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Early Striatum Shrinkage—Canary Warning of Extra-pyramidal Symptoms?

17 June 2010. New findings challenge the prevailing view that first-generation antipsychotic drugs, such as haloperidol, only enlarge structures in the basal ganglia. Heike Tost, of the University of Heidelberg in Mannheim, Germany, and colleagues found that a single infusion of haloperidol quickly, but reversibly, shrank striatal regions in healthy men. Their study, published online in Nature Neuroscience on June 6, ties striatal volume loss to extra-pyramidal symptoms, which may reflect an uncoupling of key brain regions involved in movement. The researchers suggest that dopamine D2 receptors, a target of all antipsychotic drugs, mediate short-term neural plasticity and that striatal volume loss may serve as marker for extra-pyramidal side effects.

Any antipsychotic drug can cause tremors, muscle rigidity, involuntary muscle contractions, slowed movement, physical restlessness, or other extra-pyramidal symptoms. These side effects can hinder patients’ work, social interactions, and treatment adherence (see Haddad and Dursun, 2008).

The striatum, a region of interest in schizophrenia (see SRF related news story; SRF news story), serves as a hub for integrating cortical function with movement (for an overview, see Tisch et al., 2004). When antipsychotic drugs block too high a percentage of striatal D2 receptors, they increase the risk of extra-pyramidal symptoms (see Wong et al., 2007). Because these drugs can trigger gene expression changes in rodents within 15 minutes (Kovács et al., 2001), Tost, colleague Dieter Braus at the University of Heidelberg, and others examined the short-term effects of antipsychotic drug administration on human brain structures. Specifically, they looked at the so-called “typical” antipsychotic haloperidol, known to confer a high risk of extra-pyramidal symptoms (see SRF related news story and SRF news story).

Too little teamwork in the brain
A sample of seven men, ages 22 to 27, who had no history of mental illness or antipsychotic drug use, received haloperidol intravenously. All underwent neuroimaging before they received the drug, one to two hours after the infusion, and 24 hours later, a time corresponding to the drug’s half-life.

High-resolution structural magnetic resonance imaging showed a loss of gray matter in the striatum, particularly in the ventral putamen, from baseline to an hour or two after the infusion. The striatum lost more volume than any other brain region, but regained some of it within 24 hours. To assess extra-pyramidal symptoms, the study used a reaction time task that required subjects to press a computer key whenever they saw a certain stimulus. The greater the early striatal volume loss, the worse subjects did on this task.

Covariance analysis showed that, within two hours of infusion, a structural disconnect appeared between the ventral putamen and other regions important for movement—specifically, the dorsal putamen, thalamus, and motor cortices. This trend later reversed, in line with haloperidol’s pharmacokinetics.

Function seemed to echo structure. As subjects performed a finger-tapping task, an indicator of short-term motor control, functional magnetic resonance imaging revealed an unyoking of the motor pathways between the striatum and the motor cortex one to two hours after drug administration. In all but one subject, the functional ties normalized by the end of the study. The early striatal volume loss explained 67 percent of the variance in the functional uncoupling. In turn, the latter accounted for 74 percent of the variance in motor impairment.

The changes seen in these subjects did not appear in unmedicated, but otherwise matched, control subjects, bolstering the case that they reflect drug effects. As for the mechanisms behind the findings, Tost and colleagues think that the time course rules out changes in blood flow or cell number as an explanation. They noted that, over the long haul, D2 receptor blockers may foster remodeling at synapses, but on an acute basis, they may actually do the opposite. “Although previous work in humans has reported structural changes on a timescale of days to months, the drug-induced remodeling that we found suggests that dopamine D2 receptors have a role in short-term human neural plasticity,” they wrote. They suspect that brain-derived neurotrophic factor (BDNF) might be involved.

What to make of it?
If replicated, this study will need to be reconciled with prior findings that first-generation antipsychotics bulk up striatal structures, including the caudate and the putamen, over weeks or months of treatment (for related reviews, see Brandt and Bonelli, 2008; Smieskova et al., 2009; Navari and Dazzan, 2009). It leaves unresolved the issue of whether second-generation antipsychotics would produce the same effect, but some prior studies (e.g., McClure et al., 2008) hint that these drugs leave striatal volume relatively unchanged after weeks or months.

Since the study looked only at healthy subjects, its ramifications for schizophrenia have yet to crystallize. Other questions that need answering include whether the findings will hold up in larger samples (that include female subjects), in subjects who receive haloperidol orally, and in those exposed to antipsychotic drugs other than haloperidol. Clarifying the short- and long-term effects of antipsychotic drugs on striatal structures could keep researchers busy for some time!—Victoria L. Wilcox.

Reference:
Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A. Acute D(2) receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010 Jun 6. Abstract

Comments on News and Primary Papers
Comment by:  Stephen Lawrie
Submitted 20 June 2010
Posted 22 June 2010

This is a striking finding, but it is difficult to know what motivated the study or how to interpret the results. The study is very small and was probably of an exploratory rather than hypothesis-testing nature, making replication doubly important. It is also unclear what sort of biological changes may underlie the apparent loss of volume in the putamen—as the authors say, it is unlikely to be cell damage or vascular. A reversible change over such a short period of time suggests possible changes in cellular fluid balance. Regardless, these results on exposure to IV drug in young healthy men may bear no relation to the effects of the drug in the routine and usually oral treatment of patients with schizophrenia and related conditions.

View all comments by Stephen LawrieComment by:  Georg Winterer (Disclosure)
Submitted 10 January 2011
Posted 10 January 2011

I fully agree with the comment made by Stephen Lawrie on the paper of the Meyer-Lindenberg group (Tost et al., 2010) published in Nature Neursocience. In particular, I agree with his suggestion that cellular fluid balance may account for the haloperidol neuroplasticity finding in the striatum. This is because it is well known among psychiatrists with some pharmacology training that haloperidol has an effect on fluid balance. Canary stories (to borrow Victoria Wilcox's metaphor) with retrospective analysis of seven (!!) healthy subjects and without prior hypothesis that would have helped to account for potentially confounding variables (e.g., body fluid, electrolyte parameters, hormonal levels, etc.) in the study design should not be published. What we need in schizophrenia research are high-flying eagles—not canaries in golden cages (high-impact journals).

References:

Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010 Aug; 13(8):920-2. Abstract

View all comments by Georg Winterer

Comments on Related News


Related News: Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

Comment by:  Jan Volavka
Submitted 2 April 2008
Posted 3 April 2008
  I recommend the Primary Papers

The EUFEST study found that haloperidol, in comparison with several SGAs, was associated with a higher rate of overall treatment discontinuation, a higher rate of discontinuation because of lack of efficacy, a higher rate of discontinuation because of side effects, and worse outcome on the CGI and the GAF. Surprisingly, the authors’ last sentence reads: “It cannot be concluded that SGAs are more efficacious than is haloperidol….” Although restraint in scientific conclusions is generally admirable, I think that these authors are being too conservative in the interpretation of their important findings.

The reason for their hesitancy, it appears, is that the PANSS and the rehospitalization rates have not shown significant differences among drugs. Furthermore, they are concerned about the possibility of provider expectation biasing the results against haloperidol: if the psychiatrists expected haloperidol to do poorly, perhaps they were more likely to discontinue it than another treatment in which they believed. But the lack of difference on the PANSS total can have many reasons. Subanalyses of PANSS factors and data on rater training effectiveness that may be published in secondary studies could shed some light on this. Rehospitalization rates would be expected to depend on the treatment the patients received after their participation in the study was terminated; this topic is also likely to be explored later.

Provider expectations are difficult to demonstrate. The authors polled the site coordinators, asking them whether they expected haloperidol to lead to the worst outcome, or whether the outcome would be similar to that with SGAs. The authors then tested the hypothesis that the sites where haloperidol was expected to do worse would have higher discontinuation rates with haloperidol than the other sites. They found a non-significant difference in the expected direction. It should be noted that the poll occurred after the end of data collection, and that the coordinators were not blinded to the treatment assignments. Therefore, the result of the poll could have reflected experience as well as expectation.

Is it possible that the differences between haloperidol and the SGAs on CGI and GAF (but not on the PANSS) were due to their greater vulnerability to bias of these two scales than the PANSS? There are two speculations here: one, that a bias existed in this study, and two, that the scales have inherent differences in their liability to rater bias. No empirical evidence supports either of these speculations.

In summary, the EUFEST study results, based on data from close to 500 patients collected by dozens of investigators, permit more definitive conclusions than the authors have drawn in their first paper. We are looking forward to follow-up articles by this outstanding group of investigators. Practicing psychiatrists will particularly appreciate a presentation of the clinical implications of this landmark study.

View all comments by Jan Volavka

Related News: Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

Comment by:  Peter F. Buckley
Submitted 11 April 2008
Posted 11 April 2008

This timely study, conducted by a stellar group of European investigators, adds to the continued debate about choice of medications for schizophrenia, informed by other similarly impressive pragmatic trials such as CATIE and CUTlass. Unlike the other recently published first-episode treatment study—the CAFE study (McEvoy et al., 2007)—which was double blind and compared SGAs only (risperidone versus olanzapine versus quetiapine), EUFEST better fits the model of a pragmatic trial and also included a FGA comparator. Although readers, particularly policy makers, will inevitably be drawn to the “Should I choose an FGA or SGA” content of this study, it seems to me that the most striking finding is (yet again) how frequently patients stop their medications. The 72 percent overall “All Cause” Discontinuation rate bears an uncanny resemblance to the 74 percent in CATIE and to the similar rate in the one-year CAFE first-episode study. Thus, medication non-adherence is a major treatment issue right from the onset of treatment. Set in that light, the differences observed in the study between agents are relatively modest. The data do not endorse the preferential “lead off” with any particular agent. Indeed, much like the discussion that followed the publication of the CATIE study, these data make the case for wide availability and choice of antipsychotic medications, rather than confining to a selective FGA first or X drug before trying Y among the SGAs. I agree with Dr Volavka's comment that subsequent analyses of these valuable data may bring additional insights to the surface.

References:

McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski SD. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007 Jul ;164(7):1050-60. Abstract

View all comments by Peter F. Buckley

Related News: Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

Comment by:  Leslie Citrome
Submitted 18 April 2008
Posted 19 April 2008
  I recommend the Primary Papers

Although in EUFEST, psychopathology improved to a similar extent among the different groups, durability of the medication was quite different. This is of the utmost importance when it comes to treating patients—no one would disagree that continuation on medication is crucial in the successful treatment of patients with schizophrenia. If my goal is to pick the antipsychotic that my first-episode patient will stick with the longest, olanzapine or amisulpride appears to be what the data recommend. The alternative is to prescribe something else and then switch if necessary. Curiously, amisulpride and olanzapine (and risperidone) appeared to perform better than haloperidol in the Davis meta-analysis published when EUFEST was being launched (Davis et al., 2003).

As an exercise in looking at EUFEST through the lens of evidence-based medicine, I calculated the number needed to treat (NNT) for all-cause discontinuation (Citrome, 2008). NNT yields statistically significant pair-wise advantages for olanzapine vs. haloperidol and quetiapine; amisulpride vs. haloperidol and quetiapine; and ziprasidone vs. haloperidol. The strongest effect sizes were olanzapine or amisulpride vs. haloperidol with an NNT of four, meaning for every four patients randomized to olanzapine or amisulpride instead of haloperidol, one additional patient on olanzapine or amisulpride completed the study on his or her initially assigned medication. Overall, the EUFEST NNT results for all-cause discontinuation are consistent with what has been observed in an NNT analysis of the CATIE data (Citrome et al., 2006).

References:

Citrome L: Interpreting and applying the EUFEST results using number needed to treat: antipsychotic effectiveness in first-episode schizophrenia. International Journal of Clinical Practice. 2008;62(5):837-840. Abstract

Citrome L, Stroup TS: Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians? International Journal of Clinical Practice. 2006;60(8):933-940. Abstract

Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003; 60: 553–64. Abstract

View all comments by Leslie Citrome

Related News: Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

Comment by:  Herbert Meltzer (Disclosure)
Submitted 29 April 2008
Posted 29 April 2008

EUFEST, CATIE, and CUtLASS: Should Atypical Antipsychotic Drugs Remain the Most Prescribed Treatment for Schizophrenia?
The EUFEST (Kahn et al., 2008) study is the third major effectiveness-style study published in the last three years whose goal has been to compare typical and atypical antipsychotic drugs in the treatment of specified subgroups of patients with schizophrenia, the others being CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006). The authors of EUFEST close their report with: “…it cannot be concluded that second-generation antipsychotic drugs are more efficacious than is haloperidol in the treatment of these (first-episode schizophrenia) patients” despite the fact that the discontinuation rate was the primary endpoint, and there was a significantly lower rate of discontinuation of the atypical drugs: 40 percent for amisulpride, 33 percent for olanzapine, 53 percent for quetiapine, and 45 percent for ziprasidone, vs. 72 percent for haloperidol; p <0.0001). However cautious this statement, it was still not acceptable to Robert Rosenheck (2008) who, in the accompanying Lancet commentary, states: ”There clearly seems to be much less, if any [my emphasis] ground for enthusiasm about these costly drugs now than in 2002, precisely because of the finding of large, independent double-blind trials, ” by which he refers to the CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006) studies. The EUFEST authors chose to downplay their primary outcome measure, which was robustly achieved, because rating scale changes were not significantly different between the atypical antipsychotic drugs and haloperidol and because CATIE and CUtLASS had reached similar conclusions with regard to more chronically ill patients.

As I will show, the disconnect between continuation with therapy and equivalence of changes in psychopathology confirmed what we had found more than a decade ago in a randomized, blinded, small N trial comparing clozapine and typical antipsychotic drugs in recent onset patients with schizophrenia who had a history of good response to typical antipsychotic drug treatment (Lee et al., 1994; 1999). The EUFEST articles ducked the more pressing question of which type of medication should be administered to first episode patients if, indeed, it cannot be concluded that one is more effective than another.

What in the “real world” is going on? Efficacy, effectiveness and hybrid studies
It is important to consider whether the EUFEST, CATIE, and CUtLASS studies should be considered hybrid rather than effectiveness studies, because these studies urge greater significance be paid to them than to efficacy studies. They are supposedly “real world,” while claiming efficacy studies are much less so, or not at all. As pointed out by Hogarty et al. (1997), studies such as EUFEST, CATIE, and CUtLASS are much closer to what is generally called a hybrid than a true effectiveness study, because of the elaborate and extensive research apparatus they employ, making it highly likely that usual clinical practice, patient behavior, and outcome were influenced by protocol design and execution, just as they are in efficacy studies. For example, the CATIE study design most certainly encouraged switching drugs within its large-scale Phase 1 component comparing perphenazine with atypical antipsychotics, and did so in a variety of ways (Meltzer and Bobo, 2006). In addition, the CATIE study design did the same in the treatment failure phase of the study by comparing unblinded clozapine with blinded comparators and using time to discontinuation as the primary endpoint. Unblinding clozapine clearly favored it since the small proportion of eligible patients who entered that phase of the study were mainly those who wanted to receive a trial of clozapine in the first place. (McEvoy et al., 2006). Kenneth Wells, a distinguished authority on the issue of effectiveness and hybrid studies concluded, and I concur: “We do not yet know whether the findings of such hybrid studies will be clinically and socially useful” (Wells, 1999). Until we do so, it would seem prudent to withstand the pressure to make the atypical antipsychotic drugs second line treatments, which has been the explicit message from some of the authors of CATIE and CUtLASS, if not EUFEST.

Clozapine and expectations for superiority of other atypical antipsychotic drugs
Consideration of the issue of whether atypical antipsychotic drugs have advantages over typical antipsychotic drugs, the driving force behind these three hybrid studies, can begin with a consideration of whether even clozapine has advantages with regard to efficacy and time to discontinuation over typical antipsychotic drugs. Though the typical and atypical antipsychotic drugs, e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole, are referred to in all three studies as first- and second-generation antipsychotic drugs, I prefer to refer to them as typical and atypical, as they were originally called, and as they are almost universally referred to by preclinical scientists. Labeling them as “first- and second-generation” drugs is inaccurate with regard to the time frame in which clozapine, the first of the atypical antipsychotic drugs, was initially discovered and developed (which was at the same time, or even prior to, many of the so-called first-generation drugs) and contrasts it mechanistically from the typical antipsychotic drugs.

Clozapine was labeled atypical shortly after its discovery by both preclinical and clinical investigators, solely because of its lack of extrapyramidal effects (EPS) in both laboratory animals and patients. This critical advantage is due to major differences in its pharmacology, one which is shared by all of the currently marketed atypical antipsychotic drugs developed since clozapine, with the exception of sulpiride and amisulpride. The critically important shared pharmacology of the clozapine-like atypical antipsychotic drugs—olanzapine, quetiapine, risperidone, and ziprasidone—is more potent blockade of serotonin (5-HT) 2A than dopamine (DA) D2 receptors, at optimal clinical doses (Meltzer et al.,1989; 2003). Aripiprazole substitutes partial D2 receptor agonism for relatively weaker D2 antagonism but retains the 5-HT2A antagonism common to the other atypical antipsychotics other than sulpiride and amisulpride. The so-called “fast-off” hypothesis of Kapur and Seeman (2000) to explain atypicality in antipsychotic drugs is valid only for clozapine itself and quetiapine, both of which have low affinities for the D2 receptor, but not for asenapine, olanzapine, risperidone, sertindole, and ziprasidone, which have high affinities for the D2 receptor. How important fast dissociation is for even clozapine and quetiapine is unknown.

The pharmacology of sulpiride and amisulpride, which had a decisive influence in the CUtLASS study and has never been differentiated to my knowledge, involves highly selective and potent D2 and D3 receptor blockade (Caley and Weber, 1995; Scatton et al., 1997; NIMH Psychopharmacology Drug Screening Program website), yet sulpiride was the most extensively prescribed (showing clinician insight?) of the “first-generation” drugs (49 percent of patients in that arm), while amisulpride accounted for 12 percent of the atypical drugs in the “second-generation arm” in the CUtLASS study. Both drugs, while not free of EPS, meet the definition for atypicality (Rao et al., 1981; Gerlach, 1991) and have been so identified in important meta-analyses (see Rummel et al., 2003; Leucht, 2004). Regardless of whether one believes them to be typical or atypical, it would have been prudent for the CUtLASS investigators to exclude both agents rather than risk compromising the study, as I believe they did. Their inclusion is sufficient by itself to invalidate CUtLASS in my opinion, but there were at least two other major problems that affect the validity of that study. Thus, significantly greater proportions of patients who had failed prior antipsychotic drug treatments were randomized to the atypical arm—to receive either 5-HT2A/D2 antagonists or amisulpride—than to the sulpiride plus typical antipsychotic drug arm, a major flaw which was not only not corrected for, but was not mentioned anywhere in the article to my knowledge. Next, the use of long-acting medications, with their potential for better compliance, was permitted in the patients in the typical antipsychotic arm, further biasing the results for that group of agents, while there was no use of long-acting risperidone in the atypical arm. Thus, three major biases, all favoring the typical agents, were operative in the CUtLASS study. The atypicals hardly had a chance to do well, competing against themselves, with more treatment-resistant patients assigned to that group, and utilizing only oral medications.

Clozapine, for more than a decade beginning in 1975, was rejected for all but research and compassionate need purposes, because it caused a higher rate of agranulocytosis than the typical antipsychotics. We now know this occurs approximately 30 times more frequently with clozapine (~7.5/1000 vs. 0.25/1000). The US Clozapine Multicenter Trial, of which I was an author, found that clozapine was more effective than chlorpromazine for poor-outcome, treatment-resistant patients with schizophrenia (Kane et al., 1988). The conclusions of that study have been supported by many other studies, including CATIE, CUtLASS, and a recent study of treatment-resistant first-episode patients (Agid et al., 2007). Subsequent studies from my laboratory and others showed additional benefits for clozapine over other antipsychotic drugs for cognition and suicide in non-treatment-resistant as well as treatment-resistant patients (Hagger et al., 1993; Meltzer and McGurk, 1999; Woodward et al., 2005; 2007; Meltzer and Okayli, 1995; Meltzer et al., 2003), as well as quality of life (Meltzer et al., 1993). These studies included the type of patients in the CATIE and CUtLASS study. The result of the body of research from many laboratories all over the world establishing clozapine as the “gold standard” for treating schizophrenia was that the bar was set very high for the inevitable attempts to develop drugs with the efficacy of clozapine, but without its spectrum of serious, sometimes fatal side effects, which discouraged many patients and clinicians from even trying it then and now. There are, today, no more than 60,000-90,000 of the two million patients with schizophrenia who are receiving clozapine in the U.S.

Atypical antipsychotic drugs with pharmacology similar to clozapine
Publication of the serotonin-dopamine ratio hypothesis (Meltzer et al., 1989) introduced a simple means to identify drugs other than clozapine which had a low EPS potential and facilitated the development not only of aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone, which are currently marketed, but also asenapine, iloperidone, laurasidone, perospirone, and sertindole (none of which are consistent with the “fast off” hypothesis), which are in advanced stages of development in the U.S., or already marketed in other countries. In addition, a host of other novel chemical structures with preclinical characteristics of atypical antipsychotic drugs consistent with the serotonin-dopamine ratio hypothesis have been reported on. The similarity of the pharmacologic profile of the marketed agents with that of clozapine may have contributed to the expectation that all drugs which had this pharmacologic profile would be superior to typical neuroleptics in all patients with schizophrenia (Lewis and Lieberman, 2008). The publication of a pivotal large, international study comparing risperidone with haloperidol and placebo, which did find some doses of risperidone to be superior to haloperidol, although only marginally so (Marder and Meibach,1994), was a likely contributor to this expectation. However, as pointed out by the authors in an accompanying editorial (Kane, 1994), it should have been noted that many of the patients in that study were possibly treatment-resistant. It is noteworthy that risperidone at a dose of 20 mg/day was one of the two risperidone doses that were reported to be more effective than haloperidol. This high dose might be expected to be more effective than haloperidol in treatment-resistant patients (see below).

The pivotal industry studies for quetiapine and ziprasidone did not claim superiority to haloperidol, except slightly greater benefits for negative symptoms, while those for olanzapine were mixed in this regard. The major pivotal study for olanzapine, as well as the overview of its pivotal trials, claimed no advantage of olanzapine over haloperidol for improvement in total psychopathology or positive symptoms (Beasley et al., 1996; Beasley et al., 1997). However, a multicenter trial conducted in countries outside the U.S. did find olanzapine superior to haloperidol (Tollefson et al., 1997). Geddes et al. (2000) provided the first meta-analysis comparing efficacy and tolerability of typical and atypical antipsychotic drugs and found no difference in efficacy between them, but fewer EPS with atypicals. Ironically, it was two academic-based meta-analytic reviews (Davis et al., 2003; Leucht et al., 2000), which concluded that the atypicals were superior to the typical agents in efficacy, that are frequently cited as the basis for the claim that the atypical agents are superior for the non-treatment-resistant patient. In a subsequent article, Davis et al. (2008) reported that the CATIE results were consistent with the Davis et al. (2003) meta-analysis in showing superiority for olanzapine, and that there was no evidence of industry bias of the studies they reviewed. Thus, CATIE and EUFEST are largely confirmatory of what industry and other studies had reported from the start: no difference in total psychopathology and positive symptom control between typical and atypical antipsychotic drugs other than clozapine. CATIE reported advantages for olanzapine, which we have suggested was due to the high dosage permitted for olanzapine and inclusion of a high proportion of treatment-resistant patients (Meltzer and Bobo, 2006), while CUtLASS reported trends for greater improvement in Quality of Life and symptom scores for their mixed typical/atypical antipsychotic-treated group, possibly for the reasons noted above. I suggest that it is possible to obtain further insight into the comparative efficacy of typical and atypical antipsychotic drugs by consideration of clozapine vs. typical antipsychotic drugs in non-treatment-resistant patients.

Is clozapine superior to typical antipsychotics in non-treatment-resistant patients?
The issue of whether clozapine itself is superior to the typical antipsychotic drugs, let alone whether the other atypical antipsychotic drugs are as well, for the non-treatment-resistant patients with schizophrenia, is one that has been explored and provides information relevant to the ongoing discussion about the merits of the two classes of drugs for treatment of the majority of patients with schizophrenia. In a trial with neuroleptic responsive patients, my colleagues and I found that clozapine had no advantages for psychopathology, compared to typical neuroleptic drugs, but that discontinuation from the treatment initially randomized to occurred significantly more frequently with the typical antipsychotic drugs ( Lee et al., 1994; 1999). (A more detailed report of the results of this study is in preparation because of its increased importance in light of some of the issues I address here). We reached this conclusion as the result of a study comparing clozapine and typical neuroleptic drugs in 85 patients with schizophrenia or schizoaffective disorder who were within a few years of the onset of psychotic symptoms, and who had been selected for being neuroleptic-responsive, These patients were randomly assigned to receive clozapine or typical neuroleptic drugs and evaluated over a two-year period. All ratings of psychopathology (baseline, 6 weeks, 3, 6, 12, and 24 months) were videotaped and rated by a single rater blind to treatment. The same, single but unblinded clinician treated all patients and made all decisions about drug continuation. Equivalent improvement in BPRS Total, Positive, or Negative symptoms, SANS and SAPS ratings CGI and Quality of Life measures was found. There were, however, significant differences in the number of dropouts. Of the 85 patients, nine (22.5 percent) assigned to clozapine and 19 (42.2 percent) to typical neuroleptics (χ2 = 3.73, p = .05) discontinued the typical antipsychotic drug treatment, for a variety of reasons. Significantly, two of the patients treated with typical neuroleptics developed tardive dyskinesia, and both were switched to clozapine, as were two patients who became resistant to typical neuroleptics during the course of treatment. There was no incentive for the patients, who were permitted to choose the typical agent they had had the best prior experience with, to discontinue the initially assigned typical neuroleptic, as the only other available treatment at the time was another typical antipsychotic drug.

The most important difference between clozapine and typical antipsychotic drugs in the Lee et al. study (Lee et al., 1994; 1999) was that treatment with clozapine improved some domains of cognition, particularly psychomotor speed and attention, as assessed by the Digit Symbol Substitution Test, and verbal fluency, as assessed by the Category Instance Generation and Controlled Word Association tests at six weeks, which was maintained throughout the one-year study. These improvements were not related to improvement in psychopathology or differences in EPS. We concluded that these results indicated that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in some recent onset, neuroleptic-responsive schizophrenia, but not with regard to improvement in psychopathology. Carpenter et al. (1995) also called attention to the lack of advantage of clozapine over typical neuroleptic drugs in non-treatment-resistant patients, citing additional published literature to support their conclusion. The EUFEST results with atypical antipsychotic drugs other than clozapine, in first-episode patients, are in agreement with the results of Lee et al. and support the conclusion that expectation of advantage for symptom change should not be the reason for using an atypical antipsychotic drug in first-episode and non-treatment resistant-patients. But there are other reasons for preferring the atypicals as first-line treatment.

Is clozapine uniquely effective in treatment-resistant patients?
So if the typical and atypical drugs do not differ in their ability to reduce overall psychopathology in non-treatment-resistant and first-episode patients, are there any reasons to use atypicals, given their greater cost and metabolic side effects, in some cases, as first-line treatment? The International Psychopharmacology Algorithm Project (IPAP), a group of international experts including Jeff Lieberman and Wolfgang Fleishhacker, principal authors of CATIE and EUFEST, respectively, a project which I chaired, concluded that atypicals should be first-line for non-treatment-resistant schizophrenia (see www.IPAP.org). Contrast this with Rosenheck (2008), whose list of possible uses of atypicals is limited to patients with tardive dyskinesia, akathisia, or pseudo-parkinsonism. Rosenheck et al. (2008) recommends that clozapine is first-line in treatment-resistant patients. But is it truly superior to the other serotonin-antagonists in this regard?

Recently, my colleagues and I reported that olanzapine is equivalent to clozapine in improving psychopathology and cognition for treatment-resistant schizophrenia, when the doses of both are comparable: i.e., two to four times the doses needed for non-treatment-resistant patients (Meltzer et al., 2008). (It is generally not appreciated that the average dose of clozapine used for treatment-resistant patients, 300-700 mg/day, is two to three times the dose needed for non-treatment-resistant patients, i.e., 100-300 mg/day). Treatment for up to six months was required for the majority of treatment-resistant patients to respond to olanzapine, mean dose 35 mg/day, or clozapine, mean dose 550 mg/day (Meltzer et al., 2008). This small N study, though consistent with many uncontrolled studies, and the results of CATIE, where olanzapine was used at doses as high as 30 mg/day, needs to be replicated and extended. The benefits of high doses and prolonged monotherapy of clozapine or olanzapine for treatment-resistant patients may also hold for other serotonin-dopamine antagonists that are direct-acting dopamine antagonists, including quetiapine (1200-2000 mg/day), risperidone (12-20 mg/day), and ziprasidone (>160-640 mg/day) (Pierre et al., 2005; Deutschmann and Deutschmann, 2007). It does not hold for high doses of typical antipsychotic drugs (Kane et al., 1988). The recent report that standard doses of aripiprazole, a partial agonist with 5-HT2A antagonist and 5-HT1A agonist properties, is effective in treatment-resistant schizophrenia (Kane et al., 2007) needs to be confirmed, and, if valid, examined as to mechanism.

Are there reasons to use atypical antipsychotic drugs in non-treatment-resistant patients as first-line treatment?
Tardive dyskinesia
The consensus has been that about 30 percent of patients with schizophrenia are treatment-resistant. Clearly, clozapine itself, or possibly high doses of an atypical agent related to clozapine, is the treatment of choice for such patients. Should they, at lower doses, also be the first-line treatment for the other 70 percent, or, should they be second-line treatments, as some of the CATIE (Rosenheck et al., 2008; Lewis and Lieberman, 2008) and CUtLASS (Jones et al., 2006) authors sometimes seem to suggest. Clearly, reducing the risk for tardive dyskinesia is an important reason, as advocated by Gardos (1999), with partial concurrence by Lieberman (2007). I do not agree with those who minimize this risk—most patients with schizophrenia need to take antipsychotic drugs on a lifetime basis. Those who advocate the typical drugs as the ethically appropriate first-line treatment realize they must minimize the risk of TD to argue for using these drugs routinely (Rosenheck, 2008; Rosenheck and Lieberman, 2007). At least 20 percent of neuroleptic-treated patients are afflicted with tardive dyskinesia, and roughly 4-5 percent are expected to develop tardive dyskinesia with each year of neuroleptic treatment (Kane et al., 1988). Margolese et al. (2005), in a recent comprehensive review of tardive dyskinesia, which took into account dosage issues, age, and sex as risk factors, concluded that there is significantly less risk of developing tardive dyskinesia with atypical antipsychotic drugs. While the metabolic side effects of some of the atypicals—olanzapine and clozapine, in particular—must be given every consideration, there are serotonin-dopamine antagonists, e.g., amisulpride, aripiprazole, risperidone, and ziprasidone, which have mild adverse effects that are in the same range as those produced by typical neuroleptic drugs. Olanzapine and clozapine can then be reserved for those patients who do not respond to the drugs with better metabolic profiles, until and if it is shown that these other atypical antipsychotics are effective and safe at higher doses in treatment-resistant patients.

Cognitive improvement
The second major reason for continuing to favor the atypicals as a class is that cognitive improvement is more likely with the atypical antipsychotics than the typical antipsychotics. This is not the place to argue this hotly debated point, which is supported by mean changes in cognition favoring the atypicals (Woodward et al., 2005; 2007). The cognition data from CATIE (Keefe et al., 2007) did not support advantages for the atypical agents, but there are many unusual features of that study, which is still undergoing intensive reexamination (Harvey P, personal communication). Imaging studies show better brain function during cognitive tasks and positive changes in brain grey and white matter in patients receiving atypical versus typical antipsychotic drugs (e.g., Surguladze et al., 2007). Additional studies of this kind are needed. There is already extensive and rapidly growing preclinical evidence which shows that the atypical, but not the typical, antipsychotic drugs can reverse cognitive dysfunction produced by chronic NMDA receptor antagonists, e.g., PCP and MK-801, in rodents (Grayson et al., 2007), a model of cognitive dysfunction in schizophrenia that has many supporters in the basic neuroscience community. This may be related to their ability to enhance dopamine and acetylcholine release in the cortex (Ichikawa et al, 2002, Kuroki et al., 1999). What is evident to those familiar with this literature is that if these highly replicated preclinical findings have no clinical relevance, than there is an enormous waste of effort ongoing in the many academic and industry laboratories worldwide which use these surrogate measures as the basis for developing new drugs to improve or further improve cognition in schizophrenia. There is, I believe, too great a readiness to dismiss the evidence in support of the cognitive advantages of the atypical over the typical antipsychotic drugs for a significant proportion of patients, advantages which lead to beneficial changes in function in some.

In summary, the EUFEST study provides additional evidence that typical and atypical antipsychotic drugs do not differ in their ability to improve psychopathology in non-treatment-resistant patients, something we have known for some time, in my view. The EUFEST study also adds to the evidence that despite this, patients may remain on treatment with atypical agents for longer periods than with typical antipsychotics, including first-episode patients who are more prone to stop medication than more chronic patients. However, the take-home message is not that these drugs should become second-line (risperidone, clozapine), third-line (aripiprazole, quetiapine, ziprasidone), or fourth-line (olanzapine) therapy because of their supposed lack of cost effectiveness, as advocated by Rosenheck (2008) and Rosenheck et al. (2008). Rather, I believe it is the need for further research about the differences between these classes of drugs with regard to cognition and effects upon brain structure and function, in better described and circumscribed populations, using the most rigorous kind of experimental design, and more complete acknowledgement of the typical antipsychotics' greater risk to cause tardive dyskinesia.

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www. IPAP.org; The International Psychopharmacology Algorithm Project

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Related News: Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

Comment by:  Erik JohnsenHugo A. Jorgensen
Submitted 12 May 2008
Posted 14 May 2008

In our recently published systematic review of randomized effectiveness trials on SGAs (Johnsen and Jorgensen, 2008), the main findings were that chronically ill patients treated with olanzapine had longer time until treatment discontinuation and/or better drug compliance compared to those treated with the other SGAs, as well as the FGAs in those studies that had an FGA arm. The SGAs and FGAs did not differ on efficacy measures, and there were surprisingly few differences among SGAs on tolerability outcomes. The most consistent tolerability difference among the SGAs was in the area of metabolic adverse effects, where olanzapine-treated patients had more weight gain and adverse influence on cholesterol and triglyceride levels. The most pronounced difference between FGAs and SGAs on tolerability outcomes was that the FGAs were associated with significantly more extrapyramidal side effects (EPS) or discontinuation owing to EPS in the majority of studies. We noticed that this finding was also replicated in the EUFEST.

In summary, we believe the evidence thus far indicates superiority for olanzapine on the effectiveness outcome of time to discontinuation in patients with chronic schizophrenia, but olanzapine-treated patients also have more weight gain and metabolic side effects, which means that this drug does not necessarily have the most beneficial ratio of numbers needed to treat (NNT) and numbers needed to harm (NNH). The FGAs have not demonstrated superiority over SGAs in effectiveness, efficacy, or tolerability measures, and are associated with more EPS in a majority of studies, indicating a less favorable NNT/NHH ratio compared to the SGAs on this outcome measure.

As a closing remark, we believe that due to very different pharmacological properties, results from studies with a single drug FGA arm cannot be inferred to the collected FGA group. In reality only haloperidol, fluphenazine, and perphenazine have been evaluated versus SGAs in the effectiveness studies thus far, and conclusions can only be drawn for these FGAs.

References:

Johnsen E, Jorgensen HA. Effectiveness of second generation antipsychotics: A systematic review of randomized trials. BMC Psychiatry. 2008 Apr 25;8(1):31. Abstract

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Related News: High Dopamine Levels in People With Evidence of Prodromal Schizophrenia

Comment by:  Anissa Abi-Dargham
Submitted 28 January 2009
Posted 28 January 2009

This paper introduces new knowledge and at the same time replicates many of the themes that have emerged in the area of dopamine research and schizophrenia. The new knowledge is that DA dysregulation precedes onset, and is present in the same anatomical area and with a similar magnitude to that observed in schizophrenia. It shows once again that the dopamine dysregulation in schizophrenia is one of the most replicated and consistent findings in the field.

The area of pathology within the striatum is, as described in schizophrenia, the associative, rather than the limbic or sensorimotor striatum (Kegeles et al., 2006). This represents the main area of projection of the DLPFC. Furthermore, this part of the striatum receives input from other limbic cortical areas (Haber et al., 2006) and may play a role in integrating emotions and cognition. Alterations in this integrative function could lead to misattributions or mislabelings leading to paranoia or “inappropriate” affect, in addition to the cognitive deficits.

The relationship to baseline psychotic symptoms, present for the prodrome but not detected in schizophrenia, as we have previously shown, too (Laruelle et al., 1999), is worth commenting on. It suggests that dopamine may play an essential role in the genesis of psychotic symptoms. This role may be most predominant early on in the disease, rather than later in the course of the illness. Later, symptoms may perpetuate for other reasons. Alternatively, it may be that their partial improvement due to treatment prior to the scan may make the relationship more difficult to detect, and that relationship would be detected if studies included only drug naïve patients. Either way, the relationship to severity of symptoms in the prodromal stage suggests that dopamine dysregulation may be an early part of the pathogenetic pathway, and not a subsequent consequence of other events. This is strengthened by the relationship to deficits on a verbal fluency task, suggesting again a general role for dopamine in the genesis of all symptom domains.

The next questions that emerge from these data are, How early in life is the DA alteration present and what are its effects on the developing brain and the relevant circuitry? As D2 overexpression in the striatum during development resulted in long-lasting alterations in cortical dopamine and cortical function in mice (Kellendonk et al., 2006), it may be that early alterations of D2 signaling within the associative striatum have effects on other targets within the associative striatum and along the whole integrated cortico-striato-thalamocortical circuit that become obvious only at onset. Identifying and halting this process early on are needed in order to prevent long-lasting deficits. In this regard, the paper does not present evidence that increased dopamine predicts conversion, which would be needed if one should propose a test of striatal dopamine for therapeutic intervention. For this to happen, large-scale imaging studies showing sensitivity and specificity of [18F]-DOPA as a biomarker for conversion are needed, similarly to studies conducted now in the field of Alzheimer disease using PET and tracers to label β amyloid.

References:

Kegeles L, Frankle W, Gil R, et al. Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs. J Nucl Med. 2006(47):139P.

Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J Neurosci. Aug 9 2006;26(32):8368-8376. Abstract

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46(1):56-72. Abstract

Kellendonk C, Simpson EH, Polan HJ, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. Feb 16 2006;49(4):603-615. Abstract

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