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Keywords:

  • Antipsychotic drugs;
  • Dopamine receptors;
  • Positron emission tomography;
  • Schizophrenia

SUMMARY

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D2 dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [11C]-raclopride has been the most widely used for binding to the D2/D3-dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65–80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D2-occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.


Prologue

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

Over the last 50 years, antipsychotic drugs have been widely used to treat psychotic disorders such as schizophrenia. The drugs were discovered empirically, and initially the mechanism of action (MoA) was entirely unknown. In the mid 60s it was suggested that antipsychotic drugs work through blockade of dopamine receptors [1,2]. A few years later, the advent of radioligand binding techniques [3] and the availability of 3H-labeled radioligands allowed for direct studies of antipsychotic drug binding to neuroreceptors. For a series of antipsychotic drugs, a close correlation was subsequently demonstrated between affinity for dopamine receptors in vitro and antipsychotic potency in man [4,5]. The results provided strong support for the view that the antipsychotic effect is mediated by blockade of dopamine receptors.

The existence of two distinct dopamine receptors—the D1 and the D2 receptors—were later proposed on the basis of pharmacological observations [6]. It was soon demonstrated that antipsychotic drugs bind primarily to the D2 receptor subtype [7]. In addition, no correlation could be demonstrated between antipsychotic effect and markers for any other neurotransmission system [7].

Brain Imaging Methodology

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

With brain imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPET), it became possible to study receptor binding directly in the living human brain. Wagner and coworkers were pioneers in this field, when they in 1983 demonstrated that D2 dopamine receptors in the human brain could be visualized with [11C]-N-methylspiperone [8]. Following [11C]-N-methylspiperone, multiple new radioligands were developed for PET imaging of dopamine receptors. Among these, the selective D2 antagonist [11C]-raclopride, is the hitherto most commonly used [9,10].

The PET systems of the early 1980s had a resolution of 8–12 mm, and allowed for quantitative measurements of D2 receptor binding only in large brain regions such as the striatum [11]. The technology has since then been advanced and current high performance PET systems provide a resolution approaching 1.5 mm, which enables a more detailed mapping of the distribution of neuroreceptors in the human brain [12].

The development of iodine 123 ([123I])-labeled radioligands has allowed for detection of D2 receptors also by using single photon emission computed tomography (SPET). This imaging technique has the advantage of being widely available, and [123I]-labeled radioligands can be produced at one center and transferred across continents. Despite advancements of the technology, the spatial resolution of SPET does not reach the spatial resolution of current PET systems. The requirement to use heavy radionuclides such as [123I] or Technetium 99m ([m99Tc]) also limits the development of suitable radioligands. The following review is thus focused on the use of PET to determine occupancy in relation to antipsychotic drug treatment.

Mechanism of Action of Classical Antipsychotic Drugs

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

Shortly after the introduction of PET receptor imaging, several laboratories demonstrated high D2 receptor occupancy in single patients treated with antipsychotic drugs [13–16]. In an early study it was demonstrated that clinical treatment with any of 11 chemically distinct antipsychotic drugs resulted in 65–85% occupancy of D2 dopamine receptors [17]. This study provided direct in vivo evidence for the hypothesis that the antipsychotic effect is mediated by D2 dopamine receptor antagonism.

To corroborate the view that antipsychotic drugs act by occupying D2 receptors, the next challenge was to relate the degree of receptor binding to clinical drug effects. In an initial open study, it was observed that occupancy above 80% was associated with an increased risk of extrapyramidal syndromes (EPS) whereas occupancy above 70% was sufficient to obtain antipsychotic effect [18]. Based on these observations, an optimal therapeutic window corresponding to 70–80% occupancy was proposed (Figure 1). The observation of a therapeutic window has later been supported by double-blind studies [19,20].

image

Figure 1. Relationship between plasma concentration (arbitrary values) and D2 receptor occupancy with suggested thresholds for antipsychotic effect and extrapyramidal side effects (EPS)

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Whereas the >80% occupancy level for EPS has been rather consistently confirmed, a defined threshold for antipsychotic effect of classical antipsychotics seems to be more difficult to demonstrate. In a study of Kapur and coworkers, the threshold for antipsychotic effect was suggested to be 65% rather than 70%[19]. An indirect support for a threshold around 65–70% D2 occupancy is that recommended doses of more recently developed antipsychotic drugs correspond to this occupancy level [17,18,21,22]. However, a few antipsychotic drugs do not seem to fit the therapeutic window, which will be exemplified below.

The “Atypicality” Concept

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

The antipsychotic drug market was for many years dominated by classical antipsychotics, all known to cause EPS and serum prolactin elevations. Clozapine, introduced in the early 1970s, was the first atypical antipsychotic drug. Clozapine does not induce catalepsy in rodents and has a low propensity of causing EPS and serum prolactin elevations. In addition, clozapine has been shown to have effect also in patients not responding to classical antisychotic drugs [23], (for review see Ref. 24).

It was thus of interest to examine whether clozapine is “atypical” also with regard to the D2 occupancy induced during clinical treatment. Indeed, initial PET and SPECT studies showed that the D2 occupancy was below the 65–70% level suggested for classical antipsychotic drugs [18,25–27]. For instance, in a study including 17 patients treated with clozapine 125–600 mg/day, the D2 occupancy varied between 20% and 67%[25].

Following clozapine, a number of new antipsychotics were introduced on the market—all being discussed as “atypical.” Whereas the term “atypical” initially referred to antipsychotic drugs not inducing catalepsy in animals and not causing EPS and hyperprolactinemia, the “atypicality” concept has later been widened. Currently, there is no commonly accepted definition of atypicality, although most people seem to agree that a low risk of EPS and prolactin elevations is a common property of atypical compounds. As there is a lack of consensus regarding the atypicality concept, we will in this review entitle more recently introduced drugs as “second generation” antipsychotics.

Second Generation Antipsychotics

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

Whereas PET initially was used to understand the MoA of clinically available antipsychotic drugs, the method was subsequently applied to facilitate the development of new antipsychotic drugs [28,29].

The second generation drug risperidone was launched in 1994 [30]. For risperidone it was shown that daily dosing with 2–4 mg correspond to D2 occupancy between 70% and 80%[31]. For olanzapine, marketed in 1996 [30], the D2 occupancy of recommended doses (10–20 mg/day) was also within the suggested therapeutic window [32,33].

Ziprasidone was introduced in 2001 [34]. While the recommended dose range initially was 40–200 mg/day, it has later been suggested that a dose between 120 and 160 mg is optimal for clinical treatment [35]. The difference in bioavailability when ziprasidone is administered with a meal or in fasting conditions has been put forward as a reason for difficulties in defining an optimal dose interval [35]. The few studies made on ziprasidone and D2 occupancy indicate that also ziprasidone is clinically effective at D2 occupancy covering the suggested therapeutic interval [36,37].

Quetiapine was approved in 1997 [30]. Interestingly, quetiapine has been shown to induce D2 occupancy below the therapeutic window when administered in recommended doses [38–40]. As for clozapine, it is possible that the low D2 occupancy can explain the low risk of EPS during quetiapine treatment [41]. However, quetiapine has a short half life and only transiently high plasma concentration [42]. It can thus not be excluded that maximal D2 occupancy during quetiapine treatment has been underestimated [43,44].

In contrast, the D2 occupancy during treatment with aripiprazole in clinical doses exceeds the proposed therapeutic window [45–47]. In control subjects, no EPS were reported or observed despite D2 occupancy as high as 95%[48]. This finding is supported by the low incidence of EPS reported in clinical trials with aripiprazole [49]. The low risk of EPS despite high D2 occupancy can be explained by the pharmacological properties of aripirazole. While other clinically used antipsychotics are antagonists at the D2 receptor, aripiprazole is a partial agonist. Thus, the high D2 occupancy is at a functional level compensated for by a modest intrinsic activity at the D2 receptor [48].

Occupancy at Other Dopamine Receptor Subtypes

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

Although many attempts have been made to explain clozapine's superior antipsychotic effect, the MoA is still poorly understood. One hypothesis is that other receptors than the D2 receptor are important for the antipsychotic effect (for review see Ref. 50).

Though the D2 dopamine receptor subtype is the most widely examined, also other subtypes have been implicated in the pathophysiology and treatment of schizophrenia. Depending on coupling to second messenger system, the subtypes are divided in two families, with D1 and D5 belonging to the D1 family and D2, D3, and D4 belonging to the D2 family. A limitation with currently used radioligands is that receptors within the same family cannot be selectively examined. Thus, when measuring D2 receptors also D3 receptors are included and when measuring D1 receptors also D5 receptors are labeled. Radioligands used for measurements of the same family of dopamine receptors can also differ in their specificity for the subtypes of receptors. For example, [11C]-raclopride binds to D2 and D3 receptors whereas [11C]-N-methylspiperone also binds to D4 receptors [51].

In vitro studies have shown that most antipsychotic drugs bind to both D2 and D3 receptors. All antipsychotic drugs developed so far have about the same affinity for the D2 and D3 receptor subtype [52,53]. This represents a fundamental challenge to the present understanding of antipsychotic drug action, since it cannot be firmly established whether the antipsychotic effect is mediated by D2 or D3 antagonism. The dopamine agonist [11C]-PHNO is the only PET radioligand developed so far that may bind preferentially to the D3 receptor [54,55]. [11C]-PHNO has together with [11C]raclopride recently been used to estimate the D3 occupancy of clozapine, risperidone, and olanzapine in patients with schizophrenia. Despite high D2-occupancy no occupancy at the D3 receptor could be demonstrated, though these antipsychotics have high D3-affinity in vitro[56]. The validity of using [11C]-PHNO to examine D3-receptor binding has been corroborated further in a recent study showing a dose-dependent effect of the D3-antagonist GSK598809 in brain regions known to contain D3 receptors [57]. However, despite this progress, the field would benefit from new radioligands being highly selective for the D2 and D3 receptor, respectively.

The D4 dopamine receptor has also been suggested as a receptor potentially mediating antipsychotic effect and antagonism at this receptor has been suggested to account for the unique effect of clozapine. Most other antipsychotic drugs have similar or lower affinity for the D4 receptor when compared to the affinity for D2/D3, whereas clozapine has higher affinity for D4 than for D2/D3[58]. As suitable D4 receptor radioligands has not yet been developed, drug occupancy at the D4 receptor has not been examined in vivo by PET.

Several radioligands have been developed for the D1 dopamine receptor family. Even though occupancy at this receptor has not been related to antipsychotic effect, it has been suggested that the comparatively high D1 occupancy by clozapine could contribute to the atypical properties [18,25,27,59].

Nondopaminergic receptors have also been proposed to have relevance for the therapeutic effect of antipsychotic drugs. Among several receptors nominated, the serotonergic 5-HT2A receptor has been given particular attention (for review see Ref. 60). However, despite extensive research it has not been possible to conclusively demonstrate antipsychotic effect through mechanisms beyond dopaminergic neurotransmission.

Occupancy by Time

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

The relationship between plasma concentration and D2 occupancy can be described by a curvilinear (hyperbolic) function (Figure 1). At high occupancy levels, approaching saturation, a substantial decrease in plasma concentration is required to significantly reduce the occupancy. At lower occupancy levels, where the occupancy-plasma concentration curve is steeper, even a smaller change in plasma concentration will translate to a change in occupancy.

The drug plasma concentration required to occupy 50% of available receptors corresponds to the affinity constant, Kiplasma (the apparent inhibition constant). The Kiplasma for a drug can be obtained by definition of the hyperbola, based on a series of PET measurements of dopamine occupancy at different plasma concentrations. Once the Kiplasma is received, it is possible to estimate the time curve for occupancy corresponding to any arbitrary plasma concentration curve of the drug. Ideally, the free (not protein bound) plasma concentration should be used for this purpose. For a freely diffusible drug, the free plasma concentration should correspond to the free concentration in brain, with exception for drugs having affinity for transport proteins such as PGP (for review see Ref. 61).

An important question is if high D2 occupancy needs to be maintained during a certain time for a drug to mediate antipsychotic effect. In initial studies after oral administration of classical antipsychotics, high D2 occupancy has been shown to be maintained throughout the dose interval [17,62,63]. Several second generation drugs have also been shown to maintain D2 occupancy at a rather stable level throughout the dose interval [64]. However, during maintenance treatment with haloperidol in depot formulation it has been shown that relapse can be prevented even though the D2 occupancy was moderate (52%, mean n= 8) in the end of the 4-week dose interval [65]. Comparable results have been achieved in a study with risperidon in depot formulation, where the dose interval was prolonged to 4 weeks instead of the recommended 2 weeks. Most of the patients had D2 occupancy lower than the suggested therapeutic level at the end of the dose interval, but did not relapse [66]. However, a fundamental question is if the same time course of occupancy is required to prevent relapse as to treat acute psychosis.

An interesting observation is that the D2 occupancy obtained at clinical dosing with quetiapine is only transiently high, and reaches low or undetectable levels at the end of the dose interval [38,40,43,44]. The authors proposed that high D2 occupancy may not need to be maintained throughout the dose interval for the treatment of acute psychosis.

Striatal/Extrastriatal Regions

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

An early challenge in schizophrenia research has been to identify specific brain regions or neurocircuits of importance for the pathophysiology. With regard to the MoA of antipsychotic drugs it is of interest to understand if interference with dopaminergic neurotransmission in specific brain regions account for the antipsychotic effect. Besides the striatum, a region receiving dense dopaminergic innervation, limbic and cortical brain regions has attracted particular attention.

A considerable literature on striatal versus extrastriatal antipsychotic drug binding is based on experimental pharmacological findings in the 1970s and 1980s. From behavioral studies in rodents it was suggested that second generation antipsychotics may occupy extrastriatal D2 receptors to a greater extent than striatal D2 receptors [67,68]. In addition, the immediate early gene (IEG) c-Fos and its protein product Fos have been used as markers of neuronal activation. Both classical antipsychotics and clozapine increase Fos expression in the shell compartment of nucleus accumbens (part of the limbic system), whereas only classical antipsychotic drugs increase the expression of Fos in the dorsolateral striatum (related to EPS) [69].

Thus, already in the early days of PET research, there was an interest to examine low density receptor populations in extrastriatal brain regions. The commonly used radioligand [11C]-raclopride provides a good signal for D2 receptors in high density areas such as striatum [70]. However, the affinity is not high enough for imaging of areas with lower densities of D2 receptors. A series of radioligands having high affinity for the D2 receptor have therefore been developed. Of such radioligands [11C]-FLB 457 [71] and [18F]-fallypride [72] are the most widely used. In SPET research, the radioligand [123I]-epidepride is used for the same purpose [73,74].

In studies comparing D2 occupancy in different brain regions with classical antipsychotics (mainly haloperidol), no significant differences between striatal and extrastriatal occupancy have been found [75–79].

For second generation antipsychotic drugs, the results have been discrepant. Most studies on clozapine have shown a higher D2 occupancy in extrastriatal regions [77,80–82](Figure 2), but the observations have been questioned on methodological grounds, since the measurements may have been made at preequilibrium conditions [83,84].

image

Figure 2. Parasagittal brain sections through the thalamic level showing [11C]FLB457 binding in a control subject (above) a patient treated with clozapine 250 mg/day (middle) and a patient treated with haloperidol 3 mg/day (below) (Talvik et al., 2001) [79]

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Studies with other second generation antipsychotics have also produced incongruent results. In studies using individual baseline levels to calculate occupancy, no difference in striatal compared to extrastriatal regions has been reported for risperidone and olanzapine [75,85–87]. As these studies were small, limited to only two antipsychotic drugs and in some cases included healthy controls, further studies with second generation drugs are needed to finally establish if some of them bind preferentially in extrastriatal regions or not.

The D2 receptor was first cloned in rats [88] and soon thereafter also in humans [89–91]. It was discovered that the human D2 receptor DNA was coding for two different mRNAs, generated by alternative splicing [90]. The products of these two mRNAs are a short and a long isoform of the D2 receptor (D2S and D2L), differing by a sequence of 29 amino acids [92,93]. D2S has been suggested to be primarily presynaptic whereas D2L is primarily postsynaptic [93]. However, pharmacological characterization in vitro has shown that antipsychotic drugs have similar affinity for the two isoforms [94]. The two splice variants are thus not expected to provide a condition for regional differences in D2 occupancy.

Methodological Considerations

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

The present review includes a large number of PET studies on D2 occupancy. It may appear tempting to make attempts at a “meta-analysis” by pooling data from several studies. Caution must however be exercised before making such attempts. D2 dopamine receptor density varies several fold between individuals [95]. Some studies have controlled for such interindividual differences by using individual baseline data at untreated conditions, whereas other studies have used a baseline reference value obtained from other subjects. Another variable between studies is the time between last dosing and PET. Here, the availability of plasma concentration values at time of PET is a prerequisite for comparisons. There are also considerable differences at a technical level. The referenced literature originates from studies carried out with several different PET-systems with widely different performance [12] as well as different radioligands though [11C]raclopride has been used in most PET studies. In conclusion, a “meta-analysis” approach should ideally be limited to studies with [11C]raclopride, performed with PET-systems of similar performance, and where individual baseline binding data are available as well as drug plasma concentrations at time of PET [22].

Epilogue

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References

The clinically most important contribution from PET-studies on D2 occupancy in antipsychotic drug treated patients is probably the identification of a 70% (65) to 80% window useful for development of dose recommendations for optimal treatment. This finding has contributed to the use of considerably lower dose-regimes that alleviates patients from unnecessary side effects. A fundamental question in the treatment of acute psychosis is if high D2 occupancy has to be maintained throughout the dose interval or if intermittently high occupancy is sufficient. For future research on the pathophysiology and treatment of schizophrenia, the field would benefit from radioligands binding selectively to any of the five dopamine receptor subtypes and in particular D2 and D3 selective radioligands.

Conflict of Interest

The authors have no conflict of interest.

References

  1. Top of page
  2. SUMMARY
  3. Prologue
  4. Brain Imaging Methodology
  5. Mechanism of Action of Classical Antipsychotic Drugs
  6. The “Atypicality” Concept
  7. Second Generation Antipsychotics
  8. Occupancy at Other Dopamine Receptor Subtypes
  9. Occupancy by Time
  10. Striatal/Extrastriatal Regions
  11. Methodological Considerations
  12. Epilogue
  13. References
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