Partial Agonism and Schizophrenia Modest Success

BRITISH JOURNAL OF PSYCHIATRY (2005), 186, 7^10 EDITORIAL

Partial agonism and schizophrenia modest success. It is apparent, though, that all effective antipsychotics to date incorpo- rate D2 receptor antagonism in their A. A. BOLONNA and R. W. KERWIN mechanism of action; therefore, the current drug discovery process aims to identify drugs that primarily target the dopaminergic system with greater therapeutic efficacy (Kapur & Mamo, 2003). When considering the potential benefits of dopamine receptor partial agonists in the treatment of schizophrenia, two functional aspects of the dopaminergic system require consideration: Recent literature on partial agonists has intrinsic activity than full agonists. Partial the postulated reciprocal dysregulation of generated interest in their therapeutic agonists can elicit different receptor re- cortical and subcortical dopamine systems, potential in schizophrenia. This has been sponses depending on their environment: and the role of dopamine autoreceptors in driven, in part, by the recent approval of in the presence of agonists with higher schizophrenia. the dopamine (D2) receptor partial agonist intrinsic activity, partial agonists can aripiprazole in the USA and Europe. In demonstrate antagonist properties by comparison with conventional and atypical blocking access to the receptor, but on their DUAL PATHOLOGY antipsychotics that mediate their therapeu- own they will act as agonists (Fig. 1). tic effects by D2 receptor blockade, aripi- There are numerous reports of partial ago- The original dopamine hypothesis for prazole has a unique mechanism of action. nists that act at the D2 receptor; those of re- schizophrenia was based on the belief that However, the concept of partial agonists levance to the treatment of schizophrenia dopamine only innervated subcortical for the treatment of schizophrenia is not are discussed in detail below. regions, and that these regions were over- entirely novel, since aripiprazole is one of stimulated by excessive dopamine trans- several members of this class of drug. This mission (Seeman & Lee, 1975; Creese editorial reviews the neurochemistry of WHY IS A PARTIAL AGONIST et aletal, 1976). However, advances in bio- dopamine in schizophrenia and discusses OF THEORETICAL INTEREST chemical and behavioural techniques led the theoretical importance of partial agon- IN SCHIZOPHRENIA? to the identification of additional cortical ism as a mechanism for the treatment of dopamine projections (Thierry et aletal, 1973),1973) this illness. We also summarise the histori- The original dopamine hypothesis of which responded in an opposite way to sub- cal information on previous trials of partial schizophrenia proposed an excess of dopa- cortical dopamine systems: loss of frontal agonists in schizophrenia and evaluate minergic activity as the fundamental cortical dopamine function increased motor other dopamine receptor partial agonists neurochemical abnormality in the disorder activity, in direct contrast to the observa- that are currently under development. (Carlsson & Lindqvist, 1963). This was tions following stimulation of dopamine based in part on the observation that receptors in extrapyramidal or mesolimbic typical antipsychotics such as chlorproma- regions (Carter & Pycock, 1979). This WHAT IS A PARTIAL zine alleviated schizophrenia symptoms by seminal study and subsequent animal lesion AGONIST? antagonising D2 receptors. Hence, dopa- experiments showed an opposite and reci- mine receptor antagonists were considered procal regulation of cortical and subcortical Two fundamental properties of a drug the ideal therapeutic intervention in schizo- dopamine systems, leading the authors to determine its effect on a receptor: affinity, phrenia. In later years, the pharmacology of propose that the fundamental neurochem- the propensity of a drug to form a reversi- atypical antipsychotic agents such as cloza- ical lesion in schizophrenia involved a ble complex with its receptor, and efficacy pine and quetiapine led to a reassessment of deficit in frontal cortical dopamine and an (or intrinsic activity), the ability of a drug these assumptions; atypicals demonstrated increase in subcortical dopamine function to produce a functional response (Stephen- relatively low affinities for dopamine recep- (Pycock(Pycock et aletal, 1980,1980aa,,bb).). son, 1956; Ariens & Simonis, 1964). For tors, but were also effective in the treatment Following these early reports, neuro- a given receptor, a drug can produce a of schizophrenia (Pilowsky et aletal, 1992;,1992; imaging studies and neuropsychological maximal response (full agonist) or have KapurKapur et aletal, 2000). Atypical antipsychotics tests on people with schizophrenia demon- no functional effect (full antagonist). Full are superior to conventional antipsychotics strated impaired functioning of the frontal agonists are traditionally naturally occur- in the treatment of negative symptoms and lobe (hypofrontality) (Weinberger & Ber- ring compounds (e.g. dopamine) and full are less likely to cause extrapyramidal side- man, 1996), and a correlation with negative antagonists are chemical entities produced effects (Kerwin & Osborne, 2000), which symptoms (Andreasen et aletal, 1992) and by pharmaceutical chemists. In reality, the has been attributed to their targeting of reduced dopaminergic activity (Weinberger majority of chemically related drugs acting neurotransmitter systems other than dopa- et aletal, 1988; Egan et aletal, 2001). Furthermore, at a receptor produce a spectrum of mine, in particular the serotonergic system cortical D1 receptor levelsare reduced in functional responses that lie between full (Meltzer, 1999). Thus, the search for patients with schizophrenia (Abi Dhargam agonism and full antagonism (Ariens, relevant drug targets was broadened to & Moore, 2003). In contrast to the findings 1964). These drugs are termed ‘partial encompass other neurotransmitter recep- in the frontal lobe, amphetamine-induced agonists’ because they have a lower tors; however, this approach has met with excess release of dopamine in the striatum

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dysregulated dopamine release in schizophrenia (Grunder et aletal, 2003). However, it has been suggested that dopamine autoreceptor antagonists (sulpiride and amisul- pride) also stabilise dopamine systems in schizophrenia by increasing dopamine release and selectively blocking D2 and D3 receptors in the limbic system (Kerwin, 2000).

PARTIAL AGONISTS : OLD AND NEW

The concept of partial agonists in the correction of dysfunctional cortical and subcortical connectivity in schizophrenia dates back to the 1970s. Dopamine receptor partial agonists, by virtue of their unique mechanism of action, potentially represent a distinct class of atypical antipsychotics. All clinically effective antipsychotics mediate their therapeutic effects by blockade of D2 receptors; partial agonists are postulated to improve symptoms by stabilising dysregulated cortical and subcortical dopamine systems without generating Fig. 11Fig. Theoretical representation of receptor response to a full agonist and a partial agonist.This was initially the side-effects (movement disorders and demonstrated with muscarone-related compounds on isolatedrat jejunum (Ariens et aletal,1964).In the absence of hyperprolactinaemia) that are associated the full agonist, the partial agonist behaves as an agonist (squares), butbutproduces produces a lower maximal response than with non-specific D2 receptor blockade of the full agonist. At higher concentrations of the full agonist (triangles), the partial agonist acts as an antagonist. the nigrostriatal and tuberoinfundibular pathways (Richelson, 1999). One well-known partial agonist for thethetreatmenttreatment of schizophrenia was (77)-)- (subcortical region) of patients with schizo- and diminishing hyperactive dopamine 3-(3-hydroxyphenyl)-NN-n-propylpiperidine, phrenia compared with controls indicates a systems in subcortical regions. knownknownas (as(77)-3PPP or preclamol. This hyperactive subcortical dopamine system in compound targets D2-like receptor sub- schizophrenia (Breier et aletal, 1997). Overac- types and is selective for the dopamine tivity of the striatum was also associated AUTORECEP TORSTOR S autoreceptor (Clark et aletal, 1985; Chio etet with positive symptoms of schizophrenia alal, 1994). Placebo-controlled studies indi- (Breier(Breier et aletal, 1997).,1997). Dopamine autoreceptors may form an cated rapid improvements in positive and Thus, numerous studies on schizo- integral part of the therapeutic action of negative symptoms without the generation phrenia patients support the initial concept partial agonists in schizophrenia. Localised of motor side-effects (Lahti et aletal, 1998).,1998). of Pycock and colleagues and a subsequent to terminals and dendrites of dopaminer- However, this effect was not sustained revised dopamine hypothesis of schizo- gic neurons, dopamine autoreceptors (D2 beyond 1 week, possibly owing to desensiti- phrenia, which proposed that hyperactive and D3 receptors) exert a negative feed- sation of the dopamine autoreceptor. Other mesolimbic (subcortical) dopamine tracts back control on dopamine release and/ dopamine partial agonists that have under- contributed to the positive symptoms of or synthesis, subsequently reducing post- gone trials in schizophrenia include talipex- schizophrenia and underactive mesocortical synaptic activity (Elsworth & Roth, 1997). ole (B-HT 920), roxindole (EMD 49980) (cortical) dopamine pathways played a Dysregulation of neurotransmitter release and SDZ-HDC 912, but their effects on part in negative symptoms and cognitive by dopamine autoreceptors could contri- the symptoms of schizophrenia were, at impairment (Weinberger, 1987). This pos- bute to the postulated imbalance of corti- best, similar to conventional antipsychotics tulated imbalance of dopamine function cal and subcortical dopamine function in or not sustained at therapeutic doses (Oh- in frontal and subcortical regions may schizophrenia; for example, increased morimori et aletal, 1993; Wetzel et aletal, 1994). This bebeaa relevant therapeutic target in schizo- dopamine release due to the reduced variability in therapeutic effects may relate phrenia. Hence, a dopamine receptor activity of dopamine autoreceptors might to differences in the intrinsic activity of partial agonist (bearing in mind that partial be one source of hyperactivity in subcorti- each partial agonist at dopamine receptors agonism is a relative concept) could act cal systems. Thus, partial agonists that (Tamminga, 2002). However, two recent as a dopamine stabiliser by increasing display affinity for dopamine auto- dopamine receptor partial agonists (aripi- dopamine activity in the frontal cortex receptors are potential stabilisers of prazole and bifeprunox) are promising

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candidates for the treatment of a D2 antagonist (haloperidol), bifeprunox Bristol-Myers Squibb and Lundbeck, and schizophrenia (see below). decreases dopamine and 5-HT levels in has also acted as principal investigator for the rat nucleus accumbens (Lieberman, clinical trials of aripiprazole and sertindole 2004). Based on these observations, bife- (a Lundbeck product). Modern partial agonists prunox was classified as a partial agonist in the treatment of schizophrenia at D2 and 5-HT1A1A receptors. Bifeprunox REFERENCES AripiprazoleAripiprazole was also successful in reducing animal be- Aripiprazole (OPC-14597), a Bristol-Myers haviour associated with schizophrenia-like Abi Dhargam, A. & Moore, H. (2003) PrefrontalPrefrontal Squibb/Otsuka Pharmaceutical Co. Ltd symptoms and extrapyramidal side-effects. dopamine transmission at D1receptors and the pathology of schizophrenia. 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