In the next 45 or 50 minutes, I'm going to take you through some of the basic aspects
of the clinical psychopharmacology as it applies to the use of both first and second generation
long-acting injections.
The areas that I feel should be understood by most prescribers can be seen in this current
slide.
Effectively, we need to know about kinetics, that is the absorption, distribution, metabolism
and elimination of the antipsychotic.
And of course, the kinetics of long-acting injections are quite complex when compared
to oral medicines.
And we'll go into that in a little while.
One of the great problems in psychopharmacology is when we're changing medicines and we're
switching from one medicine to another, we've got to make sure that we are switching with
the appropriate equivalence of dose.
Now switching equivalence can be thought of in terms of which particular target receptors
of interest to us.
So for example, we consider the overall effect on positive symptoms to be related to the
amount of dopaminergic blockade at the D2-like receptors.
However, in switching, we've got to consider effects on an imbalance of other receptors
such as M1 and M4 cholinergic receptors, serotonin receptors and so on and so forth.
Now we don't cover switching in any depth at all in this tutorial, but there is a separate
2-hour tutorial available on that.
The dosey equivalence has to be considered in terms of the, if you like, the technology
of delivering the antipsychotic agent, and therefore first-generation drugs as a whole
can be considered in one block, and then the second-generation drugs are quite different
in their delivery mechanisms and therefore in their kinetic profiles.
We need to know a little bit about what is an average dose, what is an expected dose,
and what sort of factors will modulate concepts of what the average dose is.
So for example, if I am using an agent that is particularly metabolised by cytochrome
P450, 2D6 and 3A4, then I will want to be quite cautious about using polypsychotropic
prescribing with agents that are either induces or inhibitors of both of those systems.
And this might be quite relevant with respect to respiridone and aropiprazole long-acti
injections, and of course a lot of the first-generation long-acti injections are principally
metabolised by 2D6.
So we have to have in the back of our minds that an average dose isn't just an average
dose.
It will depend on a number of factors, and of course we'll go into those a little later.
We have to decide about the injection interval.
Now it seems to be that for first-generation drugs, other than haloperidone, the majority
of people receive their injections too weakly.
And whereas the wisdom of using this inter-injection interval is quite sound, for many, many years
there has been a wide range of intervals for delivering first-generation drugs, ranging
from 10 days up to 4 or sometimes 6 weeks apart.
This is absolutely dependent on the individual's response to medicine and can't easily be
predicted by any external factors.
However, in the second-generation drugs, due to the mechanics, if you like, of the type
of preparations, and really we're talking about crystal-based preparations here, all
the microspheres that we see with respiroidone, some of the injection intervals are pretty
well determined by the technology of delivery, and the flexibility isn't as broad as it
is with first-generation drugs.
The next thing we need to consider, of course, is the concept of plasma-level variations.
Now without going into this in too much depth, it has been argued that if we take the peak
levels that are achieved, the Cmax, and we look at the minimum levels in that injection
cycle prior to the next injection, which is the Cmin, that ratio of maximum to minimum
is said to be optimal when the ratio doesn't exceed 2.
So in other words, the peak dose shouldn't be more than twice the trough dose, or trough
levels I should say.
Now although this is a principle that has been identified post hoc in analysis of responders
versus non-responders, we should keep in the back of our minds that like any psychotropic
agent prescribing is often very individualized.
And so in an individual who's well-stabilized and a good responder, we may find that we're
able to lengthen out the inter-injection interval, say to four weeks, and we may at that stage
have a peak to a trough or a Cmax to C minimum ratio of three or even four, and yet in an
individual that may be satisfactory.
However, as a general principle, we would expect that these very wide ratios are more
likely to lead to relapse during the trough period.
Another consideration that should be always considered is the notion of loading or initiation
strategies.
And as we go through a number of the agents today, we'll look at aspects of initiation
strategies, both for first generation and second generation agents.
Now initiation or all loading strategies, and we can use those interchangeably to a degree,
what this is about is trying to overcome the rate limiting part of getting the blood levels
up of the agent that we're using, and that the slowest part of the mechanism of rising
blood levels is the alpha phase or the release from the actual depot site.
Now once a medication has been released from its depot site and it's into the plasma, then
its plasma half-life is just the same as it would be for the oral medication.
But the whole notion of how long-acting injections or depots work is that there is a slow and
measured release from the depot site, and that's the alpha phase.
Now sometimes we could use an oral agent, which will achieve plasma levels quite quickly,
usually within three to five days, and just keep giving that oral until we reach a sufficient
plasma level from the release from the depot site, and we'll certainly be discussing the
use of initiation oral adjunct agents in respiridone and in arypiprazole, for example.
However, in the first generation drugs, it can sometimes take months before steady state
is achieved if we just use routine injections, and so it's often advisable to instigate
an initiation strategy where either we use a bigger dose more frequently or variations
on that theme in order to get the plasma levels up early on, and that helps us to avoid the
need for using oral adjuncts.
Now the reason, obviously, we would like to not use oral adjunctive strategies at the
beginning is all to do with the reason that we've put a person on long-acting injections
in the first place, predominantly this is due to non-adherence.
So in a controlled inpatient environment, we certainly consider the oral adjunct where
we can supervise the delivery of this, but in the community this becomes much harder,
and so initiation strategies are de rigueur in those settings.
Now the next area that requires some new thinking, perhaps, is the concept of a long-acting injection
as being both an acute and a maintenance agent.
What we're standing, my comments I've just made about, it takes a long time for a lot
of the LIAIs to get to steady state unless we use initiation or loading strategies.
We should be aware that some of the crystal-based second generation agents have an immediate
release, and it's quite possible that no oral adjunctive agent is necessary in a majority
of people treated with these new agents, and for that reason, in some cases we can use
some of these new agents as the acute treatment, so we will have plasma levels say within the
first week that are satisfactory, and then the same agent maintains the protection in
its maintenance role, and this requires some quite considerable shifting of gears for those
that have been using long-acting injections for many years and are aware of the long period
it takes for plasma levels to get up to anything useful if we were just to use standard doses
at standard inter-injection intervals.
Now we also should be considering pharmacodynamic aspects of a lot of the newer medicines, but
we're not going to concentrate on that at all in the current lecture, and that will
be developed in other lectures of this series.
As I've already made mention, switching is incredibly important, getting it right in
the switch is crucial, and so that will be dealt with only to a minor extent in the current
lecture and has its own individual tutorial, which is part of this series.
Finally, when all the pharmacology is sort of understood, we've then got to think of
the real world, and the real world is all about how easy is it for us to use this agent,
how easy is it for us to get it into the person.
So administration issues become quite relevant, especially in very busy clinics.
Having an agent that you have to keep in the fridge for hours, take it out certain time
before, let it come to room temperature, shake it, not stir it, all of these things can be
an impediment to the adoption of these agents in busy community settings.
What we would like best of all is an agent that we would have to really use very little
preparation with, and if we give an injection, it lasts for a long time and we don't need
to worry about the difficulty of giving it in any way.
Well, such a medicine doesn't exist as such, but some of the medicines are approaching
that degree of ease of use, and we'll go through that where appropriate.
So everything on this slide is dealt with in our textbook on long-acting injections,
which will be in 2015 in its second edition, but not a lot will change with respect to
the pharmacology other than to add in some of the new agents.
So let's look at some take-home messages that I think if the rest of the tutorial doesn't
sort of flesh anything out for you, let's look at the things that I think would be very
helpful.
First is equivalence.
Now, as you can see here, the standard four agents that are used in Australia, first-generation
agents, flupenthexyl, zooclopenthexyl, haloperidol, and flufennazine are all esters of long-chain
fatty acids.
That makes them soluble in oil, and so all of them share a common delivery mechanism.
Now they do come in different volumes of injection, and there are concentrated forms,
as they're called, in some of the agents that allow quite a lot of material to be injected
in a small volume, but by tradition they have all been gluteal, and there's quite a difference
between gluteal delivery and using the deltoid, and we'll discuss that a little later when
we're dealing with some of the new agents.
So for the new agents, they're all given in the same way and utilize the same mechanism
of sort of the agent itself being deesterified and released into the plasma.
The equivalences, as you can see, are notionally to 300 milligram equivalence of chlorpromazine.
Now the 300 milligrams per day is really what is thought to be the sufficient dose, all
other things being equal, that a person would need for maintenance schizophrenia.
However, in reality our own pharmacoepidemiological database shows that probably the average
in community psychiatry, and that seems to be pretty similar between Victoria and New
South Wales, is about 410 milligrams per day on average.
That slightly higher dose than what is recommended is probably an artifact of things other than
the pharmacokinetic and dynamic parameters of the agents, it's probably much more to
do with poor adherence and other factors.
But whatever the case, our starting point for interconversion is if I had to give 300
milligrams a day and I know it's going to get into the body because I'm giving an injection,
what are the various doses?
And as you can see, for flu penfixol, it's 40 milligrams every two weeks.
For Zucchlor, it's 200 milligrams every two weeks.
For haloperidol, there's some variation on this, but somewhere between 90 and 110 milligrams
four weekly, we use 100 in our own conversion software, and that again is equal to 300 milligrams
of chlorpromazine equivalents a day, and then for flu phenazine, 25 milligrams two weekly.
Now due to the reasonable linear nature of how these oil-based long-acting drugs work,
we can sort of work out chlorpromazine equivalents when we change interval frequencies and so
on.
So you can use very basic arithmetic to work out daily chlorpromazine equivalents, should
you reduce the dose by lengthening the interinjection interval.
Now if we look at the second generation agents, rather than pull everything back to a 300
milligram per day chlorpromazine equivalent, which we could still do of course, here I've
actually used some of the common doses to demonstrate the equivalents.
So if we look at respiradone first, two milligrams of respiradone is somewhat close, a bit lower,
but close to 25 milligrams two weekly.
Four milligrams is about 50 milligrams of respiradone long-acting two weekly, and therefore
37.5 is right in the middle, and that's probably about three milligrams of respiradone
oral, which is about 290 milligram equivalents of chlorpromazine.
Now in our own textbook we used a different value, and that was more to do with the vagaries
of other cultures use of conversions rather than what I think can be scientifically supported.
The figures I put on the page here actually can be defended using the established pharmacokinetic
PI studies.
That should alert us to say, well if I need more than four milligrams of respiradone, so
that's roughly say 380 equivalents of chlorpromazine, if I actually want to use bigger doses then
we get into the issue of having to use either two injections and so on with respiradone.
And no amount of massaging the data to make people feel that 50 milligrams equals 6 milligrams
will actually do the patient any good because that's actually not right.
So keep that in mind when you're doing your conversions.
Now if we move to palaperadone, the palmitate, here the range I've just put two figures in,
the 6 milligram is probably equivalent to 75 milligrams for weekly, once we're into
the monthly injection routine, and 9 milligrams is equivalent to about 100 milligrams for weekly.
Now the interconversion between palaperadone and respiradone is somewhere in the two to
three range, depending, and so these figures are broadly, linearly equivalent to the respiradone
ones.
Now when we move to a landscaping, there were probably three common doses that are used,
as you can see here, that's 10 milligrams, 15 milligrams, and 20 milligrams orally.
And the equivalence in terms of the injection of a landscaping pamoate, the 10 milligrams
is about 300 milligrams of the long-acting four weekly.
If we want to give 50 milligrams, 15 milligrams, we would then use 405 milligrams of the pamoate
every four weeks.
And if we wanted to use 20 milligrams, well there is no four-weekly equivalent, and the
20 milligrams ends up being 300 milligrams two weekly.
So it's using the same arithmetic linear extrapolation that we used for some of the other conversions.
Now this is just a brief overview, and in the switching software that we use, we obviously
can convert any dose to any equivalent dose, but in the real world we have to match that
to what's actually commercially available.
Now the latest cap off the rank in terms of second generation drugs is aropiprazole long
acting, and it's early on in its use, and so the dose equivalences are still somewhat
vague.
By vague I mean these are the values that have been proffered by the manufacturer, and
so at the present state of play we'd say if we're using somewhere between 10 and 30 milligrams
of aropiprazole oral, then this will be an equivalent to 300 to 400 milligrams four weekly
of the long acting.
Of course there is some concern that really you don't need any more at steady state than
10 milligrams of the oral a day, and so that might roughly be equivalent to 300 milligrams
of the long acting, and that would probably be an optimal dose for a majority of people.
So there we have our rough equivalence, so if I'm going through it, if I'm trying to
estimate roughly 300 milligrams a day, then an exercise that you might wish to undertake
later on is to actually work out what all the doses of the first and second generation
drugs would be to give you 300 milligrams a day of chlorpromazine equivalence.
The first generation drugs I've done for you, the second generation ones you can calculate
from this table, but there are a couple of other agents that we don't necessarily use
in Australia, but are used widely in other places in the world.
Now the first is pipithizing, which is used in New Zealand and Britain and other countries,
and here the equivalent to 300 milligrams a day is probably 80 milligrams every four weeks.
In the Scandinavian countries, perfenozine in its long acting form is very popular, not
available in Australia or New Zealand, and here probably the range is somewhere between
70, 75 to 102 weekly to give us the equivalent 300 milligrams per day.
Now in the real world, the data shows that perhaps the agents aren't being used with
full equivalence.
So for example, the first four agents are from our big pharmacoepidemiological database,
this covers about seven years of prescribing in Victoria, and what you can see here that
is on the far right, when these agents are used in monotherapy, they're all pretty well
equivalent to each other except for fluphenazine, and fluphenazine is significantly higher in
its chlorpromazine equivalent dose.
Now this is an interesting finding.
We have surmised, and this is something you wish to discuss afterwards, but we've surmised
this is probably due to the fact that this was the first agent that was commercially
available and people have been on it a long time, and of course when you've been on an
agent for a very long time, you will develop what's called slow super sensitivity, and
you'll require larger doses to achieve the same degree of clinical improvement.
So it is possible that this accounts for the higher dose of fluphenazine that's given.
However, other explanations might also be germane, and it could well be that some people
use the American conversions, which are frankly completely wrong.
We would just use the standard European and Australian conversions.
Whatever the cause, we know that fluphenazine, which is an agent we really wouldn't want
to instigate in modern suncaretry, has been used in the public sector in significantly
higher doses than the orals.
Now if we look at pipithazine and perfenazine, the agents we don't use in Australia, we can
see that their equivalence is probably not well understood, and when they're used in
polypharmacy where they're used with other agents, they do seem however to end up being
roughly the same equivalent as the other first generation agents in Australia that are used
in polypharmacy, when in that context what their dose would be.
So overall it looks like that you can see here that in monotherapy you're likely to
get a touch below 300mg equivalence per day on average, pretty much according to what
the original theorising was with regard to what would be an average day's dose for a
person with schizophrenia for maintenance.
When we consider the doses used in polypharmacy, we can see that all the first generation agents,
again with the exception of fluphenazine decanide, are all used at approximately the same level,
just a little bit over 300mg equivalence of chlorpromazine a day.
Of course therein lies the problem of polypharmacy that when we look at oral supplementation
on top of that it usually drives the average day dose towards 700mg.
Polypharmacy is dealt with in a separate tutorial.
So it looks like the way people use things at the moment, roughly 300mg a day or a bit
less in monotherapy seems the way to go.
Now what about the practical issues of administration?
Well, let's start off with the first generation agents and what we can see of course is that
all of the agents are traditionally given in injection into deep gluteal muscle.
Now the way that first generation drugs are delivered in depo form is that the parent
molecule is esterified with a fatty acid and what this tends to do is allow the esterified
molecule to be dissolved in an oil, it's traditionally now sesame oil but has involved
other oils from time to time like coconut oil or viscolio and so on but let's just say
sesame oil is one of the most common and once the depo is in that the long chain fatty acid
and the hydrophobic part of the anti-psychotic molecule tend to orientate towards the oil
whereas the lipophobic part, the hydrophilic part that feels more comfortable in water
tends to orientate itself towards the outside of the oil globule that's been injected and
eventually when it reaches the surface it makes itself available for de-esterification
and release into the interstitial fluid.
So the tension if you like is between the hydrophobic or lipophilic part of the molecule
wanting to stay in the depo oil and the hydrophilic part wanting to be out in the plasma and that
tension if you like is what causes the slow release, the alpha phase in terms of the kinetics.
Now there are a number of problems when we're using injections in oil and these are dealt
with to some great degree in our textbook but very briefly one of the things we've got
to be aware of is there have been reports not only of injection site reactions but of
actual development of sclerotic nodules in the buttocks and there was an early publication
from Lundbeck that actually showed that with haloperidol injections there was actually
a little bit of myonecrosis in some cases.
The other thing to remember especially with people with schizophrenia of whom 76% are now
obese according to our own clinic population stats, it's quite possible that sometimes
gluteal injections don't get into muscle but they get into subcutaneous fat and we're
not absolutely certain of the kinetics of release from fat, I would suggest it's not
very predictable compared to what release from muscle sites is.
So one thing we have to be very clear about and this will apply to all the other agents
not just first generation drugs but not only do we need to check to make sure that we haven't
got sort of fibrotic nodules from previous injections but we also have to make sure
if we're using these injections with a very obese person that we try to find a way of
injecting that will reach muscle.
And there is research currently being undertaken in Melbourne to look at really determining
the best way of inject.
Now if we move on to respirodone, in Australia this is still given principally as a gluteal
injection but a formulation was devised at some stage for deltoid injections.
But independent of whether the deltoid or gluteal is used, it's administratively, it's
a little harder to use this agent as easily as some of the others.
Now the reasons are well known to you but let's quickly summarise them by saying the
agent itself has to be stored in the fridge.
It is a plasticised polymer which is sort of like the same stuff that surgical sutures
might be made out of in a sense and so we've got to keep it fairly cold but when we're
ready to use it, we've got to take it out of the fridge half an hour at least before
we use it and there's quite a complicated three needle system to prepare it for injection.
Now one of the key things about the injections of course is that we have to make sure that
the actual microspheres, the little plastic polymers, are well dispersed throughout the
whole of the diluent.
Now otherwise you can get clumping and you will not get the expected delivery of the
agent that you want.
But even in the best circumstances you can't always guarantee that you have got even mixing
throughout the whole of the vial and so it wouldn't make too much of a difference when
we're injecting the whole vial but some people have attempted to use say half of a vial to
be able to inject 12.5mg for example or to add another half a vial on to say a 50mg injection
in order to get to 62.5mg.
When you're doing that, there is no guarantee that if you take half, you've actually got
half of the amount of respiratory and microspheres because the gluggy white suspension of the
microspheres is quite hard to get it really evenly distributed throughout the solution.
So that's one of the traps for young players is wanting to use a lower dose for example
in the elderly but the problem is when they're not absolutely certain how much is going to
be delivered to the patient when we try to split a normal vial's contents and really
should use the whole vial if possible.
Now the advantage to this and the agents that follow is we don't have to undertake what
is called Z-tracking.
Now in some of our other tutorials we've shown how the agent when it's injected, the first
generation agent that's used, injected we actually have to grab the skin and pull it
back, pop the needle in, inject, of course checking first that we haven't pranked any
vessels, when you take the needle out you then let the skin go and it sort of pops
back and this is called a Z-tracking technique because it doesn't allow a direct outflow
channel for the oil to seep out from the injection site.
It's a very easy technique to learn how to do but it's still another step that one has
to undertake.
In the second generation agent Z-tracking, or at least with respiridone and palaperidone
Z-tracking is not required.
Now if we move on to palaperidone, here the administration is probably the simplest of
all agents, the reason for that is the actual material is pre-dissolved, it's all ready
to go if you like in the syringe, it's just a matter of appropriate needles.
Now the kit also comes with two different needle sizes, ostensibly to help overcome
the problems of people with a lot of subcutaneous fat.
Even using the longer of the two needles in very obese people, one has to be fairly cautious
about whether or not deep muscle has been reached but it's certainly at least an acknowledgement
and an aid to making sure that we do get it into muscle.
So the ease of use is very high but there's another advantage to this agent and that is
that it can be and should be given in the deltoid muscle at the initiation stage and
this actually gives us a fair degree of control over the kinetic profile.
So even though over say a month injection in the buttock and injection in the deltoid
will give us the same area under the curve meaning the total amount that's actually absorbed
into the system, the deltoid kinetics are such that we will get quicker and higher peaks
and then it will fall off more quickly and this is why we use it in the early stages
and the initiation strategy to make sure that we get the blood levels up.
So overall in our sort of rank ordering of what would we use in the very busy clinic,
palaperadone is sort of ahead at the moment because of this pre-filth syringe and different
needle sizes and it's very easy to use.
Now a lanzipine is only given in the gluteal muscle at this stage and it comes in a yellow
powder form.
Now the trouble with this preparation is the yellow powder tends to cling a bit to the
side of the vial and you've really got to tap and bang away to make sure it's all off
of the glass before you add the diluent in.
Now in some cases this can be as short as 30 seconds or a minute, in some cases you've
got to tap away for quite a few minutes and this can be a bit of a pain for the busy clinic.
The other notion is that if you're using partial amounts, not the full injection amount from
the diluent then the calculations have to be thought through somewhat carefully.
Now unrelated to the actual delivery of the agent but mixed up in its overall management
of course is this issue of having to observe the patient for it's now two hours after the
injection to make sure that they don't have a reaction to the rapid release of a lanzipine
from the injection site and we'll discuss this in a little later in the tutorial.
With respect to the aropiprazole injection at this stage we'll wait to see what comes
back from the real world in terms of its ease of use in the daily clinic.
Now if we would summarize the delivery mechanisms of the first and second generation drug and
because of their kinetics whether or not we need to be using an oral agent in the first
while before blood levels are adequate we can see in this table that this covering the
gap issue do I need an oral agent this is assuming I'm not going to be using an initiation
or loading strategy is moderate in the first generation agents all of them do take some
time to come to steady state and as we'll see later in the tutorial this can be sometimes
up to six months but with a loading strategy probably adequate levels can be achieved within
eight to twelve weeks and then we move down to the second generation drugs with the respiridone
being delivered in the microsphere form the release kinetics are like the crystal spheres
of the universe and they're invariant to a large extent and really we are just not going
to have any release that can do any good for about three and a half weeks after the injection
and so we are duty bound at the beginning to make sure there is cover now this could
be oral cover obviously respiridone oral would be the most easy way of doing that or if we're
coming off a previous long-act injection that would suffice because it would take some months
for that to decrease as the new agent builds up but that gap has to be met has to be filled
with some agent you can't just give respiridone and think oh that looks good enough it'll
be okay because for many patients that three and a half to four week gap before it starts
releasing appreciably is too long plus of course then you've got to wait a few days
before the levels get sufficiently high in the brain to do some good now if we move on
then to a Lanzapine and Palo peridone these are both crystal based so this is the great
departure from all that's gone before so microspheres were the first departure from
the standard oil based delivery and then but the great departure has now been with the
crystal based agents what these are are very specifically and finely milled particles of
a salt of the agent so with the Lanzapine it's the Pamoate and with the Palo peridone
it's the Parmitate and these fatty acid salts are milled into crystal form and when we inject
the crystals in suspension they are essentially insoluble but of course at the surface the
agent comes off the crystal and is absorbed into the systemic circulation now the actual
crystal technology if you like that is used in these two agents is quite different they
use different companies that make different type of crystals and that may or may not be
of relevance in the acute sort of pseudo delirium or real delirium that occurs as an effect
in some people with a Lanzapine it's thought that if the crystals come in contact with
blood which may occur as you prang a small vessel as the injection is given then this
causes a rapid dissolution of the agent and so what you end up with is a Pica Lanzapine
effect which may cause a cause a delirium endicolinergic delirium that doesn't seem
to be the case with the Palo peridone and blood doesn't seem to affect it in the same
way now the final change if you like in delivery mechanism is with the Arapiprazolemia acting
injection and here it's again somewhat different though of course more akin to the crystal
based agents in as much as the Arapiprazolemia is just made into a lot really just a freeze
dried preparation without being made into a salt or anything else and then that freeze
dried preparation is just reconstituted with water and injected into the muscle now because
the Arapiprazole particles themselves pretty insoluble in muscle very slowly absorbed into
the systemic circulation so this is again a bit like the crystal way of slow release
from the depot site without involving oils or micro spheres but it doesn't actually
involve an intermediate form if you like as a salt of the parent agent with this agent
we do have to have an agent an oral agent Arapiprazole for the first two weeks at least
whilst the initial release from the depot site is occurring and I should point out with
the as I've already mentioned earlier in this tutorial when we're looking at a Lanzapine
and Palaparadone we don't need to really have an oral adjunct in the first few weeks
for the majority of people the actual release from the depot site in the first week of so
the Palaparadone that's injections at day one day eight and for a Lanzapine just at
zero and then probably two weeks these for most people will provide adequate blood levels
not all though and we'll discuss that in a little more depth in this tutorial so again
we come back to our use of use we prefer an agent we can just take out of the packet
screw on the correct needle and inject it if we inject it into the arm it can be very
less stigmatizing for the patient it makes the clinic run much more quickly we don't
need to worry about long and drawn out psychoeducation about the need to maintain an oral during
the crossover to depot steady state and so on and so forth so this is an important consideration
in when we're choosing one of our agents.
