So some of what this lecture is going to talk about was discussed in previous content when we were talking about specific dopamine pathways and we alluded to some of the ways that those pathways are normally functioning when you have a person who has schizophrenia that's not being treated and we also alluded to how sometimes it is the treatment of schizophrenia that can cause problems in some of those pathways. So some of this might be a repeat from then, but the other content that this will go into is how to treat some of those side effects that are caused by antagonizing dopamine 2 receptors. Specifically as that relates to the motor side effects that are associated with dopamine 2 blockade. The nigrostriatal dopamine pathway starts from the substantia nigra and projects to the basal ganglia or the striatum and it's traditionally been thought to be part of the extrapyramidal nervous system and plays a key role in regulating movements and does this through its connections with the thalamus and cortex and the corticostriatal thalamocortical circuits or the CSTC loops too little dopamine in this area can cause parkinsonism with tremor rigidity and bradykinesia when there's too much dopamine here it can cause hyperkinetic movements like ticks and dyskinesias in an untreated schizophrenic individual this pathway is believed to function normally and on the next slide we'll talk more about how dopamine itself can regulate motor movement directly and indirectly.
Dopamine regulates these CSTC loops and motor movements in the striatum in a direct and indirect pathway. The so-called direct pathway is populated primarily with dopamine 1 receptors and they are excitatory. They project directly from the striatum to the globus pallidus interna and they stimulate movements so you can think of this as the go pathway the indirect pathway on the other hand is populated with d2 dopamine receptors and they are inhibitory they project indirectly to the globus pallidus interna via the globus pallidus externa and subthalamic nuclei normally this pathway blocks motor movements So you can think of this as the stop pathway. So dopamine inhibits this action at the D2 receptors in the indirect pathway. So it says don't stop to the stop pathway or another way to think of that is go more.
So to summarize, dopamine stimulates motor movements both in a direct and indirect motor pathway and the synchronizing the outputs of these pathways is thought to lead to the smooth execution of motor movements normally. So GABA neurons are also involved in this direct and indirect pathway in terms of activating motor movement. And so in the direct pathway, which remember the direct pathway is the GO pathway, A GABA neuron that projects from the striatum to the globus pallidus interna is activated. And when that happens, GABA is then released and it inhibits activity of another GABA neuron that projects to the thalamus.
So in the absence of GABA release in the thalamus, a glutamate neuron is activated. And it releases glutamate into the cortex and that therefore will stimulate movement. Over on the indirect pathway.
A GABA neuron would be projecting from the striatum to the globus pallidus externa, which would then be activated. And GABA then would be released, which would inhibit the activity of another GABA neuron that projects to the subthalamic nucleus. So without GABA release in that subthalamic nucleus, a glutamate neuron would be activated, and it would release glutamate into the globus pallidus interna.
which then would stimulate a GABA neuron to release GABA into the thalamus. So when the GABA that's released there in the thalamus binds to a glutamate neuron, it inhibits that neuron from releasing glutamate into the cortex, so then that would inhibit movement from happening. Motor side effects are caused by the dopamine 2 antagonists or even partial agonists blocking dopamine 2 receptors in the nigrostriatal motor pathway. So when these dopamine 2 receptors are blocked acutely in the nigrostriatal pathway, which is the same pathway that degenerates in Parkinson's disease, then you will see a condition that's known as drug-induced parkinsonism because it looks very similar to parkinson's disease with the tremor the muscular rigidity and just the slowing of movements or the loss of movements so often any abnormal motor symptom caused by d2 receptor blockers they tend to be lumped together collectively called extrapyramidal symptoms But it's a very imprecise term describing the motor side effects of dopamine 2 antagonists or partial agonists.
And part of the problem with sort of lumping them all together is that different conditions will have very different treatments, and they certainly manifest differently clinically. So more precise terms than extrapyramidal symptoms would include calling them by their specific name. clinical manifestation and what they are like drug induced parkinsonism, akathisia, dystonia, and tardive dyskinesia. So with this slide here what you are getting a glimpse of are the main four types of involuntary motor movements that are due to the acute or chronic blockade of the dopamine 2 receptors and the nigrostriatal pathway. And in addition to being able to differentiate them from just their clinical features the timeline of when these things will manifest is also different so you'll notice that acute dystonia and akathisia tend to happen pretty early on as does parkinsonism or pseudo-parkinsonism so those three are much more likely to occur you know early into treatment whereas tardive dyskinesia is a late occurring involuntary motor condition that happens.
So sometimes exposure to dopamine tube blockers, particularly those that don't really have any serotonin activity or anticholinergic properties, they can lead to a condition that's called dystonia. And often that happens upon first exposure to the dopamine tube blocker. So an important Kind of distinguishing characteristic of acute dystonia is that it happens acutely within, you know, a few hours of being exposed to the dopamine 2 blocking agent. And other characteristics of dystonia would be intermittent spasmodic or even sustained involuntary contraction of the muscles. And this could be really anywhere there are muscles.
So the face, the neck, trunk, pelvis, your extremities, your eyes. They can be very frightening and severe and fortunately they're easy to treat. You would give an intramuscular injection of an anticholinergic and that's usually effective within 20 minutes of giving it.
So your options there would be benztropine again or Benadryl. So one of the very common side effects of drugs that target the D2 receptors for psychosis is this drug-induced parkinsonism and The signs and symptoms of that would look identical to regular Parkinson's disease, where you have tremors, muscular rigidity, and slowing of movements, which we call bradykinesia, or just the loss of movements, which is akinesia. And the classic treatment for drug-induced Parkinsonism is the use of anticholinergics, particularly drugs that block the muscarinic cholinergic receptors, specifically the postsynaptic M1 receptor. And the reason why those are so effective is this approach exploits the normal reciprocal balance between dopamine and acetylcholine in the striatum. As you can see in this picture here, dopamine and acetylcholine have this reciprocal relationship in the nigrostriatal dopamine pathway.
And dopamine neurons make postsynaptic connections with the dendrite of a cholinergic neuron. And so normally dopamine binding to the D2 receptors would suppress. the acetylcholine activity so no acetylcholine would be released from that cholinergic neuron there. So to reiterate, under normal conditions when dopamine is acting on those D2 receptors, they will inhibit that acetylcholine releasing from the postsynaptic nigrostriatal cholinergic neuron. So they will suppress that release.
However, if you were to block D2 with an antipsychotic or some other antagonist at the D2 receptor site, then dopamine since it's blocked, can no longer suppress that acetylcholine release. So that acetylcholine becomes disinhibited, and more of it then is released from those cholinergic neurons. So the scale then is tipped, and it's out of balance. So with there being excitation of those postsynaptic muscarinic cholinergic receptors on those GABAergic neurons, this hypothetically would lead to inhibition of movements into symptoms of drug-induced parkinsonism. When the enhanced downstream release of acetylcholine is blocked then by an anticholinergic at the muscarinic cholinergic receptors, this restores that normal balance between dopamine and acetylcholine and that striatum and therefore the drug-induced parkinsonism is reduced.
So the more common agents that we use in this case for drug-induced Parkinsonism would be Benztropine or Cogentin or even Benadryl is another thing you'll see. Now while anticholinergic medications do work to reduce drug-induced Parkinsonism, especially that caused by older dopamine tube blocking medications that lack really any serotonin action, there are many potential problems with administering anticholinergic medications. and examples of that would be like cogentin which is also called benztropine or even benadryl and you know your typical anticholinergic side effects would be peripheral side effects like dry mouth blurred vision urinary retention constipation but you also have central nervous system side effects like drowsiness and impaired cognition problems with memory and concentration and just general slowing of cognitive processing and just As if that was not difficult enough, many drugs for psychosis themselves have a lot of anticholinergic properties, which we'll look at when we look at more of the individual drugs.
And many patients are on psych medications and non-psych medications that have anticholinergic properties. So as clinicians, we really have to be aware and alert to the total anticholinergic. burden that a certain patient might have and be wary of the side effects that could interfere with normal cognitive functioning and potentially lead to life-threatening bowel motility problems like a paralytic ileus. Akathisia is another syndrome of involuntary motor movements and it's probably one of the more common forms of what collectively we lump together as extrapyramidal symptoms and it's very easy to miss it's often mistaken and misdiagnosed as anxiety and this commonly happens with treatment with dopamine 2 blocking agents there are subjective and objective features to akathisia subjectively patients will typically report this sensation of inner restlessness or Mental unease or just general dysphoria.
Objectively, you will see restless movements, most typically being lower limb movements like rocking from foot to foot, walking or marching in place when standing or pacing. And sometimes drug-induced akathisia can be really difficult to distinguish from agitation and repetitive restless movements that are part of underlying psychiatric disorders. It is not particularly treated well with anticholinergic medications.
So more effective treatments tend to be the beta blockers, benzos, or other things that work on serotonin 2A and antagonize it may also be helpful. But the general standard of treatment would be beta blockers first and or benzos. Sometimes medications like amantadine which is a weak antagonist of the nmda glutamate receptor cogentin which again like i said anticholinergics really are not great at helping with this 5-ht-2a antagonists which trazodone and rimeron are meds that we prescribe often that have some action there at that receptor. Ciproheptadine and apparently vitamin B6 at 600 milligrams twice a day can help patients with the subjective symptoms of akathisia, but not so much with the objective symptoms.
Now there is a rating scale, like a standardized rating scale called the Barnes Akathisia Scale that you can use in clinical practice to help identify and potentially treat then symptoms of akathisia. Tardive dyskinesia is another abnormal involuntary movement disorder that can be caused by chronic blockade of dopamine 2 receptors in the nigrous triadal dopamine pathway. It's called tardive dyskinesia because unlike the other motor symptoms caused by D2 blockade, these involuntary movements are late and delayed in onset, often after months to years of treatment.
Tardive dyskinesia emerges only after chronic treatment with D2 blockers, and it can be irreversible, and it consists of involuntary, continuous movements. Often you'll see this in the face and the tongue, and it looks like constant chewing, tongue protrusions, facial grimacing. And sometimes you'll see limb movements that can be quick, jerky, or choreoform, which looks kind of like dancing.
Now, again, it tends to get lumped into the grand category of just extrapyramidal symptoms, but it really has its own distinct treatment now, and it looks very different from all the other involuntary motor movements that we're talking about. And about 5% of patients who are maintained on a dopamine 2 blocker, particularly ones that have little to no serotonin receptor action, they'll develop tardive dyskinesia every year. And that's about 25% of patients after five years, basically.
So that's not a very encouraging prospect when you think about... Typically, psychosis, like schizophrenia, starts in a person's early 20s and it requires lifelong treatment. And that's for young patients. The risk for developing tardive dyskinesia in elderly individuals, it could be as high as 25% within the first year of being on a D2 blocker. So with the newer dopamine 2 blocking drugs for psychosis, there a bit different because they have that serotonin action and it's been difficult to really obtain data on this because many patients who are taking these newer ones had been on older drugs in the past but for those who have only taken the newer dopamine and serotonin antagonists it's suspected that the rate of tardive dyskinesia might be about half the rate of the older drugs and these newer agents definitely mitigate drug-induced parkinsonism with mechanisms that we'll talk about and that might also be what mitigates the chances of developing tardive dyskinesia at least that's what we think so what causes the phenomenon of tardive dyskinesia to happen in the first place Well, one theory is that nigrostriatal dopamine 2 receptors most sensitive to the blockade trigger a form of undesirable neuroplasticity, which is called supersensitivity, in reaction to dopamine 2 receptor blockade.
And so if the dopamine 2 receptor blockade is removed early enough, the tardive dyskinesia may reverse on its own. And this reversal is theoretically due to a resetting the super sensitive dopamine 2 receptors and they then appropriately return to normal and the number or the sensitivity that they had prior to the antipsychotic drug being there in the first place but after a long-term treatment sometimes the dopamine 2 receptors apparently cannot reset back to normal even when that drug is discontinued so this leads to tardive dyskinesia that is irreversible persisting whether or not dopamine 2 blockers are administered interestingly the dopamine 2 receptors and the motor striatum also appear to react in much the same way to chronic stimulation by levodopa and parkinson's disease as they do to chronic blockade by dopamine 2 antagonists or partial agonists and schizophrenia So in both cases, whether it's the chronic levodopa, it can lead to levodopa-induced dyskinesias that look very similar to tardive dyskinesia. So we think that there's a similar pathophysiology going on here of this aberrant striatal plasticity and this abnormal neuronal learning.
So looking at this slide here on the left hand, The picture here shows us that under normal circumstances, meaning without antipsychotics on board, dopamine acts on the D2 receptors in the indirect motor pathway. And this so-called indirect pathway, as you might remember, is the pathway for stop actions. So the D2 receptors are inhibitory, therefore dopamine causes an inhibition of the stop pathway. So in a roundabout way then it sort of triggers the indirect pathway as like a go signal because it's inhibiting the inhibitory pathway.
So it's stopping the stop pathway if that makes sense. So then what happens when you block dopamine there? Well when you have drugs like antipsychotics that acutely block D2 or at least partially do so, it blocks the ability of dopamine to say go because those drugs inhibit dopamine's action at that stop pathway. So another way to think about that is that dopamine 2 blockers basically stop in that indirect pathway.
So if there's too much stop, then this can result in pseudo-Parkinsonism. And when that stop is not inhibited by dopamine, being able to act on those D2 receptors there in that indirect pathway, because you have an antipsychotic blocking it, then movements are stopped. Sometimes so much that you will get that lead pipe motor rigidity, the sort of slow movements.
And if that situation is allowed to persist, those D2 receptors in that... indirect pathway hypothetically react to that dopamine 2 blockade and we'll look at this slide that follows to show how that can theoretically lead to tardive dyskinesia so if we have chronic blockade of those dopamine 2 receptors from an antipsychotic or other d2 blocking drug then those D2 receptors hypothetically learn to have tardive dyskinesia because they basically proliferate excessive numbers of those D2 receptors in that indirect motor pathway. It's like the dopamine system attempts to overcome that blockade by making more dopamine receptors, which then results in the indirect pathway being overly sensitive.
So another word for this is upregulation. So supersensitivity or upregulation of the dopamine 2 receptors and the indirect dopamine pathway is what we believe is the cause behind tardive dyskinesia. So in the past, we really did not have hardly any, truthfully, treatment options for tardive dyskinesia but fortunately recent developments have shown that tardive dyskinesia can now be successfully treated by inhibiting the vesicular monoamine transporter type 2 or the VMAP2.
Now as you might recall we discussed this when we were talking about dopamine transporters and so these transporters are localized on presynaptic axon terminals and they're known as reuptake pumps targeted by many drugs for depression and these transporters also exist for neurotransmitters that are inside the neurons and so it is these inside neuron transporters that are located on synaptic vesicles that are called vesicular transporters so they're inside the neuron and there's very different types there's one for GABA and glutamate acetylcholine, the monoamines, and so on. But the specific transporter known as VMAT2 is located on synaptic vesicles inside dopamine, norepinephrine, serotonin, and histamine neurons. And it acts to store those neurotransmitters inside the neurons until they're needed for release during neurotransmission.
And there's two types. There's VMAT1. which is localized on synaptic vesicles of the neurons in both the peripheral and central nervous system. And then you have VMAT2, which is really only localized within the central nervous system.
And so there's two known types of VMAT inhibitors. There's reserpine, which irreversibly inhibits both VMAT1 and VMAT2. And then there's tetrabenazine-related drugs, which reversibly inhibit. only VMAT2.
So the reason why that's important is because the reserpine drug inhibits both, then it has a lot more peripheral side effects like orthostatic hypotension, stuffy nose, itching, GI side effects. And although VMAT2 transports multiple neurotransmitters into synaptic vesicles, remember there's dopamine norepinephrine serotonin and histamine that use vmat2 transporters the tetrabenazine preferentially affects dopamine transporters at clinical doses and we'll look at the various drugs that are part of that kind of family of meds but basically what happens is when these tetrabenazine related drugs block that vmat2 transporter of that dopamine vesicle the dopamine is rapidly degraded by the monoamine oxidase enzyme that's within the presynaptic neuron and so then that leads to the depletion of presynaptic dopamine that's proportional to that degree of that bmat2 inhibition so tetrabenazine itself is an inactive pro drug that once it goes to liver metabolism is converted into four active dihydro metabolites so there's the four that's explaining that tetra tetra being four so all four of those are inactivated by the cytochrome p450 2d6 pathway most of the VMAT2 inhibition by tetrabenazine is done by the beta dihydro enantiomer because it has the greatest potency for the VMAT2 of all of its metabolites So it's only approved for the treatment of Huntington's Chorea. It's not approved to treat tardive dyskinesia. That doesn't mean that it doesn't get used off-label sometimes.
But the downsides to this drug is that it has a very short half-life, so you have to dose it three times a day. It tends to be pretty sedating, and at peak dose can also induce Parkinsonism. Since it's primarily metabolized through 2D6, you would have to do potentially genetic testing to see if someone's a poor metabolizer, since that's a common thing for that particular pathway. And there's a risk for depression and even suicide when used to treat Huntington's disease.
So the scientists were very clever and they found a way to... affect the way that tetrabenazine basically is metabolized via the cytochrome P450. And they did it through this process called deuteration. And so it basically converts a drug that's a good substrate for 2D6 into a poorer substrate for 2D6, which when you do this allows for a longer half-life, therefore less frequent dosing.
and then lower peak plasma levels and the process of deuteration is kind of complicated and it's not really critical that you know that but basically what this lets you do is because of the kind of change of that drug it allows you to dose it twice a day so you can remember that duet is like two people singing so Ostato, which is dutetrabenzene, it is dosed twice a day. It is FDA indicated to treat both Huntington's Chloria and Tardive Dyskinesia. So because it has that longer half-life and it doesn't really go through 2D6, you can dose it twice a day, but it does need to be given with food. There's no specific calorie amount that's required.
And it doesn't have the risk of suicide for treating tardive dyskinesia. And another form of tetrabenazine is the drug valbenazine. and it's called this because it links to an amino acid valine and so whenever it's swallowed the valbenazine is hydrolyzed into valine and then the metabolite of tetrabenazine and all that just makes it much longer as far as half-life goes so that's good so it's just just once a day and it is only FDA approved to treat tardive dyskinesia.
Similar to Ostato, it doesn't go through 2D6, so you don't really need to do genetic testing to see whether someone's a poor metabolizer, and you don't have to take food with Ingreza, so that's a nice plus. And there's no suicide warning compared to tetravenosine. So let's connect the dots between how inhibiting VMAT2 would help improve the symptoms of tardive dyskinesia. What we do know is it doesn't really matter what form, you know, which one of the four metabolites of tetrabenazine that you use to block VMAT2, it appears that about 90% of VMAT2 inhibition is required to kind of get the best balance between efficacy for tardive dyskinesia tolerability. VMAT2 inhibition fundamentally is a mechanism that reduces dopamine stimulation without blocking the D2 receptors.
So the action of doing that reduces the overstimulation of those D2 receptors in the indirect pathway which results in less inhibition of the stop signal there. there's also a benefit of inhibiting bmat2 in the direct pathway which is where the go signals are being amplified normally by dopamine at those d1 receptors so even though these d1 receptors and this direct extrapyramidal pathway may not be the site of pathology in tardive dyskinesia they do drive go signals for movement normally and thus lowering dopamine there by VMAT2 inhibition would be expected to lower the GO signals arising from the direct pathway. Combined with more stop signals from the indirect pathway, motor output to drive abnormal involuntary hyperkinetic movements is reduced by that combination of effects of the dopamine depletion in both the direct and indirect pathway.
So the VMAT2 inhibition basically trims the GO drives of dopamine. both of those pathways to compensate for the abnormal learning just in the indirect pathway after you've chronically blocked those D2 receptors. And this slide here is just another way to look at what was mentioned on the previous slide that blocking the VMAT2 transporters trims the go drives of dopamine in both the direct and the indirect motor pathways and it compensates for the abnormal hypersensitivity and upregulation of the d2 receptors that happen in the indirect pathway after you've chronically blocked d2 receptors so with the emergence of abnormal involuntary movements that are associated with tardive dyskinesia this is something that should be specifically monitored Using a neurological examination and there's a rating scale that's specifically designed and used to monitor in a very systematic and organized way.
It's called the abnormal involuntary movement scale or the AIMS scale. This should be done periodically. The best practices for this are to monitor movements in anyone who's taking any medication that affects dopamine, although this is not often done. And specifically for patients who are being treated for mood disorders like depression or bipolar, it's really... really often not done.
So then because of that, that really does put patients who have mood disorders at a greater risk for tardive dyskinesia, in part because it's just not as closely monitored. So remember that for any patients taking any medication that affects dopamine by blocking it specifically, those drugs can cause tardive dyskinesia regardless of what they are being used for. so whether it be for mood disorders or schizophrenia slash psychotic symptoms or if we're using it for off-label use like for sleep or anxiety or something don't forget that this side effects kind of like an equal opportunity effector the dopamine neurons that project from the hypothalamus to anterior pituitary gland are known as the tubero-infundibular dopamine pathway normally these neurons are tonically active and they inhibit prolactin release but in cases like postpartum however the activity of these dopamine neurons is decreased so when prolactin levels rise during breastfeeding lactation occurs if the functioning of this tuberoinfindibular dopamine neuron is disrupted either by tumors or some of the drugs that we prescribe prolactin levels can also rise elevated prolactin levels are associated with symptoms like galacteria which is breast secretions gynecomastia which is enlarged breasts especially seen in men amenorrhea which is the loss of ovulation and menstrual periods and possibly other problems like sexual dysfunction and bone demineralization These problems can occur after treatment with many drugs for psychosis that end up blocking dopamine D2 receptors.
We'll discuss those particular drugs later on. If in an untreated schizophrenic individual though, the functioning of this tuber infundibular pathway is generally preserved and there aren't any abnormalities here. So as you can see on this slide here, there are many things that can contribute to elevated prolactin levels that are not exclusively due to antipsychotic or D2 dopamine receptor blockade. You can look at all of these examples here, but it's important to consider that there could be other comorbid and contributing causes to elevated dopamine besides the medications that we use to treat.
psychosis because many times people fail to work up alternative causes and this can lead to unnecessary medication changes or unnecessary disruptions in treatment so when should a prolactin level be checked well it used to be common practice that if we had patients on antipsychotics that we would periodically and routinely check prolactin levels. More current guidelines, particularly from the Endocrine Society from 2011, they recommend that you do not routinely check prolactin levels in a patient who is otherwise asymptomatic. Of course, many of the signs and symptoms of elevated prolactin are not going to be readily apparent to you as the provider, so that's going to require the patient to either spontaneously report those signs and symptoms or probably a better approach would be for you as the provider to ask about signs and symptoms of elevated prolactin but when you're going to check a prolactin level remember that it peaks during sleep so ideally you want to check a prolactin level in the morning preferably a few hours after waking and the patient should be fasting since food or having eaten a large meal can affect prolactin levels and the patient should avoid strenuous exercise 20 to 30 minutes before the lab is drawn since strenuous exercise can also affect your prolactin levels and elevate them if a patient has this you know horrific fear of needles then that's something you need to consider and actually address beforehand because Stress or anxiety can also lead to falsely elevated prolactin levels. So what are you supposed to do if and or when you have a patient who develops signs and symptoms that are concerning for hyperprolactinemia?
And so you do your due diligence and you check and sure enough that prolactin level is elevated. Well it's interesting that there is no single authoritative recommendation as to when hyperprolactinemia requires an intervention. So it's very interesting.
Now think back to what some of the consequences are if we don't treat elevated prolactin. You can have gynecological disturbances like changes in menses, gynecomastia with prolonged elevated prolactin. You can have osteoporosis or infertility. And in men, it can affect their testosterone levels, leading to sexual dysfunction and hypogonadism. So what do you do?
Well, there's a couple of options. One of those would be watch and wait. It's something that very well could be... You know, there could be many variables that could lead to that elevated prolactin level like we talked about before. So maybe just watching, waiting, and rechecking is all you need to do.
I'd say that's probably not going to help most patients, so that wouldn't be my first-line option, but it is one option. Now your next option is you could discontinue the antipsychotic. Now that's gonna be problematic if your patient is dependent on an antipsychotic or if they have a disorder that can only be treated. by an antipsychotic.
That's not going to be feasible, but if the antipsychotic is something that you could get rid of, then you would expect the prolactin levels to go back to normal about three days or so after you've stopped the drug. Of course, that's going to depend on the half-life of the drug. Some medications with much longer half-lives, it might take longer for those levels to normalize, but the point there is we would expect the prolactin levels to normalize if they're being elevated because of the drug.
so if you can't stop the drug altogether then reducing the dose sometimes helps because prolactin elevation often is a dose related phenomenon um but there are some meds like risperidone and paliperidone that can increase prolactin levels even at very low doses so you might be on the lowest dose and you still have elevated prolactin and of course reducing the dose puts you in the position of taking the gamble that the dose might not be adequate to sort of treat the problem that you're treating. So if you can't stop the antipsychotic and you can't decrease the dose, then the next logical option would be is to switch the antipsychotic. And generally, this would be what I would probably do in my own real world practice.
If there was some reason. that I knew I couldn't stop or reduce it or if I didn't think that reducing or stopping it was really going to help the situation. Usually switching is the better option. So you want to switch to a prolactin sparing antipsychotic. So your best options are going to be aripiprazole, which is the bilify, brexpiprazole, which is rexulti, cariprazine, which is vraylar, or clozapine.
So, you know, switching... the antipsychotic does decrease prolactin levels. Now what we don't know though is is it because of the difference in the mechanism of action of the medication or is it because you stopped the offending agent?
That part we're not really sure, but switching an antipsychotic is usually the best option. Now you could if for some reason the patient has tried a million different things and they have not responded to anything but this particular med that's causing this elevated prolactin, and at that point it's like the risks of destabilizing this patient are greater than any, you know, slim benefits that you might get from trying to switch them to something else, since you've kind of already been there and done that, right? Then it is a reasonable strategy to actually adabilify as kind of an adjunctive treatment to lower prolactin levels.
That seems to work, interestingly. You could also very cautiously, and I would say this is probably like the last line approach. You would not really want to jump to this option first. But you could add very cautiously a dopamine receptor agonist. So that would be like cabergoline or bromocriptine.
And those do suppress prolactin secretion. You just have to be careful because they could... increase the risk of psychosis and so that could be problematic depending on what you're using an antipsychotic for you know what you're treating the patient with um other interesting options that i found are there are some herbal preparations that can be helpful in lowering prolactin levels i'm not even going to attempt to pronounce these some of these looks like they might be um more from like chinese medicine perhaps but this first one here where it has like a specific dose the 45 grams per day apparently in the clinical in the clinical trial that looked at this it significantly reduced risperidone-induced hyperprolactinemia over a four-week period and the magnitude of that reduction was comparable to what would be seen with bromocriptine five milligrams a day so that's just something interesting for you to know but typically most guidelines are going to suggest either switch the antipsychotic if you can and or atabilify if otherwise stopping or reducing the antipsychotic is not an option or you've tried that and it didn't really help