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Teaching excerpts on dopamine and schizophrenia.

Originally published at
https://thingsididntknowinpsychiatry.wordpress.com/

I thought I’d share some of the teaching I’ve been doing with junior doctors.
The way I tend to teach, is to canvass for questions over the preceding few
days. I then pick one of the questions. I record myself answering it with voice-
to-text software, then on any places I seem to have stumbled I annotate. The
next step is error checking. After that, I put together a series of slides
(powerpoint) and it’s essentially ready to present.
This is a portion of material where I was explaining the basics of dopamine-
related side effects of schizophrenia.
“However. To solve this problem, we needed to know how the heck this
medication worked.
Now, the old theories were very hit and miss. There was the reticular
depression theory. There were NMDA and glutamate theories. These were
respectable attempts, some of which has descendants today. But that wasn’t
the theory that allowed an unpacking of the effects and side effects of this
antipsychotic. We’re going to talk about the dopamine theory, which is still
the basic-level knowledge you’d be expected to know today.
A chap called Arvid Carlsson did a lot of the work. He identified that
dopamine was a neurotransmitter. Then he identified that if you deplete
dopamine in the brain, you get some antipsychotic-like effects, along with a
few parkinsonian symptoms. This was the basis of the hypothesis. He argued
too much dopamine causes psychosis. Antipsychotics reduce it- somehow.
As to how they did it? Another scientist, Peter Seeman, identifies this. He
identifies that the antipsychotic operates at the membrane, binding
somewhere there. It’s only a few short hops until it’s identified it is binding
to the dopamine receptors, and blocking them. Antipsychotics block the
dopamine receptor.

This was supported by the knowledge that dopamine agonists- such as


amphetamines- can provoke psychosis, and dopamine antagonists, like
chlorpromazine, can reduce it.
So, here is an approximation of the original hypothesis.
The original dopamine (DA) hypothesis of schizophrenia
proposed that sub cortical hyperactivity of DA transmission in
brain is responsible for the positive symptoms of the illness.
Obviously, this isn’t the full story, but it’s a good shot. It’s later found out it
might not be that there’s too much dopamine, but maybe that the receptors
are over reactive. But it has a similar effect.
The theory was further strengthened by evidence that all of the drugs of the
time with proven efficacy at relieving the positive symptoms of
schizophrenia blocked D2 (that is, dopamine- 2) receptors to some extent.
It’s from this D2 blockade that a lot of side effects flow.
Question. In a patient with schizophrenia, is there too much dopamine- or
the equivalent by the means of dopamine hypersensitivity, everywhere in the
brain?
< This is a bit of a gimme question>
Basically, what we found is that there are differing areas of dopamine hypo-
function and hyperfunction in the brain. These different pathways have
different effects when blockaded.
Only one of the pathways appears to have the equivalent of far too much
dopamine in it.
When you blockade the rest, I’m afraid, it’s collateral damage.
Anyone know the pathways?
<I expect crickets- but I may luck out>
Meso-limbic pathway is the one we want to blockade.
This is where the positive symptoms of schizophrenia are believed to reside.
The stuff which causes delusions. The hallucinations. The paranoia, and over
interpreting things. It’s where dopamine operates as a type of reward
chemical. It reinforces stray thoughts, and turns them into delusions. It
takes quizzical perceptions, like checking whether that thing over there is
really a face, and becomes full blown delusions. A lot of what people think of
as “schizophrenia” comes from this circuit. So, obviously, it’s the bit that we
want to decrease dopamine in.
Now, dopamine isn’t the whole story here. There are other receptors. But
I’m keeping it simple. We are targetting the D2 in the mesolimbic.
Unfortunately, over here, you have a bunch of other pathways. Which have
more normal levels of dopamine activity in them- or even, in some cases,
reduced. And then you essentially scattershot blockade them all. This is the
collateral damage. I’ll talk through the pathways.
Mesolimbic. This is a pathways which drives your reward and motivation.
It’s wanting things, liking things.
Mesocortical. This is more executive functions. Cognitive control. Some
types of forecasting.
Nigrostriatal. This is a pathway which is involved with movement.
Tuberoinfundibular. This is to do with lactation.
There are other ones, but more minor.
Basically, if you give an old fashioned antipsychotic, you help fix the
mesolimbic stuff. The positive symptoms improve.
But, potentially, when you treat that mesolimbic system you crush
someone’s limbic-linked motivation. They don’t seek reward in the same
way. Now, for those of you who are still with me, what is the likely impact of
that?
<Await response>
If possible, it would be good for you to draw on your images of patients in
the ward who are described as over medicated. There’s almost invariably one
of them.
Normal motivational activities aren’t sufficient for them. The only thing that
gets through to them are profound highs. Perhaps why so many of them are
drawn to illicit drugs. Cognitive effort- planning- becomes difficult. They
can’t forecast their joy, and they struggle to even remember it. It barely
encodes. Without motivation, it’s incredibly hard to learn anything.
Consider it from your perspective. Imagine yourself at your least motivated.
Perhaps trying to study a topic you loathe. The topic you’ve never had any
interest in. The mental sluggishness of it. The difficulty in holding a focus in
your mind. For a patient with motivational suppression, that’s them for
every activity.
Incidentally, these negative symptoms are some of the worst parts of
schizophrenia, or psychosis. Someone who reacts to hallucinations, we can
treat well. But someone who have been driven to a point where they’re
physiologically unable to care, emote, empathise or forecast- that’s a lot
harder. Now, you might be able to use logic and discipline to force yourself
through that. And that’s where some types of cognitive retraining comes in.
But there’s a severe disadvantage.
And what about the other pathway? You’ve just blockaded the mesocortical
pathway. That, as you know, is linked with cognition. You’ve already
interfered with motivation, but now cognition is affected too. And here, you
can have an increase in the so called “negative symptoms”.
Let’s talk about negative symptoms a little, because this is one of the most
important parts of prescribing antipsychotics.
Why are they called negative symptoms? Because they are things that
a person had before schizophrenia, which the disease took away. This is in
contrast with positive symptoms, where the disease adds something on.
For example, the disease adds on an auditory hallucination. It takes away
the joy of many basic activities.
There are a list of common negative symptoms. Many patients manifest with
apathy, avoilition, absent emotional responses, impaired emotional
responses. A peculiar type of time-linked anhedonia is also common. These
are things that are all classically linked to the mesocortical pathway, and
which are worsened with the blockade. (In truth, it’s a bit more complex-
emotions, after all, are not just linked in with one pathway or area of the
brain. But that’s for another, more comprehensive, teaching session)
These symptoms are crippling to the person, but not so obviously to society.
They leave the person suffering, but perhaps not fully knowing it. A story
about a man hearing voices and standing on a bridge yelling makes the
news. A man slowly starving to death due to a limited desire to reach the
food bowl until he is so ravenous the remnants of his pathway finally
activates? Perhaps not.
Later on in teaching, we’ll devote a lot more time to this topic. So I’ll move
on for the moment.
Let’s look at another pathway.
Nigrostriatal. If you crush the pathway which gives you the ability to move
easily, your movements slow. Overmedication does this. You get a shaking, a
rigidity, a slowness of movement. At first you may move like an old person-
prematurely aged. The posture is harder to change, and you risk falling. The
face can go stiff, unemotive.
That said, the body fights back. Those last few receptors that aren’t
blockaded out become hyperactive. And sometimes, you get the opposite
effect. Hyperkinesis. You just can’t stop moving. Tardive dyskinesia, and
related disorders. You may have seen clients with the mouths that won’t stop
moving- that’s one of the milder forms. In more severe cases, there’s a
consistent inner restlessness; the whole body being compelled to
continuously move.
Anyone know how common these hyperkinetic movement disorders are in
people on typical antipsychotics? How about just tardive dyskinesia?
Well, a reasonable estimate, from neurology 2017, was between twenty and
fifty percent of patients on antipsychotics. We have evidence that it’s worse
at higher doses, and it’s worse when people have been on it for longer time
periods. There’s a certain level of blockade at which is becomes very
common, and that level does not necessarily match with the therapeutic
level! Keeping a patient at a therapeutic level, without triggering these side
effects, is a part of your job. But we’ll come back to that later.
Tuberoinfundibular. As dopamine levels alter due to the blockade, levels
of prolactin alter in response. Prolactin goes up, and up. Sexual side effects
kick in- impotence, infertility. Loss of period. And in men, breasts often
develop. This is also linked to depression, albeit not too robustly. It’s not
clear if this is direct, or due to the other side effects of the raised prolactin.
So, an over medicated psychotic patient, on high doses with no oversight, is
apathetic, either constantly moving or almost entirely immobile, sexually
impotent and with breasts. They are also heavily sedated, due to
antihistamine effects.
They also tend to have metabolic issues like crazy.
How do we avoid this? Maintain the blockade where you want it, but not
absolutely, and not everywhere else?
Now, that’s an interesting topic. And part of the art of basic
psychopharmacology.
Before I continue, can anyone tell me the difference between typical and
atypical antipsychotics?