. I don't even know whether I want to take this stuff at the moment. The only thing I can find on it are well-documented side effects haha. But I have taken my first dose.
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    #5
    Quote Originally Posted by amapola View Post
    I skimmed this article and it seems quite detailed on its use in seizures, bi-polar, and migraines.


    edit:
    summary for those without access.
    Holy shit, that's quite beyond the scope of my uneducated understanding of the brain. If someone could translate that a little? I'm really keen to learn.
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    #6
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    I think the link amapola provided (and the text he pasted, thank you again amapola ) is about as in-depth as its going to get. I recommend reading through that first.

    There is little doubt that valproate directly inter-
    feres with GABA metabolism to increase GABA
    brain levels
    , and that this effect likely plays a
    significant role in the immediate control valproate
    exerts over epileptic seizures [5] and possibly also
    mediates some early therapeutic effects of val-
    proate in bipolar disorder [8] and migraine [11] . The
    direct inhibition of GSK-3 by valproate, however
    That's probably the more important part.

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    #7
    Quote Originally Posted by NeighborhoodThreat View Post
    I think the link amapola provided (and the text he pasted, thank you again amapola ) is about as in-depth as its going to get. I recommend reading through that first.



    That's probably the more important part.
    So, basically it's an inhibitor of the breakdown of GABA inducing *insert intelligent word here* and would potentate drugs that promote GABA stimulation/inhibition. Meaning Valium should work better on this?
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    #8
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    ^In theory yes. It's exact method of action still isn't completely understood but it looks like the most likely way its working is by causing there to be more GABA levels...

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    #9
    So, it's basically the SSRI of GABA, instead of Serotonin.

    So as Lexepro (or another SSRI) is to MDMA
    Sodium Valproate is to a Benzo (or other GABA enhancing/breakdown-inhibiting) drug.

    Am I right?
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    #10
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    So, it's basically the SSRI of GABA, instead of Serotonin.
    I wouldn't say that, I would just say the "method of action is still unknown". We know increased levels of GABA are the end result of whatever that method of action is.

    Possibly, I wouldn't go so far as to make the comparision between GABA-related drugs and 5-HT (serotonin) related drugs, because those two neurotransmitters are quite different in their function in the first place.

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    #11
    Bluelight Crew amapola's Avatar
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    Here is how it increases GABA levels.
    As an acute biochemical effect, valproate has been
    shown to increase brain levels of the inhibitory
    neurotransmitter g-aminobutyric acid (GABA) prob-
    ably by inhibiting succinic semialdehyde dehydrogen-
    ase, consequently increasing brain levels of succinic
    semialdehyde, a metabolite that inhibits GABA
    transaminase thus preventing GABA catabolism [5] .
    Evidence also suggests a direct inhibitory effect of
    valproate on voltage-gated Na+ channels, suppressing
    high-frequency firing of neurons, and possibly indirect
    effects on non-GABAergic neurotransmission [5, 6] .
    The big question about it's mode of action is on the other bipolar, epileptic, and migraine and how these might be treated in the long run. Reread the article's summary.
    ...valproate directly inter-
    feres with GABA metabolism to increase GABA
    brain levels, and that this effect likely plays a
    significant role in the immediate control valproate
    exerts over epileptic seizures [5] and possibly also
    mediates some early therapeutic effects of val-
    proate in bipolar disorder [8] and migraine [11] .
    It then goes on to list other possible mechanisms of action which are unproven but could have important effects.
    Last edited by amapola; 06-04-2011 at 19:18.
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    #12
    Quote Originally Posted by NeighborhoodThreat View Post
    I wouldn't say that, I would just say the "method of action is still unknown". We know increased levels of GABA are the end result of whatever that method of action is.

    Possibly, I wouldn't go so far as to make the comparision between GABA-related drugs and 5-HT (serotonin) related drugs, because those two neurotransmitters are quite different in their function in the first place.
    I believe you, everything I read basically says "well we really don't know." Purely assumptions, based on theoretically-accurate assumptions. It's sort of scary really... Do I really want to be taking a drug that we know little to no about?
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    #13
    Quote Originally Posted by amapola View Post
    Here is how it increases GABA levels.
    I can follow that context to some extent. But it honestly confuses me, there's a lot of unfamiliar terms and expressions in there. Can anyone give a 'crash course' on the terminology step by step. In simple terms, basically a 'for dummies' explanation. This is intriguing me, I want to be able to understand this stuff so badly.
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    #14
    I think it inhibits GABA-transaminase also, preventing breakdown of GABA.

    As well as its known ion channel interactions at voltage-gated sodium channels.
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    #15
    So GABA-transaminase = the amino acids that break down GABA-acid? I know nothing of ion channels or what they are, what they do and what they are related to either. But hey, if someone can explain I'll do my best to comprehend. I wish I could have done this full-time at school... I probably wouldn't have failed.
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    #16
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    Here's your crash course on voltage-gated ion channels. (Wiki does a much better job of explaining it than I do).

    Here's the bigger article on ion channels in general. That will probably help to.

    Article on GABA. Also important that you read that as well, GABA's function in the CNS is a special one. It's job is to regulate the activity (or excitability) of the neurons in the CNS.

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    #17
    Bluelight Crew amapola's Avatar
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    Try this thread in ADD for some bedtime reading
    Erowid/BlueLight Neuropharmacology Text

    I can follow that context to some extent. But it honestly confuses me, there's a lot of unfamiliar terms and expressions in there. Can anyone give a 'crash course' on the terminology step by step. In simple terms, basically a 'for dummies' explanation. This is intriguing me, I want to be able to understand this stuff so badly.
    It doesn't really matter. All it means is that Valproate is working on the GABA levels indirectly by inhibiting an enzyme, which increases the levels of a substrate, which inhibits another enzyme, which increase the levels of the substrate GABA... or something like that.
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    #18
    Quote Originally Posted by amapola View Post
    Try this thread in ADD for some bedtime reading
    Erowid/BlueLight Neuropharmacology Text


    It doesn't really matter. All it means is that Valproate is working on the GABA levels indirectly by inhibiting an enzyme, which increases the levels of a substrate, which inhibits another enzyme, which increase the levels of the substrate GABA... or something like that.
    I'll note that I have taken in the advice of the previous poster before you and will read up on those Wikipedia pages and articles. Thank you for your productive responses.

    Now, you basically did what I was asking for. Simplifying a complex formula for me into something understandable. Thank you very much. So I'm basically taking something that indirectly inhibits something in a chain reaction. I wonder what repercussions come from that? Haha...
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    #19
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    ^Hopefully the repercussions that your doctor intended.

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    #20
    I was thinking more long-term, unknown/lab-rat type discoveries. Lets pray. I know it comes down to the person most of all when it comes to drugs, but in my situation (from the information provided), does anyone have any input on whether or not this drug would actually add much of an anti-anxiety and anti-depressive effect (on top of the Valium and SSRI's)?
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    #21
    Bluelight Crew amapola's Avatar
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    If your doctor thinks it might be beneficial he is much more qualified to make that decision that we are. It might merely be one of many option he is considering if it doesn't work as well and the only way of finding out is by giving it a shot.
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    #22
    Quote Originally Posted by amapola View Post
    If your doctor thinks it might be beneficial he is much more qualified to make that decision that we are. It might merely be one of many option he is considering if it doesn't work as well and the only way of finding out is by giving it a shot.
    To be honest, for some reason I trust a collaboration of the more intelligent/knowledgeable/qualified people here than single qualified (to what standard?) doctors or even Psychiatrists.
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    #23
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    When it comes to treatment the method of action is not nearly as important as the results. There are many medications where we don't know how they work, just that they do work. So we use them. Your doctor will know what this drug is indicated for and statistics on how it has helped others in the past. It is true they can sometimes be wrong, but in a case like this I doubt there is someone who is going to be able to say it would be better to not take it, and doubt even more that you should listen to them.
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    #24
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    When it comes to treatment the method of action is not nearly as important as the results. There are many medications where we don't know how they work, just that they do work. So we use them. Your doctor will know what this drug is indicated for and statistics on how it has helped others in the past. It is true they can sometimes be wrong, but in a case like this I doubt there is someone who is going to be able to say it would be better to not take it, and doubt even more that you should listen to them.
    Seconded. We're not doctors, I am a patient of psychiatry myself (I have really bad anxiety disorder), and I feel that, they, on a whole, do a great job. They do need to test things to see if they're working, the best thing to do is give the Epilim a shot, and if it doesn't work, talk to your doctor. Chances are he'll switch to something else until he finds something that works best for you. In all probability, the Epilim will work. The last thing you should do is go against his advice after taking just one dose...

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    #25
    Ion channels come in two main flavours, voltage-gated and ligand-gated, although voltage-gated ion channels can have binding sites for modulatory compounds, many nasty plant toxins, and an awful lot of the toxins produced by invertebrates, and cnidarians affect voltage gated ion channels.

    Examples of such include the famous tetrodotoxin, puffer fish poison, of fugu fame, that imfamous sushi produced from very, very carefully prepared blowfish, which blocks TTX-sensitive sodium channels (and also found in the venom of the blue-ringed octopus, the california newt, a certain species of marine flatworm, and toads of the genus Atelopus)

    TTX blocks those sodium channels, preventing an action potential (the current passed though nerves when the ion channels open and the cell fires in response to stimulation), causing paralysis, saxitoxin, or paralytic shellfish poison acts in the same way, although at a different binding site, whereas veratrine and related alkaloid toxins from Hellebore species, along with the venoms of the deadly, and very bad-tempered brazillian wandering spider, along with delta-atraxotoxin and the versutoxins of the funnel webs spiders in of the genus Atrax and Hadronyche lock sodium channels open, causing spontaneous, repetitive firing of nerves, resulting in a massive adrenergic storm, causing muscle cramps, sweating, severe tachycardia and severe increase in blood pressure, along with possible pulmonary oedema. Most scorpion toxins act by fucking with voltage-gated sodium or potassium channels (with the exception of the species Hemiscorpius lepturus, which is exclusively cytotoxic, and rather than neurological symptoms, causes horrendous flesh-eating effects, like that caused by recluse spider bites)

    There are two main superfamilies of receptor expressed on cell surfaces (I am ignoring nuclear receptors located within cells here), metabotropic receptors such as GABAb do not form an ion channel, and instead of directly inducing ion currents within cells, signal more slowly than ionotropic receptors, and mediate their effects by inducing the release of second-messenger chemicals within the target cell, such as enzymes, transcription factors etc.

    Ionotropic receptors on the other hand, such as GABAa, and the NMDA, AMPA and kainate type glutamate receptors signal far faster, and like other receptors are composed of complex protein subunits, arranged in such a manner as to form a central pore. this is the ion channel, and activation of the receptor by binding of an agonist drug/the natural neurotransmitter to those protein subunits, which can be complex enough to have multiple different binding sites, always one for the endogenous neurotransmitter, but often one or more allosteric modulatory sites causes a change in the 3d conformation of the receptor protein/ion channel complex which allows the channel to open for a time, and pass an ion flux.

    The ionotropic receptors are those which express a ligand-gated channel, and induce the firing of an action potential by the binding of an agonist, voltage-gated ion channels do not depend on binding of a neurotransmitter or drug, but instead, the chance of firing an action potential depends on the voltage potential the cell is at, after a certain threshold is reached through sufficient depolarization of the cell, the voltage-gated ion channel opens, and passes current.

    An allosteric binding site is a recognition site seperate from that for the main neurotransmitter, and can bind either positive (stimulatory in nature of the receptor expressing it) or negative (doing the reverse, inhibiting neurotransmission) and is dependent upon binding of a ligand at the orthosteric site, the main binding site for neurotransmitter.

    GABAa is a good representative receptor of the ligand-gated ion channel flavour, it is made up of 5 seperate subunits, which form a central pore, and which passes chloride ions. Different subunit pentameric combinations result in receptors selective for different allosteric ligands, of which there are many types, and which expresses a large variety of allosteric sites, including that which binds benzos, another for barbs, one binding loreclezole and one of the active compounds from the sedative herb valerian, one for neurosteroids such as pregnanolone, and negative modulator recognition sites also.

    These are seperate from the binding site that binds the endogenous neurotransmitter GABA, the main CNS inhibitory neurotransmitter (damping down other signalling processes and neurotransmitter release), an allosteric modulator of any kind will not cause any action in and of itself, if applied to a cell in the absence of the orthosteric ligand no effect will ensue, benzos work by potentiating the action of bound GABA, increasing the frequency of channel opening, whereas barbiturates more directly gate the chloride channel, and hold it open for longer, allowing longer duration of the resultant ion flux, and are thus more dangerous, as the body has far less ability to compensate for overactivity at the receptor.

    Applied on their own though, in an environment free of GABA, benzos, barbs etc will do sod all in the way of causing current flow, not unless GABA is also bound to the main site, or another agonist.

    An example of a couple of representative orthosteric agonists at GABAa (there are not nearly as many direct agonists of this type as there are positive allosteric modulators, the structural requirements for an orthosteric GABAa agonist are much more demanding) include muscimol, the active psychedelic-ish, dissociative-ish drug from the fly agaric mushroom, Amanita muscaria, isoguvacine, and isonipecotic acid.

    Sometimes an ionotropic receptor can have some characteristics of both ligand, and voltage-gated activity, the NMDA-type glutamate receptor targeted by the dissociative anaesthetics such as PCP, ket and memantine is such a beastie. Activation of the NMDAr requires binding of either glutamate or aspartate, the endogenous neurotransmitters, and the main excitatory neurotransmitter expressed in the brain (along with a co-agonist, glycine, at an allosteric binding site, and there is also another allosteric site recognising polyamines), once the agonists bind, activation of the receptor causes a magnesium ion, which at the resting electrical potential of the cell expressing the NMDAr sits in the ion channel, blocking current flow to be spat out, in a voltage-dependent manner allowing the now open channel to pass current.

    There are a great many seperate kinds of ion channel of the voltage-gated flavour, the main superfamilies being channels for sodium, calcium and potassium, and within those families, there are a crapload of subtypes, with varying sensitivities to different ion channel toxins, for example, I will use the calcium channel.

    A non-exclusive list, includes N-type calcium channels, which are expressed in neurons, along with P and R types also found within the brain. L-type channels which are involved in mediating muscle contraction, such as that of the heart (medicinally important drugs acting here are calcium channel blockers, heart medications which act to slow the heart rate down by inhibiting opening of L-type Ca++ channels), T-type and a couple of others.

    Some of these are sensitive to say, tetrodotoxin, saxitoxin etc, whilst being insensitive to other drugs/toxins, for instance the neuronal N-type channel is powerfully blocked by omega-conotoxin derived from the venom of the venomous marine cone snails, whilst the L-type channels are highly resistant to blockade from omega-conotoxin, but are blocked by the heart drug nifedipine, whilst nifedipine doesn't block the neuronal type recognising ω-conotoxin.

    Does that clear things up some? Valproate blocking Na+ channels (sodium channel activation is excitatory in nature, I don't know if this is exclusively the case, but it is certainly vastly the predominant nature) will decrease neuronal excitability, and result in the requirement of a greater stimulation of the nerve before an action potential can be fired, thus having an overall stabilizing effect on neurotransmission, and acting to prevent or decrease the propagation of the uncontrolled shitstorm of random nervous firing that is characteristic of an epileptic seizure.

    Incidentally, valproate was discovered by accident, it used to be thought inert and be used in neurochemistry experiments on animals (uggh!) merely as a delivery solvent for drugs being tested, it was only discovered when eventually it was used to deliver a convulsant poison to an animal, and it was found to have lesser effect than expected, exposing it as an antiseizure drug.

    Don't know if you are female or male, but do not take during pregnancy, it is well known to be teratogenic, and cause lots of nasty mutations (bad thing) and increase the frequency of autism (good thing)
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