Mechanism of Action of Dopamine Depleters

[peiyueng]

I had my weekly psychopharmacology seminars with my mentors.

We talked about a class of antipsychotics that is little used anymore: The dopamine depleters:

Where as usually the antipsychotics such as the phenothiazines, butyrophenones, and atypical antipsychotics work by blocking post-synaptic dopaminergic receptors, the dopamine depleters such as reserpine and tetrabenazine inhibits VMATs (vesicular mono amine transporters).

As you may recall, neurotransmitters (monoamines) are packaged into vesicles presynaptically at the axonal terminal. When an action potential is propagated by the neuron via Voltage Sensitive Sodium Channels (VSSC) all the way down to the axonal terminal, the change in the electric charge across the membrane causes the Voltage Sensitive Calcium Channels to open, allowing calcium into the intracellular space. At the same time, a spring like amino acid arm that is hooked to the vesicle is sprung like a mouse trap and causes the vesicles to dock onto the axonal membrane, releasing its contents into the synpatic cleft.

Well, the those particular vesicles of which I speak are first loaded with monoamines such as serotonin, norepinephrine, and dopamine. How those monoamines get into the vesicles in the first place is via VMAT. VMATS are analogues to Serotonin Reuptake Transporters (SERT --which is the site of action for SSRI's). In a similar fashion, VMATS bind monoamines and transport them across the membrane into pre-synaptic vesicles.

So, this class of antipsychotics could probably just as well be renamed "Vesicular Monoamine Transporter inhibitors" (similar to SSRI's). As you can see, it is a variation on a theme. Biological systems often finds one theme and repeat the same mechanism across a wide variety of systems.

The reason we do not use dopamine depleters (actually the more proper name is monoamine depleters) is that they inhibit all monoamines from getting into their proper vesicles. Hence, the side effects are terrible: suicidal depression, hypotension, and bradycardia among others. So, imagine someone with schizophrenia who is already exhibiting indifference and negative symptoms. Now you deplete all their monoamines and they get suicidally depressed.

Other side effects include Parkinsonianism and other EPS (dopamine is depleted by the same mechanism in the striatal/basal ganglia substantia nigra area.


c.t.
Psychopharmacology Fellow
picture follows:
cheers.

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[shan564]

Interesting... any useful application to this knowledge?

 

[novopsych]

I had my weekly psychopharmacology seminars with my mentors.

We talked about a class of antipsychotics that is little used anymore: The dopamine depleters:

Where as usually the antipsychotics such as the phenothiazines, butyrophenones, and atypical antipsychotics work by blocking post-synaptic dopaminergic receptors, the dopamine depleters such as reserpine and tetrabenazine inhibits VMATs (vesicular mono amine transporters).

As you may recall, neurotransmitters (monoamines) are packaged into vesicles presynaptically at the axonal terminal. When an action potential is propagated by the neuron via Voltage Sensitive Sodium Channels (VSSC) all the way down to the axonal terminal, the change in the electric charge across the membrane causes the Voltage Sensitive Calcium Channels to open, allowing calcium into the intracellular space. At the same time, a spring like amino acid arm that is hooked to the vesicle is sprung like a mouse trap and causes the vesicles to dock onto the axonal membrane, releasing its contents into the synpatic cleft.

Well, the those particular vesicles of which I speak are first loaded with monoamines such as serotonin, norepinephrine, and dopamine. How those monoamines get into the vesicles in the first place is via VMAT. VMATS are analogues to Serotonin Reuptake Transporters (SERT --which is the site of action for SSRI's). In a similar fashion, VMATS bind monoamines and transport them across the membrane into pre-synaptic vesicles.

So, this class of antipsychotics could probably just as well be renamed "Vesicular Monoamine Transporter inhibitors" (similar to SSRI's). As you can see, it is a variation on a theme. Biological systems often finds one theme and repeat the same mechanism across a wide variety of systems.

The reason we do not use dopamine depleters (actually the more proper name is monoamine depleters) is that they inhibit all monoamines from getting into their proper vesicles. Hence, the side effects are terrible: suicidal depression, hypotension, and bradycardia among others. So, imagine someone with schizophrenia who is already exhibiting indifference and negative symptoms. Now you deplete all their monoamines and they get suicidally depressed.

Other side effects include Parkinsonianism and other EPS (dopamine is depleted by the same mechanism in the striatal/basal ganglia substantia nigra area.


c.t.
Psychopharmacology Fellow
picture follows:
cheers.

View attachment 184452

Let me guess. Dance therapy didn't come up once in spite of its proven efficacy, did it?

Intellectual masturbation is not out on the front lines saving patients. But I am. We've got to throw everything including the kitchen sink at our patients. Even the suicide pills you mentioned if you think they'll help.

 

[SmallBird]

I had my weekly psychopharmacology seminars with my mentors.

We talked about a class of antipsychotics that is little used anymore: The dopamine depleters:

Where as usually the antipsychotics such as the phenothiazines, butyrophenones, and atypical antipsychotics work by blocking post-synaptic dopaminergic receptors, the dopamine depleters such as reserpine and tetrabenazine inhibits VMATs (vesicular mono amine transporters).

As you may recall, neurotransmitters (monoamines) are packaged into vesicles presynaptically at the axonal terminal. When an action potential is propagated by the neuron via Voltage Sensitive Sodium Channels (VSSC) all the way down to the axonal terminal, the change in the electric charge across the membrane causes the Voltage Sensitive Calcium Channels to open, allowing calcium into the intracellular space. At the same time, a spring like amino acid arm that is hooked to the vesicle is sprung like a mouse trap and causes the vesicles to dock onto the axonal membrane, releasing its contents into the synpatic cleft.

Well, the those particular vesicles of which I speak are first loaded with monoamines such as serotonin, norepinephrine, and dopamine. How those monoamines get into the vesicles in the first place is via VMAT. VMATS are analogues to Serotonin Reuptake Transporters (SERT --which is the site of action for SSRI's). In a similar fashion, VMATS bind monoamines and transport them across the membrane into pre-synaptic vesicles.

So, this class of antipsychotics could probably just as well be renamed "Vesicular Monoamine Transporter inhibitors" (similar to SSRI's). As you can see, it is a variation on a theme. Biological systems often finds one theme and repeat the same mechanism across a wide variety of systems.

The reason we do not use dopamine depleters (actually the more proper name is monoamine depleters) is that they inhibit all monoamines from getting into their proper vesicles. Hence, the side effects are terrible: suicidal depression, hypotension, and bradycardia among others. So, imagine someone with schizophrenia who is already exhibiting indifference and negative symptoms. Now you deplete all their monoamines and they get suicidally depressed.

Other side effects include Parkinsonianism and other EPS (dopamine is depleted by the same mechanism in the striatal/basal ganglia substantia nigra area.


c.t.
Psychopharmacology Fellow
picture follows:
cheers.

View attachment 184452

Similiarly AMPT depletes dopamine and other monamines, ostensibly through competitive inhibition of tyrosine hydroxylase. By contrast with reserpine its effects are more quickly reversible. I am unaware of clinical applications but it has been used in some imaging studies to study the dopaminergic system.

 

[SmallBird]

Let me guess. Dance therapy didn't come up once in spite of its proven efficacy, did it?

Intellectual masturbation is not out on the front lines saving patients. But I am. We've got to throw everything including the kitchen sink at our patients. Even the suicide pills you mentioned if you think they'll help.

Perhaps you can recommend a good segue to dance therapy that could be used in a future session?

 

[peiyueng]

Interesting... any useful application to this knowledge?

Now a days, usefulness of this info is mostly in the understanding of underlying mechanism. Since biological systems repeat variations on the theme, knowing this mechanism will add to the overall understanding and appreciation of psychopharmacology. More specifically, reserpine can be used as an antipsychotic (it was, for a time, one of the only things with which we had to treat psychosis).

These days, better agents exist with fewer side effects.

Still, knowing every step in the cascade of electrical chemical neural transmission opens the doors for novel ways to target disease processes. Suppose, for example, one day you could find a receptor specific VMAT antagonist that is specific for Dopamine 2. Then, you'd be able to use it to treat psychosis without the unwanted 5HT and NE depletion.

Also, theoretically guided and evidence based understanding of all these mechanisms aids in choosing the right treatment for the right disease. This is the bread and butter of psychopharmacology.

My fellowship is a consultation based service. We consult on cases where usual care has been attempted, but patient still needs further treatment. We use an evidence-based approach to arrive at all our recommendations.

cheers.

 

[shan564]

Reserpine seems pretty risky... this might be another example of Step 1 knowledge messing with my head, but if I ever saw a patient on reserpine, I'd be deathly afraid of the suicide risk... is it really reasonable to consider using it over clozapine in a patient who isn't responding to dopamine blockers? Or are you assuming that clozapine has also failed? I know of a particular patient on our unit who has spent most of his life there for the past couple of years and clozapine hasn't done the job yet...

I wonder how many of those patients with glutamatergic dysfunction actually have an anti-NMDA receptor antibody.

That seems like an interesting fellowship though. I know a couple of our attendings who have done similar fellowships, and they are generally recognized as magicians. But they never use dance therapy, so clearly horizons can still be broadened.

 

[smalltownpsych]

these things are overblown. why aren't you deathly afraid of prescribing SSRIs in that case? there is much stronger data showing association between suicidality (not completed suicide) and SSRIs in young people than there is data showing resperine "causes" suicide. if a patient is not responding to dopamine antagonists then they should not be on any neuroleptic at all. that was my point. instead of exposing them to harm, dont give them any of these drugs. if there is partial response (as opposed to no) i would try clozapine or reserpine. the guidelines from the 90s recommend reserpine after clozapine but remember that the vast majority of patients aren't clozapine patients (in terms of lab monitoring etc) and in that case it may be reasonable to try reserpine, it should be started on an inpatient unit though.

I think we should be more afraid of prescribing SSRIs to adolescents. I spent the last 3 years working in a long-term adolescent treatment setting and found that for the vast majority if the social-environmental effects on mood are not addressed, then anything else we do just makes them feel more hopeless.

 

[shan564]

these things are overblown. why aren't you deathly afraid of prescribing SSRIs in that case?

Because we have a lot more experience with SSRIs than we do with reserpine.

 

[strangeglove]

Sounds like a good way to make someone depressed.


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