Schizophrenia, Dopamine Receptors, and Neuroleptics

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

The highly complex and heterogenous disorder of schizophrenia is characterized by a diversity of symptoms that cannot realistically be ascribed to a unitary, discrete neuroanatomical or neurochemical lesion: positive (delusions, hallucinations, etc.), negative (alogia, flattened affect, social withdrawal), and cognitive-attentional (sensory-gating, working, and verbal memory, etc.). Correspondingly, any one single mechanism of drug action is unlikely to correct this panoply of symptoms in the absence of disruptive side effects.

Conventionally, schizophrenia has been treated with neuroleptics, such as haloperidol, which interact preferentially with dopaminergic systems. Reflecting the involvement of hyperactive (or hyper-reactive) mesolimbic dopaminergic pathways, blockade of limbic D₂ receptors improves positive symptoms (Brunello et al., 1995; Kapur et al., 2000). However, a significant population of resistant patients remains refractory to treatment, while concomitant antagonism of normosensitive, striatal D₂ receptors elicits extrapyramidal motor side effects. Furthermore, negative and cognitive symptoms are little improved, probably because they reflect, at least partially, diminished function of mesocortical dopaminergic projections (Knable and Weinberger, 1997).

There are several strategies through which novel agents interacting principally with dopaminergic mechanisms might offer an improved antipsychotic profile: 1) low affinity, rapidly dissociating and/or "neutral" D₂ receptor antagonists which, in contrast to potent and slowly dissociating "inverse agonists", such as haloperidol, may less markedly and durably perturb basal dopaminergic activity (Seeman and Tallerico, 1999; Kapur et al., 2000); 2) partial D₂/D₃ receptor agonists permitting dual presynaptic (via autoreceptors) and postsynaptic attenuation of mesolimbic dopaminergic transmission (Lahti et al., 1998); 3) preferential antagonists at D₃ versus D₂ receptorsno currently employed antipsychotic agent distinguishes these sites (Brunello et al., 1995); and 4) regarding cognitive deficits, selective D₄ receptor antagonists or D₁ receptor agonists (Friedman et al., 1999).

Nonetheless, recent years have seen increasing commitment to the concept that nondopaminergic mechanisms play a crucial role in the pathogenesis and, potentially, improved treatment of schizophrenia (Brunello et al., 1995; Roth and Meltzer, 1995). One major factor underpinning this conviction is the atypical dibenzodiazepine, clozapine.

	Clozapine: A Multireceptorial, Monoaminergic, Atypical Antipsychotic

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

Clozapine is active in many patients that are not responsive to neuroleptics and exerts antipsychotic activity in the virtual absence of an extrapyramidal motor syndrome (atypical profile). Furthermore, it moderates negative and cognitive symptoms in a subpopulation of patients and, generally, stabilizes mood (Brunello et al., 1995; Meltzer et al., 1999). Clozapine is not, however, an ideal agent because its use is associated (in a small minority of patients) with serious hemotoxicity, while its blockade of muscarinic and histaminergic receptors provokes marked cardiovascular-autonomic side effects (Cunningham-Owens, 1996).

The significance of antagonist properties of clozapine at mesolimbic D₂ receptors in the control of positive symptoms should not be neglected. In fact, at clinically relevant doses, clozapine may elicit lower (and, perhaps, more transient) D₂ receptor occupation than haloperidol (Seeman and Tallerico, 1999; Kapur et al., 2000), but such observations fail to provide a satisfactory explanation for the unique clinical profile of clozapine, which cannot as yet be attributed to a single receptorial mechanism. Indeed, clozapine interacts with a broad array of dopaminergic, serotonergic (and adrenergic) receptors, and this global receptorial profile may account for its distinctive pattern of clinical activity (Fig. 1) (Brunello et al., 1995; Millan et al., 1998a). Within this multireceptorial framework, the relatively pronounced interaction of clozapine at specific receptor types relative to its modest antagonist properties at D₂ receptor actions may be the key to its improved functional profile.

View larger version (14K): [in this window] [in a new window]   Fig. 1.   Radar representations of the binding profile of clozapine compared with haloperidol at multiple dopaminergic and serotonergic receptors. All data were generated in the author's laboratory at cloned human (h) receptors, cloned rat (r) (5-HT6 and 5-HT7), and cloned mice (m) (5-HT3) receptors. Note the broad-based and "equilibrated" interaction of clozapine at diverse dopaminergic and serotonergic sites, whereas haloperidol shows pronounced affinity for hD2 (hD3 and hD4) receptors versus modest or weak affinity at other sites.

In accordance with this concept, while retaining significant antagonist properties at D₂ receptors, the incorporation of additional components of activity may permit optimization of beneficial versus deleterious properties. In this regard, serotonergic mechanisms have attracted particular interest, not in the least because the fifteen 5-HT types identified to date offer a broad palette of potential targets for novel, antipsychotic agents (Roth and Meltzer, 1995).

	Serotonergic Mechanisms in the Treatment of Schizophrenia

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

Of this plethora of receptors, 5-HT₃, 5-HT₆, and 5-HT₇ subtypes have all been advocated as involved in the innovative mechanism of action of clozapine. However, data are limited and the arguments are not overly compelling (Brunello et al., 1995; Roth and Meltzer, 1995). On the other hand, hallucinogens stimulate 5-HT_2A receptors, and the relatively pronounced antagonist activity at 5-HT_2A versus D₂ receptors of clozapine and certain other antipsychotics may improve their therapeutic window concerning separation of antipsychotic from extrapyramidal side effects (Roth and Meltzer, 1995). Moreover, blockade of mesolimbic 5-HT_2A receptors by clozapine underlies its potent antagonism of the effects of phencyclidine, an agent unique in reproducing both positive and negative symptoms of schizophrenia in normal subjects (Millan et al., 1999). More recently, attention has focused on closely related 5-HT_2C receptors, which antipsychotics generally fail to discriminate from their 5-HT_2A counterparts (Brunello et al., 1995). Although it has been suggested that 5-HT_2C receptor blockade might compromise the benefits of 5-HT_2A receptor antagonism (Ichikawa and Meltzer, 1999), this contention underplays the prominent 5-HT_2C receptor antagonist properties of clozapine. Moreover, selective blockade of 5-HT_2C receptors reinforces frontocortical dopaminergic transmission, attenuates the extrapyramidal versus antipsychotic actions of haloperidol, and exerts anxiolytic properties, observations suggestive of a favorable influence in psychotic patients (Millan et al., 1998b, 2000; Reavill et al., 1999).

Irrespective of their relative importance, 5-HT_2A and 5-HT_2C receptors display functional interactions with 5-HT_1A receptors. For example, 5-HT_2A antagonists modify the influence of 5-HT_1A agonists upon dopaminergic transmission (Ichikawa and Meltzer, 1999) while 5-HT_1A agonists attenuate 5-HT_2A and 5-HT_2C receptor-mediated actions of hallucinogens (Schreiber et al., 1995). These findings raise the possibility that 5-HT_1A receptors may likewise be implicated in the pathogenesis and treatment of schizophrenia.

	5-HT1A Receptors: Neuronal Localization and Organization

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

5-HT_1A receptors are localized dendritically as inhibitory autoreceptors on serotonergic cell bodies of the median raphe nucleus (MRN), which predominantly innervates the dorsal hippocampus, septum and hypothalamus, and the dorsal raphe nucleus (DRN), which provides a major input to frontal cortex (FCX), ventral hippocampus, and striatum (Barnes and Sharp, 1999). In addition, postsynaptic 5-HT_1A sites are enriched in the FCX, hippocampus, and other corticolimbic structures implicated in the etiology of schizophrenia and in the actions of antipsychotic agents. In line with this organization, both pre- and postsynaptic 5-HT_1A receptors fulfill an important role in the modulation of mood, cognition, and motor behavior (Barnes and Sharp, 1999), functions perturbed in schizophrenic patients and profoundly affected by antipsychotic agents.

It is important to underline the greater sensitivity of 5-HT_1A autoreceptors compared with their postsynaptic counterparts (Barnes and Sharp, 1999). Correspondingly, certain drugs of intermediate efficacy simultaneously activate and antagonize dendritic and postsynaptic 5-HT_1A receptors, respectively (Fig. 2). As exemplified in the ensuing discussion, such partial agonist properties appear appropriate to the improved control of schizophrenia.

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Schematic representation of a serotonergic neuron summarizing the potential importance of actions at pre- and postsynaptic 5-HT1A receptors in the management of schizophrenia. Full agonists (such as 5-HT) stimulate both pre- and postsynaptic populations of 5-HT1A receptor, pure antagonists (such as WAY100,635) block both, whereas drugs of intermediate efficacy (such as clozapine) preferentially activate 5-HT1A autoreceptors while blocking their postsynaptic counterparts. As detailed in the text, engagement of 5-HT1A autoreceptors activates frontocortical dopaminergic and adrenergic pathways by suppressing their tonic inhibition by 5-HT2C sites. Reduction of activity at 5-HT2C sites is also involved in their anxiolytic properties. Blockade of postsynaptic 5-HT1A receptors may impart complementary anxiolytic properties and, in analogy to stimulation of 5-HT1A autoreceptors, facilitate cortical and hippocampal glutamatergic and, possibly, cholinergic activity. The reinforcement in frontocortical catecholamine release may counter negative symptoms (hypofrontality) and this action, together with the harnessing of glutamatergic and cholinergic transmission, likely improves cognition. The use of agonist properties at 5-HT1A autoreceptors in suppressing extrapyramidal motor effects of D2 receptor blockade is not illustrated since the underlying neuronal mechanisms remain unclear.

Three principal lines of evidence implicate 5-HT_1A receptors in the pathogenesis and management of schizophrenia: first, alterations in levels of 5-HT_1A receptors in schizophrenia; second, functional actions of selective ligands at 5-HT_1A receptors; and third, partial agonist properties of clozapine at 5-HT_1A receptors.

	Alterations of 5-HT1A Receptor Density in Schizophrenia: Neurodevelopmental Aspects

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

Studies of schizophrenic brain have identified a reproducible elevation in 5-HT_1A receptor density in FCX (Burnet et al., 1996, 1997; Gurevich and Joyce, 1997). This increase is independent of the radioligand and is not an effect of medication. Furthermore, it is specific to schizophrenia because depressed patients revealed a diminution in 5-HT_1A sites in a positron emission tomography (PET) study (Sargent et al., 2000), a technique that could instructively be applied to characterize 5-HT_1A receptors in the precocious phase of schizophrenia. The mechanism underlying the increase in 5-HT_1A receptor density remains uncertain but, because 5-HT_2A sites are decreased in parallel (Roth and Meltzer, 1995; Burnet et al., 1996), it is unlikely to reflect up-regulation due to deficient serotonergic transmission. In line with this assertion, no consistent alteration in extracellular levels of 5-HT has been documented in schizophrenics (Roth and Meltzer, 1995). Furthermore, levels of mRNA encoding 5-HT_1A receptors are not modified (Burnet et al., 1996), implying that post-transcriptional processes are involved. Challenge studies with the 5-HT_1A agonist, ipsapirone, revealed no marked change in 5-HT_1A receptor sensitivity in schizophrenicsalthough it is debatable to what extent endocrine parameters provide insights into the functional state of cortical 5-HT_1A receptors (Roth and Meltzer, 1995; Ichikawa and Meltzer, 1999). The pathophysiological significance of the increase in 5-HT_1A receptor density in schizophrenia, and its relationship to hypofrontality, remains, thus, to be elucidated. Furthermore, it needs to be established whether all schizophrenic patients, or only certain subpopulations, show elevations in frontocortical levels of 5-HT_1A receptors.

Interestingly, the alteration in frontocortical 5-HT_1A receptors is largely restricted to superficial laminae and likely includes a subpopulation localized on glutamatergic cortico-cortical neurones implicated in cognitive processes and possibly disrupted in schizophrenic patients (Francis et al., 1993; Burnet et al., 1996, 1997; see below). A comparable increase in 5-HT_1A sites has been detected in orbital and temporal cortex, hippocampus, and nucleus accumbens but would profit from independent confirmation (Burnet et al., 1996). Interestingly, Burnet et al. (1997) reported an augmentation in the density of 5-HT_1A autoreceptors in raphe nuclei, although functional correlates remain to be identified.

A final, intriguing finding was an elevation in levels of 5-HT_1A receptors in the cerebellar vermis of schizophrenic patients, a structure implicated in sensory-attentional processes and motor function (Slater et al., 1998). This observation, which resembles the immature state, may reflect a failure to regress in maturity and be a consequence of neurodevelopmental abnormalities presaging schizophrenia. On the other hand, 5-HT_1A receptors themselves exert a trophic role. Indeed, in both immature and adult brain, they can modify synaptic architecture and plasticity via interactions with astrocytes and neurones, including monoaminergic and cholinergic pathways (Riad et al., 1994; Azmitia et al., 1995). Thus, the possibility that 5-HT_1A receptors might be causally involved in the aberrant, neurodevelopmental processes underlying schizophrenia would be interesting to evaluate.

	Functional Actions of 5-HT1A Receptor Ligands

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

Relevance to Positive Symptoms. 5-HT_1A agonists attenuate induction of DA release in the nucleus accumbens by the psychostimulant, amphetamine (Ichikawa et al., 1995; Ichikawa and Meltzer, 1999). However, upon administration alone, in neurochemical and behavioral studies, no consistent pattern of data has emerged, with reports that they facilitate, suppress or fail to modify mesolimbic dopaminergic transmission (see Ichikawa and Meltzer, 1999; De La Garza and Cunningham, 2000; Millan et al., 2000). Furthermore, although 5-HT_1A agonists block discriminative stimulus properties of amphetamine in primates (Nader and Woolverton, 1994), a complex pattern of effects has been obtained in rodents, including both attenuation and, albeit rarely, facilitation of the actions of amphetamine and cocaine (see Herges and Taylor, 1999; De La Garza and Cunningham, 2000).

Relevance to Negative and Cognitive Symptoms. 5-HT_1A receptor agonists consistently enhance the activity of the mesocortical dopaminergic pathway via actions expressed proximally to ventrotegmental dopaminergic cell bodies. Currently, the prevailing hypothesis is that engagement of 5-HT_1A autoreceptors relieves a tonic, inhibitory influence of 5-HT_2C receptors exerted via excitation of inhibitory GABAergic interneurones in the ventrotegmental area (Millan et al., 2000). In addition, GABAergic interneurones may be directly inhibited by postsynaptic 5-HT_1A receptors, but evidence of this mechanism is weak, and it is probably of secondary importance (Millan et al., 2000).

Relevance to Mood. 5-HT_1A agonists express anxiolytic properties (Jann et al., 1990; Schreiber and De Vry, 1993) that may predominantly be ascribed to activation of 5-HT_1A autoreceptors. Although early studies suggested that postsynaptic 5-HT_1A sites likewise mediate anxiolytic actions, recent work indicates that their antagonism is associated with anxiolytic properties (Schreiber and De Vry, 1993). In view of the exacerbation of comorbid anxious states both by psychotic symptoms per se as well as by neuroleptic treatment, auxiliary anxiolytic properties would be advantageous for an antipsychotic agent. Anti-aggressive properties of 5-HT_1A receptor agonists in experimental studies are likewise attributable to activation of 5-HT_1A autoreceptors (Miczek et al., 1995). Because hostile behavior is often encountered in psychotic patients, such properties would also be beneficial. However, the relationship of serotonergic transmission to aggressive behavior remains ambiguous and rigorous demonstration of anti-aggressive actions of selective 5-HT_1A ligands in man is awaited, so such potential advantages require cautious interpretation (Miczek et al., 1995).

Relevance to Extrapyramidal Side Effects. 5-HT_1A receptor agonists attenuate induction of catalepsy by D₂ receptor antagonists in rodents, a response predictive of extrapyramidal motor side effects (Wadenberg, 1996; Wadenberg et al., 1999). They also inhibit extrapyramidal motor effects of neuroleptics in primates (Casey, 1993). 5-HT_1A receptors are virtually absent from the striatum, and these actions primarily reflect engagement of 5-HT_1A autoreceptors localized in the MRN, although the DRN may also be implicated (Wadenberg, 1996; Wadenberg et al., 1999). Involvement of the latter would be consistent with projection of DRN-derived serotonergic neurones to the striatum, raising the possibility that subsequent to a reduction of 5-HT release, postsynaptic mechanisms integrated therein abrogate cataleptogenic effects of striatal D₂ receptor blockade. Modulation of nigrostriatal dopaminergic transmission is unlikely to be implicated, because 5-HT_1A agonists exert a variable influence upon striatal DA release and fail to modify its enhancement by haloperidol (Millan et al., 1998a; Ichikawa and Meltzer, 1999, 2000). Nevertheless, other mechanisms may potentially be involved: e.g., actions in structures downstream of the striatum or modulation of corticostriatal glutamatergic afferents (Francis et al., 1993).

	Actions of Clozapine at 5-HT1A Receptors

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

In light of the above comments, the demonstration that clozapine behaves as a partial agonist at human 5-HT_1A receptors is clearly of significance (Assié et al., 1997; Newman-Tancredi et al., 1998), particularly because this action is expressed with a potency similar to that antagonizing D₂ receptors. Indeed, several lines of experimental evidence suggest that actions of clozapine at central 5-HT_1A sites participate in its functional actions.

First, much has (justifiably) been made of 1) the higher (100-fold) potency of clozapine at 5-HT_2A versus D₂ receptors, and 2) its superior potency at 5-HT_2A sites compared with haloperidol, whereas the opposite holds for D₂ receptors (Roth and Meltzer, 1995). However, clozapine is clinically used at doses substantially higher than those of haloperidol and at which significant D₂ receptor occupation is detected in PET imaging studies (Seeman and Tallerico, 1999; Kapur et al., 2000). If D₂ receptors are occupied then so, presumably, are 5-HT_1A sites for which it displays similar affinity. That clozapine genuinely occupies 5-HT_1A receptors at therapeutically effective doses was recently suggested by PET imaging studies in primates (Chuo et al., 2000), an approach which should be extended to the clinic.

Second, in experimental studies, many of the above-described actions of 5-HT_1A autoreceptor agonists have been observed with clozapine, which similarly activates and blocks pre- and postsynaptic 5-HT_1A receptors, respectively (Millan et al., 1998a,b; Newman-Tancredi et al., 1998). Notably, frontocortical (versus subcortical) release of DA and NA, enhancement of social interaction, anxiolytic and anti-aggressive properties, and attenuation of the cataleptogenic effects of neuroleptics (Corbett et al., 1993; Millan et al., 1998b; Ichikawa and Meltzer, 1999). Arguing by analogy, agonist actions of clozapine at 5-HT_1A autoreceptors may contribute to these effects. Correspondingly, they may contribute to the clinical improvement of negative symptoms and mood in the absence of extrapyramidal motor side effects. However, the "isolation" of a 5-HT_1A receptor-mediated component of action of clozapine is complicated by its other receptorial interactions. For example, apart from activation of 5-HT_1A autoreceptors, blockade of DRN-localized ₁-ARs contributes to suppression of serotonergic transmission by clozapine (Millan et al., 2000). Furthermore, blockade of postsynaptic 5-HT_2C receptors also participates in its acceleration of DA and NA release in FCX, as well as the expression of its anxiolytic properties (see Millan et al., 1998b, 2000).

The third line of evidence is, nevertheless, derived from interaction studies with WAY100,635 which neutralizes 5-HT_1A autoreceptor agonist properties of clozapine. Thus, in several but not all reports, WAY100,635 attenuated the increase in FCX levels of DA elicited by clozapine, as well as its anxiolytic properties and its ability to moderate the cataleptogenic actions of haloperidol (see Millan et al., 1998b; Ichikawa and Meltzer, 1999). This variable pattern of data reflects the above-mentioned implication of mechanisms other than 5-HT_1A autoreceptor stimulation in these effects of clozapine.

Clearly, further study is required to underpin the importance of 5-HT_1A receptors in the actions of clozapine. In this regard, the potential involvement of 5-HT_1A receptors in its influence upon cognitive-attentional function remains to be elucidated.

	Other Antipsychotic Agents Interacting with 5-HT1A Receptors

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

In light of the above, there is considerable interest in the potential role of 5-HT_1A receptors in the actions of antipsychotics (Roth and Meltzer, 1995; Ichikawa and Meltzer, 1999). Several drugs are illustrated in Fig. 3. Certain ones justify brief commentary.

View larger version (18K): [in this window] [in a new window]   Fig. 3.   Chemical structures, and affinities for 5-HT1A compared with dopamine D2 receptors, of diverse antipsychotic agents. Affinities are indicated as pKi values for 5-HT1A/D2 receptors. Data (at cloned human sites) for haloperidol, clozapine, S16924, and ziprasidone are taken from Millan et al. (1998a and M. J. Millan, unpublished observations); other values are taken from relevant publications. Haloperidol, clozapine, and ziprasidone are in clinical use, perospirone is in phase III, and the other agents are in phase I/II clinical trials or discontinued.

First, like clozapine, ziprasidone shows equilibrated, but more potent, partial agonist and antagonist activity at 5-HT_1A and D₂ sites, respectively, in cellular models. However, the functional actions of ziprasidone at 5-HT_1A receptors in vivo are paradoxically weak relative to D₂ receptor blockade (Perry et al., 1998; Sprouse et al., 1999). Second, S16924 possesses a clozapine-like multireceptorial profile and shows pronounced partial agonist activity at 5-HT_1A receptors. Stimulation of 5-HT_1A autoreceptors plays a key role in its functional actions in experimental studies: notably, potentiation of mesocortical DA and NA release, anxiolytic properties, and blockade of haloperidol-induced catalepsy (Millan et al., 1998a,b). Third, clozapine, ziprasidone, S16924, and other antipsychotics shown in Fig. 3 display marked antagonist activity at ₁-ARs, 5-HT_2A, and/or 5-HT_2C receptors. On the other hand, the novel benzodioxane derivative, BTS79018 (Birch et al., 1999), may be distinguished by modest affinity for these sites. Experimental and clinical exploration of its functional profile should, thus, prove instructive in elucidating the significance of partial agonist properties at 5-HT_1A receptors for antipsychotic agents.

One "absentee" from Fig. 3 is the azaspirone and 5-HT_1A receptor agonist, buspirone, which possesses modest affinity at D₂ receptors and low affinity at ₁-ARs and 5-HT₂ sites. Buspirone, a clinically employed anxiolytic and antidepressant, was originally evaluated as a potential antipsychotic agent but yielded disappointing and inconsistent results in several small trials. In fact, it appeared to improve mood and reduce extrapyramidal motor symptoms in patients concurrently administered neuroleptics (Jann et al., 1990; see Sharma and Shapiro, 1996). However, the significance of these observations is difficult to discern because buspirone is rapidly degraded to 1-pyrimidinylpiperazine. This metabolite is virtually devoid of activity at the 5-HT_1A and D₂ receptors, although a potent antagonist at ₂-ARs, the blockade of which improves mood and motor function (see Millan et al., 2000). In addition, buspirone displays substantial efficacy at postsynaptic 5-HT_1A receptors (Schreiber and De Vry, 1993), whereas, as discussed above, low efficacy at these sites appears desirable for antipsychotic agents.

	Optimal Efficacy and Potency at 5-HT1A Receptors: A Crucial and Complex Question

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

As exemplified throughout this review, modest intrinsic activity permitting activation and blockade of pre- and postsynaptic 5-HT_1A receptors, respectively, appears to be the most appropriate profile for improved management of schizophrenia.

However, relative functional roles of pre- and postsynaptic 5-HT_1A receptors require clarification (Barnes and Sharp, 1999). Furthermore, drug efficacy at specific populations of the 5-HT_1A receptor in human brain in vivo depends critically upon a diversity of unknown variables, such as G-protein availability, receptor number and sensitivity, pre-exposure to 5-HT, and constitutive activity. Thus, it is virtually impossible to predict the precise actions of 5-HT_1A receptor ligands at specific populations of 5-HT_1A receptors in schizophrenia patients. This assertion isunfortunately!particularly valid for partial agonists. As a corollary of this uncertainty, it is difficult to ascertain the optimal degree of efficacy at 5-HT_1A receptors required for potential antipsychotic agents. Yet this is a crucial factor sinceat least upon initiation of treamentexcessive activation of postsynaptic 5-HT_1A receptors may be deleterious (amnesic and anxiogenic actions, perturbation of sleep, and a constellation of physiological signs loosely termed the "syndrome"). On the contrary, a "pure" antagonist, in blocking postsynaptic sites, would exert procognitive properties, yet be deprived of potential advantages of autoreceptor stimulation. Indeed, 5-HT_1A autoreceptor blockade may exacerbate extrapyramidal symptoms provoked by the D₂ receptor blockade (Prinssen et al., 1999).

In addition to efficacy, the relative potency of actions at 5-HT_1A receptors versus D₂ receptor blockade is an incompletely resolved conundrum. That is, whether equilibrated affinity at 5-HT_1A and D₂ sites is desirable or, alternatively, a clear preference in favor of the former. This will likely be a function of whether the drug interacts with other sites ("multireceptorial profile") or exclusively recognizes 5-HT_1A and D₂ receptors.

	Clinical Evaluation of Antipsychotics Interacting with 5-HT1A Receptors: Key Issues

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

In concluding, it is appropriate to specify certain important considerations in the clinical evaluation of antipsychotic agents possessing marked activity at 5-HT_1A receptors.

First, a crucial issue is the demonstration that, at doses exploited for efficacy studies, there is significant occupation of central 5-HT_1A receptors. PET studies have proven indispensable for characterization of drug actions at 5-HT_2A versus D₂ receptors and, with the availability of [¹¹C]WAY100,635, this strategy may likewise be adopted for 5-HT_1A receptors. This approach permits, further, observations of the relative occupancy of pre- versus postsynaptic receptors, which may not necessarily be identical. Although PET imaging yields no information on drug efficacy, measures of core temperature, corticosterone, and growth hormone secretion may be of use (Roth and Meltzer, 1995). Drug influence upon such parameters can be extrapolated from experimental studies, although the relative contribution of pre- and postsynaptic 5-HT_1A receptors to their modulation remains uncertain. Whether 5-HT_1A receptor ligands generate an idiosyncratic electroencephalographic signature remains unclear, but their influence upon sleep patterns is well characterized, so such information would be important to acquire.

A second fundamental issue concerns patient selection and clinical assessment. It is improbable that actions at 5-HT_1A receptors per se control positive symptoms in neuroleptic-responsive patients, although any potential improvement in resistant subjects patients justifies examination. Otherwise, therapeutic benefits are more likely to be encountered for deficit and cognitive symptoms. Their quantification should be a principal focus of studies adopting appropriate rating scales and, if feasible, models of cognitive-attentional function.

Third, activation of 5-HT_1A autoreceptors is, in general terms, "activating" rather than sedative and/or motor-suppressant, so the introduction of antipsychotics possessing such actions in patients accustomed to neuroleptics (and tranquilizing agents) should be undertaken cautiously, in particular, if concurrent D₂ receptor blockade cannot be guaranteed. In this light, for an optimal appreciation of the potential benefits and disadvantages of agents interacting with 5-HT_1A receptors, if possible, it would be advisable to avoid recent or simultaneous utilization of other classes of psychotropic agent.

Finally, because 5-HT_1A receptors modulate sympathetic outflow, the potential modification of cardiovascular parameters, particularly in association with ₁-AR and 5-HT₂ receptor blockade, requires careful surveillance.

Such potential complications are arguably inherent to any drug class possessing a novel mechanism of action. Furthermore, these issues are most relevant at the onset of treatment and do not appear unsurmountable within the framework of prudent and appropriately designed, long-term clinical trials.

	Conclusions

Top Abstract Schizophrenia, Dopamine... Clozapine: A Multireceptorial,... Serotonergic Mechanisms in the... 5-HT1A Receptors: Neuronal... Alterations of 5-HT1A Receptor... Functional Actions of 5-HT1A... Actions of Clozapine at... Other Antipsychotic Agents... Optimal Efficacy and Potency... Clinical Evaluation of... Conclusions References

In conclusion, selective 5-HT_1A receptor ligands are unlikely to be of use in the treatment of schizophrenia. Nevertheless, antipsychotics possessing partial agonist properties at 5-HT_1A receptors (allowing stimulation and antagonism of pre- and postsynaptic populations, respectively) may offer advantages. In this respect, both dual 5-HT_1A/D₂ receptor and multireceptorial ligands are of interest. Additional study is necessary to define the precise degree of potency and efficacy at 5-HT_1A receptors requisite for optimization of clinical benefit. Antipsychotics interacting with 5-HT_1A receptors are unlikely to provide a panacea for the problem-free treatment of all schizophrenic patients, and well designed, thorough, and imaginative clinical trials are required to more precisely characterize the potential use of this mechanism of action in the management of psychotic disorders.