Hello, and welcome to the webinar on Treatment Refractory Schizophrenia.
And this is a broad introduction.
What is Treatment Refractory Schizophrenia?
The acronym is TRS, and sometimes TRS stands for Treatment Resistant Schizophrenia, not
a term that we would encourage you to use.
The label of treatment resistance is particularly used to refer to a condition in which patients'
positive symptoms, that's including delusions, hallucinations, positive thought disorder
and so on, in which those symptoms do not respond to adequate treatment and how we define
adequate treatment will be discussed later.
Now this is really a focus on positive symptoms that comes out of perhaps older ways of thinking
about the illness, where the predominant syndrome that was the focus of care was really whether
of course you were experiencing these sort of symptoms.
What about the other symptoms, negative symptoms, cognitive symptoms, affective symptoms and
so on?
And it's probably at the time that the treatment resistance appellation was first formulated
that negative symptoms weren't really well understood or well described, though they
had been in the literature since Kreplen.
And also if they were considered without or a priori to be non-responsive to treatment
as they probably would have been with older generation anti-psychotics, perhaps these
symptoms weren't ever considered in the definition because everyone would have shown some degree
of treatment resistance.
There are a number of reasons that we'd like to change the term treatment resistance to
an alternative term and really it's because resistance suggests that nothing can be done
really to improve the symptoms of schizophrenia for the patient.
But more importantly in my mind it embeds the notion that it's the patient that is resisting.
It's as though in many ways when things don't go well in medicine the patient tends to be
blamed unconsciously, I'm sure in most cases, but it's not the patient's fault that their
structure of their brain and their pharmacology of the agents we use is not a good match.
So we want to get away from blaming the patient and resistance tends to make it an active
role of the patient.
And I guess treatment resistance is no longer in tune with current therapeutic alternatives
or with our more recent understanding of the basis of schizophrenia.
So the term we've been using for quite a long time now, probably more than 15 years, is
incomplete recovery. Now it's a term reflecting the sort of basis that you might improve your
therapeutic outcomes with perhaps the use of special or new antipsychotics or perhaps
with new add-on devices which may be pharmacotherapeutic or there may be psychosocial.
It might be in specific domains, for example on investigations at the moment, still with
the glutamatergic agents or with an acetylcystine, for example, in negative symptoms, or it might
be specifically an individually tailored psychosocial intervention.
All of these things may actually work on the different dimensions of the person's illness
that we'll discuss shortly.
Now the Australian National Mental Health Survey of Psychotic Disorders suggests that
the disability suffered by people with schizophrenia really includes such a broad range of domains
and not just positive symptoms.
So the first thing you've got to disabuse yourself is that if you don't get better in
terms of positive symptoms, that means you're treatment resistant.
Sure, in a very limited sense, you would think much more broadly.
So here the multi-dimensional structure of outcomes in schizophrenia that we would look
at and suggest when we are looking at whether people are treatment refractory or having
incomplete recovery and they may have incomplete recovery in one of the domains or one of the
dimensions and really the importance of the, if you like, difficulty in improving that
individual dimension will define whether or not you can say this person has a truly refractory
illness because it affects their behaviour in functioning and engagement in the community.
And it may differ from person to person.
For one person it may be negative symptoms for another, it may be their cognitive deficits
that actually lead to their inability to function and therefore impairs their engagement with
life and our medicines aren't working.
But they respond very well to positive symptoms, for example, to me that person is still suffering
from incomplete recovery refractory type, but perhaps negative symptoms.
So here on the screen you can see we have the psychopathology for positive, negative,
cognitive, and effective and excitement domains.
These are the classical factor structure of one of the common instruments used to measure
psychopathology in psychosis, the PANS and the BPRS from which it's derived.
But we also have to add in the other dimensions where people can get stuck, suicidality.
So persistence, suicidal ideation, planning and lethality, behaviour, dangerous behaviour,
poor self-care, hostility, odoric centric behaviour that leads you into contact with people in
the community who are uncomfortable with that and end up putting you in hospital.
And of course social function.
Now many would argue, and I would be among them, that asociality is at the core, is the
heart of schizophrenia.
And so the ability of a person to socialise and show warmth to others, engage in friendships
and all the rest of it is really that's at the core of the illness and that should be
a dimension we work very hard to improve.
But ultimately, if we were in a perfect world and we had as many resources as were needed,
we would really try to achieve some role of enhanced vocation for the patients.
Even a few hours of paid employment a week does enormous good to both self-esteem and
overall functioning.
But we should never assume that a person is not able to re-engage as a member of society
in a working capacity, we should always be aiming for that.
So these multi-dimensional aspects are where people can be stuck.
Now the Australian Consensus Statement on Treatment Refractory Illness and Close Opinions
suggests that we should extend the definition of TRS to include anyone who's failed to achieve
one or more agreed treatment goals on the multi-dimensional scale and therefore would
remain incompletely recovered.
This would be in the usual background with exposure to two classes of different anti-psychotics
of adequate length and adequate degree of ensuring the person took them etc.
And these are explained in the consensus guidelines in more depth.
So we want to broaden it.
That means we want to put a lot more effort into people who are not getting better rather
than condemning them to long-term units and so on.
We'll discuss how we actually go about the assessment of multi-dimensional domains of
outcome in another video.
Now what we have to decide though, when we think a person has got treatment refractory
illness before we decide which dimensions is incomplete recovery in, we have to make
sure they actually do have treatment refractory illness or they have something called resistance
to treatment.
Now in this figure here you can see that if an inadequate outcome is found, we have to
work through a whole lot of issues that describe what resistance to treatment is.
Now resistance to treatment is adequate but something is getting in the way of the treatment
actually doing its job and it's something either which is modifiable or not modifiable.
Once we've worked through those, and I will quickly review those factors in a minute,
once we've worked through them and tried to achieve as many of these factors that lead
to resistance, we're often left with the notion is this person actually adherent?
Is all of the resistance to treatment actually down to the fact that the person has never
taken any medicine or inadequate medicine and we're dealing with adherence in another
video?
Now if that's the case then we go on to manage it.
But what are these steps that are called resistance to treatment?
So here's our patient comes along, outcomes aren't as good as we'd like, we then look
at okay, what are the constitutional resistance to treatment factors and what are the modifiable
ones and how do I manage them and how do I investigate adherence?
In examining resistance to treatment there are three broad factors that we should consider
relating to the patient, the illness and the treatment.
Here we can see in the patient factors that these factors are classified as unmodifiable
which is not to say we can't do something about it such as remove this unmodifiable
factor from the person's environment for example and there are of course potentially modifiable
factors.
So considering patient factors we know that unmodifiable factors that lead to more difficult
treatment are seen in what we call poor prognosis patients characterized by being male, single
and having some form of intellectual disability or severe cognitive impairment.
Similarly schizophrenia itself confers a level of difficulty in treatment.
In terms of potentially modifiable factors, well of course there we have substance use
disorders and mood disorders as common comorbidities that occur in a very substantial minority
of patients.
These are quite amenable to specific interventions.
In terms of psychological adjustment to the illness, now this is perhaps more germane in
early episode psychosis, there are two broad styles of dealing with the fact that you've
had a psychotic break.
Firstly we have the ceiling over style in which the patient cannot incorporate the break
into the narrative of their own life and they tend to somehow cover it over or explain it
away or even just deny completely that it's occurred.
The integrative recovery style on the other hand is where the psychotic break is understood,
its antecedents are examined and the person incorporates this into the forward flow of
their life, which is obviously going to include behaviors that will help protect the person.
Those with the ceiling over style usually have a poorer outcome and are more difficult
to treat.
The psychosocial milieu itself includes where the person lives, who's around the person
and their influence on them, but one of the most common things we must always examine with
respect to the family is looking for the presence of, for example, high expressed emotion, which
can lead to poor outcomes.
If we consider illness factors in terms of the unmodifiable factors, those that have
actually occurred, we can find poor premorbid adjustment, marked cognitive impairment, early
and insidious onset, a long duration of the prodrome or a long duration of untreated psychosis,
or a variety of organic factors such as demonstrating an abnormal CT or MRI when we first see someone
or having an abnormal EEG.
Additionally, anything in which there has been impairment of the integrity of the dorsal
lateral prefrontal cortex will lead to difficulty in treatment.
In terms of modifiable illness factors, we've got to consider severity of psychopathology
in each domain.
Notionally, we can treat everyone.
Poor response to treatment, negative symptoms at first admission, unawareness of negative
symptoms, and poor cognitive functioning at stabilization, all are factors that will probably
lead to difficulties in treatment in the long run and are amenable to specific psychosocial
and biological interventions.
In terms of the treatment factors, the unmodifiable ones often relate to pharmacokinetic problems
such as the person has been given the incorrect dose.
The incorrect dose may be too little or too much.
Many psychotropic agents have a curvy linear response, meaning as we reach the optimal
dose, higher doses may actually lead to a worse response.
This may actually be in relationship to the risk benefit of the drugs, of the side effects
start to outweigh the drug, or it may actually be a pharmacological process that leads to
a poorer response to the drug at the higher doses.
And Haloperidol was an example of that.
There are drug-drug interactions that are often missed by prescribers, because very
unfortunately polypharmacy is very common in schizophrenia.
There's not a lot to recommend it, unless it is a rational application of mixing different
drugs together, and the problems of polypharmacy dealt with in another video.
We've also got to consider bioavailability problems, and this may be a function, for
example, of the formulation that the person's given, the actual microbiota, in other words
the gut bacteria that the person's carrying with them, and how their liver is going to
deal with first-past elimination.
So there are a number of barriers that stop the medicine actually getting in.
Potentially modifiable treatment factors, well the most common one that one finds is
there's been an inadequate, that's inadequate rehabilitation program, or there's just a lack
of services and resources available to the patient.
Often people with treatment refractory illness are put on clozapine and sent to a clozapine
clinic, which seems to obviate any further ongoing psychosocial work.
Often these patients are the most complex and difficult, and require the most resources,
and yet, due to the way that public services are structured in many OECD countries, the
patients often end up with monotherapy with clozapine and not much else.
If we haven't applied a quite strong psychosocial approach to the person, we don't know if they
really are going to recover a lot more.
We need to combine the clozapine, if that's what we're using, with psychosocial treatments.
Also side effects, which masquerader symptoms often lead to difficult outcomes.
So for example, the neuroleptic induced deficit syndrome, which looks like negative symptoms,
extra pyramidal symptoms, looking like depression or cognitive disturbance, and so on and so
forth.
And of course, impaired adherence.
Ultimately then, we come to saying, well, what are we going to do about this adherence
issue?
And I can't determine if they are truly refractory, or if they still have a resistant picture,
because I can't solve the issue of the adherence.
For many years, in this flow diagram, which is based on clinical practice, we would introduce
a trial of a long-acting injection, in which we would know the adherence, because we would
deliver the injections, and by optimizing the pharmacotherapy, we could clearly then
tell whether or not the person's inability to recover in any of the key dimensions that
are at least responsive to the medicine we use were due to non-adherence, or just they
weren't taking the medicine.
So in any work for differentiating resistance to treatment versus treatment refractory states,
the use of long-acting injections, which is dealt with in another video, must be considered.
Now the trial of LAIs is important, because we know that the partial adherence rate is
about two-thirds in any one year, and if we are going to use a long-acting injection to
decide whether someone has got treatment refractory illness or resistance to treatment, we've
got to know exactly what our time frame is, we've got to know what symptoms are targeted
by the medicine in which we're going to measure, we can't just look for a global outcome which
may be totally unrelated to the intervention we've made, we've got to know who's going
to measure these outcome symptoms and signs and dimensions, and how are they going to
be measured, and what are the minimum threshold shifts we would use to define that's an improvement
if a person might move statistically, like they move two points on a scale, but we've
got to decide is that actually clinically relevant?
After a reasonable trial, once we've excluded that non-adherence is the issue and the person
is not just getting sort of stuck because the medicine just doesn't work, then it's
likely we need to move on to the treatment of a refractory state, which will require
clozapine as the mainstay of the pharmacotherapeutic intervention, and it's beyond the remit
of this talk to discuss clozapine therapy today, but will be discussed in another video.
Ultimately, and I'll finish at this stage because we've not going to do the management,
this is the way we would consider the multi-dimensional treatment of people with incomplete recovery.
What you can see here is that there are the different levels that we've already identified
or dimensions, starting with symptoms, suicidality, behavioural, social and family functioning,
and role and vocational levels of outcome we would like to improve.
All of that will most likely proceed if it's built on an optimised bedrock of pharmacotherapy.
Much pharmacotherapy is not optimal, there's irrational polypharmacy or inadequate doses
or drug-drug interactions that worse than the situation are not accounted for and so
on and so forth.
It is worth getting an expert opinion from a clinical psychopharmacologist if you're
interested.
However, one thing that's pretty certain to me after all these years is even optimising
pharmacotherapy doesn't make you better.
What it does is make your whole, I guess, system more amenable to psychosocial interventions.
Those are the things that make you better.
And in those with incomplete recovery, treatment of fractal illness or whatever, delivering
just close a pin, for example, and no psychosocial treatments is actually not to be treating
the treatment refractory state.
It's partial treatment.
And for the treatment of incomplete recovery, in terms of the pharmacotherapy, we'll deal
with that in another video.
Thanks very much.
This is a very brief introduction and I welcome your questions.
Thank you.
