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.
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.
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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