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Live Discussion Transcript


Posted 29 September 2006

E-mail discussion
Printable version

Live Discussion: The Lack of Delay in the “Onset” of Antipsychotic Action: Implications from the Bench to the Bedside

Return to Discussion Text

Attendees/Participants
Ofer Agid, CAMH-University of Toronto
A. G. Alias, Retired
Michael Browne, Ottawa University
William Carpenter, University of Maryland
Lei Chen, Eli Lilly and Company
Steve Derry, Eli Lilly Canada
Carlotta Duncan, Prince of Wales Medical Research Institute, Sydney Australia
Mauro Fa, Columbia University
Judith Gault, UCDHSC
Hakon Heimer, Schizophrenia Research Forum
Mi Hillefors, Experimental Therapeutics Branch, DATR, NIMH
Amir Kalali, ISCDD
Shitij Kapur, CAMH-University of Toronto
Bruce Kinon, Eli Lilly and Company
Ming Li, University of Nebraska-Lincoln
Eileen McGinn, Hunter-Brookdale Program in Aging
Janet Munro, Institute of Psychiatry
Patricio O’Donnell, University of Maryland
Eugenia Radulescu, CBDB/ NIMH
Ema Saito, The Zucker Hillside Hospital
Dapo Tomori, Eli Lilly and Company

Note: The transcript has been edited for clarity and accuracy.


Hakon Heimer
I’ll start by thanking Ofer Agid and Shitij Kapur for their very complete discussion text. They are both currently at the Centre for Addiction & Mental Health at the University of Toronto, and have been active in many areas of clinical research. Also joining us for the chat is Patricio O’Donnell, recently moved from Albany to the University of Maryland. Patricio can help us with questions that arise about the underlying biology of the effects of antipsychotic drugs.

Ofer Agid/Shitij Kapur
Welcome, all. Thanks for joining us. Let us begin by asking your opinions on whether you think that “onset” is delayed or not?

Bruce Kinon
Onset is not delayed.

Ofer Agid/Shitij Kapur
Clearly patients do not get all better quickly, and some aspects do not improve even after many weeks. So, what is it that is not delayed?

Bruce Kinon
Response is not delayed in patients who are likely to respond. A response may not occur for a long time in patients who are less likely to respond later on.

William Carpenter
Onset is not delayed. Improvement gradually accumulates.

Ofer Agid/Shitij Kapur
But, Will, what is it that improves first? The question itself suggests that there is more than one thing to be treated, perhaps even within psychosis.

William Carpenter
Ofer/Shitij, not sure, of course, but reality distortion symptoms and disorganization can show early beginning improvement.

Patricio O’Donnell
Will, the way I've seen this phrased sometimes is that the early effect may be a sedative or even a placebo action, while the true antipsychotic effect takes time. I believe Shitij and Ofer have addressed this clearly in their review, but how certain can we be that the early effects are not non-specific?

William Carpenter
Patricio, welcome to the University of Maryland, Baltimore! I think early response occurs with sedating and non-sedating antipsychotics. You can see emergency room responses to IM haloperidol within a few minutes.

Ofer Agid/Shitij Kapur
So, we have several issues on the table: (a) Patricio raises the issue of specificity; (b) Bruce raises the issue of individual differences. Bruce, as for different subtypes… that is important. In the comment left on SRF by Robin Emsley, he points out how one-fourth respond, but start later. So, there may be different trajectories, though it is yet to be shown in large databases that there are two (or more) trajectories rather than just normal variance.

Bruce Kinon
We agree.

Ofer Agid/Shitij Kapur
Patricio, we have clearly shown that the early antipsychotic effect is still significant after removing the placebo effect, and there is a significant early antipsychotic effect in the core psychotic symptoms. Will/Bruce/Patricio, most recently, Mizrahi in our group did a study where she tracked what within psychosis improves first (Mizrahi et al., 2006). What we observed was that patients first stop acting (commission or omission) on their psychotic material and are less cognitively and emotionally preoccupied with it. The innate conviction, the psychotic story, and their insight on it changes rather slowly (if at all).

Patricio O’Donnell
Shitij/Ofer, yes, I've seen that. Now, is this seen in first-time antipsychotic users? My recollection is that the studies were done after a couple of weeks of withdrawal from the drugs. Could there be a lingering effect that makes the "true" antipsychotic action appear earlier?

Ofer Agid/Shitij Kapur
Patricio, unpublished (yet) data from our first-episode program shows that there is early response among first-episode, neuroleptic naive patients as well.

Bruce Kinon
Core psychotic symptoms, particularly the positive symptom cluster, appear to be more predictive of early response.

Ofer Agid/Shitij Kapur
Bruce, a lot of those "late responders" are "non-responders." These non- or partial responders might respond to clozapine. And you are right that core psychotic symptoms do improve, and we think what they do predict is longer-term improvement in psychotic symptoms—not negative or cognitive.

Bruce Kinon
So, patients who fail to show an early response may need an early rescue with an alternative antipsychotic.

Ofer Agid/Shitij Kapur
Bruce, you raise a very interesting point. Studies by Szegedi et al. in depression show exactly that—that lack of early response in depression bodes poorly and you should switch sooner (see, e.g., Stassen et al., 1996; Montgomery et al., 2002; Posternak and Zimmerman, 2005). The more important question is whether the second strategy really works any better. “Unpublished data," coming up at the ICOSR, from our first-episode program shows that patients that did not respond to the first line of atypical antipsychotic will not respond to dose increase or to a different atypical antipsychotic. Most of those non-responders will respond to clozapine.

Bruce Kinon
Further research needs to be done in this area.

Ofer Agid/Shitij Kapur
We agree. You see, early switching would be a good idea if switching had greater efficacy than just waiting. This has been hard to show in good trials, as you know. Certainly switching to clozapine helps. But, most would say that that is an important enough and serious enough decision that a few weeks extra of waiting is worth it.

William Carpenter
Bruce, all the antipsychotics share the same mechanism of action, and there’s little reason to expect that one would work better than another except for adverse effects (and the modest clozapine superiority in treatment-resistant cases).

Bruce Kinon
Will, although early response may be seen in a similar proportion of patients across all antipsychotics, differences may appear with continued treatment, particularly on parameters such as treatment duration.

Amir Kalali
Kapur and Agid, several thoughts: first, there are many methodological issues to think about in detail before we can be sure we can conclude correctly from some studies. These include possible rater inflation, whether subtle changes in the PANSS are underrated versus obvious positive symptoms. Also, obviously the literature on this is quite extensive in depression, with much disagreement, but perhaps that literature can be informative.

Ofer Agid/Shitij Kapur
Amir, rater inflation is subtracted by the placebo arm.

Amir Kalali
Kapur and Agid, I can share with you offline some very interesting data on effects of rater inflation and other methodological issues that make us cautious about how we interpret.

Hakon Heimer
All, Shitij and Ofer suggest that clinical trials could be shorter. Any thoughts about this?

William Carpenter
Hakon, Shitij and I have a panel on this for the December ACNP meeting. We anticipate a number of advantages for shorter trials including better recruitment, less time exposure to placebos, less non-random attrition, and good early separation of efficacious drug from placebo. Still to be worked out is effect on power, and whether the placebo response is most robust in the first week or two.

Ofer Agid/Shitij Kapur
Bruce/Amir, to follow on Will's comments, does the industry see the potential advantages of shorter trials with somewhat increased numbers of patients?

Bruce Kinon
For early drug development and proof-of-concept studies, this paradigm may have value.

Amir Kalali
As for shorter trials, I think it can depend on the drug, and the need for titration. Also, in-patient versus outpatient differences is currently an underestimated issue.

Ofer Agid/Shitij Kapur
Bruce, we would suggest that for later-stage development, short trials (whether they are 3 weeks or 6 weeks) are non-representative. Trials need to be longer. So, it may be that early trials are very highly controlled efficacy kinds, focusing on positive symptoms, and 3 weeks. Then, one can have longer (6 months) effectiveness-type trials to see if the drug really works in patients in real life.

Bruce Kinon
Acuity and severity may have great importance in facilitating early response.

Ofer Agid/Shitij Kapur
Bruce, regarding acuity and severity, most of the drug trials were done with chronic stable patients.

Bruce Kinon
Most of the drug trials are in patients who are chronic, but acutely exacerbated.

Amir Kalali
Shitij/Ofer, to answer your question to Bruce, most trials are in acute with PANSS of at least 70 and median in the 90s, and a few trials have targeted even more severely ill patients.

Ofer Agid/Shitij Kapur
Patricio, this brings us to the issue of mechanism. Let’s say that this idea about an early onset is sustained. How does one reconcile the latest thinking on depolarization block with this?

Patricio O’Donnell
Shitij/Ofer, I was waiting for that question. I do not think that an early onset is necessarily inconsistent with the idea of depolarization block. Almost all basic studies on this issue were done testing whether dopamine neurons entered depolarization block 24 hours or 3 weeks after haloperidol administration. There is very little information on what happens in between. It is indeed conceivable that depolarization block itself is a process that builds with time. If it is tested 3 weeks after treatment onset, most cells will be in depolarization block; it would be useful to test whether at 3 days, 7 days, or any time point in between, there has been a slow increase in the percentage of cells showing depolarization block.

Ofer Agid/Shitij Kapur
Patricio, we agree with your take. We think an early response is not inconsistent with depolarization block. It just requires a slightly different take on it. It could be that early on, the decrease in dopamine transmission is due to blockade. And later on, an additional measure (depolarization block) adds on. The reason why this may be helpful is because antipsychotics do not stop working when occupancy goes. The rate of relapse is much slower than the exit of drugs. So, it could be that patients are maintained by a mixture of both.

Patricio O’Donnell
Shitij/Ofer, yes. And if there is some problem with dopamine function to begin with (say, if Dave Lewis's data on loss of dopamine terminals in the prefrontal cortex is taken as evidence of a diminished mesocortical system), depolarization block can occur even earlier and faster than in the intact brain. Tony Grace has shown way back that depolarization block could be induced with a single administration in animals with a partial dopamine denervation (Hollerman and Grace, 1989).

William Carpenter
Patricio, Paul Shepard suggested that depolarization may help explain why antipsychotics do not lose their effect as the brain adapts to receptor blockade.

Patricio O’Donnell
Will, yes, Paul's idea is quite possible. As Shitij/Ofer mentioned, we have to keep in mind that drug occupancy may change and receptors can sensitize with longer drug exposure. This could indeed help sustain the "acute" effects.

Ofer Agid/Shitij Kapur
Will/Patricio, in some of our animal studies, we find that animals over a period of days develop more D2 receptors in the "high state" as a compensation. This could in theory explain why some patients (who have weak upregulation or strong depolarization block) stay in remission, whereas others (who have high upregulation or low depolarization block) relapse early. Patricio, not only are you right about that in terms of depolarization block, but you raise another important question about modeling antipsychotic action in "normal" “rats.” That’s twice removed from "abnormal" and "human."

Carlotta Duncan
Kapur and Agid, do you believe that this "early" onset of antipsychotic effect indicates that most of the mechanism of action of APDs is occurring as a direct result of neurotransmitter receptor binding? For example, dampening the salience aberrantly attributed in schizophrenia by decreased DA release? What does this indicate about gene expression studies to try and elucidate mechanism of action? Should we only concentrate on changes that are immediate and show a similar trend in expression levels as the clinical profile?

Ofer Agid/Shitij Kapur
Carlotta, what we should look for in terms of mechanism is to find a "system level" alteration that tracks the behavioral change. My thinking is that it is unlikely that any single intermediary molecule could explain that. Perhaps some measure of change in reward-related indices that follows the trajectory seen in patients would be ideal.

Carlotta Duncan
Agid/Kapur, absolutely. A system-level alteration consistent with behavioral changes would be the most interesting and perhaps have the greatest potential for future drug targeting. Thank you.

William Carpenter
Enjoyed and learned. Hakon, thanks for organizing. I have to go.

Ofer Agid/Shitij Kapur
Thanks, Will.

Hakon Heimer
Will, thanks for coming.

Ofer Agid/Shitij Kapur
One of the further issues that is raised by early onset is the fact that it applies only to psychotic symptoms, which brings into sharper relief that our current drugs work well (if) only for the positive type of symptoms. It may well be that the negative symptoms are the kind of thing that does not improve overnight.

Hakon Heimer
Shitij/Ofer, does the recent attention to bipolar/schizophrenia overlap bear on this? Do bipolar patients respond similarly?

Ofer Agid/Shitij Kapur
We can see early onset of action in psychotic bipolar patients as well.

Mauro Fa
Studies in normal animals of course produce results that it is tricky to generalize to pathology, but please take also into account that we do not have an animal model for all seasons, and schizophrenia is a cluster of variegated syndromes.

Patricio O’Donnell
Shitij/Ofer and Mauro, your prior point is important. We cannot solve the rodent/human gap, as we do need experiments in rodents to understand the basic elements in the brain pathways involved. But we can bridge the abnormal/normal gap. Nowadays there are several "neurodevelopmental" models that to some extent reproduce schizophrenia phenomena. Depolarization block has not been tested in these models, and I would be interested in finding out whether it emerges faster in those "abnormal" animals. Animals with early manipulations (antimitotics, hippocampal lesions, early stress, or social isolation rearing) do show anomalies that emerge after adolescence. Of course, the animal models I was referring to may be better at reproducing cognitive deficits and/or negative symptoms. Unless we can ask them if they hear squeaks, it will be a stretch to claim they are modeling positive symptoms.

Ofer Agid/Shitij Kapur
Patricio, we agree. And as we do that, we also need to make sure we are treating our sick rats the way we treat humans. Single daily dosing in a rat with a half-life of 2 hours ... is like treating a human with one dose per week. So, we need to move towards representative pathology and representative pharmacology models. It will be interesting to see if depolarization block is observed when antipsychotic is administered by a pump, which resembles the human condition much more than single daily injections. Patricio, why do you think Grace and colleagues picked the 3 weeks point of time when looking for the depolarization block?

Patricio O’Donnell
Shitij/Ofer, I think the 3 weeks was taken based on the clinical literature at that time (early 1980s) of full effects at that time point.

Ofer Agid/Shitij Kapur
Patricio, here is the confusion regarding full effect versus onset of action.

Patricio O’Donnell
Shitij/Ofer, you are absolutely right. Add the pharmacodynamics gap to our studies. These are not trivial issues, and changes in the rate/frequency of drug delivery can play a large number of tricks on receptor expression, affinity, etc., and change dramatically the manner in which a drug acts.

Hakon Heimer
We have a few minutes left. A good time for closing statements, where to from here, etc. However, this being the Web, there's no real limit for those who want to keep typing.

Bruce Kinon
Early response is an important concept in pharmacotherapy and likely to be an epiphenomenon across a variety of psychotropics, including antipsychotics and antidepressants.

Mauro Fa
Why do we still need to be focused on depolarization block, instead of searching for alternative mechanisms such as the residual sensitivity to glutamate after chronic treatment?

Ofer Agid/Shitij Kapur
Good point, Mauro. Marc Laruelle, on the basis of his dopamine studies, concluded that there may be two components to response: an early dopaminergic one, and a more sustained change in glutamate control of dopamine systems.

Mauro Fa
Please try also to think about the possible clinical consequences of a depolarization block in the dopaminergic system, and then try to remember whether you have ever seen a patient with chronic dysphoria or chronic depression after chronic haloperidol or clozapine.

Patricio O’Donnell
Mauro, we do not need to stay married to depolarization block. It is a phenomenon that was observed more than 20 years ago, and can provide some (maybe limited) explanations for antipsychotic actions. Now, you bring glutamate into the picture, and I agree with you that we may need to open up and explore how other transmitters (perhaps with deficits preceding those of the dopamine projections, i.e., glutamate or even GABA) are affected by antipsychotics.

Ofer Agid/Shitij Kapur
Our sense is that glutamate must be involved, not because we know much about it, but because it is the currency with which the brain functions. The challenge, of course, is whether one can perturb the system without unintended consequences. Sometimes we feel the reason why dopamine-based drugs have been successful is that they may be a more targeted way of interfering, eventually, with glutamate transmission.

Patricio O’Donnell
Shitij/Ofer, I agree. If the primary deficit is at the glutamate synapse level (or GABA), targeting D2 receptors is a good way to modulate glutamatergic synapses that are under dopaminergic control.

Steve Derry
Thanks Drs. Agid and Kapur.

Ofer Agid/Shitij Kapur
Thanks for coming, Steve.

Mauro Fa
Thanks for the discussion.

Ofer Agid/Shitij Kapur
It appears to be time for people to have real lunch, rather than just intellectual fulfillment. Thanks for joining us. Hopefully, this sparked some new ideas. Please do write to us if we can clarify something we said or mis-said.

Hakon Heimer
Ofer and Shitij have posed three questions with which to leave us, and I'd encourage you to leave a comment on the website in reply. They are (a) Do you think onset is early? (b) Does it make a difference to clinicians? (c) Does it make a difference to scientists and drug developers? Thanks so much for sharing your ideas and time with us, Shitij and Ofer! And thanks for holding up the biologic end of things, Patricio.

Amir Kalali
Thanks, Kapur and Agid, for an interesting discussion.

Ofer Agid/Shitij Kapur
Thanks, Amir. Patricio, thanks for bringing science to this. Hakon, thanks for organizing this. And Nico, thanks for making it work.

Patricio O’Donnell
Thank you all for a nice discussion. Hakon, hope to see you soon (Atlanta?).

Hakon Heimer
Yes, I'll be in Atlanta. Let me put in a plug for the Schizophrenia Social on Monday, October 16, at the conference center. I've organized a panel of funding officers from NIMH and NARSAD to talk about funding for basic science of relevance to schizophrenia. And, of course, we'll eat, drink, and socialize.

Patricio O’Donnell
Great! See you then. I have to go now. Thanks for organizing this!

Hakon Heimer
Off to lunch then!

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