Schizophrenia Research Forum - A Catalyst for Creative Thinking

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

Ofer Agid

Shitij Kapur

We held a lively discussion on September 12, 2006, led by Ofer Agid and Shitij Kapur of the University of Toronto, with Patricio O'Donnell, of the University of Maryland, Baltimore, joining us as moderator. As introduced in a series of papers over the past few years, Agid, Kapur, and their colleagues in Toronto believe that antipsychotic drugs begin to work clinically within days of treatment onset. Please read the background text they prepared below, and also their recent review article that covers this text in more detail. The edited transcript of the live chat will soon be posted.

We invite you to leave a comment, either on the clinical or the preclinical implications of these ideas. Among the questions Agid and Kapur have posed are the following:

  • If it takes 3 weeks for onset of action, why are most admissions for schizophrenia shorter than that?
  • Is early improvement all just placebo or non-specific?
  • Why are clinical trials 6 weeks long? Are shorter trials possible?
  • Is early improvement just random, or does it actually predict what happens further along?

Free access: Agid O, Seeman P, Kapur S. The "delayed onset" of antipsychotic action—an idea whose time has come and gone. J Psychiatry Neurosci. 2006 Mar;31(2):93-100. Review.

View Transcript of Live Discussion — Posted 29 September 2006

View Comments By:
William Carpenter — Posted 30 August 2006
William Carpenter — Posted 1 September 2006
Patricia Estani — Posted 4 September 2006
Robin Emsley — Posted 11 September 2006
Aaron Lohan — Posted 28 June 2007

Background Text
By Ofer Agid and Shitij Kapur

Half a century ago (Delay et al., 1952), the introduction of chlorpromazine marked the beginning of the modern era of psychiatric pharmacotherapy, leading eventually to the atypical antipsychotics available today. While the efficacy of these medications for the treatment of psychosis is well established, debate continues over their precise mechanism of action. In the 1960s, Carlsson et al. (Carlsson and Lindqvist, 1963) proposed that the effect of antipsychotic medications was due to their effects on the monoaminergic systems. In the 1970s, it was reported that antipsychotic drugs displace dopamine from its D2 receptors with an affinity that correlates with their clinical potency (Seeman and Lee, 1975; Creese et al., 1996; Seeman et al., 1976). As a result of these findings, it has been generally accepted that at least one central pharmacological property of antipsychotic drugs is that they act by blocking the effects of dopamine at D2 receptors (Kapur and Remington, 2001).

However, while a stable level of dopamine blockade is obtained within a few days of starting treatment, clinically satisfactory improvement may not occur for a number of weeks. Understanding this apparent delay is a question of fundamental concern to the field. This delay in obtaining clinically satisfactory improvement has been extensively discussed in the field as a “delayed onset” of antipsychotic action. But, is the “onset” really delayed? That is the question. And, if it is not delayed, what implications does that have for the field? As a prelude to a live discussion on Schizophrenia Research Forum, we outline here the background, some recent pertinent empirical findings and the pertinent implications of these findings. All the data presented here has been published before and these issues have also been covered in a recent review by our group; readers interested in further details and references are referred to Agid et al., 2006.

The earliest reports of chlorpromazine treatment in the 1950s (Delay et al., 1952; Delay et al., 1952; Elkes and Elkes, 1954; Winkelman, 1954) described responses within days. Some of these 1950s studies report an early anti-”psychotic” response that is over and above changes in sedation or level of agitation. These reports described changes in the thought content of the psychotic patient within days after administering the medications. Over the subsequent years, several other authors have also raised the issue of an early onset of antipsychotic response in different settings (e.g., Stern et al. [Stern et al., 1993; Stern et al., 1994], McDermott et al. [McDermott et al., 1991], Garver [Garver et al., 1988; Garver et al., 1997], Keck [Keck et al., 1989] and others).

While one can find a sprinkling of findings supporting an early onset of action, in the 1970s the idea that antipsychotic action is delayed took hold ( Bunney et al., 1973; Bunney, 1974). It is hard to track where this notion actually arose, but it clearly gained credence within the field as leading basic researchers started looking for an explanation for why antipsychotic response was delayed (Grace, 1992; Grace et al., 1997). The suggested explanation for this delayed onset of action was the depolarization block theory. This hypothesis was based on preclinical studies that involved recordings of dopamine neuron firing in paralyzed anaesthetized rats, suggesting that the effect of repeated antidopaminergic (Grace, 1992) administration on dopaminergic neurons in the brain is inactivation of this firing, and this inactivation is observed after 3 weeks of continuous treatment. This delay in the onset of the biological marker for 3 weeks was thought to coincide with, and explain, the delay in onset of both the therapeutic effect and the neurological side effects of these drugs on patients with schizophrenia (Bunney, 1984; Grace and Bunney, 1986). This idea of a clinical “delayed onset” of antipsychotic action and the “depolarization block” that explains the delay, is now firmly embedded in standard psychiatric textbooks.

An important distinction needs to be made between a delayed “onset” and a delayed realization of substantial and clinically meaningful improvement. While there can be no debate that full therapeutic benefits take several weeks to realize, this by itself does not imply a delay in the “onset” of action. The above considerations lead to two competing hypotheses: an early onset with progressive accumulation or a true delay in onset (Fig. 1). Both of these hypothesis can account for the observation that sufficient clinical improvement takes weeks to achieve—but they differ significantly in what happens in the first few weeks.

Figure 1: Delayed onset hypothesis vs. early onset hypothesis.

Questioning the Idea of Delayed Onset
One of the major issues raised by the idea of the delayed onset was the disconnection between the onset of treatment and the onset of therapeutic effect. The question is thrust into an even sharper contrast by the data available from brain imaging studies that provided a direct window to the dopamine blockade system in humans. Nordstrom et al. (Nordstrom et al., 1992) observed the speed-of-onset of dopamine blockade in response to receiving haloperidol, and Tauscher et al. (Tauscher et al., 2002) have reported the effects of the atypical antipsychotic medications, risperidone and olanzapine. These studies show a robust blockade of the dopamine system within hours after drug administration and this blockade of the dopamine system is sustained through the next day.

Agid et al. (Agid et al., 2003) reviewed the English-language published data from controlled, double-blind studies of antipsychotic treatment in schizophrenia spectrum patients during the first 4 weeks of antipsychotic treatment. Forty-two double-blind controlled studies including 7,450 patients were identified. Meta-analysis of the data shows that overall clinical improvement within the first week of antipsychotic treatment was significantly greater than what was observed in later weeks. Most notably, the decrease in scores over the first week was almost three times as great as the observed effect in weeks 3 and 4 (see Fig. 2 of Agid et al., 2006).

In order to test whether the onset of action of the antipsychotics was early versus delayed, tests were undertaken to determine whether greater improvement is seen in the first two weeks (as per the “early onset” hypothesis) or the next 2 weeks (as per the “delayed-onset” hypothesis). These tests found a significant difference (p <0.0001) indicating that the decline in scores within the first 2 weeks of treatment (21.9 percent) was significantly greater than the decline observed in the third and fourth weeks (9.8 percent). Change in core psychotic symptoms over time was measured by the change in BPRS (Brief Psychiatric Rating Scale) thought subscale and PANSS (Positive and Negative Syndrome Scale) positive subscale. The decline in these scores was considerably greater over the first week than in later weeks (p <0.01). As predicted by the early-onset hypothesis, the decline in scores within the first two weeks (24.4 percent) of the initial treatment was almost three times as much as the decline observed in the third and fourth weeks (7.7 percent), (p <0.01).

To account for the placebo effect, the mean weekly improvement obtained in the placebo-treated group was removed from that observed in the drug-treated group. After subtracting the placebo group response, the improvement in scores on active antipsychotic treatment remained significantly greater in the first week than in the third week (p <0.001). The improvement in the second week was significantly larger than the effect in the third week (p <0.001) and the fourth week (p <0.01). Improvement in the first 2 weeks (17.2 percent after subtracting placebo effect) was significantly higher than in the subsequent 2 weeks (6.7 percent; difference: p <0.001). The rate of decline in the core psychotic symptoms after removal of the placebo effect was also greater within the first 2 weeks of treatment. A contrast of the average effect observed during the first 2 weeks of treatment versus the following 2 weeks confirms that the psychotic items also show a decidedly “early onset” of improvement (p = 0.019) (see Fig. 3 of Agid et al., 2006).

Leucht et al. (Leucht et al., 2005) replicated the above study using a different approach. Unlike the Agid study that relied on meta-analysis of group data, Leucht et al. used individual patient data from seven randomized and double-blind studies on the efficacy of amisulpride in acutely ill patients with schizophrenia spectrum disorders pooled for a post hoc analysis. Data for 1,708 patients with psychotic symptoms were examined for the incremental reduction in percentage of the BPRS scores over time.

Results of the Leucht analysis show that the weekly improvement of the total BPRS score and its psychotic subscales in the entire study sample (n = 1,708) was significant over time. The mean percentage change of the BPRS total score and the psychotic subscales score up to week 2 of the treatment was greater (32.1 percent) than the additional change up to week 4 of treatment (12.5 percent). The 1-year subset analysis also revealed that the reduction in the BPRS score acquired during the first 4 weeks of treatment was significantly higher than the additional change in the BPRS during the rest of the year. Accordingly, 68 percent of the total BPRS effect and 70 percent of the positive symptoms effect was already achieved after only 4 weeks of treatment (see Fig. 4 of Agid et al., 2006).

If It’s Not Delayed—How Early Is It?
Kapur et al. investigated the effect of intramuscular antipsychotics on response in an Eli Lilly multicenter study (Kapur et al., 2005). In this study, patients were rated twice during the first 24 hours after starting treatment. Three hundred eleven patients with a diagnosis of schizophrenia spectrum disorder and an acute exacerbation of symptoms were randomly assigned to receive 10 mg intramuscular of olanzapine (n = 131), 7.5 mg intramuscular of haloperidol (n = 126) or intramuscular placebo (n = 54). Patients were rated using the PANSS (Kay et al., 1987) and CGI (Clinical Global Impression) rating scales (Guy, 1976) at baseline, 2 hours, and 24 hours.

Analysis of the data demonstrates that after 24 hours of treatment, olanzapine as well as haloperidol show a significant effect on three psychotic symptoms (conceptual disorganization, hallucinatory behavior, and unusual thought content) compared to placebo. One might argue that this very early improvement in the BPRS scores is secondary to improvement in the nonspecific behavioral items of the BPRS rating scale. Kapur and colleagues addressed this question by using covariance to adjust for the effects of improvement in the nonspecific behavioral factors. There was a statistically significant effect of the antipsychotic medications on the BPRS-thought-subscale score after correction for the BPRS component dealing with agitation, excitement, and hostility. In addition, change in the BPRS psychotic items after 2 hours predicted change in psychosis after 24 hours of treatment, suggesting that the early response in psychosis is distinct from changes in BPRS items describing the agitation and excitement component.

In two 24-hour, double-blind studies (Warrington, 2006), hospitalized patients with psychotic disorder and acute agitation were randomized to treatment with fixed doses of ziprasidone 2 mg IM (n = 94), 10 mg IM (n = 64, Study 1), or 20 mg IM (n = 40, Study 2). Efficacy evaluation was based on the PANSS scale at baseline, 4 hours, and 24 hours. Improvement in psychosis was evaluated by the PANSS positive subscale and an additional early psychosis factor score (conceptual disorganization, hallucinatory behavior, and unusual thought content). Ziprasidone IM showed a significant (p <0.05) dose-related effect (20 mg vs. 2 mg) on the PANSS early psychosis factor score and PANSS positive subscale at the first post-baseline time point (4 hours) and at 24 hours. Dose-related response in overall psychopathology (p = 0.02) and reduction of acute agitation symptoms (p = 0.02) were also observed as early as 4 hours.

Generalizability to Other Drugs and Settings
Recently, studies exploring other second-generation antipsychotic medications pointed out early onset of action for these medications as well.

A combined analysis of data from three double-blind placebo-controlled randomized trials of quetiapine (Borison et al., 1996; Arvanitis and Miller, 1997; Small et al., 1997) shows that within 1 week after initiating treatment, the overall improvement in symptoms with quetiapine was significantly greater than achieved via placebo, as measured by the total score of the BPRS. The BPRS positive subscale score during the first week of antipsychotic treatment showed a significantly higher proportion of responders.

In a 4-week double-blind placebo-controlled study involving 404 subjects (Potkin et al., 2003), aripiprazole was shown to be significantly better than placebo on PANSS and CGI scores. Separation from placebo occurred already at the first week of treatment according to PANSS total and positive scores.

In a 6-week double-blind placebo-controlled study (Daniel et al., 1999), 312 patients were randomized to receive ziprasidone or placebo. Both doses of ziprasidone were shown to be significantly more effective than placebo in treating psychosis after 1 week of treatment. Reduction was measured in all assessments of global (BPRS total score) and positive (BPRS core psychotic items) scores.

Caveats and Limitations

Why have these findings been missed, and why has the concept of delayed “onset” been so widely accepted?
The answer may depend on issues surrounding the power of clinical trials and the clinical relevance of percent changes in PANSS or BPRS scores. From a clinical trial perspective, the mistaken perception of delay may have resulted from confusion between the concept of “onset” of action versus the time required to achieve a given level of improvement or statistical significance. In almost all of the studies that were included in the meta-analysis by Agid et al. (Agid et al., 2003), the antipsychotic group numerically separates from the placebo group in the very first measure (usually in the first week of treatment). The degree of improvement in the first week (13.8 percent on average) is smaller than the size of total cumulative improvement at the end of the third or fourth week (26.1 percent and 30.8 percent, respectively). Because most studies are powered to detect an effect in the range of 25-30 percent, they may have inadequate power to declare the early change as significant—even though this was evident in the data from each of the trials.

From a clinical perspective, clinicians may not “see” the early response to treatment, because it has not as yet crossed their threshold of clinical noticeable improvement, even though the very same clinicians are rating that improvement on a scale. According to some recent studies (Leucht and Engel, 2006; Leucht et al., 2005; Leucht et al., 2005), clinicians declare having observed a “minimal improvement” (using the CGI rating scale) corresponding to a 19 percent improvement in PANSS and a 23 percent improvement in BPRS. To reach criteria of “much” or “very much” improved, patients have to show 45 percent or 70 percent improvement (Leucht et al., 2005; Leucht et al., 2005). Considering the recent data regarding the degree of improvement during the first week of treatment (13.8 percent on average on a combined BPRS and PANSS scale or 17.7 percent reduction on the BPRS scale alone) (Agid et al., 2003; Leucht et al., 2005) and second week of treatment (21.8 percent on average on a combined BPRS and PANSS scale or 30.7 percent reduction on the BPRS scale alone), it is possible that the changes during this first week, although highly statistically significant and documented using objective scales, fall below the threshold that clinicians find clinically notable.

Early onset of anti-“psychotic” effect—not anti-“schizophrenia” symptoms
Schizophrenia is multidimensional. Change in positive symptoms may begin early during the course of treatment; however, negative and cognitive symptoms respond in a different pattern. Although new-generation antipsychotics seem to have a role in the treatment of negative and cognitive symptoms of the disorder, it remains unclear as to whether the effect of these medications relates to a primary or a secondary effect (Peuskens et al., 2005; Rummel et al., 2006). Thus, while a change in the positive symptoms may be early and fast, changes in other aspects of the illness and changes in “real-world” functioning may take longer—though this itself is an idea that should be tested before it is accepted.

Type of patients and stage of illness
The studies that the early onset hypothesis relies on are those of patients who are acutely ill and starting trials, especially in the case of Kapur’s and Warrington’s studies (Kapur et al., 2005; Warrington, 2006). The picture might be different for the “onset” of further improvement in the case of partially responsive patients or treatment-resistant patients. Although the view that an adequate trial for an apparent non-responder is 6 to 12 months (Meltzer et al., 1989; Meltzer et al., 1990; Meltzer, 1992; Meltzer, 1992) is not universally held, there is still general acceptance that the onset of treatment action in these cases is expected much later (Safferman et al., 1991; Lieberman et al., 1994). Onset of antipsychotic action may also be different for partially responsive patients who are switched from one stable course of an antipsychotic to another.

Relevance and Implications For

Mechanism of action of antipsychotics
Apart from the fact that all antipsychotics block the dopamine D2 receptors (Kapur and Mamo, 2003), there is little agreement about the molecular and systemic mechanisms mediating the antipsychotic effect. To identify these mechanisms, different authors have sought drug-induced gene-induction, electrophysiological and synaptic alterations. Given that antipsychotics induce hundreds of such changes, the delayed onset theory has been one way to guide this search. Thus, the attention has often focused on biological markers that were absent immediately after the first few doses, but emerged only after 2-3 weeks of treatment (Lynch and Carey, 1990; Grace et al., 1997; Atkins et al., 1999). The current findings call for revision of this strategy. If there are simple molecular markers (as an aside, the authors doubt that there are) that track antipsychotic response—their course is likely to be as depicted in Figure 1—with features of an early onset, progressive accumulation over repeated dosing and final asymptote of an effect.

Clinical guidelines for treatment
At a clinical level, focusing on the drug's activity in the first few weeks after administration has the potential to provide information regarding predictors of response to antipsychotic treatment. It is a common clinical practice to treat patients for 4 to 6 weeks with one medication before deciding if the patient is responding to that drug (Kaplan and Sadock, 2000). While it may well take 4 to 6 weeks to get a clinically meaningful response in those in whom the drug works, it is an open question whether one has to wait that long to predict whether a patient will be responding to that drug. If the greatest rate of improvement is in the first week or two of treatment, it raises the possibility that early response to treatment may predict the effectiveness of a drug for a given individual. A recent study by Correll et al. (Correll et al., 2003) shows this to be the case: 131 acutely ill patients with schizophrenia received 4 weeks of fluphenazine treatment. BPRS scores were obtained at baseline and on a weekly basis thereafter. All the patients that showed 20 percent (or less) improvement after 1 week of treatment were classified as non-responders after 4 weeks of treatment. Thus, patients with minimal improvement in the BPRS total score or the BPRS positive symptoms after 1 week of treatment are unlikely to respond to a 4-week treatment trial. If this finding is confirmed by others and generalized to other settings, it may make sense to revise clinical guidelines to reflect the predictive value of early response.

Shorter and more efficient clinical trials
Current clinical trials of schizophrenia are 4-8 weeks in duration—and the reality of these trials is that they suffer from 50 percent dropout rates by the end of the trials. If the antipsychotic response is not delayed, do we really need trials that last for 4-8 weeks? We think not. Since the majority of the improvement (and differentiation from placebo) is seen by 2-3 weeks, we think that one could gain sufficient power and greater clinical validity by acute trials that last only 3 weeks. Since the total improvement expected at the end of 3 weeks is somewhat smaller than at the end of 6 weeks (about 24 percent) the number required may rise somewhat. But, several other advantages will ensue. First, since the trial duration is decreased more than the number of patients is increased, overall patients’ exposure to experimental medications will be decreased. Further, many more patients (and much more representative patients) will be willing to try an experimental drug for 3 weeks than are willing to try it for 6 weeks. And finally, we think that these shorter trials will have much higher completion rates (our prediction is dropouts in the range of 20-30 percent), thereby decreasing the impact of statistical approaches to deal with dropouts and increasing the clinical validity of the trials. Now, any such short trial is only a proof-of-principle. But, regardless of whether it is a 3- or a 6-week trial, neither represents the full reality of treatment of chronic schizophrenia. So, one will still need longer-term (6 months-1year) pragmatic clinical trials to really understand the place of a new drug in the therapeutic armamentarium, but the approach proposed here will help us get to those pivotal trials faster.

In summary, several converging lines of evidence seriously question the conventionally held notion about the delayed onset of antipsychotic action. It may be time to give up on that idea. Our work and that of others proposes an early onset, progressive accumulation hypothesis instead. It should be pointed out that while the new findings may change our understanding about how fast antipsychotics work, this does not by itself change how quickly drugs act. The drugs did not act any slower when the field believed in the delayed onset hypothesis, and nor will the drugs act any faster just because we have a different way of understanding them. However, the hypothesis generated here opens the door for new basic science findings and new clinical approaches. We hope some of them will come to fruition.

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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!

Comments on Online Discussion
Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 29 August 2006
Posted 30 August 2006

For SRF members who attend the ACNP meeting, a panel will focus on the time of onset for antipsychotics and for antidepressants and include implications for clinical trial length, placebo-drug separation, and FDA and ethical implications.

View all comments by William CarpenterComment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 1 September 2006
Posted 1 September 2006

This should be a very interesting live discussion. The idea of a delayed onset of action with antipsychotic drugs is peculiar. It was reinforced in neuroscience by the depolarization blockade findings which were delayed. But any clinician administering acute treatment knows that antipsychotic effects occur right away. And this happens with non-sedating as well as sedating antipsychotic drugs. The view was also reinforced by looking at clinical trials and determining the time when p <.05. If this was week 3, then there must be a delay. This is silly, of course, since a gradually accumulating response would reach p = .05 at different time points depending on how robust the placebo response was and the number of subjects and the dependent measure.

I think Kapur and Agid will make clear why getting the concept correct matters so much. The implications for mechanism of action and for drug discovery are considerable. A focus on late occurring molecular events and downplaying acute effects can lead (and, no doubt, has led) to erroneous conclusions about mechanisms and targets.

Some years ago, Wyatt and colleagues looked at this issue at day 3 (their earliest ratings of change) and found robust antipsychotic effect. My impression from the clinical trials literature is that drug/placebo separation is seen at earliest rating points, and simply grows larger over time.

I look forward to this discussion to learn what Drs. Agid and Kapur think the implications of rapid onset are for understanding mechanism of action.

View all comments by William CarpenterComment by:  Patricia Estani
Submitted 3 September 2006
Posted 4 September 2006

The discussion of Dr.Kapur and Dr.Agid will be very interesting becouse of its particular and also new point of view in psychopharmachology. About the early or late onset of antipsychotic drugs, I think that sometimes it is difficult, at a behavioral level, to observe in a clinical trail, in which statistical significance should be reached, what was observed in a clinical set. This problem appears in the data of the studies.

Thus,I would like to agree with the previous comments of Dr. Carpenter about the relationship placebo/drugs across the time. This relationship, in the bibliography, is seen with perhaps an early onset and it develops more robustly with time (late onset).

View all comments by Patricia EstaniComment by:  Robin Emsley (Disclosure)
Submitted 11 September 2006
Posted 11 September 2006

The evidence for early onset of antipsychotic is compelling, and the correlation between early symptom reduction and long-term outcome appears to be strong. However, at least in first-episode patient samples there appears to be a subset of patients who respond slowly - 1/4 taking more than 4 wks to achieve 20% PANSS reduction. This has implications for treatment trials and guidelines (Emsley et al., 2006).

View all comments by Robin EmsleyComment by:  Aaron Lohan
Submitted 28 June 2007
Posted 28 June 2007

For what it is worth, in my experience as a consumer of antipsychotic drugs—I have schizophrenia—I have noticed early effects of medications, or even modest increases in medications. I have taken quetiapine, olanzapine, zotepine, and risperidone; all of these had very early effects, i.e., less than a week.

The main effect is that I start to become better organized: I always seem to clear out a lot of old junk from my house every time I try a new medication or have the dosage increased. Additionally, I feel a stronger inclination to socialize in the first week of a change in dose or drug. Of course, the experience of one person is not statistically significant, but I do know of others who get this response.

View all comments by Aaron Lohan