Psychiatry & Psychotherapy Podcast - Valproic Acid: History, Mechanism, Treatment in Bipolar, Schizophrenia, Aggression and Side Effects with Dr. Cummings

Episode Date: January 16, 2020

In this episode, David Puder, M.D. and Michael Cummings, M.D. discuss the history, uses, and side effects of Valproic Acid which is a mood stabilizer for various conditions including: Bipolar Disorder, Schizophrenia, and Borderline Personality Disorder.  By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

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Welcome back to the podcast. Today I am joined with Dr. Michael Kahneman. Hummings, he has no conflicts of interest, nor do I. And today we will be discussing valproic acid. We will be going through the history of valproc acid, the mechanism of action, the efficacy, talking about bipolar, schizophrenia, borderline personality disorder, anger, aggression, agitation in dementia. And then we'll be going through some of the side effects, you know, thinking about it as someone who treats people, and what are the things that we look out for? what are the contraindications and drug monitoring and maybe some things about how valproic acid

actually helps people reopen critical periods of learning like absolute pitch. Did you share that one with me or did I find that one outside? I shared that one with you. Maybe we should start with the history and we'll get to that eventually. Okay. Essentially, valproic acid is actually derived. from valeric acid. People may be familiar with valerian root and herbal products sometimes used for anxiety or sedation. One of the compounds produced by that plant is valeric acid. Valproic acid,

valpric acid essentially is a derivative. It's an eight-carbon branch chain fatty acid, a carbonyxylic acid, formally named it would be two propionic. valproic acid or valeric acid in terms of structure function relationships. If you just had a straight fatty acid of eight carbon atoms, it would not be active in terms of the brain. If you increase the number of carbons to nine, the substance becomes overwhelmingly sedating. If you reduce it to less than eight, it rapidly loses any central nervous system effect. So it's unique in terms of structure, function, relationships in that regard. It comes naturally of valproic acid itself is a clear colorless liquid.

If you make sodium valproate the salt, it's an oily off-white powder. If you make sodium divalprox, two acid molecules joined to the sodium-o-yte, ion, you simply have a dry off-white powder. And we'll talk about that a bit later in terms of the commercial formulations that are available for medicinal purposes. Valproic acid was originally synthesized not as a medication, but was intended to be an inactive solvent for use in medical research. It was synthesized in 1882 by B.S. Burton in France.

It was used as a solvent for a number of decades. And until 1962, indeed people thought that it was an inert solvent. In 1962, research was done in which they were attempting to give animals compounds to make them have seizures. But those seizureogenic compounds that had been dissolved in valproic acid resulted in the animals not having seizures, which led the researchers to look at the molecule more closely and say, well, how come this vehicle is preventing the seizures? But if we use a different vehicle, the seizures occur. And that led to the realization that valproic acid is an anti-epileptic drug. and indeed it was approved as an anti-epileptic in 1972 in France,

leaped forward another decade to 1982, and we come to Robert Post at the National Institutes of Mental Health. He had been doing mouse research looking at kindling of limbic neurons using electrical stimulation, one second stimulus per day. if you do that in the temporal lobe of a mouse, after a few days, the mouse will have a complex partial seizure, a temporal lobe seizure. And if you keep doing it, the mouse will eventually have seizures,

even if you take the electrode away. Basically, the limbic system kindles over time and becomes overexcited in an independent manner. Post, in his research group, made a leap of logic, at that point and said, well, maybe people with bipolar illness suffer from increasing rates of mood cycling over time because the mood cycles are kindling the limbic system

the same way that our electrical stimulus did. So they initially tried carbamazapine, another anti-epileptic, to see if that would stabilize mood. It did, but carbamazepine comes with a whole host of adverse effects, and is a very potent hepatic inducer, so it had a lot of problems with its usage. That led post in his group to turn to valproic acid

as the second anti-epileptic they investigated, and indeed they found that valproic acid is a mood stabilizer. It's much more effective against the manic pole of bipolar illness than against the depressed pole, but it also does provide prophylaxis, that is it lengthens the amount of time between mood disturbances or mood cycles in the illness,

which is how Valpropac acid made its way from inert solvent to neurology and eventually into psychiatry. Wow. How would you define the mechanism of action and how it works for us in psychiatry. In the broad sense, as was suggested by Post's work, it dampens the excitability of the limbic portion of the nervous system, the circuit of pepest, including the superchaismatic nucleus,

the biological clock. The mechanisms by which it does that appear to include direct blockade of voltage-dependent, sodium channels. Influx of sodium via those channels is how neurons fire. It also alters the concentrations of guanine synthase kinase, which helps regulate cell excitability, as well as the activity of protein kinase C, which also is a second messenger modulator. of just how excitable neurons are. Those taken in concert are thought to underlie

why valproic acid provides greater stability in the limbic system. Over and above that, valproic acid also increases the synthesis and release of gamma amino and butyric acid, GABA, which is the brain's primary inhibitory neurotransmitterer, so it may be providing some direct inhibition by that route as well. What about the NMDA receptors?

Do you think that has much to do with it? It does have effects at the NMDA receptors. Frankly, so far, we don't know how much that contributes to the mood stabilization. It may well contribute to the drug's ability to decrease overall neuronal activity. You know, this is a case of because the drug does a number of different things, and we don't have the ability to change one thing at a time, we don't know what the relative importance of these various underlying mechanisms are. Do you think the efficacy has something to do with modulation of the dopamine and serenergic transmission?

Certainly in terms, I think it does. in the sense that valproic acid alters the responsivity of limbic neurons to monoamine neurotransmitters, including dopamine, serotonin, noraphenephrine. They are, of course, modulators of limbic activity. And in the case of valproic acid, it may be stabilizing the target neurons for those. and indeed when we see overt clinical illness, often what we seem to be looking at is the limbic system is either overactive or underactive outside of homeostatic boundaries. In essence, the limbic system has gotten beyond the ability of the naturally occurring modulators,

noraphyrin, dopamine, and serotonin to modulate the system within the system within, homeostatic boundary. So that's when illness crops up. Valproic acid and the other mood stabilizers, for that matter, may be functioning, essentially to move the activity of the limbic system back into a range that the naturally occurring modulators can then manage.

Okay, so let's talk about efficacy. Let's start with bipolar disorder. And so in a recent, systemic review, Joquim 2019, it talked about the different studies that have been done. Is that one you shared with me? Yes, it was. Okay. The review found that phalprote is efficacious in acute mania compared to placebo,

45% versus 29%, so an odds ratio of two, basically. And when they compared Valproate with lithium, they found that there was little or no difference in response rate, 56% versus 62%. And they also found that little or no difference in the response rate between Valprote and olanzapine, 38% versus 44%. So anything else that you would mention about efficacy with bipolar disorder? Yes, there are differences among the drugs, although they are, rather than response and acute mania, the differences appear to crop up more with respect to prophylaxis. Avalproic acid and lithium appear to have a longer survival curve between mood episodes than, say, olanzapine or the other second-generation antipsychotics indicated for mood stabilization.

When they've compared the antipsychotics alone versus antipsychotic plus lithium or valproic acid, addition of the classic mood stabilizers provides longer-term stability for those people who tolerate them well. Lithium has the broadest range of efficacy. It's effective against both hypomania and mania and also is inherently somewhat antidepressant. Valproic acid, in contrast, is as effective as lithium for the hypomanic or manic symptoms, but appears to provide much less benefit with respect to bipolar depression. What about rapid cycling? historically

Valproic acid was held to be more affected for rapid cycling disorder more recent analyses suggest that there isn't that much difference between lithium and valproic acid

with respect to efficacy and rapid cycling bipolar illness So at what blood level is it going to be helpful for someone with bipolar, like hypomania or mania? In people who are taking valproic acid for seizure disorders, the typical quoted therapeutic

range is 50 to 100 micrograms per milliliter. The effective range for people with mood disorder or impulsivity or traumatic brain injury or personality disorder appears to be somewhat higher, more in the range of 80 to 120. 20 microgams per milliliter. And that may simply be that modulating the limbic system is a somewhat more difficult task and requires a higher brain concentration of alproic acid. One of the pharmacokinetic properties of alpric acid is that it's very highly protein bound to plasma albumin primarily.

At lower concentrations, it's 90% or greater. or bound. So if you're if you have a fairly low plasma concentration, eight, nine, ten percent of the drug is free and available to enter the brain. The rest of it's floating around attached to album and into bloodstream and not doing anything. By the time you get the concentration up though to 130 micrograms per milliliter, a little under 30 percent of the drug is now free and only 70 percent is bound, largely because the albumin sites have gotten filled and any additional drug is now available and free in the plasma. It's only the active drug that provides any treatment benefit. And so this isn't like a linear relationship, is what you're saying? No, when you get to

about 80 micrograms per milliliter, further increases in dose produce a greater than linear effect in terms of increasing the free fraction of the drug available. Are we talking about blood levels 12 hours after? Yes, like most of the drug studies, even for drugs that have longer or shorter half-lives, most of the plasma concentration ranges you see cited are based on 12-hour post-dose measurements. So if a patient comes in with bipolar, how would you select depicote or viparic acid over lithium or over olanzapine?

Certainly if the person has had a positive past response to valproic acid, that would be an element in its favor. If the person has reasons they can't tolerate lithium, they're not a candidate. For example, somebody with renal impairment is not a good lithium candidate, then valproic acid may become the favored drug. On the other hand, if the person is intolerant of both valproic acid and lithium or hasn't responded to either drug in the past, then olanzapine may become the drug of choice. The other thing that's available, of course, with olanzapine that isn't available with. either Valproate or lithium is olanzapines available in an injectable form if the person is reluctant or refuses to take oral medications. So what were you saying, say that one more time about like if you're trying to keep someone out of mania, like in a stabilized state, is Depakot

better or lithium or more of an antipsychotic? Which one? Deppicoat and lithium were about the same in terms of survival curve. That is the average length of time until the next mood disturbance occurs. Olanzapine is somewhat shorter. Okay. So that olanzapine doesn't provide prophylaxis that is as good as the classic mood stabilizers. Now, in clinical practice, often what you'll see, especially if the person's

bipolar illness includes psychotic signs and symptoms when they are in the throes of either depression or mania. They'll often be treated, especially initially with both the mood stabilizer and an antipsychotic like olanzapine or other antipsychotic. Yeah, I think that's something we see pretty frequently. It's like we want to get them out of that manic state. They're coming in, they're sleeping, you know, to one hour. a day for several weeks now and immediately, you know, several medications are started to try to get them out of it. And even then it takes a couple days for them to get, you know, six hours of sleep. It may take four or five days for them to start getting six hours of sleep per night.

Yes. Part of that has to do with, for these drugs, even once you've reached a therapeutic concentration, there is still an inherent lag time before the drugs began to produce their clinical benefits. And that may have a lot to do with the fact that the underlying physiological changes require time for both lithium and valproic acid. That's one of the reasons that loading strategies have been developed for both drugs. In acute mania, the typical loading for Valpropic acid is 20 to 30 milligrams per kilogram. That is, you weigh the person, calculate what their total daily dose should be, and then give them, usually most people these days start with divalprox.

You divide that dose into a BID schedule, and you can simply start at the dose. There's no need to titrate. In fact, one of the common errors made with valproic acid is to start at a low dose. The problem with that is that, frankly, at concentrations of less than 50 micrograms per milliliter, almost all of the drug is bound to plasma albumin, and not much may happen because there isn't anything actually entering the brain. Okay, so let's say you had like 100 kilogram male, so about 2,70 or so.

And this person was coming in, so you said 20 to 30. So it would be basically 2,000 to 3,000 milligrams divided over two doses. Yeah. Which means you'd be starting with 1,000 milligrams to 1,500 milligrams twice a day. Okay. And then do you change it or do you wait for the level level? Well, basically, the nice thing is with valproic acid is it will reach steady state for everything except the extended release formulation,

it will reach steady state in about 70 hours. So three days later, you get a concentration. And you know where you are. Now, the 20 to 30 milligrams per kilogram kilogram will typically land you somewhere in that 80 to 120 micrograms per millilitre range. So you'll be in the therapeutic ballpark. And then you can fine tune based on measure.

a plasma concentration. Okay. And this kind of brings us to the discussion of the different formulations that are available because there are a number. The most commonly used preparation these days tends to be divalporex known as Depakote DR, D as in dog, for delayed release. Now, the delay in this case is only until the drug hydrolyzes, in the distal stomach.

It essentially was created to avoid upper GI upset acid reflux, which can occur with valproic acid in its liquid form or natural form. Depakene, the trade drug, is valproic acid and causes quite a bit in terms of nausea or GI problems. And some people also there's a liquid preparation that is valpric acid. Acid. Depakote ER, the extended release, is essentially divalprox embedded in a wax matrix that melts very slowly in the GI tract. And the drugs actually delivered for absorption over about 22 to 23 hours.

So it's almost like being connected to a continuous ongoing drip of valproic acid. It has a lower peak, produces fewer sizes. effects produces however somewhat lower plasma concentration for the same total dose by about 10 to 15 percent the liquid is also often more poorly absorbed and may produce a plasma concentration that's anywhere from 10 percent to 50 percent less than the dival proex So a lot does depend on which formulation you're choosing. The extended release is intended to be given once a day. The Dival ProxDR can be given once a day.

However, you have somebody who's toward the more rapid end of the metabolic range for the drug. That is, they have a short half-life. That can result in an up to 80% decline across 24 hours. and that can put the person at risk of having a seizure due to the rapid fall off in plasma concentration. Wow. Okay. So anything else you would like to say about bipolar and this medication? No, I think that pretty much sums it up for bipolar illness. Again, better for the manic end of the spectrum than for depression. lithium has efficacy at both ends of the bipolar spectrum. Both are roughly equivalent in terms of prophylaxis

and both are slightly superior to olanzapine and other antipsychotics in terms of bipolar prophylaxis. Okay. Let's talk about schizophrenia. In schizophrenia, valproic acid has proven useful in part because of its rapid onset of action. Again, particularly if you load the drug initially,

if you have somebody who is psychotic and agitated, valproic acid is pretty good at calming the agitation because, of course, psychomotor agitation is driven by the limbic system, and particularly by the amygdala. And phalprok acid is pretty good at dampening that, whereas the antipsychotics take a substantial amount of time to begin to actually work on the underlying positive psychotic signs and symptoms. It can take one, two weeks. Most of the antipsychotics begin to separate from placebo sometime in the second week.

but you'd like to have a less agitated person during the first week. And that's often the reason for adding valproic acid. Now, in schizophrenic patients who do not have any element of bipolar diathesis, after the antipsychotics become fully available, valproic acid then does not add anything to their treatment. if however they do have elements of bipolarity because remember there is a great deal of overlap between schizophrenia spectrum disorders and bipolar illness they share some 50% in terms of genetic risk sites those people who have some elements of bipolar diathesis they may benefit from the mood

stabilizing component on an ongoing basis if somebody is just purely schizophrenic though, by the time they're out beyond around 16 weeks, the valproic acid is no longer really actually doing anything for them because by that point, the antipsychotic has taken hold and is providing the bulk of the therapeutic benefit. In terms of studies I've seen that it can reduce days in hospital like one, you know, or like not a lot. It's not a huge effect in terms of hospitalization. for the person who is very agitated initially, it can be a useful tool.

My own impression is that in many cases we sometimes leave the valproic acid in place too long in those people who are purely schizophrenic. Now, if they have a vulnerability toward elements of bipolarity, they have a tendency toward irritable mood, impulsivity, mood elevation, those people may indeed benefit from ongoing treatment with valproic acid over and above what they're getting out of the antipsychotic. Conversely, I've also seen people admitted whose psychotic symptoms respond well to the antipsychotic, but who then continue to have irritable mood difficulty sleeping, some elements of psychomotor agitation. And you may be looking at

somebody who has an element of bipolar diathesis, even if they don't meet full criteria for hypomania or mania. And indeed, those people may benefit from valproic acid treatment on an ongoing basis. So in the studies you gave me, I think it was weighing 2016, KC, 2008. It seemed like they were pointing to, there was not much of a significant difference in the PAN's positive scores. however there was a slight difference in the pan's negative subscale with the diphyproprochs. Yes, which may speak to the issue that the negative symptom scale appears to be more related to

what could be termed affective elements in schizophrenia spectrum disorder patients. and indeed it's that area where valproic acid may provide a benefit and indeed lithium as well. It's clear neither lithium or valproic acid is an antipsychotic per se. If you had somebody present with positive psychotic symptoms, hallucinations, delusions, giving them valproic acid or lithium monotherapy would make them calmer, but it would not do a great deal for their core psychotic symptoms. On the other hand, if they have affective elements in the negative symptom domain, valproic acid or lithium may indeed be helpful to that person.

Again, I would not characterize either of these drugs as an antipsychotic, but they may make useful adjuncts in those patients who have more negative symptoms or who clearly have an affective component as part of their illness. Which kind of brings this to other uses. Valproic acids also shown efficacy in treating things like the mood liability present in borderline personality disorder, the mood liability or impulsivity present in traumatic brain injury, and even the behavioral disturbances sometimes that occur,

and neurocognitive disorders, although in the latter case in the elderly demented valproic acid does produce an increased rate of mortality, not unlike that scene with the antipsychotics in that population. So there was this Hollander 2005 article where they looked at valproate for borderline personality disorder. They looked at 52 patients randomly assigned

to treatment of divalproics or placebo for 12 weeks, they said that the median baseline aggression scores on the overt aggression scale was 35, or sorry, 33.5 in the DiVal Prox group and 35.2 in the placebo group, which doesn't, it's like a two difference. It doesn't seem like a very big difference between the two groups. It is not a huge difference, and what you'll see is that some patients have a better than average response, but you're looking at a subpopulation. Certainly in terms of overall practice, the mood stabilizers have become the dominant pharmacologic treatment

in borderline personality disorder. Or I think ICD actually has it more correctly named. It's affective discontrol disorder. But it would be fair to say that none of the pharmacological agents are a primary treatment. in personality disorder, including borderline personality disorder. Instead, they are adjuncts that may be useful for specific target symptoms in specific patients.

That's also true of the antipsychotics. If a patient is prone to frequent dissociation or to what has been termed many psychotic episodes, then indeed antipsychotics, particularly those that also have mood stabilizing properties, may benefit those patients. But the pharmacologic treatments are certainly not the mainstay of treatment for those patients. Yeah, I think there's, I see a lot of polypharmacy with people with borderline per size order, like they come in on nine, 10 medications. I think in large part that's a byproduct of what could be called clinical desperation. There are people who are relatively refractory to treatment. I'm not sure, though, however, that we're doing them any favors by

loading them with a lot of medications. I think a more reasonable approach is to try to identify one or two specific target symptoms that are impairing the person's ability the most. and then to target those with truly therapeutic amounts of a chosen medication. One of the errors I see made over and over again in doing consultations is clinicians will give, oh, a little of this, a little of that, a little of the other. Giving six or seven drugs at sub-therapeutic doses does not really add up to a good therapeutic trial. one thing I've noticed is that the partial hospitalization is really the best place for the patient that's just not getting better with weekly therapy or weekly monthly psychiatry visits.

There was one really nice study on mentalization-based treatment where they looked at the medications and they compared it to controls. And they found that treatment as usual had quite a bit more medications after. you know, the eight-year follow-up, then the people in the partial program. What this shows me is that when people get effective treatment, and, you know, this is partial for a couple, in this case, it was, you know, twice a week for a year. That's a lot of therapy.

And a lot of times in the U.S., the most you can get is like six weeks, if that. Yeah, which indeed is unfortunate, because it's clear that people with personality disorders, benefit greatly from effective psychotherapy, either mentalization or the classic dialectical behavioral therapy, those patients improve and change beyond simply having symptom reduction. I think the appropriate role of pharmacology in this context

is as an adjunct to psychotherapy, to reduce specific problematic symptoms rather than a shotgun sort of approach of, oh, let's try to cure personality disorder with pills. Frankly, that's just not going to work. I think one of the really helpful things from this discussion is that if the level of the valproate is under 80 for any psychiatric patient,

it's probably not doing very much. It's not because, again, below 80, about 10% of what you're giving the person is available to enter the brain, which means that, say, you're giving somebody has a plasma concentration that is right at 80. That means you have eight micrograms per milliliter to enter the brain and actually do something. By the time you get to 120, you've got almost 30. percent as free fraction. So you've now gone from 8 to 36 micrograms per milliliter in terms of free drug, which is a huge change, a much greater than a linear increase in the drug that's actually in the brain and doing something to benefit the person.

Yeah. And it's interesting, I find that I get a lot of new referrals of people who are on like 500 milligrams at night. That's it. you know and they're full grown males or females and so it's like that yeah that's largely a placebo right the level in their blood is like point two point three and yeah some of them think that it's helped right and so that's probably well placebo's do help as you can you know i you know if you look at any research study i have yet to see a research study done in which the placebo response rate is zero

giving somebody a sugar pill does things because the person believes that it will. Yeah. In one of my episodes I did with Markard, we talked about this one study on Parkinson's disease where they actually found that the placebo increased dopamine in the brain, which Parkinson's disease is not, you know, it's not a psychiatric illness. It's an illness where there's a dopamine deficiency. And so to find that a placebo actually increased the dopamine was pretty phenomenal to me. Yeah.

Same thing with studies of, for example, placebo's for pain, giving person placebo increases the amount of encephalin released because the person believes that it will help their pain. And indeed, it does help their pain, albeit not by a direct pharmacological effect. We should also talk about some of the adverse effects and risks of valproic acid,

because indeed it's not a drug to be taken lightly. Before we get to that, can we talk a little bit about your thoughts on anger, aggression, both predatory and impulsive? Okay. There's no really good evidence that valproc acid is effective for predatory violence. Impulsive violence, yes. Impulsivity or impulsive violence as well, essentially, appears to result from a lack of adequate top-down inhibition of the limbic system. By and large, the ventral prefrontal cortex is responsible for evaluating the potential consequences of our impulses. And in the case of somebody who's having violent impulses, essentially their prefrontal cortex

is sitting there saying, no, don't do that. this is going to happen if you do that when it's working. For a lot of our patients who've had traumatic brain injury or who suffer from schizophrenia or who suffer from an inadequate input from the temporal lobe to the frontal lobe and psychopaths, for example, that top-down inhibition is inadequate. And consequently, the person behaves impulsively without adequate, considerate. of the consequences. They leap before they look.

The baleproic acid can help that by essentially putting a break on the activity of impulse generation. It makes the limbic system less active overall and can make the person less vulnerable to impulses arising, for example, from the amygdala toward being violent. The other way that we can address that, of course, is if we're not a lot of course, is if we can improve the functioning of the prefrontal cortex, we can improve the top-down inhibition. We see that with drugs like with chlozapine, for example,

or in the case of ADHD with dopamine stimulants. But for those patients who, for whom we can't improve their prefrontal functioning, the other side of the coin, if you will, is to decrease the limbic impulse generation. One quick question on the closopine. What blood levels needed for that frontal lobe optimization? Depends on the diagnostic context. And people with personality disorders, it appears to be well below the concentrations

needed to treat psychosis. Probably the best study in that area was Brown et al. at the Broadmoor Hospital in England where they looked at seven severely psychopathic individuals. These were antisocial personality disordered individuals who were very violent. They put them all on chlozapine. The average concentration in that case series was 171 nanograms per melloleter. For schizophrenia spectrum disordered patients, the minimum threshold appears to be around 350. nanograms per milliliter with most people having an initial target range of 350 to 600 and in more

treatment resistant cases up to a thousand nanograms per milliliter okay the one other group i wanted to ask you about is agitation and dementia um we looked at a couple studies and it seems like it doesn't do very much but do you have thoughts on when it's indicated or if it's over prescribed for agitation in dementia specifically? It probably is, in part because its efficacy is limited, as you point out. The other element, though, in the elderly demented is that, at least based on the VA study by Moused et al, it had a number needed harm of 26. In that study, they defined harm as death within.

six months. So if you treated 26 patients with valproic acid and among the elderly demented, you would cause one of them to die within six months. So is there any indication for someone with agitation in dementia for using this medication? There may be in some patients. One of the other elements that came out of that study in terms of relative risk was that the very safest drugs in the demented elderly were the SSRI antidepressants. They produced a number needed to harm that was not that different than the placebo rate for number needed to harm. Trazidone also fell into that very low-risk group, multiple low doses per day can help

decrease agitation and behavioral problems. After that, you got into the acetyl-colon esterase inhibitors in Mementine, also provided some benefit in terms of reducing behaviors that were undesirable. Valproic acid did have an effect, but it was small and had harm similar to that of the antipsychotics. So what we've tended to recommend to people is if you have an elderly person who has behavioral disturbance, start with altering the environment. Environmental cues orientation can go a long way toward reducing adverse effects. If those don't work, next steps to consider would be the SSRIs or chrazzadone or Mementia. and acetyl colon esterase inhibitors.

Again, not much evidence of increased harm. Only if those didn't work, would you move on to the mood stabilizers or to the antipsychotics? In other words, you would make the person earn the more dangerous treatment, only by failing the less dangerous treatments. Okay, we will be going into side effects now.

Let's talk a little bit about the risk of neutropenia when it's used in conjunction with clozapine? Okay. Closapine, of course, can produce an autoimmune nutropenia. Voproic acid can also produce a neutropina in part because it is a high stone deacetylase inhibitor, which gives it some of the properties of a chemotherapy agent, so it can lower cell mitosis by inhibiting DNA activity. where that's problematic clinically seems to be primarily in terms of those people who are near a threshold

for legal requirements in clozapine treatment you may worsen their neutropenia. There's not any real evidence to suggest that treatment with valproic acid has a huge effect in terms of worsening the likelihood of an immune response. to closeopine, but it can make the person more vulnerable to sliding below thresholds for mild neutropenia, moderate neutropenia, and perhaps in some people who are already in the moderate range, pushing them into more severe neutropenia. That has not been, that's been held to be essentially a precaution rather than a contraindication, because, for example, in patients who develop chlozapine-induced seizures,

valproic acid is a highly desirable drug in those patients in terms of controlling the seizures. Let's talk about hepatotoxicity. Hepatotoxicity is present. Valproic acid can cause hepatitis and indeed it's contraindicated below two years of age

because it can cause acute hepatic necrosis. in older persons some elevation of transaminases is not unusual elevation of ammonia occurs in almost everyone that's not a call to measure ammonia in everyone because you should really reserve measurement for those people who develop evidence of delirium because everyone will develop some increase in ammonia most of those cases will not have any clinical effect where valprocate is

when it induces pancreatitis, which is another risk and that then also comes to involve a hepatitis that goes along with the pancreatitis. That can be very dangerous and indeed the acute pancreatitis can be severe and can result in essentially the death of the pancreas. Are there any things to consider

consider when watching people for acute pancreatitis. Obviously, the pain of acute pancreatitis is usually like in the middle of the stomach and it's like stabbing to the back or just very, very painful. Yeah. Indeed, you should look at the person and educate, of course, the patient to if they have abdominal symptoms that have central pain with radiation to the back, they should report that immediately. Like most medications, adverse effects with valproic acid tend to occur early in treatment, which is why the monitoring advice tends to be monitor more frequently early in treatment. For example, in the Department of State Hospitals, measurement of valproic acid, plasma concentrations, amylase, lipase, hepatic functions occurs.

weekly for the first month, and then every two weeks for the months two and three, monthly for weeks, for months three through six, and then after that it's every six to 12 months, or as clinically indicated. Because indeed, if there's going to be an adverse effect, it will be early in treatment in most cases. That seems pretty frequent. I mean, I don't think we're doing that outpatient or, no, in the community attention to be less frequent since we're, we have people inpatient and the labs are more easily available, and we're often treating people very aggressively in the state hospital system,

the monitoring is correspondingly more aggressive as well. So would you say that if someone had hepatic dysfunction, it would be a contraindication for this medication? If they have a urea cycle disorder, yes, because indeed one of the effects of alpropac acid is to inhibit the, urea cycle and you may produce hepatic encephalopathy and if in the in people who already have a urea cycle disorder can you tell me like just what is a urea cycle disorder oh usually an inherited disorder in which the person does not adequately attach ammonia uh to uh to make the molecule

urea. Essentially, the liver manufactures urea and then the kidney clears it in the urine. If that cycle is defective and the person already has difficulty with making urea, adding valproic acid to the mix will make them worse and very likely may give them an episode of hepatic encephalopathy. So I know like a really common board question is and maybe you have a seizure patient or bipolar patient and they come in with them and they have an isolated very, very high ammonia level. How would you manage that person or would that person have liver disease just with that isolated high ammonia? High ammonia by itself may or may not produce. encephalopathy.

Now obviously, if you get ammonia high enough in anyone, you will begin to impair neuronal function. But people vary widely in terms of how sensitive they are to their own ammonia. Some people tolerate levels under 150. No problem. With most people, by the time you're getting up to levels of ammonia around 200, you'll begin to see evidence of confusion, difficulty concentrating, some loss of orientation ability,

and beyond that, eventually, at some point, the person will develop an overt delirium. What you often see with ammonia in the context of valproic acid treatment, though, are elevations, but elevations up to around 80, 90, and most of those people walk around just fine with no adverse effect at all, which is why we don't typically encourage routine monitoring of ammonia. Because you'll get abnormal lab values, but well, what do you do with it if the person's not clinically ill?

The other area I wanted to touch on, which is very, very important, is valproic acid should not be given to women who are pregnant. aside from what everyone has learned about neural tube defects, which are bad enough, the fetus suffers tremendously on exposure to valproic acid. There's roughly a 10-point decline in IQ if the fetus is exposed to valproic acid and the rate of autistic spectrum disorder doubles with such exposure. That goes back to the role of valproic. acid is a high stone deacetylase inhibitor. It essentially impairs DNA functioning. And that's critically important when you have cells that are differentiating and trying to adhere to the right

places, migrate to the right places. Valproic acid can interfere with all of those processes. Now in the adult brain, interestingly, valproic acid can also cause a much milder de-differentiation of neurons. And that brings us to the point you raised early on that you can make people, you can teach adults perfect pitch if you give them a valproic acid, which is something that normally in the differentiated brain you can't do.

Most of us learn the ability to gain perfect pitch by around age four years. But there was a study done that was a fascinating study looking at cell differentiation in which they gave adults, otherwise healthy adults, valproic acid, and they were able to teach the majority of them perfect pitch. Yeah, and all of these studies will be in the resource library, handout, the PDF that will go in the free resource library. If you follow the show notes or just go to Psychiatrypodcast.com, it's pretty easy to find.

What about hyponetremia? Hyponatremia is also a potential adverse effect of valproic acid. It can cause inappropriate secretion of anti-diuretic hormone, which acts, of course, to prevent the kidney from clearing water, which leads to, of course, a build-up of free water in the plasma and consequent hyponatremia. It is moderately dose-dependent, that is, the higher the concentration of our plasma. acroic acid, the greater the effect becomes. An important issue in many psychiatric patients is distinguishing between S-I-A-D-H, syndrome of inappropriate antidiarrotic hormone secretion by the pituitary versus simply excessive water intake, polydipzia, psychogenic polydipsia.

You can tell the difference by looking at both the plasma and urine at the same time. In the case of too much water intake, the kidney. are still clearing water just fine, so you'll wind up with a very dilute plasma and a very dilute urine. In the case of S-I-A-D-H, the problem is the kidneys are not clearing water, so you'll wind up with a very dilute plasma and a relatively concentrated urine. So if you look at both, you can tell which you're looking at. Okay. Any other side effects that you wanted to mention?

and we know there's hercetism, so increased hair. There's hercetism. There's also, conversely, alopecia, which in particular will be a problem for some female patients who don't particularly want to have thinning, hair or balding. And in those patients, often treatment with selenium may help prevent the hair loss. Minoxidil also can be helpful both in preventing and in reversing the hair loss as long as it's applied early enough. If you wait until the person's completely bald, the monoxidil is not so effective.

Wait, so it both bald and increases hair? How does that way? Well, this is a drug that inhibits cell activity at the DNA level. in some cases where there's a chronic inhibition of the follicle by other cells, if those regulatory cells get turned off, you get hair growth, particularly on the face. On the other hand, for follicles that are supposed to be active in dividing, just like any other chemotherapy agent, you can cause hair to fall out and be lost.

So not the best drug for young women who are sexually active or just young women in general? No, it has also been associated with polycystic kidney disease in young women. In young women. Okay. Any final thoughts on side effects that you monitor for with this drug? I think the principal ones are to indeed monitor the person for any neural side effects such as a taxi or confusion, and also to at a reasonable level monitor for any GI effects.

Again, adverse effects are much more likely to occur early in treatment when you're introducing the drug as opposed to in people who've been on the drug for a long period of time. And of course, in women in their childbearing years, they need to be very carefully educated about the risks of valproic acid. Okay. Any other final thoughts on, you know, this medication? Just I've always been impressed that for something that was supposed to have been an inert molecule, it turned out to do a lot of things, everything from being an anti-epileptic to a mood stabilizer

to now a chemotherapy agent that's being used adjunctively to treat cancer. That's quite a range of things for something. that was supposed to be inert. Yeah. Okay, well, we will leave it there for today. Once again, we'll have these notes, the links to the studies, things that you can explore further,

share with your colleagues or students that work under you, and we'll put that in the resource library for free. You can just go there and get the PDF and share it, and we'll leave it there. Okay, sounds good.