stimulants in psychotic patients

[Attending1985]

I'm a new attending inheriting a couple of patients with chronic psychotic disorders on stimulants. They are being treated for co-morbid ADHD. This is not something I saw practiced in residency and I know theoretically it makes no sense. But I also know that psychosis is more complex than simply too much dopamine and these people claim they're doing better without exacerbation of their psychosis. Was wondering what people's thoughts are on this?

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[SmallBird]

I'm a new attending inheriting a couple of patients with chronic psychotic disorders on stimulants. They are being treated for co-morbid ADHD. This is not something I saw practiced in residency and I know theoretically it makes no sense. But I also know that psychosis is more complex than simply too much dopamine and these people claim they're doing better without exacerbation of their psychosis. Was wondering what people's thoughts are on this?

I wouldn't worry about this simply because of the supposed 'theoretical' issues; as you point out psychosis is more complicated than dopamine and we absolutely don't know enough to assert confidently that stimulants and antipsychotics can't be used together effectively. Until our neurosciences is orders of magnitude more advanced, this is best framed as an emprical question, and as far as I am aware there is no good evidence supporting the use of these medications in combination, nor is there consensus on the necessary considerations for diagnosing a comorbid ADHD in someone with psychotic illness. That said, if the patients had a prominent inattentive symptom dimension, and are experiencing some benefit, I wouldn't dogmatically refuse to continue prescribing.

The issue of antipsychotics and stimulants comes up in children quite often, since risperidone has evidence for reducing reactive-impulsive aggression in adolescents with ADHD. Interestingly, a trial was conducted showing that the combination of risperidone and methylphenidate was particularly effective for managing both core and behavioral symptoms of ADHD and nobody's brain exploded despite this contradicting the radically oversimplified models found in Stahl.

 

[tr]

I wouldn't be willing to continue that regimen. Amphetamines are well documented to precipitate psychosis

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-12-221

And I have definitely seen Adderall-induced psychosis that looks exactly like schizophrenia, including repeated hospitalizations when the individual refused to stop using.

This entirely aside from the fact that it makes no sense mechanistically to co-administer dopamine agonist and antagonist.

 

[PistolPete]

Interesting. I know a psychiatrist in the state hospital system who has used stimulants to decrease aggression, and it's worked very well without worsening psychosis. Looks like you really have to tailor the regimen to the patient, rather than just saying "no stimulants for the psychotic patients."

You can definitely have amphetamine-induced psychosis but I'd wager it is much above the FDA maximum for Adderall or Ritalin. If someone uses meth and gets psychotic, they're probably using quite a lot of meth.

 

[hamstergang]

This entirely aside from the fact that it makes no sense mechanistically to co-administer dopamine agonist and antagonist.

Do antipsychotic and amphetamines or methylphenidates preferentially target different pathways? If not, then I agree that it's hard to make sense of such a regimen.

 

[tr]

Do antipsychotic and amphetamines or methylphenidates preferentially target different pathways? If not, then I agree that it's hard to make sense of such a regimen.

Amphetamine mostly acts presynaptically, dumping more neurotransmitter into the cleft. Antipsychotics act postsynaptically, blocking the signal from being received. Antipsychotics are selective for particular receptor subtypes, so wouldn't be expected to unselectively block all amphetamine effects. Still not a great idea IMHO.

One issue of concern is that chronic dopamine blockade by antipsychotics results in a homeostatic increase in dopamine secretion. This is what ultimately causes dyskinetic effects via the dopaminergic motor pathways.

Co-administering amphetamine would augment this effect, so even if you block the pro-psychotic effects of amphetamine with the antipsychotic, you still are putting the patient at increased risk of the motor side effects of the antipsychotic.

 

[nitemagi]

I would not continue that regimen.

 

[Liquid8]

While I don't think this combination is a great idea, if you did decide that it was appropriate then at the very least I'd want to document a detailed risk/benefit analysis and things like the longest period they've had without a psychotic episode both on and off stimulants. If you felt it was risky but wanted to go ahead, I'd probably consider getting a second opinion as well.

Unless there are some clear timelines about when the ADHD symptoms first occurred, I'd also be querying this diagnosis because as we know impaired cognition can be a feature of schizophrenia.

In anycase, while there's been quite a few things being looked in terms of treating impaired cognitive, I don't think the evidence is overwhelming. For those interested, Donald Goff has written a few papers on the issue: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114283/ and http://onlinelibrary.wiley.com/doi/10.1002/wps.20026/pdf

 

[hamstergang]

Amphetamine mostly acts presynaptically, dumping more neurotransmitter into the cleft. Antipsychotics act postsynaptically, blocking the signal from being received. Antipsychotics are selective for particular receptor subtypes, so wouldn't be expected to unselectively block all amphetamine effects. Still not a great idea IMHO.

One issue of concern is that chronic dopamine blockade by antipsychotics results in a homeostatic increase in dopamine secretion. This is what ultimately causes dyskinetic effects via the dopaminergic motor pathways.

Co-administering amphetamine would augment this effect, so even if you block the pro-psychotic effects of amphetamine with the antipsychotic, you still are putting the patient at increased risk of the motor side effects of the antipsychotic.

Sorry, by pathway I meant dopamine tracts. These meds aren't affecting dopamine equally throughout the brain, right?

 

[tr]

Sorry, by pathway I meant dopamine tracts. These meds aren't affecting dopamine equally throughout the brain, right?

Right so the presynaptic action (amphetamine release of DA) is relatively nonspecific. Increasing release of dopamine itself into the synaptic cleft should occur pretty nonspecifically at all dopaminergic terminals.
The postsynaptic action (antipsychotic blocking of DA receptors) is more specific, because different tracts will contain different receptor complements.
Antipsychotic agents vary in their receptor affinities but in general the antipsychotic will block DA transmission at a subset of all the terminals where amphetamine acts to increase DA release.

 

[thoffen]

As stated above, they are not directly antagonistic in mechanism, thus there is theoretical rationale for combined treatment. Data isn't exactly high quality, but it does exist, for using stimulant medications for treatment of negative symptoms or antipsychotic-related sedation, and it does suggest some benefit without worsening of positive symptoms.

But I would only try it under pretty select conditions. Mostly, though, you'd have to evaluate the most important treatment goals and risks.

 

[dl2dp2]

Right so the presynaptic action (amphetamine release of DA) is relatively nonspecific. Increasing release of dopamine itself into the synaptic cleft should occur pretty nonspecifically at all dopaminergic terminals.
The postsynaptic action (antipsychotic blocking of DA receptors) is more specific, because different tracts will contain different receptor complements.
Antipsychotic agents vary in their receptor affinities but in general the antipsychotic will block DA transmission at a subset of all the terminals where amphetamine acts to increase DA release.

I asked Jeff Lieberman this question: can you try XR stimulants for treating negative symptoms in stable patients with schizophrenia? He said: there's no answer because the study was never done (because of safety concerns). It's in theory possible because though they are all D2 active, antipsychotics are probably active at the limbic sites whereas stimulants are active at the cortical sites.

I think someone should design an inpatient study making some attempts with people who have really bad negative symptoms.

 

[tr]

As stated above, they are not directly antagonistic in mechanism, thus there is theoretical rationale for combined treatment

The fact that relative degrees of antagonism are going to differ at different sites does not make this a smart idea.
At sites where you have total DA antagonism by the antipsychotic you are just having the two drugs battle each other which is pointless.
At sites where you have incomplete antagonism by the antipsychotic you are going to have additive effects of dopamine hypersensitivity induced by the antipsychotic, enhanced by the increased release courtesy of the amphetamine. This will put you at risk of dopaminergic side effects in those pathways.

I think someone should design an inpatient study making some attempts with people who have really bad negative symptoms.

I strongly suspect you'd see increased rates of TD and other motor side effects.