CLINICAL HANDBOOK OF SCHIZOPHRENIA

32 I. CORE SCIENCE AND BACKGROUND INFORMATIONaffinity, or affinity at other receptors. However, the fast-off theory also has difficulties:Several of the atypical antipsychotics have rather high affinities and slow dissociation(e.g., risperidone, sertindole); several of the newer atypicals in development have evenhigher D 2 affinities and presumably slower dissociation (e.g., lurasidone, asenapine); thefast-off idea is focused mainly on the dopamine D 2 blockade properties, and may henceexplain the anti-“psychotic” aspect of atypicals, but it does not address the negativesymptom and cognitive deficit efficacy of the newer agents.As is evident, a consensus on the mechanism of action of atypical antipsychotics hasyet to emerge. To complicate matters, a so-called third generation of antipsychotic medicationsis now emerging. The clinical effects and receptor binding profiles of these newagents are distinct from either first-generation/typical antipsychotics or second-generation/atypicalantipsychotics.Third-Generation AntipsychoticsA number of recently developed antipsychotics have promising effects on negative and cognitivesymptoms and refractory cases. These agents have receptor profiles that do not clearlyfit with either 5-HT 2A –D 2 or a fast dissociation from D 2 as their primary mode of action.An example of this new class is aripiprazole, which is a partial agonist rather than anantagonist at D 2 . Partial agonists block the usual transmitter from binding. However, unlikeantagonists, they also provide a partial degree of stimulation. Aripiprazole effectively behavesas a weakened version of dopamine at the D 2 receptor. Interestingly, the structure ofaripiprazole falls within the Class II (e.g., haloperidol) rather than the Class I (e.g., clozapine)antagonists described previously. In other words, aripiprazole is structurally more similar to atypical antipsychotic, but clinically it acts as an atypical antipsychotic. Additional effects ofaripiprazole at 5-HT 2A and 5-HT 1A complicate its pharmacology even further.Another new agent in schizophrenia is amisulpride, which is a selective D 2 and D 3antagonist acting on presynaptic autoreceptors at low doses and postsynaptically at highdoses. The presynaptic effects result in enhancement rather than blockade of dopamineneurotransmission at low doses. Amisulpride shows particular promise for treating thenegative symptoms of schizophrenia.One final point is that the optimal pharmacological strategy for treating schizophreniamay not lie in searching for a single “one-size-fits-all” agent with a precisely optimizedsuite of dopamine, serotonin, and other receptor binding properties. Rather, it maybe more effective to use a regimen of multiple complementary agents tailored towardtreating the distinct positive, negative, and cognitive symptoms of each individual patient.The role of complementary nonpharmacological treatments may be equally important, asdescribed in the next section.LINKING BIOLOGY, PHENOMENOLOGY, AND PHARMACOLOGYPatients with schizophrenia present to the emergency room complaining of delusions andhallucinations, not dopamine overload. The symptoms of psychosis are perceptual, behavioral,and cognitive, yet the predominant theories are neurochemical. How may thisgap be bridged?Perception, behavior, and cognition are functions of widespread, distributed networksof neurons operating across the brain. These networks link value-neutral sensoryrepresentations to value-laden representations of the internal milieu: homeostasis, basic