The D₂ receptor blockade hypothesis

Without exception, effective antipsychotic drugs have at least some degree of antagonism of the dopamine D₂ receptors. The observation that antipsychotic drug affinity for the D₂ receptor and the average daily dose required to control symptoms were directly correlated (Reference Peroutka and SnyderPeroutka & Snyder, 1980) led to confirmation that it was a major site of action of antipsychotic drugs (Reference Creese, Burt and SnyderCreese et al, 1976; Reference Seeman, Lee and Chau-WongSeeman et al, 1976; Reference Johnstone, Crow and FrithJohnstone et al, 1978). These findings rationalised clinical observation and practice at the time. Efforts to treat partially or poorly responsive patients revolved around ‘mega-dose’ antipsychotic therapy, although many contemporaneous papers questioned the usefulness of this approach (Reference Baldessarini, Katz and CottonBaldessarini et al, 1984; Reference Van Putten and MarderVan Putten & Marder, 1986). More D₂ receptor blockade was better, the theory went, and concomitant movement disorder (secondary to striatal D₂ receptor blockade) and hyperprolactinaemia (secondary to pituitary D₂ blockade) were an inevitable, if unfortunate, corollary of treatment.

Re-evaluation of the dopamine hypothesis of antipsychotic drug action

In the 1980s and 1990s the simple understanding that dopamine D₂ receptor blockade was linearly related to clinical response was reversed (as is so often the case in schizophrenia research) by powerful new research tools, which forced the re-evaluation of the role of D₂ receptors in antipsychotic drug action. These included receptor imaging in vivo with positron and single photon emission tomography (PET and SPET). One PET study showed that up to 12 different typical antipsychotic drugs had 65-85% occupancy at D₂ receptors in living patients (Reference Farde, Wiesel and NordstromFarde et al, 1989). Subsequent studies revealed that the degree of D₂ receptor occupancy was directly correlated with the dose (or plasma level) of traditional antipsychotic drugs; but did D₂ receptor occupancy also correlate with clinical benefit?

Chinks in the ‘dopamine hypothesis’ armour appeared with the clear demonstration that some patients taking therapeutic doses of typical antipsychotic drugs not only failed to benefit from the treatment, but also had levels of central D₂ receptor blockade in excess of 90% (Reference Wolkin, Barouche and WolfWolkin et al, 1989; Reference Pilowsky, Costa and EllPilowsky et al, 1993). This finding obviated pharmacokinetic explanations that poor clinical effect was the result of low brain penetration or increased wash-out of typical antipsychotic drugs in treatment-resistant individuals. Indeed, some patients who responded well to treatment showed remarkably low levels of D₂ receptor blockade (Reference Pilowsky, Costa and EllPilowsky et al, 1993). These data contributed greatly to the consensus that high-dosage antipsychotic treatment was, in the main, unhelpful in the treatment of poorly responsive schizophrenia (Reference ThompsonThompson, 1994). Finally, clozapine, a therapeutically superior antipsychotic drug without extrapyramidal side-effects (and modest affinity for D₂ receptors in vitro) had consistently low levels of D₂ receptor blockade (ranging from 20% to 60%) in association with excellent clinical response, even in patients previously poorly responsive to standard or high-dosage typical antipsychotic drug therapy (Reference Pilowsky, Costa and EllPilowsky et al, 1992).

This evidence prompted a careful reinterpretation of the importance of D₂ receptor blockade to therapeutic efficacy. Other receptor systems were probed as potential sites of antipsychotic drug action, and a call was made to abandon preconceived ideas of particular neurochemical profiles determining atypical drug activity until potential sites for drug discovery were better understood (Reference KerwinKerwin, 1994). Simple behavioural or clinical definitions of atypicality (low or no extrapyramidal symptoms or hyperprolactinaemia at therapeutically relevant doses) would preserve an open field for novel therapeutic targets. Most notable of these was the 5-hydroxytryptamine type 2 (5-HT₂) receptor subclass. Meltzer et al (Reference Meltzer, Matsubara and Lee1989) proposed, on the basis of drug affinity data, that the ratio of 5-HT_2A to D₂ receptor affinities was the major determinant of a drug's likelihood to behave as an atypical antipsychotic. Studies using PET and SPET found that many atypical antipsychotic drugs, including clozapine, olanzapine, risperidone and quetiapine, shared a strikingly high degree of 5-HT_2A receptor occupancy (> 90%) over their entire dose range (Reference Nordstrom, Farde and HalldinNordstrom et al, 1993a ; Reference Nyberg, Farde and ErikssonNyberg et al, 1993; Reference Travis, Busatto and PilowskyTravis et al, 1998; Reference Kapur, Zipursky and RemingtonKapur et al, 1999; Reference Jones, Travis and MulliganJones et al, 2001). This is unsurprising given that olanzapine, risperidone and quetiapine were developed on the basis of their high 5-HT_2A: D₂ receptor affinity profiles. It appears from the results of further studies (particularly the failure of pure 5-HT_2A antagonists to show striking therapeutic effects) that 5-HT_2A receptor occupancy alone is unlikely to be sufficient to determine clinical efficacy for antipsychotic drugs (Reference Kapur, Zipursky and RemingtonKapur et al, 1999).

The central primacy of dopamine to antipsychotic action

The notion that D₂ receptor occupancy was central to therapeutic response never really went away. Compounds that lack even modest activity at these sites are therapeutically inactive. Nordstrom et al (Reference Nordstrom, Farde and Weisel1993b ) and later Kapur et al (Reference Kapur, Zipursky and Jones2000a ) showed that symptom reduction and side-effect induction could be fitted to a threshold model of striatal D₂ receptor occupancy (at least in acutely relapsed patients and excluding excellent responders and treatment-resistant cases). In one study of 22 patients (5 women and 17 men) with first-episode schizophrenia, Kapur et al (Reference Kapur, Zipursky and Jones2000a ) demonstrated that striatal D₂ receptor occupancy values exceeding approximately 65% predicted clinical benefit, values exceeding 72% predicted hyperprolactinaemia, and values exceeding 78% predicted motor side-effects. For the clinician, maintaining patients within a therapeutic window of 7-15% D₂ receptor occupancy is not straightforward, especially when prescribing haloperidol, since doses as low as 2.5 mg of this drug result in a wide variation in striatal D₂/D₃ receptor occupancy (38-87%).

Furthermore, individual responses to similar degrees of D₂ receptor occupancy may vary, based on other as yet undefined pharmacogenetic characteristics and on the individual's underlying dopaminergic tone (Reference Laruelle, Abi-Dargham and Van-DyckLaruelle et al, 1996). It is pertinent to this point that hyperprolactinaemia occurred in 80% (4 out of 5) of the women and 24% (4 out of 17) of the men in the study by Kapur et al (Reference Kapur, Zipursky and Jones2000a ) despite similar levels of D₂ receptor occupancy. Melkersson et al (Reference Melkersson, Hulting and Rane2000) reported that in a group of patients receiving long-term typical antipsychotic therapy, the women developed symptomatic hyperprolactinaemia at half the chlorpromazine equivalent dose of that in men (approximately 250 mg chlorpromazine equivalents).

Dopamine transmission is abnormal in schizophrenia

Post-mortem studies of D₂ receptors in schizophrenia were crucial to the genesis of the dopamine hypothesis. Increased striatal D₂ receptor density was reported by some authors (Reference Lee and SeemanLee & Seeman, 1980; Reference Mackay, Iversen and RossorMackay et al, 1982), but these findings were questioned on the basis that the data were obtained by studying antipsychotic-treated patients. Classical antipsychotic therapy could, in itself, cause D₂ receptor upregulation (Reference Clow, Theodoru and JennerClow et al, 1980). Imaging studies using PET and SPET could control for this confound by studying never-treated people with schizophrenia. These studies did not, on the whole, support increased striatal D₂ receptor density in schizophrenia (Reference Farde, Wiesel and Stone-ElanderFarde et al, 1990; Reference Martinot, Peron-Magnan and HuretMartinot et al, 1990; Reference Pilowsky, Costa and EllPilowsky et al, 1994), although the possibility that endogenous dopamine concentration was abnormal (Reference Mackay, Iversen and RossorMackay et al, 1982; Reference ReynoldsReynolds, 1983) remained untested in vivo. Support for the central importance of dopaminergic antagonism in antipsychotic efficacy eventually came from [¹²³I]-iodobenzamide SPET data suggesting that dopamine transmission was indeed disrupted in schizophrenia. Using dynamic challenge paradigms, Laruelle et al (Reference Laruelle, Abi-Dargham and Van-Dyck1996) demonstrated an aberrant response in people with schizophrenia to a drug that elevated dopamine levels. Following administration of amphetamine, mean occupancy of striatal D₂ receptors by amphetamine-stimulated endogenous dopamine release was approximately doubled in the patient group compared with the control group. This effect was more striking in the more acutely ill patients, although findings in many patients overlapped with those in controls. These data, replicated using a different PET technique (Reference Breier, Su and SaundersBreier et al, 1997), provided concrete proof of disturbed dopamine control, at least in some people with schizophrenia. Drawing on these and other data, Moore et al (Reference Moore, West and Grace1999) have thoughtfully argued that overactive phasic dopamine transmission in limbic regions (including the amygdala and nucleus accumbens) could account for misinterpretation of innocuous external stimuli (resulting in delusions) and improper filtering of perceptions (causing hallucinations). Blockade of D₂ receptors in these regions would help control the positive symptoms of schizophrenia. In cortical (especially frontal and prefrontal cortical) regions, these authors propose that tonic dopamine transmission is relatively underactive, resulting in disrupted executive function, poverty of thought, speech and action, and low motivation. Antipsychotic occupancy of D₂ receptors in these regions would worsen these negative features. This attractively parsimonious model synthesises available data and meshes with the finding that atypical antipsychotic drugs (particularly clozapine and quetiapine) exhibit cortically selective D₂ receptor occupancy (primarily temporal cortex, including amygdala and hippocampus) at clinically useful doses in vivo (Reference Pilowsky, Mulligan and ActonPilowsky et al, 1997; Reference Lidow, Williams and Goldman-RakicLidow et al, 1998; Reference Meltzer, Park and KesslerMeltzer et al, 1999; Reference Stephenson, Bigliani and JonesStephenson et al, 2000; Reference Xiberas, Martinot and MalletXiberas et al, 2001). This effect is not seen for standard doses of typical antipsychotic drugs (Reference Bigliani, Mulligan and ActonBigliani et al, 1999). Importantly, drugs with modest affinity for D₂ receptors exhibit this effect robustly across their whole dose range, whereas atypical drugs with higher affinity for the D₂ receptor (e.g. risperidone) display dose-dependent limbic selectivity (Reference Xiberas, Martinot and MalletXiberas et al, 2001; Reference Bressan, Erlandsson and JonesBressan et al, 2003; Fig. 1).

Fig. 1

Preferentially high occupancy of dopamine D₂/D₃ receptors in the thalamus and temporal cortex by risperidone in a patient treated with risperidone (dose <4 mg) compared with a healthy volunteer (see Reference Bressan, Erlandsson and JonesBressan et al, 2003). (a, b) Normal volunteer: (a) striatum and thalamus, (b) temporal cortex and cerebellum. (c, d) Patient treated with risperidone: (c) striatum and thalamus, (d) temporal cortex and cerebellum.

These data could not be replicated by Talvik et al (Reference Talvik, Nordstrom and Nyberg2001), and full in vivo PET or SPET confirmation awaits further study. Nevertheless, regionally selective dopaminergic action of atypical antipsychotic drugs is supported by both electrophysiological and animal studies (Reference Lidow, Williams and Goldman-RakicLidow et al, 1998; Reference StrangeStrange, 2001).

How much D₂ blockade is too much?

The advent of antipsychotic drugs with very low affinity for dopamine D₂ receptors (most notably clozapine and quetiapine) begged the question whether D₂ receptor blockade was invariably required for antipsychotic efficacy. Imaging studies using PET reveal that striatal D₂ receptor occupancy by these drugs changes considerably over a 24 h period, even in steady state (Reference Gefvert, Bergstrom and LangstromGefvert et al, 1998; Reference Kapur, Zipursky and JonesKapur et al, 2000b ). Consideration of the D₂ receptor affinity and occupancy data relating to typical and atypical antipsychotic drugs led Kapur & Seeman (Reference Kapur and Seeman2001) to conclude that owing to low affinity for the D₂ receptor (driven, as these authors see it, by fast dissociation ‘off’ the receptor) clozapine and quetiapine exhibit transiently high D₂ receptor occupancy (not exceeding the threshold required to induce adverse movement or hormonal side-effects), which declines to very low levels over a 24 h period. This suggests that low-affinity drugs, with modest effects at D₂ receptors, may antagonise the system in a manner that preserves physiologically responsive endogenous dopamine transmission across a wide dose range (Reference Kapur, Zipursky and JonesKapur et al, 2000b ). The effect may presumably also be achieved by higher-affinity drugs that are cleared rapidly from the synapse, or given at doses producing low synaptic concentrations of the drug (Reference StrangeStrange, 2001). These data still do not explain the well-documented discrepancy between the rapid D₂ receptor blockade induced by antipsychotic drugs and the gradual remission of psychotic symptoms over several days or weeks. This delay could result from longer-term effects of antipsychotic drugs on brain plasticity, including (for example) synaptogenesis (Reference Konradi and HeckersKonradi & Heckers, 2001).