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Updated 20 August 2010 E-mail discussion
Printable version

Forum Discussion: Antipsychotic Dosing: How Much, But Also How Often?

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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a recent article. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on….

Send in your comments now! The paper under discussion:
Remington G, Kapur S. Antipsychotic Dosing: How Much but also How Often? Schizophr Bull. 2010 Sep 1;36(5):900-3. Abstract

View Comments By:
Donald Goff — Posted 20 September 2010
Herbert Meltzer — Posted 21 September 2010
Christoph U. Correll — Posted 22 September 2010
Giorgio Marchese, Luca Pani — Posted 22 September 2010
Gloria Reeves — Posted 24 September 2010
Bryan Roth — Posted 27 September 2010
Ripu Jindal, Matcheri S. Keshavan — Posted 27 September 2010
David Mamo — Posted 27 September 2010
Srihari Gopal, David W. Hough, Keith Karcher, Justine Kent, Andreas Schreiner, Larry Alphs, Joseph Palumbo — Posted 27 September 2010
John Kane — Posted 29 September 2010
Jeffrey Lieberman — Posted 28 October 2010
Gary Remington, Shitij Kapur — Posted 24 November 2010
Kenneth Subotnik, Keith Nuechterlein, Joseph Ventura, Gerhard S. Hellemann, Michael Gitlin — Posted 31 January 2011

Background Text
By Gunvant Thaker, Professor and Chief, Schizophrenia Related Disorders Program, Maryland Psychiatric Research Center and Deputy Editor, Schizophrenia Bulletin

In the September 2010 issue of Schizophrenia Bulletin, Remington and Kapur review preclinical and clinical literature on the effects of continuous versus intermittent antipsychotic drug treatment. This review paper draws interesting and provocative conclusions that challenge the established clinical lore regarding the optimal dosing of antipsychotic drugs. The authors point out that while a certain amount of D2 occupancy is critical for the antipsychotic response, continuous high occupancy is not needed. This would suggest that non-continuous antipsychotic dosing would be as effective as continuous dosing, and data from targeted antipsychotic treatment and drug holiday treatment trials support this approach.

Any treatment strategy that reduces total exposure to drugs has advantages and likely reduces side effects. However, does continuous treatment do more harm by modulating the responsivity to the treatment following extended use? This seems unlikely, although a thought-provoking question. The paper also challenges the benefit of extended release formulations. It is somewhat surprising that after half a century of antipsychotic medications, some of the fundamental questions such as frequency of dosing remain. As suggested by the authors, the field needs to focus on several questions in this context. What are effective alternatives to continuous antipsychotic drug treatment? Is the shift toward slow-release formulations wrong-headed? Should one invest in compounds with short half-lives?

Comments on Online Discussion
Comment by:  Donald Goff
Submitted 20 September 2010 Posted 20 September 2010

Remington and Kapur present a new and impressive challenge to the assumption that continuous D2 occupancy is optimal for the treatment of schizophrenia, a belief that has guided antipsychotic development and dosing over the past few decades and which is behind current advocacy of depot antipsychotics and sustained release formulations. As the authors note, there is a long history to this debate. Back in the 1970s, the etiology of tardive dyskinesia (TD) was believed to involve antipsychotic-induced dopamine supersensitivity, as evidenced by increased D2 receptor density and behavioral response to dopamine agonists (Tarsy and Baldessarini, 1977). This led to studies of intermittent and targeted administration of antipsychotics, but the prolonged discontinuation of treatment resulted in unacceptable rates of relapse (Carpenter et al., 1990). In addition, intermittent dosing did not reduce the incidence of tardive dyskinesia and may even have increased risk (  Read more

View all comments by Donald Goff

Comment by:  Herbert Meltzer (Disclosure)
Submitted 21 September 2010 Posted 21 September 2010

Remington and Kapur (Remington and Kapur, 2010) cling to the outmoded notion that D2 receptor blockade is the only means to achieve an antipsychotic response. Their only justification offered for this view is that all currently approved antipsychotic drugs for schizophrenia have some D2 receptor antagonism. This is accurate, but misleading. It should be clear to them by now that this unfortunate state of affairs is not because we lack antipsychotic drugs that could treat psychosis without directly blocking D2 receptors, but because of the time, money, and effort needed to gain approval for a new drug. This fact of life in the drug discovery and approval world would be true even for a clone of haloperidol.

There are many reasons to believe that there are other bases for treating psychosis that do not involve D2 receptor blockade but are not yet approved as monotherapies. It is already known that D2 receptor blockade is a contributor, and an important one, to antipsychotic drug action of drugs like clozapine, olanzapine,...  Read more

View all comments by Herbert Meltzer

Comment by:  Christoph U. Correll
Submitted 22 September 2010 Posted 22 September 2010

Antipsychotic Dosing: How Often Is Too Much and How Infrequent Is Too Little?
Optimal dosing of antipsychotics in patients with schizophrenia has remained a formidable challenge. This has been true in drug development, regulatory trial design, and clinical practice. Questions that have remained unresolved include: the dose requirements in the acute and maintenance phases of schizophrenia, whether overstepping the neuroleptic threshold that is associated with the emergence of extrapyramidal side effects is helpful in non-responding patients, and whether dose or blood levels are useful for predicting antipsychotic response (Baldessarini and Davis, 1980; Janicak and Davis, 1996; Citrome et al., 2009; Liu and De Haan, 2009; Hartung et al., 2008; Barbui et al., 2007;   Read more

View all comments by Christoph U. Correll

Comment by:  Giorgio MarcheseLuca Pani (Disclosure)
Submitted 22 September 2010 Posted 22 September 2010

The effort to optimize atypical antipsychotic treatment continues to stimulate a significant number of hypotheses and studies within the field of antipsychotic therapy. "Second-generation" or atypical antipsychotics have been analyzed in order to extrapolate possible relationships between the therapeutic benefits of atypical antipsychotics and their ability to mitigate schizophrenia symptoms. It was proposed that a correct receptor D2/HT2 ratio might provide an advantage in antipsychotic therapy in terms of efficacy and tolerability (Leysen et al., 1993). Furthermore, Kapur et al reported on the clinical relevance of correct D2 receptor occupancy levels in order to obtain an optimal ratio between positive symptoms control and extrapyramidal side effects incidence (Kapur and Remington, 2001).

Recent attempts to improve antipsychotic therapy focus on the variable of “time” (the dissociation rate from the receptor, occupancy level overtime, drug half-life, etc.). In line with this...  Read more

View all comments by Giorgio Marchese
View all comments by Luca Pani

Comment by:  Gloria Reeves
Submitted 24 September 2010 Posted 24 September 2010

This manuscript by Remington and Kapur (2010) raises some interesting and unconventional (“any strategy other than continuous antipsychotic exposure…seems tantamount to heresy”) questions about the potential risks and benefits of prescribing intermittent antipsychotic treatment. The potential strategy of intermittent dosing (either scheduled medication holidays or dosing less frequently than daily) is explored as a theoretical option to reduce side effects and/or reduce likelihood of tolerance/lower effectiveness of a dose.

I'd like to pose a few comments about this theoretical dosing option. First, it is important to consider that antipsychotic medications are often prescribed concurrently with other psychotropic medication. The duration of time between dosing should also be considered in terms of potential impact on drug interactions. Yanofski’s (2010) article on the concurrent use of stimulants and antipsychotics in which the “the dopamine dilemma” is articulated raises concerns about the need to further study how...  Read more

View all comments by Gloria Reeves

Comment by:  Bryan Roth, SRF Advisor
Submitted 27 September 2010 Posted 27 September 2010

Intermittent dosing of antipsychotic drugs: pharmacokinetic and relapse time-course considerations
Remington and Kapur propose that less-than-daily antipsychotic drug administration might be helpful for many patients. They state, “Does this mean we need to (or should) administer antipsychotics at least daily? There is a body of evidence challenging this long-established clinical axiom….”

They cite clinical findings from a paper published in 2005 (Remington et al., 2005) as well as one in press, which demonstrate that every-other-day dosing might be suitable for some patients. The authors’ main scientific rationale is that continuous occupancy of D2 receptors might be deleterious.

A pharmacokinetic primer
I note that many of the drugs used in the 2005 paper (as well as most clinically approved antipsychotic drugs) have relatively long biological half-lives:

Olanzapine: 21-54 hours
Haloperidol: 12-36 hours
Fluphenthixol: 19-39 hours

Risperidone has a short half-life (three hours), but its...  Read more

View all comments by Bryan Roth

Comment by:  Ripu JindalMatcheri S. Keshavan
Submitted 27 September 2010 Posted 27 September 2010

Consider intermittent dosing of antipsychotics, but tread with caution!
Remington and Kapur (Remington and Kapur, 2010) ask a thought-provoking question: do we need to (or should we) administer antipsychotics at least daily? This is a valid question given that daily antipsychotic treatment has become the standard of care by default, but without solid supporting evidence. We agree that intermittent antipsychotic therapy was perhaps prematurely abandoned and see many good reasons to reconsider it.

First, historically the concern about worsening tardive dyskinesia was an important reason for moving away from the intermittent dosing strategy (van Harten et al., 1998). Though it is unclear whether the newer generation of medications is more efficacious over those available in the 1970s (Jones et al., 2006; Lieberman et al., 2005), it is hard to dispute that as a group, the newer...  Read more

View all comments by Ripu Jindal
View all comments by Matcheri S. Keshavan

Comment by:  David Mamo
Submitted 27 September 2010 Posted 27 September 2010

Directions in Antipsychotic Dosing: Proceed With Caution
Indefinite continuation of antipsychotic medication for schizophrenia is considered standard care, and “compliance” with this recommendation is the focus of a large part of clinical work with this population, and a primary outcome measure in studies evaluating psychosocial interventions. To challenge this, therefore, is indeed as close to heresy as one can get in the pharmacotherapy of schizophrenia. One fundamental question that is often asked of prescribers of antipsychotic medication is whether the prescription is expected to cause any “changes” in the brain. The standard answer is a reassuring “no.” Remington and Kapur remind us that, good intentions aside, antipsychotic medications do indeed induce receptor and downstream changes (Remington and Kapur, 2010), and structural effects of long-term antipsychotic medication have been documented in the literature (Kosten, 1997). The second frequently asked question in...  Read more

View all comments by David Mamo

Comment by:  Srihari GopalDavid W. HoughKeith KarcherJustine Kent
Andreas Schreiner
Larry AlphsJoseph Palumbo
Submitted 27 September 2010 Posted 27 September 2010

Thank you very much for the invitation to provide commentary on the article by Professors Gary Remington and Shitij Kapur. The authors rightly point out that there is much discussion in the literature about dosing and receptor occupancy, but less discussion regarding frequency of dosing and the relevance of peripheral and central effects of dosing intervals. The article raises a number of thought-provoking issues and deserves further discussion.

Professor Kapur published a seminal hypothesis in March 2001 suggesting that fast dissociation from the D2 receptor might explain the mechanism of action of atypical antipsychotics. In this paper, Kapur proposed that fast dissociation may make antipsychotics more accommodating of physiologic D2 transmission (Kapur and Seeman, 2001). Based upon this hypothesis, it is reasonable to believe that antipsychotics which spend less time blocking the D2 receptor (due to rapid on-off binding) provide testable advantages over conventional high-potency D2 antagonists. The relationship between D2...  Read more

View all comments by Srihari Gopal
View all comments by David W. Hough
View all comments by Keith Karcher
View all comments by Justine Kent
View all comments by Andreas Schreiner
View all comments by Larry Alphs
View all comments by Joseph Palumbo

Comment by:  John Kane
Submitted 29 September 2010 Posted 29 September 2010

Remington and Kapur have raised some important questions that both highlight the limitations of our current knowledge and assumptions and suggest important avenues for further research.

The degree and consistency of D2 occupancy that is required for antipsychotic effect is a critical question influencing routine clinical practice, benefit-risk judgments, and clinical drug development. Remington and Kapur have played an important role in drawing attention these issues.

The brief review of the data on intermittent treatment in relation to both efficacy and adverse effects is informative. As the authors imply, it is critical to identify the type of intermittency to which we are referring. Drug “interruptions/holidays” lasting weeks or months can produce very different effects than the “transient” exposure to which the authors are referring. Where to draw the line becomes an important empirical question. The new clinical evidence that is emerging (largely with the leadership of the authors) is encouraging, and hopefully larger-scale, more definitive research will...  Read more

View all comments by John Kane

Comment by:  Jeffrey Lieberman, SRF Advisor
Submitted 28 October 2010 Posted 28 October 2010

“No thing is without poison. The dosage makes it either a poison or a remedy.”—Paracelsus

Despite the proven efficacy of antipsychotic drugs, their mechanism of action and optimal dosing are not fully determined. Beyond their antagonism of dopamine (DA) at the dopamine 2 receptor (D-2) at some requisite threshold dose, we do not know definitively how they work and at what schedule to optimally administer them (Miyamoto et al., 2005). The paper by Remington and Kapur provides an intriguing formulation of several lines of investigation of the pharmacodynamic actions of APDs and proposes a novel dosing schedule for their administration. The gist of their argument is that continuous APD administration at doses that occupy >60 percent of striatal D-2 receptors is unnecessary and excessive, potentially causing undesirable side effects and tolerance to the drug’s pharmacologic effects. They propose that, rather than continuously blocking D-2 receptors and inhibiting their stimulation by endogenous DA, treatment can be...  Read more

View all comments by Jeffrey Lieberman

Comment by:  Gary RemingtonShitij Kapur (Disclosure)
Submitted 24 November 2010 Posted 24 November 2010

We would first like to thank those who took the time to respond to our article. We appreciate the many thoughtful points made and shall respond broadly to the themes that seemed to emerge.

Potential—but safety first
It is reassuring that clinically related concerns were repeatedly raised, ranging from the heterogeneous nature of schizophrenia and lack of markers for subtyping response/outcome to the very preliminary nature of our hypotheses, limited clinical data, and practical concerns (e.g., problems that arise with not taking medications daily). These points are all valid, but it remains that we have at least preliminary data indicating there may be a subgroup that will do at least as well, and possibly better, with alternative strategies to daily dosing. This cannot be ignored, especially in the face of current interest in individualized medicine.

We do echo the concerns of others around the need for further carefully controlled studies and agree that, beyond replication, there are numerous nuances that warrant consideration. What constitutes a...  Read more

View all comments by Gary Remington
View all comments by Shitij Kapur

Comment by:  Kenneth SubotnikKeith Nuechterlein (Disclosure)Joseph VenturaGerhard S. Hellemann
Michael Gitlin
Submitted 31 January 2011 Posted 31 January 2011

Remington and Kapur have challenged the existing dogma of the need for continuous daily dosing of antipsychotic medication and present several compelling arguments in favor of an extended dosing strategy. Our experience at the UCLA Aftercare Research Program has been that, even in our very carefully controlled research setting, two-thirds of recent-onset schizophrenia patients will experience some level of non-adherence over an 18-month period (Subotnik et al., 2011). In many cases, the non-adherence was partial and/or brief. One might say that we should “listen” to this finding because it tells us that most patients might not want to take antipsychotic medication, or at least not at the dosage usually prescribed. However, it also suggests that adherence with an extended dosing regimen would also confront similar problems with many schizophrenia outpatients. As Remington and Kapur note, adherence with a more complex schedule of every-other-day dosing might be even more challenging than daily dosing. Something that was quite...  Read more

View all comments by Kenneth Subotnik
View all comments by Keith Nuechterlein
View all comments by Joseph Ventura
View all comments by Gerhard S. Hellemann
View all comments by Michael Gitlin
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