Burger's Medicinal Chemistry and Drug Discovery || Antipsychotic Agents

ANTIPSYCHOTIC AGENTS

JEFFREY M. BROWN

JIE JACK LI

MICHAEL W. SINZ

Drug Discovery, Bristol-Myers SquibbCompany, Wallingford, CT

1. INTRODUCTION

Schizophrenia is a devastating and complexpsychiatric illness that remains a major med-ical problem in our society. Although theman-ifestations of this disorder have been knownand described for over a century, our under-standing of the biology and pathology is stillin its infancy. Pharmacological treatments forschizophrenia remain limited in mechanismand largely address only one aspect or symp-tom domain of this disorder. This fact stemslargely from three challenges. First, it is ageneral lack of understanding of the complexpathological mechanisms that contribute tothe disease. Second, there is a need for up-dated diagnostic criteria that includes evalua-tion of additional symptom domains. Third, itis a lack of preclinical models that capturemultiple domains of the disease. Efforts overthe last decade have begun to address theseissues and have opened the door for newhypotheses regarding the integration ofneurotransmitter systems and neuronal cir-cuits. These efforts have lead to the develop-ment and testing of antipsychotic medicationswith novel mechanisms of action, which mayaddress multiple domains of this complex dis-order. As these new pharmacological toolsbecome available they will also help in thedevelopment and validation of new preclinicalmodels.

2. DEFINING SCHIZOPHRENIA

In the early twentieth century, it was believedthat all forms of psychiatric illness repre-sented a single common disease or pathology.This idea was challenged by Emil Kraepelinwho distinguished a manic-depressive state,“dementia praecox,” from other chronic psy-chiatric illnesses. The term schizophrenia(meaning split brain) was coined by Swiss

psychiatrist Paul Eugen Bleuler to describea psychiatric illness associated with an im-paired perception of reality manifested byhallucinationsaswell asdisorganized thoughtand speech. Schizophrenia is seen worldwidewith prevalence rates reported in the range of0.5–1.5%. [1] Initial onset usually occurs in themid to late twenties and is often noted byfamily members, friends and/or coworkers asbizarre or inappropriate behavior [1].Although genetic links have been seen in schi-zophrenia, no biological test has been vali-dated for diagnosis. Instead diagnosis de-pends on the presence of specific behavioralsigns that present for at least 6 months andare not associated with schizoaffective disor-der or other mood disorders [1]. These beha-vioral signs can be categorized into threesymptom domains: positive symptoms, nega-tive symptoms, and cognitive deficits. In orderto understand the rationale for past, current,and future antipsychotic drug design, it isimportant to have an understanding of thesesymptom domains as well as the underlyingpathologies associated with schizophrenia.

2.1. Symptom Domains [1]

2.1.1. Positive Positive symptoms in schizo-phrenia are by far the most obvious and mostassociated with the schizophrenic condition.These symptoms include delusions, hallucina-tions, and/or disorganized speech. Clear ra-tional thought and perceptions of realitybecome distorted. The manifestation of thesehallucinations may be unrealistic paranoia,usually auditory (paranoid schizophrenia sub-type) or disorganized speech and inappropri-ate behavior (disorganized schizophrenia sub-type).Catatonic schizophrenia refers to abnor-mal motor behaviors and can include a lack ofresponsiveness to danger or environmentalsituations, rigid or bizarre postures, or exces-sive purposeless movements. The term psy-chotic is often used to describe this cluster ofpositive symptoms. Antipsychotic medica-tions used in the treatment of schizophreniaare most effective in treating this symptomdomain.

2.1.2. Negative Negative symptoms of schi-zophrenia are characterized by a loss or de-

Burger’s Medicinal Chemistry, Drug Discovery, and Development, Seventh Edition,edited by Donald J. Abraham and David P. RotellaCopyright � 2010 John Wiley & Sons, Inc.

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crease in normal function. Specific conditionsrelated to negative symptoms include affec-tive flattening, alogia, and avolition. Affectiveflattening refers to abnormal facial immobi-lity, lack of eye contact or a general lack of orreduced body language. Alogia is a generalpoverty of speech or lack of normal conversa-tional dialog. Individuals often show a paucityof responses to questions or an unwillingnessto speak. Avolition describes an inability toinitiate or maintain goal-directed activities ora general lack of motivation or desire. Anti-psychotic medications are less effective attreating negative symptoms of schizophrenia.

2.1.3. Cognitive Cognitive deficits representon overall decrease in normal executive func-tion. Executive function is a general termusedto describe the integration of multiple sensoryinputs, which contributes to a specific beha-vioral response and includes aspects of work-ing memory, inhibitory control, and informa-tion processing. A number of studies havedemonstrated that cognitive deficits are apervasive and central component of schizo-phrenia. These deficits precede the develop-ment of the actual schizophrenic illness andare not associated with antipsychotic treat-ment. Initial estimates of the prevalence ofcognitive deficits in schizophrenia range from40% to 80% of the patient population.Although cognitive function is believed to bethe largest contributor ofmorbidity associatedwith schizophrenia it is not part of the overalldiagnostic requirements in the DSM-IV [1].In addition, antipsychotic medications, bothtypical and atypical (see below), are less effec-tive in treatment of cognitive deficits in schi-zophrenia. Development of new medicationsspecifically targeting cognitive deficits hasbeen hindered by the lack of a clear standar-dized test or tests for evaluation of cognitivefunction and the effect of drugs in clinicalpopulations. In an attempt to standardizemeasures of cognitive functions, members ofthe MATRICS (Measurement and TreatmentResearch to Improve Cognition in Schizophre-nia) initiative recommended evaluating sixspecific measures: working memory, atten-tion/vigilance, verbal learning and memory,visual learning and memory, reasoning andproblem solving, and speed of processing and

social cognition [2]. These efforts are critical asthey lay the foundation for establishment ofstandards for evaluating cognitive deficits inschizophrenia.

2.2. Pathology of Schizophrenia

Thepathology of schizophrenia is complex andlikely involves changes in multiple neuro-chemical substrates as well as structural re-organization within the brain. Although adetailed description of this pathology is be-yond the scope of this chapter, understandingthe key neurochemical substrates, particu-larly dopaminergic and glutaminergic/GA-BAergic systems, will help to define the ra-tional for past, present, and future drug devel-opment efforts.

2.2.1. Dopamine Design and development ofantipsychotic agents are often tailored to ad-dress a specific pathology or set of pathologiesseen in schizophrenia patients. Typical anti-psychotics that were developed based on theserendipitous finding that chlorpromazine,initially developed as an antihistamine, waseffective in an animal model of conditionedavoidance [3]. Later, it was demonstrated thatchlorpromazine and another antipsychoticagent haloperidol increased the turnover ofmonoamines in the brain [4]. In 1966, VanRossum hypothesized that dopamine receptorblockade is an important factor in the mode ofaction of antipsychotic agents [5]. This hy-pothesis was later validated by two groupsthat demonstrated the ability of antipsychoticagents to block stimulated dopamine releaseand haloperidol binding (D2 receptors) wascorrelated with clinical potencies and do-sages [6,7]. Although initial studies suggestedelevation in D2 receptors in schizophrenicpatients, this finding remains controversialand may be related to previous antipsychotictreatment or a subset of schizophrenia pa-tients [8–12]. However, evidence to supporta hyperdopaminergic state has been demon-strated. Amphetamine is a psychostimulantthat causes a rapid and pronounced dopaminerelease within the brain and can lead to apsychosis mimicking the behavioral manifes-tations seen in schizophrenic patients. Am-phetamine-induced dopamine release is in-

2 ANTIPSYCHOTIC AGENTS

creased in schizophrenic patients and in-creases in D2 receptor displacement corre-lates with a worsening of positive, but notnegative symptoms [13]. One conclusion fromthis study is that this increased dopaminerelease induced by amphetamine likely re-sults from alterations in dopamine synthesisand/or degradation and not due to differentialaffinity or expression of the D2 receptor [14].Collectively, these and other findings havelent support to a primary hypothesis regard-ing the pathology of schizophrenia, the dopa-mine hypothesis. This hypothesis states thatschizophrenia results from a hyperdopami-nergic tone within the CNS. This hypothesishas been aprimary driver for the developmentof dopaminergic antagonists, particularly D2antagonists, termed “typical psychotics” overthe past half century. However, a major draw-back to typical antipsychotic is that potentinhibition of D2 receptors can cause unwantedadverse events (see below). To lessen the D2associated adverse events, atypical antipsy-chotic medications that show overall lowerD2 affinity and blockade of nondopaminergic(e.g., serotonin) receptorshavebeendeveloped.

As our understanding of the pathology ofschizophrenia has developed so too has thedopaminehypothesis. Originally, though to beadisorder of hyperdopaminergic tone, it is nowbelieved that both a hypodopminergic and ahyperdopaminergic tone may exist in schizo-phrenia. Specifically, Bannon and Roth hy-pothesized that a hypodopaminergic tone inprefrontal cortical areas may result in a cor-responding increase or hyperdopaminergictone in subcortical areas [14]. This hypothesiswas echoed by Davis et al. (1991) who statedthat schizophrenia results from a hypodopa-minergic tone in themesocorticalpathwayanda hyperdopaminergic tone in the mesolimbicpathway [15]. As the positive symptoms ofschizophrenia are believed to be related to thehyperdopaminergic state, the negative andcognitive aspects may result from the hypodo-paminergic state in the prefrontal cortex. Thishas led some to evaluate both dopamine re-ceptor agonists and positive modulators forthe treatment of schizophrenia. Most notableis the new antipsychotic aripiprazole that actsas a partial agonist of theD2 receptor andmayhelp to balance a disrupted dopamine tone.

2.2.2. Glutamate/GABA As our understand-ing of schizophrenia develops, so to does thelist of possible new pharmacological targets.As early as the 1959, Luby et al. reported thatadministration of phencyclidine (PCP; Sernyl)to nonschizophrenic patients caused a psycho-pathology similar to that seen in schizophre-nic individuals [16]. When administered toschizophrenic patients, PCP intensified theprimary behavioral pathology seen in thiscohort [16]. PCP is an antagonist at the iono-tropic glutamate receptor (NMDA receptor)leading to the speculation that hypofunctionof the NMDA receptor contributes to the coresymptoms of schizophrenia [17,18]. ThisNMDA hypofunction may result fromdecreased glutamate levels in the brain(i.e., decrease receptor activation). However,glutamate levels have been shown to be un-altered in schizophrenic patients [19,20]. Inaddition to glutamate,NMDA receptor activa-tion requires the cofactor glycine and blockadeof this glycine site inhibits NMDA function.Kynurenic acid, a breakdown product of tryp-tophan, is elevated in the CSF and cortex ofschizophrenic patients [21–23]. In a study bySchwarcz et al. (2001) it was demonstratedthat, in rats, chronic treatment with haloper-idol decreased kynurenic acid levels suggest-ing increases seen in schizophrenic patientswas not a result of drug treatment [21]. This isof relevance to NMDA function as kynurenicacid may be an antagonist at the coagonistglycine site [24]. Moreover, administration ofthe kynurenic acid precursor kynurenine de-creases the PPI response in rats, an animalmodel of schizophrenia. This effect was re-versed by both a typical and an atypical anti-psychotic [25]. These findings would supportthe hypotheses that decreased NMDA func-tion, due to a kynurenic acid-mediated block-ade of the glycine site of the NMDA receptor,contributes to the pathology of schizophrenia.

In addition to kynurenic acid, NMDA func-tion can be inhibited by other endogenousNMDAantagonists. For example, activity andbinding of glutamate carboxypeptidase, theenzyme that breaks down N-acetyl-aspartylglutamate (NAAG) to NAA and glutamate, isreduced in schizophrenic patients [26,27] aneffect unlikely mediated by changes inmRNA [28]. This is of relevance since NAAG

DEFINING SCHIZOPHRENIA 3

antagonizes NMDA receptor function [29,30].These data support a hypothesis that hypo-function of the NMDA receptor may resultfrom endogenous, orthosteric, or allosteric in-hibitors of NMDA receptor function. As treat-ment with orthosteric NMDA agonists mayresult in neurotoxicity, targeting the allostericsite of the NMDA receptor would enhanceNMDA responses to glutamate without directactivation [31].

Although modulation of NMDA receptorfunction remains an interesting pharmacolo-gical target, it is not the only glutamate re-ceptor that has links to schizophrenia. Recentgenetic data suggests genetic associations be-tween schizophrenia and the metabotropicglutamate receptors (mGluRs), most notablethe mGLuR3 [32,33]. Early clinical studieswith an mGluR 2/3 agonist have shown pro-mise. Specifically, administration of a prodrugof the mGluR2/3 agonist, LY404039, wasshown to have positive clinical effects overplacebo and a comparable effect to olanza-pine [34]. This finding is of significance as itsuggests that nondopaminergic treatmentscan be developed for the treatment ofschizophrenia.

Although the dopamine and glutamate hy-potheses arose fromdifferent findings, the twomay be interrelated. Within the prefrontalcortex GABAergic parvalbumin positive(PVþ ) interneurons provide inhibitory inputto glutaminergic pyramidal neurons. Thesesame PVþ interneurons receive input fromdopaminergic afferents [35] and are inner-vated by local glutaminergic axon collat-erals [36]. Thus, under the control of dopami-nergic and glutaminergic input, these GA-BAergic interneuorns are in a position to reg-ulate the activity of prefrontal corticalglutaminergic neurons. One of the most re-producible findings in schizophrenia is a de-crease in GABAergic markers in the prefron-tal cortex and hippocampus. Specifically, ithas been demonstrated that GAD67 (the en-zyme responsible forGABAsynthesis) and theGABA transporter (GAT), both of which arelocalized to GABAergic interneurons, are de-creased in schizophrenic patients [37–40].Since these GABAergic interneurons arepoised to regulate glutaminergic pyramidalneuron activity, it would suggest a general

dysfunction of a prefrontal neuronal circuitwithin schizophrenic patients. This has leadsome to speculate that modulation of thiscircuit by enhancing GABAergic transmissionvia GABA-A receptor modulators may repre-sent a viable alternative for the treatment ofschizophrenia [41]. Since the glutaminergicpyramidal neurons in the prefrontal cortexare important integrators of sensory inputandoverall executive function, targeting thesedef-icits may represent a pharmacologic mechan-ism to address an area of unmet medical needin schizophrenia, cognitive deficits.

2.2.3. Other Neurotransmitters As dopa-mine, glutamate, and GABA may be impor-tant in the pathophysiology of schizophrenia;other neurotransmitters systems likely con-tribute either directly or indirectly to thepathology and/or efficacy of antipsychoticmedications. In a review by Meltzer et al.(2003), it was stated that the superior effectsof atypical antipsychotics are due to thereeffect on serotonin receptors, particularly 5-HT1a and 5-HT2a [42]. Preclinical as well asclinical data supports this hypothesis. Forexample, administration of atypical (cloza-pine, olazapine, and ziprasidone) but not atypical (haloperidol) antipsychotic causedgreater increases in dopamine release inthe prefrontal cortex of wild type but not 5-HT1a knockout mice [43]. Clinical studiesusing a 5-HT1a partial agonist to augmentcurrent therapy have shown some positiveresults, particularly with cognitive deficits, inschizophrenia patients [44]. Finally, poly-morphisms within the promoter region of the5-HT1a gene are reported to mediate the re-sponse to antipsychotic treatment, particu-larly in negative and depressive symptoms ofschizophrenia [45].

5-HT2a receptors have been localized toglutaminergic pyramidal and PVþ GABAer-gic interneurons in the prefrontal cortex andthus are in a position to regulate the sameprefrontal cortical circuit outlineabove [46,47]. Similar to that seen with the5-HT1a receptor, levels of 5-HT2a receptorsmay also predict response to atypical antipsy-chotics, particularly with negative symp-toms [48]. Thus, serotonin receptor functioncontributes to the effectiveness of antipsycho-


tic medications and may underlie the pathol-ogy of negative and/or cognitive aspects ofschizophrenia. Themechanismof these effectsmay be related to the regulation of dopami-nergic and glutaminergic circuits in the brain.

Nicotinic receptors may also play an im-portant role particularly in relation to cogni-tive deficits [49]. Schizophrenia patients showhigh rates of smoking and nicotine consump-tion, a phenomenon thatmay represent a formof self-medication. In fact, administration of anicotine patch with haloperidol attenuateshaloperidol-induced cognitive deficits in schi-zophrenics [50]. Nicotinic receptors are com-posed of both alpha and beta subunits. Inschizophrenia patient’s, reports of decreasesin alpha4 beta2 and decrease binding of alphabungarotoxin, presumably alpha7 subunits,in multiple brain regions has been re-ported [51–53]. Preliminary studies in schizo-phrenia patients with an alpha7 partial ago-nist have shown promising results in terms ofa cognitive benefit [54]. This has led many tospeculate that agonists, particularly alpha7agonists may be useful in the treatment ofcognitive deficits in schizophrenia.

To date multiple neurotransmittrer andneuropeptide systems (e.g., norepinephrineandneurotensin [55,56]) havebeen implicatedin schizophrenia.However, the contribution ofthese systems to the basic pathology, sympto-mology, and/or drug responsiveness remainsto be determined. Given the fact that schizo-phrenia is a polygenic (see below) and multi-system disorder, determining how theseindividual systems contribute to the overallregulation of neuronal circuits involved inschizophrenia is vital to understanding thebasic pathology and themechanism of currentand future antipsychotic medication.

2.2.4. Genetics The association of geneticalterations and chromosomal aberrations isa vital component to understanding any dis-ease. Schizophrenia clearly has a stronggenetic component as first-degree relatives ofschizophrenics show up to a 10-fold increasedrisk for schizophrenia. To date no specificmutation or dysfunction of a specific“schizophrenia gene” has been identified. Re-sults evaluating specific chromosomal regionshave shown some promising results. For

example, there is a 20- to 80-fold higher pre-valence of the 22q11.2 deletion in patientswith schizophrenia relative to that of the gen-eral population [57]. This is of interest as thischromosomal region contains some genesshowing relevance to schizophrenia [57].

Analysis of specific genes, mutations andsingle nucleotide polymorphisms (SNPs) hasfailed to identify a specific schizophrenic trait.This leads one to speculate that the geneticnature of schizophrenia is likely polygenic innature with specific groups or individualsshowing certain genetic abnormalities thatare absent in others. Thus, identifying a ge-netic “silver bullet” underlying schizophrenicpathology is highly unlikely. Although geneticassociation studies have been variable, effortsto examine these studies in total to identify acommon set of traits specific to schizophreniahas been published. In 2008, Allen et al. pub-lished results of a meta-analysis of 118 poly-morphic variants for 52 genes. The resultsidentified four genes with a “strong degree ofepidemiological credibility,” the D1 dopaminereceptor, dysbindin, 5,10-methylenetetrahy-drofolate reductase and tryptophanhydroxylase [58].

These are only two examples of numerouspublished reports of genetic association stu-dies with schizophrenia. As this list of genescontinues to rapidly grow, so too do questionsof validity and reproducibility of results.This is not surprising given the numerousconfounding factors such as genetic variabil-ity, differential diagnostic, and statisticalmethodologies and lack of diagnostic criteriafor certain symptoms domains (e.g., cognitivedeficits). Schizophrenia clearly is a polygenicdisorder andaswith evaluation of neurotrans-mitter system, understanding how theseand other genetic alterations contribute toan overall “systems deficit” in schizophreniawill greatly advance our understanding ofthe pathology and subsequent drugdevelopment.

3. ANTIPSYCHOTIC AGENTS

3.1. Side Effects

As with all drugs, administration of antipsy-chotic agents is often associated with adverse

ANTIPSYCHOTIC AGENTS 5

events. These effects can range from the un-pleasant, which can contribute to complianceissues, to serious life threatening events.Some of the adverse events may be directlylinked to themechanism of action (e.g., inhibi-tion ofD2 receptors) and as such the frequencyand severity is related to dose and potency.These adverse events include extrapyramidalsymptoms and anticholinergic effects. Withother antipsychotic-associated adverse eventsthe mechanism is less clear and may resultfrom off target effects (e.g., potassium channelinhibition) or a complex array of pathological,biological and/or genetic factors. For example,the elderly population tend to bemore suscep-tible to adverse events, women aremore proneto clozapine-induced agranulocytosis and in-dividuals with a history of epilepsy may bemore prone to seizures associated with anti-psychotic treatment. Of particular relevanceis a black box warning placed on both typicaland atypical antipsychotic medications stat-ing that antipsychotic drugs of both types(typical and atypical) are associated with anincreased risk of death when used in elderlypatients for dementia-related psychosis.Therefore, patient characteristics must beconsidered when deciding on the best antipsy-chotic regimen.

3.1.1. Extrapyramidal Symptoms [59] Themost common and challenging side effect as-sociated with use of antipsychotic medicationis the emergence of extrapyramidal symptoms(EPSs). EPS represent abnormal and un-controllablemovementsandare classified intotwo groups, acute and tardive syndromes.Acute EPS include akathisia (motor restless-ness due to feelings of distress or discomfort),dystonias (sustained muscle contractionscause twisting and repetitive movements orabnormal postures) and parkinsonian symp-toms (bradykinesia; slowness of movement,rigidity; tremor; and postural instability).Akathisia are most often acute, developingwithin a week of treatment initiation, but area reversible phenomenon. Parkinsoniansymptoms, however, can persist for monthsafter cessation of treatment. This is of parti-cular relevance to older patients as the pre-sence of parkinsonianism can reflect a purelydrug-induced effect, an exacerbation of pre-

viously undiagnosed parkinsonian pathologyor anactual pathologyunrelated to drug treat-ment. The acute EPS effects result fromblock-ade of D2 receptors in the basal ganglia, aphenomenon linked to themechanism of mosttypical antipsychotics [59]. In fact, it has beenestimated that occupancy of 65% of the D2receptors is needed for clinical efficacywhereas 78% occupancy leads to EPS [60].

To prevent or minimize acute EPS, parti-cularly akathisia, typical antipsychotics withlower affinity for the D2 receptor such aschlorpromazine can be used. As low affinitytypical antipsychotics tend to have higheraffinity for cholinergic receptors, using ananticholinergic agent in combination with alow affinity typical antipsychotic is often em-ployed. Alternatively, atypical antipsychoticcan be used. In a direct comparison of risper-idone (atypical), olanzapine (atypical), quetia-pine (atypical), ziprasidone (atypical), andperphenazine (typical), it was demonstratedthat more patients discontinued treatmentwith perphenazine due to EPS [61]. Drug-in-duced parkinsonianism is often treated byreduced dosage or switching to clozapine orquetiapine, both of which are less associatedwith parkinsonianism or left untreated if ef-fects are tolerable.

Tardive dyskinesia (TD) is a late onsetphenomena characterized by stereotypicinvoluntarymovementsmost often seen in theface, lips and tongue but can also include theextremities. Prevalence rates of TD rangefrom 10% to 25% of schizophrenic patientsalthough older patients may show a higherfrequency. Although still speculative, theunderlying pathology is believed to resultfrom a hypersensitivity of D2 receptor andpossible structural alterations within thebrain following prolonged antipsychotic treat-ment. While there remains no effective way totreat TD, atypical agents such as clozapineand quetiapine are believed to have a lowerincidence of TD. While use of anticholinergicsmay aggravate the symptoms, use of GABAreceptor agonist (i.e., benzodiazepines)maybehelpful.

In general, it is believed that EPS aremoreoften associated with typical antipsychotics,particularly high potency agents. However,the magnitude of benefit between typical and


atypical antipsychotics in terms of EPS re-mains difficult to ascertain. This ambiguityis due largely to multiple factors such as; EPSare more often associated with younger pa-tients, dosage can affect the presence or ab-sence of EPS with both typical and atypicalagents and not all studies discriminate be-tween acute and tardive types of EPS.

3.1.2. Neuroleptic Malignant Syndrome Neu-roleptic malignant syndrome (NMS) resem-bles a severe form of parkinsonianism and ischaracterized by catatonia, tremors, hyper-pyrexia, autonomic system instability, and/oraltered mental status. The reported incidencerate of NMS is 1% of all patients treated withantipsychotics and can be life threatening.LikeEPS,NMS is associatedwith antagonismof dopamine receptors, possibly those in thestriatumand hypothalamus although the pre-cise pathological mechanism remains to bedetermined. Of the available agents, haloper-idol ismost often associatedwithNMS reportsalthough cases with other antipsychoticagents have been seen. Treatment of NMSmay involve cessation of the current treat-ment, supportive therapy and possibly, ben-zodiazepines, muscle relaxants or dopamineagonists although questions remain as to theviability of pharmacotherapy options [62].

3.1.3. Cardiovascular Effects [63] Antipsy-chotic agents can negatively affect the cardi-ovascular system. Orthostatic hypotension isone of the most common adverse cardiac ef-fects and is present in approximately threequarters of patients. In elderly patients andthose with previous cardiovascular or auto-nomic system dysfunction, this risk of hypo-tension is greater. Complications resultingfrom antipsychotic-induced hypotension in-clude dizziness, visual disturbances, cognitiveimpairment and syncope. Syncope is of parti-cular concern in the elderly population due tothe risk of falls and associated bone fractures.The risk of antipsychotic-induced hypotensiondecreases with continued use as patients willdevelop tolerance to these effects. Hypoten-sion is often managed by titration of dose,particularly during initial treatment andminimizing use of agents associated withhigher potential for orthostatic hypotension.

As a general rule, typical antipsychotics thatshow lower potency are more likely to causehypotension. All atypical antipsychotics areassociated with increased risk of hypotension,however, the risk varies. Clozapine is asso-ciated with the highest risk followed by qui-tiapine, risperidone, olazapine, and finallyaripiprazole [64].Withatypical antipsychoticsthe propensity to cause hypotension may berelated to the affinity for the alpha-1 adrener-gic receptors.

Prolongation of the Q–T interval, the timefrom ventricular depolarization to ventricularrepolarization, can lead to cardiac arrhyth-mias, torsades de pointes, and possibly death.Drug-induced prolongation of Q–T intervalcan result from blockade of a delayed rectifierpotassium channel that is important for de-polarization of the ventricles. Typical and aty-pical antipsychotics are associatedwith block-ade of these potassium currents. For typicalantipsychotics, the most notable is thiorida-zine that has been associated with reversibleprolongation of Q–T interval and an increasedrate of sudden death. For atypicals ziprasi-done and quetiapine appear to have the lar-gest effect on Q–T interval whereas aripipra-zole has not been associated with an increaseof the QT interval [64]. Management of ad-verse cardiac effects involves an initial deter-mination of patient risk, selecting agents withlower propensity to cause adverse cardiaceffects, using lower doses when possible andperiodic monitoring of cardiac function.

Other adverse cardiovascular effects in-clude cardiomyopathy and myocarditis whichhave been associated with use of the atypicalclozapine. Cardiovascular disease has a high-er incidence in schizophrenics than that seenin thegeneral population.This factmaybedueto the higher rates of smoking and a generallack of physical activity or exercise. Antipsy-chotics do have negative metabolic effects in-cluding weight gain, hyperlipidemia, and al-tered glucose homeostasis (see below). How-ever, the role of antipsychotic medications inthis increased risk is still controversial.

3.1.4. Anticholinergic Effects In addition toaffinities at D2 and alpha1 receptors, mostantipsychotic medications also antagonizemuscarinic receptors leading to atropine-like


effects. These include dry mouth, blurred vi-sion, constipation, and urinary retention andcan be more pronounced in elderly popula-tions. Of the typical antipsychotics thiorida-zine, which has a higher affinity for M1 recep-tors, is associated with more pronounced an-ticholinergic effects. For the atypical agentsclozapine and olanzapine have higher anti-muscarinic effects whereas aripiprazole, ris-peridone and ziprasidonemay have less antic-holinergic effects. In a 2004 article, Watanabeet al. compared 50 schizophrenia patientstreated with either an atypical (risperidone,olanzapine, quetiapine) or a typical (haloper-idol, chlorpromazine) antipsychotic. Follow-ing treatment each patient completed a sur-vey relating the side effects including antic-holinergic effects. Results from the surveydistinguished no overall differences betweentypical and atypical antipsychotic medicationin terms of anticholinergic effects [65].

3.1.5. Metabolic Effects Psychiatric ill-nesses, particularly schizophrenia, are asso-ciated with overall poor physical health.Weight gain is common in schizophrenia andmay result from a combination of factors in-cluding disease pathology, lifestyle (smoking),and use of antipsychotic medications. Weightgain is commonwith antipsychotic treatment,particularly the newer atypical antipsycho-tics. In a review by Haddad and Sharma, theystated that of the newer atypical antipsycho-tics olanzapine and clozapine cause the great-est weight gain whereas aripiprazole causesless weight gain, although increase weightwas seen with all atypical agents when com-pared to placebo [66]. Significant weight gainwith olanzapine compared with risperidoneand ziprasidone was also reported by Stroupet al. [67]. In addition, olanzapine was asso-ciated with increases in serum levels of cho-lesterol and triglycerides [67], an effect thatmay be directly or indirectly linked to weightgain.

Both typical and atypical drug can worsenglycemic control. In general, olazapine andclozapine appear to have a higher risk hyper-glycemia when compared to other antipsycho-tics [66]. The effects of this altered glycemiccontrol in relation to development of diabetesis unclear. Collectively, studies appear to sug-

gest a link between newer antipsychotics anddiabetes, however, the effects are variable andmay be confounded by such factors as age,increased incidence of smoking and weightgain in schizophrenic populations. Lambertet al. (2006) suggested that the newer anti-psychotics olanzapine, risperidone and que-tiapine increase the risk of developing dia-betes by 60–70% in comparison with haloper-idol [68]. Overall, it is suggested thatmonitor-ing blood glucose levels, particularly duringearly treatment, as well as being vigilant forsigns suggesting development of diabetes isrecommended when using antipsychoticmedication [66].

3.1.6. Seizures Although increased risk ofseizures has been reported particularly witholder antipsychotics, the actual incidence ofseizures is estimated to be less than 1%. Onenotable exception is clozapine thatmayhave aslightly higher incidence of seizures up to 5%.For the typical antipsychotics, chlorproma-zine is regardedas themost epileptogenic [69].Caution should be taken in administration ofantipsychotic medication in patients withepilepsy.

3.1.7. Sedation Sedation associated withantipsychotic medications likely results fromantagonism of histamine receptors. Agentswith lower D2 affinity tend to have higheraffinity for the histamine receptor and aretherefore more sedating. Clozapine and olan-zapine have the highest affinity for histaminereceptors and tend to be the most sedatingwhile aripiprazole may be the least sedating.These sedating effects may be beneficial inpatientswhoare agitated butmay alsoworsenor confound evaluation of cognitive and nega-tive symptoms. Sedation associated with anti-psychotic medications is not permanent astolerance to these effects does develop.

3.1.8. Hematologic Effects Neutropenia is acondition resulting from decreased neutrophilcounts. Agranulocytosis, a severe form of neu-tropenia, has been associated with clozapineand is more often seen in Asian populations,women and older patients [66]. As such it isrecommended that clozapine be reserved fortreatment resistant patients or for reducing


the risk of suicidal behavior in patients withschizophrenia or schizoaffective disorder. Pa-tients treated with clozapine must have abaseline and regular blood cell counts as wellas follow-up blood counts 4 weeks after cessa-tion of treatment [70].

3.1.9. Sexual Side Effects Sexual dysfunctionis a psychologically distressing event that canseriously hamper compliance with antipsy-chotic agents. It is estimated that up to 43%of individuals using antipsychotic medica-tions report sexual dysfunction [71]. However,evaluation and classification of what repre-sents sexual dysfunction is unclear. Based onthe different methodologies of data collection,differential interpretation of sexual dysfunc-tion and potential underlying pathologies it isunclear as to the rates of sexual dysfunctionamong the two classes of antipsychoticmedications [66].

Sexual dysfunction may result from var-ious factors associated with antipsychoticmedications including hyperprolactemia. Do-pamine inhibits prolactin release and there-fore agents that block dopamine receptorswould be expected to increase prolactin levels.Typical antipsychotic drugs appear to in-crease prolactin levels in a dose-dependentmanner consistent with the idea of D2 recep-tor blockade. Atypical agents including cloza-pine, quetiapine, and olanzapine show little tono effects on prolactin while risperidone canincrease serum prolactin levels [72].

3.1.10. Hepatic Effects Elevations in liverenzymes have been reported with many anti-psychotics. Although these increases are com-mon they are largely asymptomatic and rarelywarrant discontinuation of treatment. Directstudies of olanzapine, risperidone, and que-tiapine demonstrated some increases in liverenzymes associated with these antipsychoticsbut significant liver enzyme elevations arerare during atypical antipsychotic treat-ment [73]. Similar results were found withrisperidone treatment in a pediatricpopulation [74].

3.1.11. Antipsychotic Discontinuation Devel-opment of adverse events or lack of efficacymay require discontinuation of antipsychotic

treatment. As with most CNS related drugs,cessation of the medication may result in ad-verse effects possibly related to withdrawal.Both motor (restlessness) and nonmotor (vo-miting) effects have been reported upon ter-mination of antipsychotic medications. Forexample, within days of stopping clozapinetreatment dystonias, motor restlessness, an-xiety, nausea, and altered consciousness havebeen reported [66].

3.2. Clinical Applications

Currently, there are a number of agents ap-proved for the treatment of schizophrenia, seeSection 5. Determining which antipsychotic isbest depends on multiple factors includingcurrently prescribed medications, cost, sideeffects, and patient populations. Much hasbeenwritten and debated regarding themeth-odology for selection of the most appropriateantipsychotic agent. In 2003, Kane et al. pre-sented results froma survey of experts regard-ing the selection of antipsychotic agents. Itwas concluded that atypical antipsychotics,particularly risperidone, were endorsed as theprimary medications for first-line treatmentof schizophrenia [75]. In a reviewbyTandon etal. (2008), itwas suggested that as the numberof prescriptions for the more costly antipsy-chotics increased, based on earlier recommen-dations, concerns were raised by governmentsregarding the usefulness of these new moreexpensive antipsychotic medications com-pared to older typical antipsychotics [76].These concerns were the catalysts for twogovernment sponsored studies, CUtLASS(CostUtility of theLatestAntipsychoticDrugsin Schizophrenia Study) and CATIE (ClinicalAntipsychotic Trial of Intervention Effective-ness). A primary conclusion from theCUtLASS study was that there was no dis-advantage to using typical antipsychotic med-ications when compared to atypical antipsy-chotic medications in the outcome measuresevaluated [77]. In a second study termed CA-TIE, Lieberman et al. (2005) reported thatthere were no significant differences in effec-tiveness between the typical and the neweratypical antipsychotic medications, althougholanzapine may have demonstrated someearly benefit [61]. Results from these studies


have been questioned based on a number offactors including methodological differ-ences [76]. To date, the question regardingthe cost benefit of typical versus atypical anti-psychotics for the treatment of schizophreniaremains unresolved

3.3. Other Indications

In addition to schizophrenia, antipsychoticmedications are effective for the treatment ofvarious psychiatric andnonpsychiatric indica-tions. D2 dopamine receptors in the chemor-eceptor trigger zone and in the stomach arebelieved to participate in the emetic response.Therefore, antipsychotic agents that antago-nize D2 receptors (e.g., chlorpromazine) areeffective antiemetic agents. Promethazine, anantipsychotic with affinity for the H1 receptorhas been used as a preoperative sedative.Other indications include chlorpromazine andhaloperidol for the treatment of intractablehiccups. Haloperidol has also been approvedfor the treatment of tics associated withTourette’s syndrome and agitation associatedwith dementia. Chlorpromazine has beenused for the treatment of psychosis resultingfrom PCP and amphetamine use. In additionto FDA approved indications, antipsychoticmedications are also used “off label” at thediscretion of the physician. Off label uses haveincluded the use of antipsychotics for thetreatment of dementia related psychosis, par-ticularly in the elderly population. However,this practice has come under scrutiny largelydue to black box warnings placed on all anti-psychotics indicating an increased risk ofdeath in elderly patients.

4. ANIMAL MODELS

Development and testing of antipsychoticmedications is dependent on the evaluationof both effectiveness and side effects at thepreclinical level. Because schizophrenia re-presents a complex disorder involving multi-ple neurochemical and structural alterationsin the brain modeling this disease in an ani-mal is challenging. In developing or validatingany animal model of psychiatric disease it isimportant to utilize models that; recapitulatea behavioral symptom or symptoms asso-

ciated with the disease, possesses pathologyor pathologies which mimics the disease andresponds to clinically relevant drugs. Effortsto develop animal models of psychiatric dis-ease include pharmacological and genetic ma-nipulations to model specific aspects of thedisease relating to efficacy, side effects or insome cases both. For schizophrenia, animalmodels are based largely on pathological find-ings in schizophrenia patients, behavioral cor-relates between human and animal modelsand/or knowledge of specific neurochemicalcircuits invoiced in the pathology of schizo-phrenia. For the purpose of this chapter, mod-els of efficacy have been divided into pharma-cological, behavioral, and genetic. However, itshould be noted that this division does notimply these models are mutually exclusive oreven independent. For example, the behavior-al measure of prepulse inhibition (PPI) can beused in combination with NMDA antagonists,amphetamine or in mice genetically predis-posed to PPI deficits. As no one animal modeltruly recapitulates the schizophrenia pathol-ogy, using multiple models to evaluate indivi-dual aspects remains the most utilized ap-proach for screening and evaluating antipsy-chotic medications.

4.1. Animal models of Efficacy

4.1.1. Pharmacology Based Models

Dopamine Model As stated above, disruptionofnormaldopaminetone isbelieved tounderliethe pathophysiology of schizophrenia, particu-larly the positive symptoms (see dopamine hy-pothesis in Section 2.2.1). Reproducing thisaltered dopaminergic state in animals repre-sents a plausiblemethod for evaluation of anti-psychotic efficacy. Amphetamine and apomor-phine increase locomotor activity in ratswhereas apomorphine can induce a climbingbehavior. Both amphetamine- and high-doseapomorphine-induced locomotor effects aremediated by the mesolimbic dopamine sys-tem [78–80]. Both typical andatypical antipsy-chotics including haloperidol, clozapine, andaripiprazole have shown efficacy at blockingdopamineagonist-inducedincreases inlocomo-tor activity and apomorphine-induced climb-ing [81–83].Athigherdoses,bothapomorphine


and amphetamine can induce stereotypic be-havior. Unlike the locomotor effects, stereoty-pic behavior may be mediated by mesostriataldopaminepathways. For example, direct injec-tion of apomorphine into the caudate inducedstereotypic behavior whereas infusion into thenucleus accumbens increased locomotor activ-ity [78]. Interestingly, typicalandatypicalanti-psychotics show differential effects on mesos-triatal and mesolimbic dopamine pathways.For example, Chiodo and Bunney (1983) de-monstrated that chronic treatment with anti-psychotics can differentially affect mesolimbicand mesostriatal dopamine neurons such thattypical neuroleptics which induce EPS inacti-vate mesolimbic and mesostriatal neuronswhereas clozapine,which lacksEPS, increasesmesostriatal anddecreasesmesolimbic cell fir-ing [84].This findingis in linewiththe ideathatmesolimbic dopamine systems may be hyper-active in schizophrenia whereas inhibition ofmesostriatal dopamine, indicative of typicalantipsychotics,maycauseextrapyramidal sideeffects.Thuswhenevaluatingagentswithanti-psychotic potential, one method employed hasbeen to couple locomotor activity with stereo-typic behavior in an attempt to differentiate amesostriatal versus a mesolimbic mechanismof action.

Dopamine-based models have long beenused for the evaluation of antipsychotic med-ications. These models capture some of thebehavioral aspects of schizophrenia, particu-larly positive symptoms. In addition, the useof amphetamine, which causes release of do-pamine, may mimic a hyperdopaminergicstate hypothesized to be important in thepathology. Finally, the use of antipsychoticmedications, particularly dopamine antago-nists are effective in these models. However,these models do posses some drawbacks. Forexample, they may not capture negative orcognitive aspects of schizophrenia. Thismodelmay show bias toward antipsychotics with adirect dopamine action. Finally, both amphe-tamine and apomorphine-induced behavioraleffects can be altered by nondopaminergicagents including serotonin agonists, picrotox-in, H3 antagonist and sigma1 receptor mod-ulators [83,85–87]. Since the effectiveness ofthese compounds in schizophrenia has not

been proven it is unclear as to the true pre-dicative validity of these models.NMDA Model [88] The finding that PCP ad-ministration caused a psychopathology simi-lar to that seen in schizophrenic indivi-duals [16] paved the way for a new hypothesisof schizophrenia, NMDA hypofunction. Ac-cordingly, use of the NMDA antagonist PCPand later ketamine have been utilized in ro-dents as amodel of schizophrenia. Although itis impossible to completely recapitulate thebehavioral effects of schizophrenia in any sin-gle animal model, the PCP/ketamine modelmay have some interesting advantages. Un-like amphetamine-induced psychosis, inhibi-tion of NMDA receptors may address someaspects of both negative and cognitive deficitsin schizophrenia. For example, inhibition ofNMDA receptor function in humans can dis-rupt cognitive function as measured by per-formance on the Wisconsin card sort and def-icits in delayed recall and verbal fluency. Si-milarly, both MK-801 [89] and PCP [90] havebeen shown todisrupt attentional set-shifting,a rodent analog to the Wisconsin card sortingtask. Although both acute and chronic admin-istration of NMDA antagonists result in cog-nitive deficits, chronic administration mayinduce a hypofunction of the prefrontal cortexand therefore be more representative of cog-nitive deficits seen in schizophrenic pa-tients [88]. NMDA antagonists also disruptbehaviors in rodents that can be linked tonegative symptoms in schizophrenia such associal withdrawal and depression. ChronicPCP administration enhances immobility inthe forced swim test [91,92], a model of beha-vioral despair [93]. This effect was reversed byadministration of atypical but not typical anti-psychotics [92]. In addition, it was shown thatPCP administration, but not amphetamine,caused social withdrawal in rats. It has beensuggested that this model may detect theability of an antipsychotic to treat negativesymptoms in schizophrenia [94].

One way to validate animal models ofNMDAhypofunction is to block the behavioraleffect of acute PCP administration in humansor alleviate behavioral symptoms in schizo-phrenics. However, data obtained show lim-ited and conflicting efficacy in human studies.For example, data from Lahti et al. demon-

ANIMAL MODELS 11

strated that haloperidol failed to block keta-mine-induced psychosis [95]. Malhotra et al.showed that clozapine blunted ketamine-in-duced positive symptoms but had no effect onnegative symptoms in schizophrenic indivi-duals [96]. Interestingly, clozapine may bemore effective in reversing PCP-induced def-icits in rodents when compared to haloperi-dol [88] consistent with animal studies.

4.1.2. Behavioral Models

Prepulse Inhibition Abnormalities in infor-mation processing and attention are charac-teristics of schizophrenia. Startle reflex, ameasure of information processing, refers tothe ability of a prepulse signal to inhibit asubsequent startle evoked by a secondary sig-nal. This process involves an inhibitory sen-sory/motor mechanism mediated by the pre-frontal cortex. PPI, an experimental measureof this phenomenon, is commonly used toevaluate sensory motor gating in animals andhumans. Schizophrenia patients show a defi-cit in the PPI response [97]. In animalmodels,PPI can be measured by delivering a prepulse(tone) followed by a louder tone to induce astartle. Decreasing the PPI can be induced bypharmacological agents (amphetamine andNMDA inhibition), developmental manipula-tions (isolation rearing) and genetic differ-ences among rodent strains (C57Bl6 miceshow PPI deficits).

Antipsychotic medications can reverse PPIdeficits in schizophrenia patients. Most nota-ble are clozapine and risperidone that may besuperior to typical antipsychotics medicationsat reversing this PPI deficit. This finding mayextend to animal models. For example, PPIdeficits caused by social isolation and amphe-tamine are reversed by most typical and aty-pical antipsychotics with equal efficacy. How-ever, atypical antipsychotics appear superiorat reversing PPI deficits induced by serotoninand NMDA antagonists [98]. This is consis-tent with the hypothesis that schizophreniaresults from a disruption of multiple neuro-transmitter systems and atypical antipsycho-tic medications antagonize a number ofreceptors to these transmitters. Overall, PPIremains a primary model to evaluate the effi-cacy of novel antipsychotic medications,

particularly those with differing mechanismsof action.Latent Inhibition [99] Attention is an aspectof executive function that allows an individualto filter out or inhibit unnecessary or irrele-vant information. Cognitive deficits in schizo-phrenia involve multiple aspects of executivefunction including attention. Latent inhibi-tion is a term used to describe a phenomenawhereby an individual or animal, whenrepeatedly presented with a stimulus in theabsence of a reinforcer (positive or negative)will decrease interest in that stimulus. A pri-mary mechanism driving latent inhibition in-volves attention and the ability to filter outsensory information from the continually pre-sented stimuli. Elevations in the basal dopa-mine state decrease measures of latentinhibition, consistent with the dopamine hy-pothesis of schizophrenia. For example, inhealthy volunteers, dopamine agonists dis-rupt latent inhibition [100,101]. Acutelypsychotic schizophrenia patients show a dis-ruption in this measure [102,103]. As in hu-mans, an alteration in the latent inhibitionfollowing treatment with dopamine agonistsand antipsychotic medications is seen in ani-mals [104]. Animal models of latent inhibitionalso have predictive ability as both typical andatypical antipsychotics enhance latent inhibi-tion [99]. Unlike PPI, blockade of NMDA re-ceptors does not decrease measures of latentinhibition. For example, Weiner and Feldon(1992) showed no effects of PCP in an animalmodel of latent inhibition [105]. Similar re-sults have been seen with other NMDA an-tagonists including ketamine and MK-801 [106,107]. Based on these findings it canbe suggested that NMDA function does notcontribute to the biological mechanismunderlying this measure of attention. How-ever, it has been proposed that NMDAinhibition does affect the latent inhibition byinducing a preservative response caused by aninability to “switch” from the initial stimulusto the conditioned stimulus [108]. Thus, basedon this hypothesis and the observation thatPPI does not require a condition stimulus ithas been suggested that these models are notmutually exclusive but may utilize discretelydifferent neurotransmitter systems and neu-ronal circuits.


Conditioned Avoidance [109] As stated pre-viously, the first suggestion that chlorproma-zine had antipsychotic properties was cap-tured in an animal model of condition avoid-ance [3]. In a conditioned avoidance model,animals are trained to perform a specific re-sponse to avoid an adverse event (e.g., shock).These responses can involve active (e.g., levelpressing) or passive (remaining in a specificchamber) behaviors. This behavioral para-digm is believed to be mediated largely by themesocorticolimbic dopaminergic system.Anti-psychotic medications reduce the avoidanceresponse at doses that do not impair normalmotor function. Both typical antipsychotics (e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine, risperidone, ziprasidone andaripiprazole) have all shown positive resultsin an animal model of conditioned avoid-ance [110–112]. Response in the conditionedavoidance and catalepsy (both D2-mediatedresponses) can be differentiated based on theextent of occupancy of the D2 receptor (i.e.,>80% causing catalepsy [113,114]). Althoughthe conditioned avoidance response has beenused as a primary screening tool for develop-ment of antipsychotic medication it does pre-sent some issues. First, false positives (e.g.,morphine) have been identified in this model.Second, this model does not clearly differenti-ate between typical and atypical antipsycho-tics. Third, antipsychotic medications are ef-fective following acute dosingwhereas chronicuse is needed for efficacy in schizophrenicpatients. Finally, dopaminergic mechanismare likely the primary driver of this behaviorand therefore this model may be limited inpredicting efficacy for negative and cognitivedomains of the disease.Drug Discrimination Drug discrimination isa commonly used model for evaluating drugreceptor interactions. This model uses a re-ference compound to train an animal to give aspecific response when the reference drug isadministered (e.g., lever press). Following thistraining a new drug is substituted for thereference drug. If the same behavioral re-sponse is produced it can be said the testcompound pharmacologically acts at the samereceptor(s) or in a similar manner. Althoughthis model does not have direct pathophysio-logical or biological links to schizophrenia it is

an effective way to determine if a test com-pound has a similar pharmacology to a refer-ence compound.

4.1.3. Genetic Based Models Pharmacologi-calmanipulation of neurotransmitter systemsis one approach to modeling the pathology ofschizophrenia. Alternatively, candidate genesassociated with schizophrenia can be deletedin mice to determine the effect on behavior.This type of genetic knockout approach hasbeen used in an attempt to model schizophre-nia. Below is a list of selected genes that havebeen associated with schizophrenia and havebeen deleted in mice. For further review, seeRef. [115].Dysbindin Dysbindin (DTNBP1, dystrobre-vin binding protein1), a protein that interactswith dystrobrevins, was identified in 2001 byBenson et al. This protein was shown to beexpressed in neurons within the brain parti-cularly the hippocampus [116]. An associationbetween schizophrenia and single nucleotidepolymorphismswithin the dysbindin gene hasbeen reported [117]. In postmortem studies ofschizophrenic brain samples significant re-ductions in dysbindin immunoreactivity with-in glutaminergic fields in the hippocampushas been seen [118]. In this latter study, itwas hypothesized that disruption in dysbin-din may alter normal neurotransmissionwithin the hippocampus an effect that maycontribute to cognitive deficits in schizophre-nia [118]. A spontaneous mutation in the dys-bindin gene has been identified in mice (sdymouse). Thesemice display decreased locomo-tor activity and decreased social interactionand may represent an animal model of thenegative symptoms associated with schizo-phrenia [119]. However, additional links toschizophrenia or the effect of antipsychoticmedications in these mice has yet to bereported.DISC1 Previous studies have identified spe-cific chromosomal regions associated schizo-phrenia. One of these regions is on chromo-some 1 (1q42) where a balanced (1;11) (q42.1;q14.3) translocation event has been asso-ciated with a psychopathology seen in schizo-phrenia aswell as depression [120]. Two genesthat fall within this disrupted region havebeen termed disrupted-in-schizophrenia 1

ANIMAL MODELS 13

and 2 (DISC1 and DISC2 [121]). Multiplestudies have linked alterations in the DISC1gene with schizophrenia. For example, aframe shift mutation in the DISC1 gene re-sulting in a nonfunctional truncated productwas associated with individuals having schi-zophrenia or schizoaffective disorder [122].

In an attempt to determine the effects ofDISC1 disruption on behavior, multiplegroups have generated mice with an alteredDISC1 gene. For example, Li et al. (2007)generated transgeneic mice with an induciblec-terminal fragment of the DISC1 gene that,when expressed, can inhibit normal functionof DISC1 [123]. Behavioral analysis of thesemice demonstrated that when the DISC1 mu-tant was expressed during early postnataldevelopment, deficits in spatialworkingmem-ory, depressive traits, and social deficits werepresent [123]. Clapcote et al. generated twoDISC1 mutants using N-nitroso-N-ethylureamutagenesis. Of these mutants one showedprofound deficits in PPI and LI latent inhibi-tion both of which were reversed by haloper-idol and clozapine [124].Other Genes A number of other susceptibil-ity genes have also been identified in schizo-phrenic populations. These include, but arenot limited to, catechol-O-methyltransferase(COMT(), neuregulin 1 (NGR1), proline dehy-drogenase (ProDH), regulator of G-proteinsignaling 4 (RGS-4) and trance amine receptor4 (TAR4), [115,125]. As with the pharmacolo-gicalmodels outlined above, no one gene likelyrepresents the sole causative factor for schizo-phrenia. Moreover, the findings related tospecific genes are often difficult to reproducein genetic population studies adding addi-tional complexity to the issue. For animalmodels, the mechanism of gene alteration (i.e., conditionknockout, embryonic knockout, orregional knockout)may results in confoundingartifacts such as compensatory up regulationof alternate genes or effects in multiple cellstypes. In addition, expression and subsequentprotein function can be altered in a mannerindependent of any DNA anomalies (i.e., mu-tations or truncations). For example, epige-netic mechanisms (e.g., DNA methylation orhistone acetylation) can affect overall proteinexpression without any detectable changes inthe DNA sequence. For example, Costa et al.

hypothesize that decreased expression of spe-cific genes (e.g., GAD67 and reelin) seen inschizophrenia results not from alteration inthe DNA but from hypermethylation of thepromoter regions of these genes [126].

In summary, the genetic models representa powerful tool for understandingpathologicalmechanisms and antipsychotic action in rela-tion to schizophrenia. As with any experimen-tal tool, interpretation of findings and predic-tion of antipsychotic efficacy data must bedone with an awareness of limitations andcaveats of these models.

4.1.4. Electroencephalogram (EEG) [127] Anemerging area of study, relating to cognitivedeficits, is EEG changes reported in schizo-phrenic patients. EEG recordings reflect syn-chronization of neuronal firing within specificcortical areas. Resting EEG recordings can bedivided into multiple frequencies rangingfrom low frequency theta (<5Hz) to high fre-quency gamma (�40Hz) oscillations. It hasbeen proposed that changes in gamma oscilla-tionsmay be ameasure of attention andmain-tenance of working memory in humans [128].In schizophrenic patients, evaluation ofevoked gamma band oscillations shows anoverall deficit in EEG power at 40Hz whencompared to nonschizophrenic patients, aneffect hypothesized to result from deficits inGABAergic interneurons that help to synchro-nize neuronal firing [129,130].

Changes in positive and negative voltagedeflections in response to presentation of astimulus (visual or auditory) can also beenmeasured by EEG. These evoked relatedpotentials (ERPs) can be further divided intoearly events (deflections that occur within thefirst 50ms which may reflect sensory-evokedresponses) and later events (deflections thatoccur within 300–400ms and may reflect cog-nitive-related components) [127]. Like gammaoscillations alterations in ERP both early(positive deflection at 50ms; P50) and late(positive deflections at 300ms; P300) havebeen reported in schizophrenic patients. Asthese measures represent a nonevasive toolfor evaluating cognitive function in patients,the potential to develop a translatable animalmodel remains intriguing; however, issueswith regard to animal models remain. For


example, no deflection is seen in animals at50ms although deflections can be recorded atother time points (e.g., 40 milliseconds). How-ever, the relationship between these changesand those seen at 50ms in human remains tobe determined [131].

4.2. Model of Side Effects

4.2.1. Catalepsy Catalepsy refers to a drug-induced behavioral state whereby an animalplaced inanawkward statewill remain in thatposition. Typical protocols for evaluation ofcatalepsy in rodents involve placing the frontpaws on an elevated platform and measuringthe length of time the animal remains in thisfixed position. This effect can be induced inanimals by administration of a D2 receptorantagonist, with haloperidol being the mostcommonly used agent. All typical antipsycho-tics induce a cataleptic state, likely reflectingtheir potent effects at the D2 receptor. Neweratypical antipsychotics have been shown toinduce catalepsy only at high doses. Thus,catalepsy may represent a method for linkingD2 receptor antagonism with a behavioraleffect. As potent inhibition of D2 receptorsmay represent the mechanism for EPS (seeabove) this model is often used as a predictorof EPS potential with novel antipsychotics.Newer atypical agents appear to have mini-mal effects on catalepsy measures possiblydue to their decreased affinity for the D2receptor.

4.2.2. Paw Test The paw test relies on thenatural tendency of an animal to retract anextended limb. The test is conducted by pla-cing the two forelimbs and two hind limbs intofour separate holes and measuring the fore-limb and hind limb retraction time (FRT andHRT, respectively). Typical antipsychoticssuch as haloperidol increased FRT and HRTwith equal potencies whereas clozapine in-creased HRT at lower doses than are neededto increase FRT. Agents with no antipsychoticactivity including diazepam, morphine anddesipramine show no effect in the pawtest [132]. With this model it is believed thatthe ability of drugs to prolong FRT is asso-ciated with a more potent inhibition of dopa-mine receptors in the dorsal striatum. In con-

trast, increased HRT may be associated withinhibition of dopamine receptors within thedorsal striatum, accumbens and olfactory tu-bercle [133]. Although most antipsychoticsshow activity in this assay it is not widelyused for evaluation and screening of novelantipsychotic medications.

4.2.3. Vacuous Chewing Movements In pa-tients treatedwith antipsychoticmedications,development of a late onset phenomenon,tardive dyskensia (TD; see above) character-ized by repetitive, choreic, involuntary, andstereotypic behavior can develop. Develop-ment of TD is hypothesized to be related toboth the percent and manner in which the D2receptors are inhibited [134]. In rodents vac-uous chewing movements (VCMs), purpose-less movements of the mouth in the verticalplane with or without protrusion of the ton-gue, are believed to represent a model of TD.As with patients, chronic treatment withtypical antipsychotics can result in the devel-opment of these abnormal facial movements.Typical antipsychotics show more develop-ment of VCM than classical atypical antipsy-chotics. For example, Gao et al. showed thatchronic treatment with haloperidol to ratsresults in development of VCM whereas olan-zapine and sertindole, administered for thesame time period, did not result in a highincidence of oral dyskinesias, an effect consis-tent with human data [135]. Based on therelative low cost of this assay it remains aviable option for evaluation of development ofTDS for antipsychotic medications.

4.2.4. Prolactin Response [72] Under basalconditions dopamine inhibits prolactin re-lease. This effect is mediated by D2 receptorsin the pituitary. As such, administration ofagents that inhibit D2 receptor activity willresult in increased prolactin release. Typicalantipsychotics tend to increase prolactin le-vels in a dose-dependent manner reflectingtheir potent inhibition of D2 receptors. Most,but not all, atypical antipsychotics, show littleeffect of prolactin levels in schizophrenic po-pulations. Of note are risperidone and ami-sulpride that cause significant increases inserum prolactin (for review, see Ref. [72]). Inanimal models the effect on prolactin is less

ANIMAL MODELS 15

clear. For example, following acute adminis-tration olazapine and risperidone both in-crease prolactin to a level comparable to ha-loperidol, although risperidone was more po-tent. Following chronic administration bothrisperidone and olazapine increased prolactinalthough the magnitude of effect may havebeen greater with risperidone [136]. In analternate study it was demonstrated that ola-zapine but not aripiprazole increased prolac-tin secretion in rats, an effect consistent withthe lack of effect of aripiprazole on prolactin inhumans [137]. Thus, it would appear thatanimal models mimic, but do not replicatefindings in schizophrenic populations. Thiscould be due to numerous factors includingacute versus chronic administration, stress ordifferences in drug exposure.

5. FDA APPROVED ANTIPSYCHOTICDRUGS

5.1. Introduction

Older antipsychotic drugs included opiates,belladonna derivatives, bromides, barbitu-rates, antihistamines, and chloral hydrates.The first conventional antipsychotic drugchlorpromazine became available in 1952.Prochlorperazine, an analog of chlorproma-zine, is now available as a generic drug. An-other conventional antipsychotic drug halo-peridol was discovered in 1958. Distinctivefrom chlorpromazine, haloperidol is a butyr-ophenone derivative which ismore potent andhas fewer side effects. Haloperidol remainedone of the most prescribed neuroleptics 40years after its discovery until the emergenceof atypical antipsychotics. Unfortunately, con-ventional antipsychotic drugs are all liable tocause severe extrapyramidal symptoms(EPSs) including parkinsonian symptoms,akathisia, dyskinesia, and dystonia.

Atypical antipsychotics, also known as ser-otonin–dopamine antagonists, effectively re-duce EPS. They are also believed to reduce thenegative, cognitive, and affective symptoms ofschizophrenia more effectively. All atypicalantipsychotics are potent antagonists of ser-otonin 5-HT2A and dopamine D2 receptors,however, they also act on many other recep-

tors includingmultiple serotonin receptors (5-HT1A, 5-HT1B/1D, 5-HT2C, 5-HT3, 5-HT6, and5-HT7), the noradrenergic system (a1 and a2),the cholinergic system (M1), and the hista-mine receptors (H1). It has been postulatedthat the additional 5-HT1A agonist activityshown by several atypical antipsychoticagents could reduce EPS and alleviate theanxiety that often precipitates psychotic epi-sodes in schizophrenia patients. The chal-lenge remains to determine which of thesesecondary pharmacological properties maylead to improved efficacy and which are un-desired and account for the side effects. Clo-zapine, the first atypical antipsychotic, be-came available in 1959 and was followed byrisperidone in 1993 and olanzapine in 1996.Additional atypical antipsychotics includequetiapine, ziprasidone, aripiprazole, zote-pine, sertindole, and paliperidone. Among theFDA approved antipsychotics drugs, there aretwo types, namely, conventional antipsychoticagents and atypical antipsychotics [138–142].

5.2. Conventional Antipsychotic Drugs

There are currently three conventionalantipsychotic agents on the market, chlorpro-mazine (1), prochlorperazine (2), and haloper-idol (3).

N

S

NMe2

Cl

1, Chloropromazine

The genesis of chlorpromazine (1) can betraced back to antihistamines: diphenhydra-mines in general and Benadryl in particular.The first was promethazine, an antihista-mine. Systematic structure–activity relation-ship(SAR) investigations by enhancingpromethazine’s “side effects” in the >centralnervous system (CNS) led to the synthesis ofchlorpromazine in 1950. The structure ofchlorpromazine differed only slightly fromthat of promethazine. Chlorpromazine (1) hasan extra chlorine atom and a slight difference


in the diamine side chain. It was introduced in1952, in France and in 1954 in the UnitedStates under the trademark “Thorazine�.” Inthe first 8 months, more than 2 million pa-tients were administered the drug. It contrib-uted to an 80% reduction of the resident po-pulation inmental hospitals. Thorazine addeda great impetus to the beginning of the psy-chopharmacological revolution. Subse-quently, chlorpromazine (1) was shown to bea potent dopamine 2 receptor (D2), antagonist(Ki¼ 3nM) with other pharmacological prop-erties that were thought to cause unwantedside effects. Thus, theD2-receptor antagonismof the conventional antipsychoticmediatesnotonly their therapeutic effects but also some oftheir side effects.

2, Prochlorperazine

N

S

N

Cl

NMe

Prochlorperazine (2) has been approved forthe control of severe nausea and vomiting andfor management of the manifestations of psy-chotic disorders. It is effective for the short-term treatment of generalized nonpsychoticanxiety.

N

3, Haloperidol

Cl

HOO

F

Haloperidol (3) is 50–100 times more po-tent than chlorpromazine (1) and a more se-lective D2 antagonist. The D2-receptor block-ade in the mesolimbic pathway is believed toreduce the positive symptoms of schizophre-nia. More importantly, it was almost devoid ofthe antiadrenergic and other autonomic ef-fects of chlorpromazine (1). However, haloper-

idol (3) is ineffective in treating the negativesymptoms and neurocognitive deficits of schi-zophrenia. In addition, administration of thedrug typically causes EPS. Thus, the D2-re-ceptor antagonism of the conventional anti-psychoticsmediates not only their therapeuticeffects but also some of their side effects.

With the discovery of newer atypical anti-psychotics, the older conventional antipsycho-tics are no longer used for first-line therapy,but can still be effective as second-line or add-on treatments.

5.3. Atypical Antipsychotic Drugs

Atypical antipsychotics, sometimes called ser-otonin–dopamine antagonists (SDAs) reduceEPS compared with conventional antipsycho-tics and are also believed to more effectivelyreduce negative, cognitive, and affectivesymptoms of schizophrenia. All atypical anti-psychotics are potent antagonists of serotonin5-HT2A and dopamine D2 receptors, however,they also act on many other receptors includ-ing multiple serotonin receptors (5-HT1A,5-HT1B/1D, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7),the noradrenergic system (a1 and a2), thecholinergic system (M1), and the histaminereceptors (H1). The challenge remains to de-termine which of these secondary pharmaco-logic properties may be synergistic leading toimproved efficacy, and which are undesiredand account for the side effects. It is generallyaccepted that anatypical antipsychotic shouldcombine a minimum of 5-HT2A antagonismwith D2 antagonism in order to provide in-creased efficacy with fewer side effects. Ser-otonin–dopamine antagonists, but not con-ventional antipsychotics (dopamine antago-nist without 5-HT2A antagonism), increasedopamine release in the mesocortical path-way. This provides a possible explanation forthe improved efficacy of atypical antipsycho-tics in the treatment of negative symptoms ofschizophrenia. Furthermore, 5-HT2A antag-onism in the nigrostriatal pathway is believedto reduce EPS and tardive dyskinesia becausedopamine release from this pathway is regu-lated by serotonin. If serotonin is not presentat its 5-HT2A-receptor on the nigrostriataldopaminergic neuron, then dopamine is re-leased. Compounds 4–11 represent atypical

FDA APPROVED ANTIPSYCHOTIC DRUGS 17

antipsychotics currently available on themarket.

N

HN

N

NMe

Cl

4, Clozapine

Clozapine (4), the first atypical antipsycho-tic was synthesized in 1967 by Sandoz–Wan-der chemists and marketed in 1972. It wasremoved from themarket in 1975 due to drug-associated agranulocytosis, a potentially fatalblood disorder that results in lowered white-cell counts, which occurred in approximately2–3% of patients. Additional side effects ofclozapine therapy include sedation (H1),weight gain (5-HT2C) and orthostatic hypoten-sion (a1). Clozapine (4) was reintroduced in1990 and is now relegated as a second-linetreatment with extensive monitoring of thepatient’s blood cell count. However, over theyears it has demonstrated efficacy againsttreatment-resistant schizophrenia and somestill consider it to be the gold standard fortreatment-refractory patients.

N

HN

S

N

Me

NMe

5, Olanzapine

Olanzapine (5) is a close analog of clozapine(4) where one of the benzene rings of thetricyclic nucleus is replaced with a methyl-thiophene ring. It has high affinity for the 5-HT2A, 5-HT2C, H1 and M1 receptors and mod-erate affinity for the D2 and a1 receptors.Olanzapine (5) is associated with high levelsof weight gain (second only to clozapine) and italso causes some EPS at higher doses.

Similar to clonazapine (4) and olanzapine(5), risperidone (6), paliperidone (7), ziprasi-

done (8), and quetiapine (9) are currentlyconsidered four additional first-line drugs forpsychosis and they will be highlighted in de-tail in this chapter. The newest antipsychoticto make its way to the market is aripiprazole(10). It has a slightly different mechanism ofaction than the atypical antipsychotic drugs inthat it is a D2 partial agonist rather than a fullantagonist. Each of these drugs has a uniquepharmacological and clinical profile thereforethe clinician must balance the benefit-riskfactors for each patient in determining whichdrug to prescribe.

N

N

ON

O N

F

Me

6, Risperidone

Risperidone (6) has high affinity for D2, 5-HT2C and a1 receptors and a very high affinityfor the 5-HT2A receptor. It is the most likely ofthe atypical antipsychotics to cause prolactinincreases, but has a lowerweight gain liabilitythan olanzapine (5) or quetiapine (9). Risper-idone (6) has a relatively narrow therapeuticwindow since doses above 6mg/day causeEPSin a dose-dependent manner.

N

N

ON

O N

F

Me

7, Paliperidone OH

Paliperidone (7), a major active metaboliteof risperidone (6) is a close analog of risper-idone (6) and was approved in 2006 for thetreatment of schizophrenia [140,141]. Paliper-idone (7) is an antagonist and thus interfereswith neurotransmitter communication in thebrain. It blocks D2, 5-HT, and a2 adrenergicreceptors, all of which have been implicated inschizophrenia.


8, Ziprasidone

NN

S N

Cl NH

O

Ziprasidone (8) has high affinity for the D2

receptor, but even higher affinity for 5-HT2A

and 5-HT2C receptors. Unlike other atypicalantipsychotics, ziprasidone (8) also has potent5-HT1B/1D antagonist and 5-HT1A partial ago-nist activity, as well as moderate SRI/NRIactivity. This receptor profile suggests thatziprasidone (8) may be useful in relievingsome of the depressive/anxious symptoms ofschizophrenia. It hasmoderate affinity for theH1 and a1 receptors and negligible affinity fortheM1 receptor. Ziprasidone (8) is more likelyto increase the QTc interval than other atypi-cal antipsychotics, but it appears to have thelowest liability for body weight gain.

N

S

N

N

OOH

9, Quetiapine fumarate

HOOC

COOH

Quetiapine (9) has the lowest affinity forthe D2 and 5-HT2A receptors among the aty-picals, and therefore relatively high doses arerequired for maximal efficacy. It causes sig-nificant weight gain, but less than that ofolanzapine (5). Other side effects include se-dation, dizziness, and hypotension.

NH

OON

NCl

Cl

10, Aripiprazole

Aripiprazole (10) is a D2 partial agonistwith an intrinsic activity of approximately30%. Therefore, it acts as an agonist on pre-synaptic autoreceptors, which have a highreceptor reserve, and as an antagonist on D2

postsynaptic receptors, where significant le-vels of endogenousdopamineexist and there isno receptor reserve. The intrinsic activity of30% for aripiprazole (10) preventsD2 blockadefromrisingmore than70%,which ismore thanthe 65% D2 occupancy needed for a clinicalresponse but lower than the 80%D2 occupancywhere EPS is observed. Consistent with thispartial agonist mechanism, EPS was not ob-served with aripiprazole even when striatalD2 receptor occupancy values where morethan 90%. Aripiprazole (10) can be consideredatypical since it is also an antagonist at 5-HT2A receptors. It is also a partial agonist at 5-HT1A receptors which may provide some ben-efit against some of the negative symptoms ofschizophrenia. Preliminary clinical studieshave demonstrated that aripiprazole (10) iswell tolerated and does not significantly in-duce EPS, weight gain, QT prolongation, orincrease plasma prolactin levels.

NN

N

NHO

F

Cl

11, Sertindole

Sertindole (11), introduced in 1996, alsobelongs to this class of atypical antipsychotics,however, it is used less frequently. It has beenshown to be efficacious for the treatment ofpositive and negative symptoms of schizo-phrenia.However, sertindole (11) has recentlybeen withdrawn from the market because itcauses significant prolongation of the QTcinterval that may lead to a ventriculararrhythmia known as torsades des pointes.

Much remains to be discovered about theunderlying pathophysiology of schizophreniaand there is still a great need for medicinal

FDA APPROVED ANTIPSYCHOTIC DRUGS 19

chemists to develop more selective drugs thataredevoid of clinically limiting side effects andalso address the cognitive impairmentsymptoms.

6. STRUCTURE–ACTIVITY RELATIONSHIPS

6.1. Drug Classes

In this section, we only summarize the struc-ture–-activity relationship of atypical antipsy-chotics because little effort is on-going in bothacademia and industry on conventional anti-psychotic drugs. Old drug classes are not cov-ered to give room formore coverage of atypicalantipsychotics. The reader is referred to ear-lier editions for the structure–activity rela-tionship of phenothiazines, thioxanthene, andbutyrophenones. The SAR discussion is fo-cused on atypical tricyclic neuroleptics andbenzisoxazole, benzithiazole and related aty-pical neuroleptics. In comparison to conven-tional antipsychotic drugs known as potentD2

antagonists, atypical neuroleptics have atleast two distinctive features: an affinity forboth the serotonin 2 receptor (5-HT2) and D2

receptor, thus the name serotonin–dopamineantagonists.

6.2. Atypical Tricyclic Neuroleptics

Further scrutiny of the full spectrum of phar-macology revealed that both conventionalantipsychotic drugs and atypical neurolepticsmodulate many G-protein coupled receptors(GPCRs) with different degrees of potency.Conventional antipsychotic drugs have atleast four actions: blockade of D2, blockadeof muscarinic cholinergic receptors (M1),blockade of a adrenergic receptors (a1), andblockade of histamine receptors (H1), whichexplains the antihistaminic actions of the con-

ventional antipsychotic drugs. On the otherhand, atypical neuroleptics have even morecomplicated pharmacology. In addition to5-HT2 and D2, they are known to have at leastfour other pharmacological actions: blockadeof D (D4 and D1), a (a1, a2), M1, and H1.

N

X

N

NMe

Cl

4, X = NH, clozapine12, X = O, loxapine13, X = CH2, perlapine

N

S

N

N

OOH9, Quetiapine

N

HN

S

N

Me

NMe

5, Olanzapine

Shown in Table 1 are the dissociation con-stants (pKi) of atypical tricyclic neuroleptics.Because the values of IC50 and dissociationconstants are dependent upon the radio-la-beled ligands used and themethods employed;therefore, intrinsic dissociation constants area better indication of the structure–activityrelationship. Shown in Table 1 is the struc-ture–activity relationship of many popularatypical tricyclic neuroleptics including cloza-pine (4), olanzapine (5), quetiapine (9), loxa-pine (12), and perlapine (13) [143–146].

Clozapine (4) is the prototype of atypicalantipsychotics. According to Meltzer’s“5TH2A/D2 hypothesis [147],” compounds hav-ing a pKi ratio for 5TH2A/D2 higher than 1.2fall into the category of atypical antipsycho-

Table 1. Dissociation Constants (Ki) of Atypical Tricyclic Neuroleptics

D2 (nM) D4 (nM) 5-HT2A (nM) KD2/K5-HT2A KD2/KD4

Clozapine (4) 44 1.6 11 4.00 28.00Loxapine (12) 5.2 7.8 10.2 0.51 0.67Perlapine (13) 60 30 30 2.00 2.00Olanzapine (5) 3.7 2 5.8 0.64 1.85Quetiapine (9) 310 1600 120 2.58 0.19


tics; therefore, clozapine (4) is an atypicalantipsychotic. Because the affinity of cloza-pine (4) for a 5-HT2 receptor is twice as highas for the dopamine D2 receptors suggests afavorable property of atypical antipsychoticsin that development of EPS caused by block-ade of dopamine D2 receptors is countered byblockade of central 5-HT2 receptors. Blockadeof 5-HT2 receptors has also been suggested tobe beneficial for treating the negative symp-toms of schizophrenia. Clozapine (4) has anexceedingly complex pharmacology, interact-ing with high to moderate potency at the D4

receptor, 5-HT2A, 5-HT2C receptors, acetylcho-line (muscarinic) receptors, adrenergic (a 1,a2,and a3) receptors, and histamine (H1) recep-tors, as well as other receptors. Its analogs5–19 possess an array of pharmacological ac-tivities. For example, loxapine (12) andclothiapine (17) are typical antipsychotics;and perlapine (13) is a hypnotic [148].

Loxapine (12) is the direct analog of cloza-pine (4) whose NH fragment is replaced byoxygen. Loxapine (12) is more potent thanclozapine (4) for theD2 receptor (5.2 nMversus44nM), but is less potent at the D4 receptor(7.8 nM versus 1.6 nM). As a consequence, theratios of KD2/KD4 are drastically different(0.67 versus 28.00), which also reflect theirrespective pharmacological and side effectprofiles. Interestingly, chronic administrationof loxapine (12) and clozapine (4) to rats for 4weeks or 10 weeks did not produce enhance-ment of striatal dopamine receptor den-sity [149]. However, there was a marked re-duction (50–60%)of cortical serotonin receptordensity associated with loxapine (12) or clo-zapine (4) administration. Acute doses of lox-apine (12) and clozapine (4) produced thesame potent effect. The possibility that thesetwo antipsychotic drugs act via the serotoninsystem in the brain has been proposed. Perla-pine (13), an old drug discovered in the 1970sasa sleep-promotingand sedativeagent, is thecarbon-analog of clozapine (4) that hasweakerbinding to the D2, D4, and 5-HT2A receptors.Although it was initially reported to lack anti-psychotic efficacy, comparison of perlapine(13) with chlorpromazine (1), haloperidol (3)and clozapine (4) was carried out with regardto dopamine metabolism [150]. All four drugsproduced a dose-dependent increase in levels

of 3,4-dihydroxyphenylacetic acid (DOPAC) intwo dopamine-rich structures, striatum andtuberculum olfactorium of rat. The potency ofperlapine (13) was similar to that of chlorpro-mazine (1).

Olanzapine (5) is a close analog of clozapine(4) where one of the benzene rings of thetricyclic nucleus is replaced with a thiophenering. It has high affinity for the 5-HT2A, 5-HT2C, H1 (Ki¼ 0.65nM) andM1 receptors andmoderate affinity for the D2 (Ki¼ 3.7 nM) anda1 receptors which fits well with the “5TH2A/D2 hypothesis.”Olanzapine is less potent as aD4 antagonist relative to its D2-antagonistproperties, compared to clozapine (4). It is alsomuch weaker than clozapine (4) as an a1 (Ki

19 nM versus 7nM), and a2 antagonist rela-tive to D2, D4, or 5TH2A antagonism [151,152].Like clozapine (4), olanzapine (5) has highaffinity for all five muscarinic (M) receptorsubtypes. The anti-M1 (Ki¼ 26nM) appearsto play an important role in the suppressionof EPS although it does cause some EPS athigher doses. In addition, it is associated withhigh levels of weight gain [second only toclozapine (4)]. Recently, olanzapine (5) hasbeen expanded to treat other psychiatric dis-orders such as bipolar disorder, anorexia ner-vosa and mood disorder.

Quetiapine (9) has the lowest affinity forthe D2 and 5-HT2A receptors among the aty-picals, and therefore relatively high doses arerequired for maximal efficacy. However, it isstill a bona fide atypical antipsychotic becauseit has a higher affinity for serotonin (5-HT2A)receptors relative to dopamine (D2) receptorsin the brain [153–155]. Quetiapine’s (9) phar-macological effects appear selective for meso-limbic and mesocortical dopamine systems,which are believed to be the area of the brainresponsible for the therapeutic effects of anti-psychotics. In contrast to most conventionalantipsychotics and some atypical antipsycho-tics, quetiapine’s (9) effects on the nigrostria-tal dopamine system, which is responsible forthe extrapyramidal (or motor) side effects, areminimal. Furthermore, quetiapine (9) alsohasminimal activity on dopamine receptors in thetuberinfundibular system, thereby avoidingthe problem of hyperprolactinemia, which iscommonwith the standard antipsychotics andsomeatypical antipsychotics. Because of these

STRUCTURE–ACTIVITY RELATIONSHIPS 21

unique pharmacological properties, quetia-pine (9) is an effective atypical antipsychoticagent with a relatively benign side effectprofile.

Shown in Table 2 are the pharmacologicalprofiles of additional atypical tricyclic neuro-leptics. Amoxapine (14) was initially mar-keted as an antidepressant, however, its invitro profile, receptor occupancy and preclini-cal effects were found to be very similar toatypical antipsychotics. Meltzer et al. sug-gested that a combination of high affinity forserotonin (5-HT2) antagonism along withmodest dopamine (D2) antagonism may pro-vide one basis for atypical antipsychosis ac-tivity [151]. A comparative clinical study ofamoxapine with risperidone (6) [156,157] de-monstrated that amoxapine (14) showed effi-cacy as an atypical antipsychotic, improvingpositive, negative, and depressive symptoms.Amoxapine (14) was also associated with less

EPS and less prolactin elevation than risper-idone (6). Since amoxapine (14) is off-patent, itmay be a valuable alternative to new atypicalantipsychotics, especially in low-income coun-

tries where the majority of patients are stilltreated with typical antipsychotics.

Pyridobenzoxazepine JL-13 (15) is the pyr-idyl analog of amoxapine (14) with an addi-tional methyl group on the piperazine ring. Itis slightly more potent than amoxapine (14)although chloro-substitution offered greaterpotency [158]. JL-13 (15) possessed an inter-esting preclinical profile that demonstrated aclozapine-like profile with less side effects;therefore, it could be a potential successor toclozapine (4).

Clothiapine (17), an older drug discoveredin the late 1960s, has a 5TH2A/D2 ratio of 1.10,hence it is a borderline atypical antipsychoticand is considered as an atypical antipsychoticin some literature [159]. A comparative study

N

O

N

NH

Cl

14, Amoxapine

N

O

NN

N

Cl

15, JL-13Me

N

HN

NN

Me

16, Isoclozapine

Cl

N

S

NN

17, Clothiapine

Me

Cl

N

S

NN

18, Isoclothiapine

MeCl

N NN

19, Fluperlapine

MeF

Table 2. Ki Values of D1, D2, and 5-HT Receptor Binding Site and Ratios for Atypical TricyclicNeuroleptics

D1 (nM) D2 (nM) 5-HT2 (nM) D2/D1 5-HT2/D2

Amoxapine (14) 7.2 7.7 8.9 1.08 1.02JL-13 (15) 5.04 4.96 4.65 0.98 0.94Isoclozapine (16) 7.55 7.90 8.75 1.05 1.11Clothiapine (17) 7.85 8.35 9.23 1.06 1.10Isoclothiapine (18) 6.62 7.52 8.38 1.14 1.11Fluperlapine (19) 6.85 6.88 8.41 1.00 1.22


of the effect of clozapine (4) and clothiapine(17) using different preparations of guinea pigand rat isolated organs was carried out [160].It was found that clothiapine (17) was a com-petitive antagonist at the 5-HT receptor, anoncompetitive antagonist at the dopamineand histamine receptors while clozapine (4)was a noncompetitive antagonist at 5-HT,dopamine, and histamine receptors. Interest-ingly, isoclothiapine (18) has a similar phar-macological profile as clothiapine (17)although the position of the chlorine atom has

been switched between the two benzene rings.In addition, isoclothiapine (18) is found to be apotentantagonist of thehistamineH4 receptorand isoclothiapine (18, pKi¼ 5.69) is signifi-cantly less potent as an antagonist for thehistamine H4 receptor in comparison to cloza-pine (4, pKi¼ 6.75) [161].

Fluperlapine (19) is the carbon-analog ofclozapine (4). In the striatum of rats, it bindsless to dopamine D2 receptor sites, but it en-hances dopamine-turnover more than cloza-pine [162,163]. Like clozapine (4) and unlikehaloperidol (3), it is equally active in the stria-tum, the nucleus accumbens and the cortex.Unlike clozapine (4), it does not significantlyenhance noradrenaline (NA) or 5-HT turn-over, and it does not increase prolactin bloodlevels significantly.

PCP and analogs such as ketamine havelong been known to induce schizophrenia-likesymptoms via antagonism of theN-methyl-D-aspartate (NMDA) subtype of glutamate re-ceptors in normal adult subjects. Fluperlapine(19), along with olanzapine (5), loxapine (12),and amoxapine (14), can prevent NMDA an-tagonist neurotoxicity in the rat to mimic theantipsychotic properties of clozapine (4) [164].

6.3. Benzisoxazole, Benzithiazole, andRelated Atypical Neuroleptics

In addition to common pharmacologicalfeatures, most novel atypical neurolepticshave high affinities for additional recep-tors [165]. While clozapine (4) and olanzapine(5) are most potent for the dopamine D1 re-ceptors with Ki values of 53 and 10nM, re-spectively, ziprasidone (8) and sertindole (11)have high relative affinities for 5-HT2C recep-tor withKi values of 0.55 and 0.51nM, respec-tively (Table 3). On the other hand, risperi-done (6) has a high affinity for a2-adrenocep-tors with a Ki value of 1.8 nM.

Risperidone (6), synthesized in 1984 byJanssen Pharmaceuticals, was one of the firstbenzisoxazole atypical neuroleptics and is amixed serotonin–dopamine antagonist. Incomparison to clozapine (4), risperidone (6)has much higher affinity for dopamine D2 and

N

N

ON

O N

F

Me

6, Risperidone

NN

N

NHO

F

Cl

11, Sertindole

8, Ziprasidone

NN

S N

Cl NH

O

STRUCTURE–ACTIVITY RELATIONSHIPS 23

5-HT2 receptors while clozapine (4) only hasmoderate affinity for dopamine D2 and 5-HT2

receptors. Therefore, risperidone (6) is used inlower dose than clozapine (4) because thedoses that are recommended for the treatmentof schizophrenia are related to the dopamineD2 receptor affinity. Resperidone studies indogs reveal potent dopamine-D2 antagonisticactivity with excellent oral bioavailability anda relatively long duration of action [166]. Ris-peridone (6) possesses the complementaryclinical effects of a ritanserin (20)-like seroto-nin-5-HT2 and a haloperidol-like dopamine-D2 antagonist. 5-HT2 antagonism may im-prove the quality of sleep, reduce negative andaffective symptoms in schizophrenic patients,and decrease extrapyramidal symptoms in-duced by classical neuroleptics. Since risper-idone (6) is a dopamine-D2 antagonist, anti-delusional, antihallucinatory, and antimanicactions are expected. Clinical studies indicatethat two additional therapeutic targets, whichare not achieved with classical neuroleptics,may be obtained with risperidone (6) in themonotherapy of schizophrenia and relateddisorders, that being very important contactand mood-elevating properties and EPS-freemaintenance therapy.

N

NS

ON

F

F

20, Ritanserin

Ziprasidone (8) [167,168] appears to discri-minate from other atypical antipsychotics byits low propensity for weight gain and by theavailability of a short-acting intramuscular

formulation. In concert with most atypicalantipsychotics, it has a receptor binding pro-file characterized by high affinity to serotonin(5-HT2A) and dopamine (D2) receptors. How-ever, in contrast to other atypical antipsycho-tics, its binding ismuchmore substantial (�11times) to 5-HT2A than D2. Ziprasidone’s (8)binding profile for serotonin receptors is com-plex and it also has potent affinity for 5-HT1A,5-HT1D, and 5-HT2c. It functions as an agonistat the 5-HT1A receptor and as an antagonist atthe remaining 5-HT receptors. As mentionedbefore, the additional 5-HT1A agonist activityshown by several atypical antipsychoticagents could reduce EPS and alleviate theanxiety that often precipitates psychotic epi-sodes in schizophreniapatients. Furthermore,ziprasidone (8) is also an antagonist at a1-adrenoreceptors. In a manner that is to someextent analogous to the newer antidepressantmedications, it also inhibits reuptake at ser-otonin and norepinephrine receptor sites. Ithas relatively little affinity for histaminergicreceptors.

As a consequence of the aforementionedpharmacological profile, ziprasidone (8) is ef-fective in decreasing the positive and negativesymptoms of schizophrenia, as well as treat-ing symptoms of anxiety and depression thatare often associated with schizophrenia. Thereceptor binding profile (e.g., agonist for 5-HT1A) also predicts a low propensity for ex-trapyramidal side effects. However, it is notsimple to pinpoint which pharmacological at-tributes are responsible for ziprasidone’s (8)weight neutral profile.

Sertindole (11) [169] is a phenylindole-de-rived atypical antipsychotic that has markedaffinity for dopamine D2 receptors, serotonin5-HT2 receptors and a1-adrenoceptors. In-deed, the fundamental mechanism of sertin-dole action is considered to be selective inhibi-tion of dopamine D2 receptors in the mesolim-

Table 3. Ki Values of D1, D2, and 5-HT Receptor Binding Site and Ratios for Benzisoxazole,Benzithiazole, and Related Atypical Neuroleptics

D2 (nM) 5-HT2A (nM) D2/5-HT2A D1 (nM) 5-HT2C (nM)

Risperidone (6) 0.44 0.39 1.13 21 6.4Ziprasidone (8) 2.8 0.25 11.2 9.5 0.55Sertindole (11) 0.45 0.20 2.25 12 0.51


bic system (ventral tegmental area) versus thenigrostriatum, together with inhibition ofCNS serotonin 5-HT2 receptors and a1-adre-noceptors. In vitro studies revealed sertindole(11) to have high affinity for dopamine D2

receptors, 5-HT2A receptors, 5-HT2C, anda1-adrenoceptors, with binding affinities of0.45, 0.20, 0.51, and1.4 nM, respectively [165].Sertindole is an inverse agonist at the 5-HT2C

receptor and has reduced agonist binding tothese receptors [170,171]. It has been sug-gested that this inverse agonism may be amechanism by which atypical antipsychoticssuch as sertindole (11) improve negativesymptoms in patients with schizophrenia.Dopaminergic neurons in the ventral tegmen-tum mediate the antipsychotic effects of anti-psychotic agents, whereas in the nigrostria-tum, such neurons can mediate EPS asso-ciated with antipsychotic compounds. Theneuropharmacological profile of sertindole(11) therefore suggests antipsychotic activity,but with fewer EPS than conventionalantipsychotics.

In patients with schizophrenia, sertindole(11) occupancy of striatal D2 receptors weresignificantly (p < 0.05) lower (61% occupancy)than haloperidol (3, 87%) or high-dose risper-idone (6, 75%) and higher than clozapine(4, 33%) in one single-photon emission com-puterized tomography (SPECT) study [172].In another SPECT study, sertindole occu-pancy was significantly (p < 0.05) higher thanclozapine (4) and olanzapine (5) and similar torisperidone (6) [36,173]

In Europe, sertindole (11) marketing wasvoluntarily suspended by themanufacturer in1998. Approval has not been achieved in theUnited States because of concerns over risk ofQTc prolongation that could lead to cardiacarrhythmia and sudden death.

In summary, these atypical neurolepticsmay be divided into four groups according totheir pharmacological profiles [143].

(a) “Loose” Neuroleptics Displaceable byEndogenous Dopamine: This group in-cludes those atypical neuroleptics thathave low affinity at D2 and thusmay bereadily displaced by high endogenousconcentration of dopamine in the cau-

date/putmen. This group includes clo-zapine (4) and perlapine (13).

(b) Combined Block of D2- and MuscarinicReceptors: This small group includesclozapine (4) and thioridazine, whichstrongly block both D2- and muscarinicreceptors. Clozapine (4), for example, isin the order of 20–50-fold more potentin blocking muscarinic acetylcholinereceptors than blocking dopamine D2

receptors.(c) Combined Block of D2- and Serotonin 5-

HT2A-Receptors: The blockade of sero-tonin increases the release of dopa-mine. Clozapine (4) and olanzapine(5) could be viewed as selective inhibi-tors of the serotonin 5-HT2A receptor.

(d) Selective Block of Dopamine D4 Recep-tor: A fourth possible mechanism foratypical neuroleptic action may be theselective blockade of dopamine D4 re-ceptors. Again clozapine (4) belongs tothis group, as do perlapine (13) andolanzapine (5).Not surprisingly, differ-ent binding affinities towards theseGPCRs are also responsible for theirdifferent pharmacological and side-effect profiles.

7. PHARMACOKINETICS,BIODISTRIBUTION, AND DRUG–DRUGINTERACTIONS

7.1. General Considerations

The collection of antipsychotic agents avail-able today is chemically varied; however, theirabsorption, distribution, metabolism, andelimination properties are similar. In general,these drugs are well absorbed and highly dis-tributed. The extent of plasmaprotein bindingtypically ranges from 74% to 99% with manyof the drugs having binding in excess of 90%.The drugs are extensively metabolized typi-cally by cytochrome P450 (CYP) oxidation andthe drugs are predominately eliminated asmetabolites. Many of the drugs have beenshown to be substrates of CYP2D6 andCYP3A4, as well as inhibitors of CYP2D6 andaldehyde oxidase. In several cases, circulatingmetabolites are pharmacologically active and

PHARMACOKINETICS, BIODISTRIBUTION, AND DRUG–DRUG INTERACTIONS 25

contribute to the overall antipsychotic activ-ity. Two notable exceptions to these genericcharacteristics are the atypical antipsychoticsamisulpride and paliperidone that are botheliminated predominately intact in urine;moreover, amisulpride is not significantlybound to plasma proteins (protein binding

17%). In addition, due to extensive first passmetabolism and/or in order to prolong expo-sure, many of the antipsychotics are availablein oral and intramuscular formulations. Inmany cases, the pharmacokinetic parametersare highly variable between subjects due tofirst pass metabolism and extensive metabo-lism. Therefore, the pharmacokinetic para-meters provided are representative andwher-ever possible, multiple references have beenprovided which span the range of values. Inaddition to the information provided for eachantipsychotic agent, there are several excel-lent review articles describing the pharmaco-kinetics [174–177], pharmacogenetics [178],metabolism [179–182], and drug–drug inter-action potential [183–188] of past and presentantipsychotic agents.

7.2. Conventional (Traditional)Antipsychotics

7.2.1. Phenothiazines The first class of anti-psychotic agents was the phenothiazines thatconsisted of several chemical analogs. Chlor-promazine (1) (Thorazine) was the originaldrug in the phenothiazine class. The averagedosages of this drug range from 400 to600mg/day (in one to four divided doses). Ithas been observed that there is a wide inter-patient variability of chlorpromazine expo-sure with dose; hence, the following pharma-cokineticparametersarehighlyvariable [166].The time to peak plasma concentration is

1–4h with a Cmax of 25–150ng/mL (100mgbid, 33 days of dosing). The oral clearance ofchlorpromazine is 0.52L/h/kg with a half-lifeof 30h. Chlorpromazine has an oral bioavail-ability of 32%, a volume of distribution of21L/kg, and its plasma protein binding is95–98% [174,189–191].

Chlorpromazine (1) undergoes extensivefirst pass hepatic metabolism and <1% of theparent drug is eliminated in urine. Metabolicpathways involve N-demethylation, N-oxide,and S-oxide formation, hydroxylation to mul-tiple phenols (that are subsequently glucuro-nidated), reductive dechlorination, and qua-ternary N-glucuronide formation on the ali-phatic amine. The major metabolites are theN-desmethylchlorpromazine, chlorpromazineN-oxide, chlorpromazine S-oxide, N,N-dides-methylchlorpromazine, and 7-hydroxy chlor-promazine (21) (along with its glucuronideconjugate) [178,180,181]. Although many me-tabolites are present in the systemic circula-tion, the 7-hydroxy chlorpromazine metabo-lite is the only metabolite that likely contri-butes significantly to the overall activity of thedrug. In vitro studies indicate that CYP2D6 isresponsible for formation of the 7-hydroxychlorpromazine metabolite with a minor con-tribution from CYP1A2. Flavin monooxygen-ase (FMO) and CYP3A4 are predominatelyinvolved in the formation of theN- andS-oxidemetabolites, respectively [192–194]. Onlyminor increases in peak plasma concentrationand exposure were observed when chlorpro-mazine was coadministered with quinidine(CYP2D6 inhibitor) indicating that this en-zyme is not predominately involved in theelimination of chlorpromazine [172,195]. Invitro studies with human liver microsomesindicate that chlorpromazine is a weak inhi-bitor of CYP2D6 (IC50¼ 1.7mM) and that

N

S

NMe2

Cl

1, Chloropromazine

N

S

NMe2

Cl

21, 7-Hydroxychloropromazine

OH


chlorpromazine is an inhibitor of cytosolicaldehydeoxidase (IC50¼ 0.6mM)[185,187,196].

There are several other notable examplesof the phenothiazine chemotype, suchas thior-idazine (22), fluphenazine (24), trifluopera-zine (25), and perphenazine (26). The averagethioridazine (22) (Mellaril�) dosages rangefrom 200 to 800mg/day (in divided doses).Similar to chlorpromazine there is a wideinterpatient variability of thioridazine expo-sure with dose. The time to peak plasma con-centration is 1.9 hourswith aCmax of 48ng/mL(25mg qd). The oral half-life of thioridazine isvariable with an average approximately24h [174,197,198].

Thioridazine is metabolized to the 2-sulf-oxide (23) (mesoridazine) and the 2-sulfone(sulforidazine), as well as the 5-sulfoxide(ring sulfoxide) andN-desmethylthioridazine.Both the 2-sulfoxide (mesoridazine, also mar-keted as an antipsychotic) and the 2-sulfone(sulforidazine) contribute significantly to theoverall activity of the drug and the 5-sulfoxidehas been shown to cause cardiotoxi-city [178,180,181,199,200]. In vitro studiesindicate that CYP2D6 is responsible for for-mation of the 2-sulfoxide and the 2-sulfonemetabolites with a minor contribution fromCYP3A4 in the formation of the 2-sulfone.CYP1A2 and CYP3A4 are predominately in-volved in the formation of the N-desmethyland 5-sulfoxide metabolites [201]. The phar-macokinetics of thioridazine was studied inslow and rapid metabolizers of the CYP2D6phenotype. Slow metabolizers demonstrated2.4- and4.5-foldhigherCmax andAUClevels ofthioridazine compared to rapid metabolizers,respectively. In addition, lower exposures ofthe two active metabolites (2-sulfoxide/sul-fone) were observed in slow metabolizers in-

dicating the importance of CYP2D6 in thismetabolic pathway [175]. In a second study,fluvoxamine (CYP1A2 inhibitor) was found toincrease thioridazine (and 2-sulfoxide/sul-fone) plasma levels approximately threefold,most likely due to reduced metabolism ofthioridazine by CYP1A2 and increased meta-bolism through the alternate CYP2D6 path-way [179]. In vitro studies with human livermicrosomes indicate that thioridazine is aninhibitor of CYP2D6 (IC50¼ 0.36mM) and cy-tosolic aldehyde oxidase (IC50¼ 0.16mM)[185,187,196].

Another phenothiazine, similar to theaforementioned compounds is fluphenazine

(Prolixen�, Permitil�) that also exhibits agreat deal of interindividual variability inpharmacokinetics. The dose range for fluphe-nazine is 0.5–30mg/day. The immediate re-lease formulation gives a Cmax of 2.3 ng/mLand aTmax of 2.8 h after a 12mg dose. The oralhalf-life is �18h and the compound has aclearance of 0.6L/h/kg. The volume of distri-bution is 11L/kg and the bioavailability is low,2.7% [174,202–206]. Fluphenazine is exten-sively metabolized and negligible parent drugis found in urine. The circulating metabolitesidentified to date include the S- andN-oxides,as well as a 7-hydroxy metabolite [205].Although little is known about the enzymesinvolved in the biotransformation of fluphe-nazine, a clinical study did show increasedclearance of fluphenazine in smokers com-pared to nonsmokers [207]. These results in-dicate that CYP1A2 most likely has someinvolvement in the elimination of fluphena-zine. In addition, coadministration of fluoxe-tine (CYP2D6 inhibitor) increased the plasmaexposure of fluphenazine 65% indicating thatCYP2D6 may be involved in the biotransfor-

N

S

S

N

N

S

S

N

O

22, Thiordiazine 23, Thioridiazine S-Oxide


mation of this compound [208]. In vitro studieswith human liver microsomes indicate thatfluphenazine is a moderate inhibitor ofCYP2D6 (Ki¼ 9.4mM) [210].

N

S

F

FF

N

NOH

24, Fluphenazine

The dose range for perphenazine (25)(Trilafon�) is 8–32mg/day. The drug gives aCmax of 0.28 ng/mL and a Tmax of 2–4h after a6mg dose [174,209–211]. Perphenazinemeta-bolism is similar to the other phenothiazines(N-desmethyl,S- andN-oxides, and a 7-hydro-

xy metabolite which is eliminated as a glucur-onide conjugate) [203,212]. The 7-hydroxyme-tabolite is active; however, it is unknown howmuch it contributes to the antipsychotic activ-ity. The N-demethylation reaction has beenshown to be catalyzed by several CYP en-zymes: CYP1A2, 2C19, 2D6, and 3A4 [212].Coadministration of paroxetine (CYP2D6 in-hibitor) increased theCmax andAUC exposureof perphenazine by 6- and 7-fold, respec-tively [211]. In addition, the Cmax and AUCof perphenazine were increased in CYP2D6poor metabolizers by 3.3- and 4-fold, respec-tively [209]. Combined, these in vivo studiesindicate that CYP2D6 is involved in the bio-transformation of this compound. In vitro stu-dies with human liver microsomes indicatethat perphenazine is an inhibitor of CYP2D6(IC50¼ 0.33mM) and a very potent inhibitor of

aldehyde oxidase (IC50¼ 0.033mM)[185,187,196].

The final compound in this chemical class istrifluoperazine (26) (Stelazine�) that has adose range 15–40mg/day (qd or bid). The druggives a Cmax of 1.1 ng/mL and a Tmax of 2.5 hafter a5mgdose. Thedrughasanoral half-lifeof 12.5 h, a clearance of 8.6L/h/kg, and a vo-lume of distribution of 122L/kg [174,213]. Tri-fluoperazine is metabolized by N-demethyla-tion,S- andN-oxidation, 7-hydroxylation, anddirect glucuronidation to form a quaternaryN-glucuronide [214]. Little is knownabout theenzymes involved in the oxidativemetabolismof trifluoperazine, however, formation of theN-glucuronide has been shown to be catalyzedby UGT1A4 [215]. In vitro studies indicatethat trifluoperazine is a potent inhibitor ofaldehyde oxidase (IC50¼ 0.24mM) [215].

7.2.2. Thioxanthenes The thioxantheneclass is similar in structure to the phenothia-zines with the addition of a double bond in thecis configuration. Thiothixene (27) (Navane�)is given in dosages of 20–60mg/day. Very littleinformation is available about the pharmaco-kinetics or metabolism of thiothixene. Afteroral administration of thiothixene the time topeak plasma concentration was 2.2 h with aCmax of 27ng/mL (20mg dose). The clearanceof thiothixene is 7.23L/h/kg, the half-life is13.7 h, andboth valueswere found to be highlyvariable [174,216,217]. Thiothixene under-goesmetabolismto two identifiedmetabolites:thiothixene sulfoxide and N-desmethylthiothixene [218,219]. The clearance ofthiothixene is higher in patients who smoke,higher in males versus females, and higher in

N

S

Cl

NN

OH

25, Perphenazine

N

S

F

F

FN

N

26, Trifluoperazine


the young population versus the elderly popu-lation [220]. The clearance is also higher inpatients who are coadministered carbamaze-pine possibly indicating involvement ofCYP3A4 in the elimination of the com-pound [220]. In vitro studies with human livermicrosomes indicate little potential forthiothixene to inhibit the major CYP en-zymes [187].

S

SN O

O

NN

27, Thiothixene

7.2.3. Dibenzoxazepines Loxapine (12)(Loxitane�) is a conventional antipsychoticthat is structurally very similar to the atypicalantipsychotic clozapine. The standard dose ofloxapine ranges 20–100mg/day, taken in di-videddoses. Loxapine is rapidly absorbedwitha time to peak plasma concentration of 2 h andaCmax of 9.8 ng/mL (25mg solution dose). Thehalf-life of the drug is reported to be biphasicwith values of 5 and 12–19h [174,221]. Addi-tional information regarding volume of distri-bution, protein binding, and drug–drug inter-actions are not well documented for loxapine.The drug is extensively metabolized with noparent drug found in urine or feces. Routes ofmetabolism include N-demethylation to formamoxepine (an antidepressant), hydroxyla-tion to the 7- and 8-hydroxymetaboliteswhichundergo further glucuronidation and sulfa-tion, N-oxidation at the 4-piperidyl nitrogen,and formation of a quarternary N-glucuro-nide [221–223]. The drug is predominatelyeliminated in urine as a variety of conjugatesderived from the hydroxylated metabolites.Several of themetabolites (amoxepine and thehydroxylatedmetabolites) have been shown tohave antipsychotic properties and most likelycontribute to the pharmacology of the drug.Loxapine has been shown to be an inhibitor ofaldehyde oxidase (IC50¼ 2.3mM), however,the efficacious plasma concentrations of lox-apine are generally low and drug interactionsare not anticipated [185].

N

O

N

NMe

Cl

12, Loxapine

7.2.4. Butyrophenones Haloperidol (3)(Haldol�) dosages range from 2–20mg/day.The time to peak plasma concentration isvariable and ranges 1.7–6.1 h with a Cmax of9.2 ng/mL (20mg dose). The oral clearanceof haloperidol is 0.71L/h/kg with a half-life of18.5 h. Haloperidol has an oral bioavailabilityof 60%, a volume of distribution of 18L/kg,and its plasma protein binding is92% [174,189,224,225].

N

3, Haloperidol

Cl

HOO

F

Haloperidol undergoes extensive first passhepaticmetabolism to a variety ofmetabolitesvia several metabolic pathways. These meta-bolic pathways include: N-dealkylation (withformation of para-fluorobenzyoylpropionicacid and 4-(4-chlorophenyl)-4-hydroxypiperi-dine), formation of a pyridinium metabolite,stereospecific reduction of the ketone to thealcohol (S-(�) isomer), and glucuronidation ofthe hydroxyl. All of these metabolites are in-active; however, the reduced haloperidol canbe reoxidized to form the parentdrug [178,180,181,189,224,225]. The majorcirculating metabolites are the glucuronideconjugate and reduced haloperidol. Approxi-mately 30% of a dose of haloperidol is excretedin urine, predominately as the glucuronideconjugate and < 1% of the dose is excreted asparent drug. In vitro studies indicate thatCYP3A4 is responsible for formation of thepara-fluorobenzyoylpropionic acid and 4-(4-chlorophenyl)-4-hydroxypiperidine metabo-lites, the pyridinium metabolite, and the re-oxidation of reduced haloperidol; moreover,


the formation of reduced haloperidol is bycytosolic carbonyl reductase [225–227].Although CYP2D6 has been implicated in for-mation of the para-fluorobenzyoylpropionicacid and 4-(4-chlorophenyl)-4-hydroxypiperi-dine metabolites, as well as the pyridiniummetabolite, the literature is notwell defined inthis regard [225–227]. However, increases inpeak plasma concentration and exposurewereobserved when haloperidol was coadminis-tered with fluoxetine or quinidine (CYP2D6inhibitors) and when administrered to poormetabolizers of the CYP2D6 phenotype [225].Therefore, although the in vitro data are notclear in regards to CYP2D6-mediated meta-bolism of haloperidol, the in vivo studiesclearly indicate that CYP2D6 is involved inthe elimination of haloperidol. In vitro studieswith human liver microsomes indicate thathaloperidol and reduced haloperidol are rea-sonably potent inhibitors of CYP2D6 (Ki

0.89 and 0.11mM, respectively) [187,228].

7.2.5. Diarylbutylamines Pimozide (28)(Orap� [229]) is not approved in the UnitedStates for the treatment of psychosis but isapproved for the treatment of Tourette’s syn-drome. Pimozide is approved in Europe as anantipsychotic where the dosage of pimozideranges 2–10mg/day (qd). Pimozide is slowlyabsorbed after oral administrationwith a timeto peak plasma concentration (Tmax) of 6–8hand a Cmax of�4ng/mL (6mg dose). Althoughthe drug undergoes extensive first pass meta-bolism, it has a low oral clearance of 0.25L/h/kg and a long half-life that ranges from 55 to111h (accumulation of the drug is observeduponmultiple dosing). The half-life appears tosegregate into two populations (�50h or�100h) depending on the study and patient popula-tion. Pimozide has an oral bioavailability of<50%, an apparent volume of distribution of28.2L/kg, and its plamsa protein binding is99% [174,230–233].

NN

O

NF

F

28, Pimozide

Pimozide (28) undergoes hepatic metabo-lism to two metabolites via N-dealkylationat the center of the molecule to form 1,3-dihy-dro-1-(4-piperidinyl)-2H-benzimadazole-2-one and 4,4-bis(4-fluorophenyl)butanoic acid.Both metabolites appear to be pharmacologi-cally inactive and the drug and itsmetabolitesare predominately eliminated in the urine. Invitro studies indicate that CYP3A4 is the pre-dominate enzyme responsible for the N-deal-kylation of pimozide, however, CYP1A2 alsocontributes to the metabolism of pimo-zide [234,235]. Whereas pimozide is predomi-nately eliminated by metabolismmediated byCYP3A4, potent inhibitors ofCYP3A4, suchasazole antifungals, macrolide antibiotics, andprotease inhibitors are all contraindicatedwhen takingpimozide. For example, clarithro-mycin (a macrolide antibiotic and CYP3A4inhibitor) has been shown to significantly in-crease pimozide Cmax, half-life, and AUC dur-ing coadministration [230]. Pimozide is asso-ciated with prolongation of the QT intervaland fatal ventricular arrhythmia, thereforeelevations in pimozide plasma exposures(especiallywhen coadminsteredwithCYP3A4inhibitors) should be avoided [229,235].

7.2.6. Dihydroindolone Molindone (29)(Moban�, [236]) is structurally unrelated tothe other conventional antipsychotics and itspharmacokinetic andmetabolic properties aresomewhat unique [174,237–239]. Mainte-nance doses of molindone for mild–moderatesymptoms are 5–25mg (three to four times aday). Molindone is rapidly absorbed after oraladministration with a time to peak plasmaconcentration of 1.1 h and aCmax of 347ng/mL(100mg dose). The drug undergoes extensivemetabolism to more than 30 metabolites andless than 3% of the drug is eliminated asparent drug in urine and feces. Plasma con-centrations ofmolindone are negligible at 12hafter dosing and the drug is almost completely(90%) eliminated within 24h. Molindone hasan extremely short half-life of 2 h; however,the pharmacological effects of molindone con-tinue 24–36h after a single dose. It has beensuggested that the majority of antipsychoticactivity of molindone is not from the parentdrug itself but one or more active metabolites.Molindone is not very lipophilic and its plasmaprotein binding is only 76%. Unfortunately,


the identification of molindone metabolitesand any potential drug–drug interactions arenot well documented.

NH

O

NO

29, Molindone

7.3. Atypical Antipsychotics

7.3.1. Dibenzodiazepines Clozapine (4)(Clozaril� [240]) is similar in chemical struc-ture to the conventional antipsychotic, loxa-pine. Dosages of clozapine range 250–400mg/day (bid), although doses as high as 900mg/dayhavebeen safelyadministered. It hasbeenobserved that there is a wide interpatientvariability of clozapine exposure with dose;hence, the following pharmacokinetic para-meters are averages, typically over a signifi-cant range [174,177,241–244]. The time topeak plasma concentration is �2.5 h with aCmax of 319ng/mL (100mgbid). The oral clear-ance of clozapine is 0.36L/h/kg and appears toexhibit a biphasichalf-life (consistentwitha2-compartmentmodel)with values of 3 and 16h.There is a linear dose proportionality relation-ship between clozapine plasma concentra-

tions and clinical doses. Clozapine has an oralbioavailability of 55% and the bioavailabilityis unaffected when given with food. Clozapinehas an apparent volume of distribution of5.4L/kg and its plasma protein biding is 97%.

Clozapine (4) undergoes extensive hepaticmetabolism to the following metabolites:N-desmethyl clozapine (30), clozapineN-oxide(31), hydroxylated clozapine, and dehaloge-nated clozapine [180,182,189]. The major cir-culatingmetabolites are theN-desmethyl andN-oxide that have been reported to be 60%and15% of circulating clozapine concentrations.Although present in the systemic circulation,it is believed that neither metabolite contri-butes significantly to the overall activity of thedrug; however, the N-desmethyl metabolitedoes have modest antipsychotic activity. Thedrug and its metabolites are eliminated inurine (50% of dose) and feces (30% of dose)with only trace amounts of parent drug inurine or feces. In vitro studies indicate thatCYP1A2 is responsible for formation of themajor metabolite, the N-desmethyl whileCYPs 2D6, 2C9, 2C19, and 3A4 have also beenimplicated in the metabolism of cloza-pine [245]. There are a multitude of drug

N

HN

N

NMe

Cl

4, Clozapine

N

HN

N

NH

Cl N

HN

N

NMe

Cl

O

30, N-Desmethylclozapine 31, Clozapine N-oxide


interactions involving clozapine and othercoadministered drugs [178,183,184,186,188].Fluvoxamine, a potent inhibitor of CYP1A2,has been shown to significantly increase theexposure of clozapine and two of its metabo-lites threefold (N-desmethyl and N-oxide).There are also several case reports of signifi-cant lowering of clozapine plasma concentra-tions when coadministered with carbamaze-pine (50% decrease) or phenytoin (65–85%decrease). Each of these studies implicatesCYP1A2 and CYP3A4 in the metabolism ofclozapine. In addition, a modest lowering ofclozapine plasma concentrations (18%) wasobserved in smokers compared to nonsmokersand the clearance of clozapine was found to belower (�30%) in woman compared to men.Minor increases in exposure were observedwhen clozapine was coadministered withfluoxetine and paroxetine (CYP2D6 inhibi-

tors). In vitro studies with human liver micro-somes indicate that clozapine is a weak inhi-bitor of CYPs 2C9 and 2D6 (IC50 values >19mM) and another in vitro study indicatedclozapine to be a weak inhibitor of aldehydeoxidase (IC50¼ 4.4mM) [185,187]. Albeit,these inhibitory parameters are well abovethe efficacious plasma concentrations of clo-zapine (350ng/mL), hence drug–drug interac-tions with clozapine are not anticipated.

7.3.2. Thienobenzodiazepine Olanzapine (5)(Zyprexa�, Symbyax� [246]), similar in struc-ture to clozapine, has a dose range from10–30mg/day (qd). Olanzapine is well ab-sorbed after oral administration with a timeto peak plasma concentration of 6h andaCmax

of 18.3 ng/mL (7.5mg qd for 8 days). The oralclearance of olanzapine is 0.36L/h/kg with afairly long half-life of 33h. Accumulation ofdrug is observed and steady state is achievedafter one week where day 7 plasma exposuresare approximately twofold higher compared today 1. The kinetics of olanzapine are linearthroughout the clinical dose range and plasmaexposures are unaffected by food. Olanzapineundergoes extensive first pass metabolismand the oral bioavailability of olanzapine is60%. Olanzapine has an apparent volume ofdistribution of 14.3L/kg and its plasma pro-tein binding is 93% [174,177,247–250].

Olanzapine (5) undergoes extensive hepa-tic metabolism to the following metabolites: atertiary N-glucuronide (32, 10-N-glucuro-nide), 40-N-desmethyl olanzapine (33), 40-N-oxide, 2-hydroxymethyl, 2-carboxylic acid,7-hydroxy, and a minor 40-quaternary N-glu-cruonide metabolite [180,182,248]. The majorcirculating metabolites are the 10-N-glucuro-nide and the 40-N-desmethyl that have beenreported to be 44% and 31% of circulatingolanzapine concentrations. Although present

N

HN

S

N

Me

NMe

5, Olanzapine

N

NS

N

Me

NMe

32, Olanzapine N-glucuronide

N

HN

S

N

Me

NH

33, N-Desmethyl olanzapine

Glucuronide


in the systemic circulation, it is believed thatneithermetabolite contributes significantly tothe overall activity of the drug, however, eachmetabolite does have a long half-life similar tothe parent drug (glucuronide �40h/N-des-methyl �93h). The drug and its metabolitesare eliminated in urine (57% of dose) and feces(30% of dose) with 7% of the parent drugeliminated in urine. In vitro studies indicatethat CYP1A2 is responsible for formation ofthe 40-N-desmethyl and 7-hydroxy metabo-lites; CYP2D6 is responsible for the 2-hydroxymetabolite; FMO3 is responsible for formationof the 40-N-oxide; and UGT1A4 is responsiblefor formation of the 10-N-glucuronide conju-gate [251,252]. Similar to clozapine, olanza-pine has the potential for multiple drug-druginteractions [178,183,184,186,188]. Potent in-hibitors of CYP1A2, such as fluvoxamine andciprofloxacin have been shown to significantlyincrease the exposure of olanzapine (84% in-crease in Cmax and 119% increase in AUC,respectively). Also, coadministration of carba-mazepine increased the clearance of olanza-pine by �50% and the clearance was alsoincreased (23%) in smokers compared to non-smokers. Minor increases in exposure wereobserved when olanzapine was coadminis-tered with fluoxetine (CYP2D6 inhibitor), butthere was no change in exposure when olan-zapine was given to poor and extensive meta-

bolizers of CYP2D6 substrates. When olanza-pine was coadministered with probenecid(UGT inhibitor) there was a modest increasein olanzapine AUCandCmax [226]. Combined,these studies imply that UGT, CYP1A2, andCYP3A4 are involved in the metabolism ofolanzapine. Interestingly, the clearance ofolanzapine is lower (�30%) inwoman, elderly,and Japanese patients. Finally, in vitro stu-dies with human liver microsomes indicatelittle potential for olanzapine to inhibit themajor CYP enzymes.

7.3.3. Dibenzthiazepines Quetiapine (9)(Seroquel� (254)) is similar in structure to theearlier phenothiazines, fluphenazine, andperphenazine. The typical dose range of que-tiapine is from 300–500mg/day (bid or tid).Quetiapine is rapidly absorbed after oral ad-ministration with a time to peak plasma con-centration of 1–2h and a Cmax of 625ng/mL(150mg tid). The oral clearance of quetiapineis 1.2L/h/kg with a half-life 3–6h. The phar-macokinetic parameters of quetiapine are lin-ear throughout the therapeutic dose rangeand a high fat meal marginally increases theAUC and Cmax of quetiapine (15% and 25%,respectively). Quetiapine has an apparent vo-lume of distribution of 10L/kg, low oral bioa-vailability (9%), and its binding to plasmaproteins is moderate, 83% [174,253–257].

N

S

N

N

OOH

9, Quetiapine

N

S

N

N

OOH

34, Quetiapine S-Oxide

N

S

N

N

OOH

35, Quetiapine carboxylic acid derivative

O

O


Quetiapine (9) undergoes extensivehepaticmetabolism to two major circulating metabo-lites, a sulfoxide (34) and a carboxylic acidderivative (35). Multiple other metabolites(11 in total) have been identified, such as the7-hydroxy, the N- and O-dealkylated metabo-lites, and several combinations of these path-ways [177,180,182,258,259]. The drug and itsmetabolites are predominately eliminated inurine (73% of dose) and partially in feces (21%of dose) with less than 1% of the dose elimi-nated as parent drug. Most of the metabolitesare pharmacologically inactive; however, the7-hydroxy and the 7-hydroxy-N-dealkylatedmetabolites do have some antipsychotic activ-ity, albeit their exposures are low and mostlikely do not contribute to the pharmacology ofthe drug [177]. In vitro studies indicate thatCYP3A4 is the predominate enzyme respon-sible for the S-oxidation and the N/O-deal-kylated metabolites of quetiapine, however,CYP2D6 also contributes to the formation ofthe 7-hydroxy metabolite [182,253]. Whereasquetiapine is predominately eliminated bymetabolism mediated by CYP3A4, potent in-hibitors and inducers of CYP3A4 have beenshown to significantly alter the exposure ofquetiapine when coadministered. For exam-ple, ketoconazole (CYP3A4 inhibitor) has beenshown to significantly decrease quetiapineoral clearance by 84% (335% increase inCmax)and both phenytoin and carbamazepine(CYP3A4 inducers) increased the oral clear-ance of quetiapine by five- and sevenfold, re-spectively [257]. In vitro studies have shownthat quetiapine is not expected to significantlyinhibit the cytochromes P450, however, it isa moderate inhibitor of aldehyde oxidase(IC50¼ .4mM). The oral exposure of quetia-pine was 30–50% lower in the elderly volun-teers compared to the young volunteers, butsmoking status had no affect on quetiapineexposure [254].

7.3.4. Dibenzothiepine Zotepine (36)(Lodopin� [260]) is not approved in theUnitedStates; however, it is approved in Europe andJapan where the standard dose of zotepine is75–150mg/day (tid). Zotepine is rapidly ab-sorbed after oral administrationwith a time topeak plasma concentration (Tmax) of 3–4h anda Cmax of 30–249ng/mL (100mg dose). The

drug has an oral clearance of 4.1–5.2L/h/kgand an oral terminal half-life of 14.8–24h. Theoral bioavailability of zotepine is unknownbutanticipated to be low based on its oral phar-macokinetics. Zotepine has an apparent vo-lume of distribution of 80–131L/kg and itsbinding to plasma proteins is 97%[175,260–264].

Zotepine (36) undergoes extensive hepaticmetabolism to metabolites such as: N-des-methyl zotepine (norzotepine), 2- and 3-hydro-xyzotepine, zotepine S-oxide, and zotepine N-oxide [179,261]. The norzotepine metabolitehas been shown to bepharmacologically activeand possibly contributes to the overall phar-macological effects [263]. In vitro studies in-dicate that CYP3A4 is predominately respon-sible for the formation of norzotepine and theS-oxide metabolites while CYP1A2 andCYP2D6 are involved in formation of the 2-and 3-hydroxyzotepinemetabolites [265]. Theurinary elimination of parent drug and zote-pine metabolites is minimal.

S

O

Cl

N

36, Zotepine

Very few clinical studies have evaluatedthe drug–drug interaction potential of zote-pine. There have been several reports whichindicate concurrent use of benzodiazepineswith zotepine significantly elevate zotepineexposure. For example, one study observed amodest increase in steady state zotepine plas-ma concentration (13.8–17.5 ng/mL) whencoadministered with diazepam [266]. Theauthors concluded that the interaction mayhave been caused by diazepam inhibition ofCYP3A4 that would have affected the meta-bolic elimination of zotepine. Finally, zotepinehalf-life and exposure have been shown toincrease significantly in the elderly popula-tions as compared to the youngerpopulations [263].


7.3.5. Benzisoxazoles Risperidone (6)(Risperdal� [267]) dosages range 2–8mg/day(bid). Risperidone is completely and rapidlyabsorbed after oral administration with atime to peak plasma concentration of 1h anda Cmax of 10ng/mL (8mg bid). The oral clear-ance of risperidone is 0.32L/h/kg with a half-life of �3h. Multiple dose pharmacokineticsof risperidone is linear from 0.5–25mg/dayand plasma exposures are not changed whentaken with food. Risperidone undergoesfirst pass metabolism and the oral bioavail-ability of risperidone is 66%. Risperidonehas an apparent volume of distribution of1–2L/kg and its plasma protein binding is90% [174,175,177,189,267–270].

Risperidone (6) undergoes extensive hepa-tic metabolism by hydroxylation to 7- and 9-hydroxyrisperidone and N-dealkylation. Thepredominate metabolite is 9-hydroxyrisperi-done (37) that is also active (known as pali-peridone (37)) [179,181,182,271]. The majorcirculating metabolite, 9-hydroxyrisperidone,is predominately eliminated in urine (31% of aresperidone dose) and contributes to the over-all antipsychotic effects of resperidone. Thedrug and its metabolites are predominatelyeliminated in urine (70% of dose) with a muchsmaller proportion in feces (14% of dose) and�10%of the parent drug is eliminated in urinewhile no parent drug is found in feces. In vitrostudies indicate that CYP2D6 is responsiblefor the formation of 9-hydroxyrisperidonewhile CYP3A4 plays a smaller role. Hydroxy-lation at the 9-position of resperidone forms achiral center and CYP2D6 has been shown toform the (þ )-9-hydroxyrisperidone whileCYP3A4 forms the (�)-9-hydroxyrisperidone(both isomers are active). As risperidone ismetabolized predominately by CYP2D6, po-tent inhibitors of CYP2D6 such as fluoxetine

or paroxetine have been shown to increase theplasma concentration of risperi-done [178,183,184,186,188]. For example,fluoxetine increases the mean plasma concen-tration of risperidone by 4.7-fold with nochange in the concentration of 9-hydroxyris-peridone [272]. Risperidone and 9-hydroxyr-isperidone exposures were evaluated ingroups of poor and extensive metabolizer ofthe CYP2D6 phenotype. Although plasmaconcentrations of risperidone increase in poormetabolizers, the ratio of risperidone to 9-hydroxyrisperidone did not change signifi-cantly [273]. Therefore, CYP2D6 genotypestatus will cause a pharmacokinetic changein risperidone exposures, but the genotype

does not result in a pharmacodynamic effectand dose adjustments may or may not benecessary. The CYP3A4 inducer carbamaze-pine decreases the plasma concentrations ofboth risperidone and 9-hydroxyrisperidonewhich results in a significant lowering of anti-psychotic activity [274]. The disposition ofrisperidone appears to be lower in the elderlyand in the hepatic or the renal impaired pa-tients. In vitro studies with human liver mi-crosomes indicate little potential for risperi-done to inhibit themajor CYP enzymes, albeitrisperidone is a weak inhibitor of CYP2D6that is probably not clinically relevant at ther-apeutic doses [187,196]. Risperidone is also asubstrate and weak inhibitor of P-glycoprotein [252].

Paliperidone (37) (9-hydroxyrisperidone,Invega� [276]) is a racemic mixture of (þ )and (�) 9-hydroxyrisperidone with dosages of3–12mg/day (qd) delivered in an extendedrelease formulation. Following administra-tion of paliperidone, the (þ ) and (�) enantio-mers interconvert reaching a steady stateAUC ratio (þ /�) of �1.6. Paliperidone is well

N

N

ON

O N

F

Me

6, Risperidone

N

N

ON

O N

F

Me

37, 9-Hydroxy Risperidone

OH


absorbed after oral administrationwith a timeto peak plasma concentration of 24h and aCmax of 9 ng/mL (1mg dose). The clearance ofpaliperidone is 0.08L/hr/kg and the half-life ofpaliperidone is 25hwhich ismuch longer thanrisperidone. Multiple dose pharmacokineticsof paliperidone is linear with steady stateconcentrations achieved after 4–5 days andthe Cmax and AUC of paliperidone are in-creased when taken with food (60% and54%, respectively). Paliperidone has an oralbioavailability of 28%, avolumeof distributionof 7L/kg, and its binding to plasma proteins is74% [175,276,277]. Paliperidone does not un-dergo extensive hepaticmetabolism, however,severalmetabolites have been identified, noneof which are active or detected in the systemiccirculation [179,182,278]. The identified me-tabolic pathways of paliperdone include: N-dealkylation, hydroxylation, alcohol dehydro-genation, and benzisoazole ring scission. Thedrug and its metabolites are predominatelyeliminated in urine (80% of dose) with a muchsmaller proportion in feces (11% of dose) and59% of the parent drug is eliminated in ur-ine [276]. Therefore, unlike many of the otherantipsychotic agents, the predominate elimi-nation pathway of paliperidone is renal elim-ination with a small proportion of the doseeliminated as metabolites. In vitro studiesindicate that CYP2D6 and CYP3A4 are re-sponsible for the metabolism of paliperi-done [278]. The disposition of paliperidone ismuch lower in patients with renal impair-ment; however, no changes were noted due toage, race, smoking status, or hepatic impair-ment [276]. In vitro studies with human livermicrosomes indicate little potential for pali-peridone to inhibit the major CYP enzymes,albeit the drug is a substrate and weak inhi-bitor of P-glycoprotein [183,184,276].

7.3.6. Benzoisothiazoles Ziprasidone (8)(Geodon� [279]) dosages range 40–160mg/day(bid). Ziprasidone is well absorbed after oraladministration with a time to peak plasmaconcentration of 6–8h and a Cmax of 68ng/mL(40mg/day bid for 8 days). The oral clearanceof ziprasidone is 0.45L/h/kg with a half-life of6.6 h. Multiple-dose pharmacokinetics of zi-prasidone is linear throughout the clinicaldose range and plasma exposures are in-

creased by twofold when taken with food.Ziprasidone undergoes extensive first passmetabolism and the oral bioavailability ofziprasidone is 60%. Ziprasidone has an appar-ent volume of distribution of 1.5L/kg and itsbinding to plasma proteins is extensive at�99.9% [175,177,279–281].

Ziprasidone (8) undergoes extensive hepa-tic metabolism to several metabolites: there isa sulfoxide (38) that is further oxidized to asulfone, the parent drug undergoes N-de-methylationat thepiperazinenitrogen to formtwo metabolites (benzisothiazole piperazine(39) and an oxindole aldehyde that is furtheroxidized to the oxindole acetic acid) (40), theparent drug is also reduced at theN–S bond ofthe benzisothizole ring to form the dihydrozi-prasidone which undergoes S-methylation toform the S-methyldihydroziprasidone(41) [179,180,182,280]. The predominant me-tabolic pathway is reduction of ziprasidonefollowed by the various oxidation reactions.The major circulating metabolite is the S-methyldihydroziprasidone which is mostlyeliminated in the feces. Other minorcirculating metabolites include the benzi-sothiazole piperazine sulfoxide and sulfonemetabolites, as well as ziprasidone sulfoxide.Although present in the systemic circulation,it is believed that none of the metabolitescontribute significantly to the activity of thedrug. The drug and its metabolites areeliminated in feces (66% of dose) and less inurine (20% of dose) with <4% of the parentdrug eliminated in urine and feces. In vitrostudies indicate that aldehyde oxidase is in-volved in the reductive cleavage of the benzi-sothiazole ring and the oxidation of the oxi-ndole aldehyde while CYP3A4 is predomi-nately involved in the oxidation of ziprasidonewith a minor contribution fromCYP1A2 [185,282]. Because ziprasidone ismetabolized predominately by aldehyde oxi-dase, potent inhibitors and inducers ofCYP3A4 have only modest affects on the plas-ma concentration of ziprasi-done [178,183,186,188]. For example, ketoco-nazole (CYP3A4 inhibitor) increases both theAUC and Cmax of ziprasidone by about 33%and carbamazepine (CYP3A4 inducer) de-creases the AUC and Cmax of ziprasidone by36% and 27%, respectively [183,283]. The dis-


position of ziprasidone does not appear to beaffected by age, gender, hepatic or renal im-pairment [279]. In addition, in vitro studieswith human liver microsomes indicate littlepotential for ziprasidone to inhibit the majorCYP enzymes, albeit ziprasidone is a weakinhibitor of CYP2D6 (IC50¼ 11mM), however,clinical studies have not demonstrated aninteraction [284].

Perospirone (42) (Lullan� [285]) is structu-rally similar to ziprasidone and currently ap-proved in Japan but not in the United States.The dosages of perospirone range 12–48mg/day (bid). Perospirone is rapidly absorbedafter oral administration with a time to peakplasma concentration of �2h and a Cmax of9 ng/mL (16mg/day bid). The oral half-lifeappears to be bi-phasic with values of 1–3hfollowed by 5–8h. The Cmax and AUC of per-ospirone are increased by 1.6- and 2.4-fold,respectively, when taken with food. Perospir-one undergoes extensive first pass metabo-lism, has an apparent volume of distribution

of 24.8L/kg, and its binding to plasmaproteinsis 92% [175,285–289].

NN

S N

N

O

O

H

H

42, Perospirone

NN

S N

N

O

O

43, 1-Hydroxyperospirone

OH

Perospirone (42) undergoes extensive he-patic metabolism to several metabolites: hy-droxylation on the cyclohexane dicarboxyi-mide (1-hydroxy perospirone, (43)),N-dealky-

8, Ziprasidone

NN

S N

Cl NH

O

39, Benzisothiazolepiperazine

NHN

S N

38, Ziprasidone S-oxide

NN

S N

Cl NH

O

41, S-Methyldihydroziprasidone

NN

SNH

Cl NH

O

40, Oxindole acetic acid

HO

Cl NH

O

O

Me

O


lation at the piperazine nitrogen, andS-oxida-tion of the isothiazole ring [179,285,290]. Hy-droxylated perospirone (43) is the major me-tabolite present in the systemic circulation atapproximately threefold the parent drug andis believed to contribute to the activity of thedrug. In vitro studies indicate that CYP3A4 ispredominately involved in the metabolism ofperospirone [290]. Because perospirone is me-tabolized predominately byCYP3A4, inducersand inhibitors of this enzyme significantlyaffect the plasma concentration of perospir-one. For example, itraconazole (CYP3A4 in-hibitor) increases the AUC and Cmax of per-ospirone by seven- and sixfold, respectively,and coadministration of carbamazepine(CYP3A4 inducer) decreases the exposure ofperospirone from 4ng/mL to below the limit ofdetection (�0.1 ng/mL) [286,287].

7.3.7. Quinolinone Aripiprazole (10) (Abil-ify� [291]) dosages range from 10–30mg/day(qd). Aripiprazole is rapidly andwell absorbedafter oral administration with a time to peakplasma concentration of 3–5h and a Cmax of242 ng/mL (15mg qd for 14 days). The oralclearance of aripiprazole is low at 0.05L/h/kgwith a long half-life of 75h. Accumulation ofdrug is observed and steady state is achievedin 14 days. The pharmacokinetic parametersof aripiprazole are linear throughout the ther-apeutic dose range and a high fat meal doesnot affect AUC or Cmax, but Tmax is increasedby 3h. Aripiprazole has an oral bioavailabilityof 87%, an apparent volume of distribution of4.9L/kg, and its binding to plasma proteins isgreater than 99% [175,177,291–294].

NH

OON

NCl

Cl

10, Aripiprazole

NH

OON

NCl

Cl

44, Dehydroaripiprazole

Aripiprazole (10) undergoes extensive he-patic metabolism to the dehydroaripiprazole(44) while other minor metabolic reactionsinclude N-dealkylation and hydroxyla-tion [182,292,294]. The drug and its metabo-lites are predominately eliminated in feces(55% of dose) and somewhat in urine (25% ofdose) with 1% of the parent drug eliminated inurine and 18% in feces. The dehydroaripipra-zole (44) is pharmacologically active and itsexposure is 40% that of the parent drug. Thehalf-life of dehydroaripiprazole is also long( 94h) and it is 99% bound to plasma proteins;therefore, the dehydroaripiprazole likely con-tributes to the overall effects of the drug. Invitro studies indicate that CYP3A4 andCYP2D6 are predominately responsible forformation of the dehydroaripiprazole and thehydroxylated metabolite while CYP3A4 is re-sponsible for the N-dealkylated metabolite.Potent inhibitors of CYP3A4 and CYP2D6have been shown to significantly increase theexposure of aripiprazole [178,183,185,188].For example, ketoconazole (CYP3A4 inhibi-tor) significantly increased the AUC of aripi-prazole and dehydroaripiprazole by �70%each and quinidine (CYP2D6 inhibitor) in-creased the AUC of aripiprazole by 112% anddecreased the AUC of dehydroaripiprazole by35%. When coadministered with the CYP3A4inducer carbamazepine, the AUC and Cmax ofboth aripiprazole and dehydroaripiprazole de-creased by 70%. In all of these instances,CYP3A4 inhibitors/inducers or CYP2D6 inhi-bitors, dosage adjustments of aripiprazole arerecommended. As would be expected, poormetabolizers of CYP2D6 substrates have al-tered aripiprazole pharmacokinetics. Thehalf-life of aripiprazole increased from 75h inextensive metabolizers to 196hours in poormetabolizers. In addition, there was an 80%increase in aripiprazole exposure along with a30% decrease in dehydroaripiprazole expo-sure. Hence in patients with the poor meta-bolizer CYP2D6 genotype, the overall expo-sure of pharmacologically active componentsincreases by �60%. Finally, aripiprazole doesnot inhibit the elimination of several drugsmetabolized byCYP’s 2C9, 2C19, 2D6, or 3A4;therefore, aripiprazole does not appear to in-teract with most coadministered drugs meta-bolized by these enzymes [291].


7.3.8. Phenylindole Sertindole (11)(Serdolect� [295]) is not approved in the Uni-tedStates; however, clinical trials areactive inthe United States and the drug is approved inEurope where the standard dose of sertindoleis 12–20mg/day (qd). Sertindole is slowly ab-sorbed after oral administrationwith a time topeak plasma concentration (Tmax) of 8-–h anda Cmax of 53–64ng/mL (12mg dose). The drughas an oral clearance of 0.2–0.6L/h/kg and anoral half-life of 50–111h. Accumulation of thedrug is observed and 1–2 weeks are necessaryto achieve steady state plasma concentra-tions. The oral bioavailability of sertindole is75% and although there is a small food effect,no dosage adjustments are necessary. Sertin-dole has an apparent volume of distribution of25L/kg and its binding to plasma proteins isextensive at 99.5% [177,295–298].

NN

N

NHO

F

Cl

11, Sertindole

Sertindole (11) undergoes hepatic metabo-lismtodehydrosertindole (45) andnorsertindol(46) and less than 4% of the drug (parent andmetabolites) is eliminated in the ur-ine [177,188,295,297]. The dehydrosertindole(45) metabolite has been shown to be pharma-cologically active andat steady state its plasmaconcentration is 80% that of the parent drug

suggesting that the metabolite may contributeto the pharmacological effects. In vitro studiesindicate that CYP3A4 and CYP2D6 are thepredominate enzymes responsible for the me-tabolism of sertindole and potent inhibitors ofthese enzymes are contraindicated when ad-ministering sertindole. Drugs such as ketoco-nazole (CYP3A4 inhibitor) and paroxetine orfluoxetine (CYP2D6 inhibitors) have all beenshown to significantly increase the plasma ex-posure of sertindole. In addition, inducers ofCYP3A4,suchascarbamazepineandphenyotinhavebeenshowntoreducetheplasmaexposureof sertindole during coadministration, some-times requiring an increase in dosage. More-over, sertindole exposures are significantly in-creased in CYP2D6 poor metabolizers whereplasma concentrations increase two- to three-fold compared to extensive metabolizers [295].

7.3.9. Substituted Benzamide Racemic ami-sulpride (47) (Solian� [299]) is not approvedin the United States; however, it is approvedin Europewhere the standard dose of amisul-pride ranges from 50–800mg/day. Amisul-pride is rapidly absorbed after oral adminis-tration with two plasma concentration peaksat 1 and 4 h (Tmax) of 42 and 56 ng/mL, respec-tively (50mg dose). The oral half-life of ami-sulpride is �12 h. The oral bioavailability of

amisulpride is 43–48% and there is a signifi-cant food effect that reduces the bioavailabil-ity by 50%. Amisulpride has an apparent vo-lumeofdistributionof5.8 L/kgand itsbindingto plasma proteins is very low at17% [175,177,300]. Amisulpride (47) under-goes very little metabolism and is predomi-nately excreted in the urine. Minor pathwaysof amisulpride metabolism that have been

NN

N

NHO

F

Cl

45, Dehydrosertindole

NH

N

F

Cl

46, Norsertindole


identified include N-demethylation, oxida-tion of the pyrolidine ring, andhydroxylation.Therenal clearanceofamisulpride is17–20L/h that is greater than glomerular filtrationperhaps indicating active drug secre-tion [127]. After IV and oral dosing, 50% and23% of the dose is excreted as unchangedparent in the urine, respectively. Given thelow protein binding and lack of metabolism,there are no reported drug-drug interactionswith amisulpride, however, amisulpride ex-posure has been shown to increase signifi-cantly in the elderly and in the renally im-paired patients [179,182,188].

O

HN

O

S

NH2

OON

47, Amisulpride

8. STRATEGIES FOR DRUG DISCOVERY

In terms of the mechanism of action (MOA),the “dopamine theories” of antipsychotic

agents have dominated the field for decades.Conventional antipsychotic drugs are dopa-mine antagonists, whereas atypical antipsy-chotic drugs are dopamine antagonists withadditional actions on serotonin receptors suchas 5-HT1A and 5-HT2A. Thanks to the diversepharmacological profile of clozapine (4), itprovides a useful roadmap to the discovery ofnext generation antipsychotics. Multiple ap-proaches being pursued include: dopaminereceptor subtypes; serotonin receptor sub-types; glutamatergic agents (mGlu, NMDA

and AMPA receptors); histamine H3 receptorantagonists; muscarinic cholinergic agonists;neurokinin3 (NK3) receptor antagonists; PDEinhibitors and cannabinoids. Newer strate-gies include nicotine acetylcholine receptoragonists, positive allosteric modulators of D1

or D5 agonists, and 5-HT6 antagonists.

8.1. Dopamine Receptor SubtypeApproaches

There are five subtypes of dopamine recep-tors, D1–D5. While historically the D2 dopa-mine receptor has attracted the most atten-tion, more and more evidence suggest thatD1, D3, and D5 dopamine receptors are im-portant for the therapeutic actions of anti-psychotics as well. For instance, many of thecognitive abnormalities in schizophrenia aresimilar to those resulting from damage to theprefrontal cortex (PFC) including attentionabnormalities, problems in reasoning andjudgment andworkingmemory deficits. Clin-ical reports suggest that PFC D1 receptorsare upregulated in schizophrenia due to alocalized decrease in dopaminergic activityand that D1 receptor antagonists aggravatepsychotic symptoms.

48 (SKF-812197) is a full agonist of the D1

receptor [301,302]. Unfortunately, in threeopen clinical trials of 48 in schizophrenia, noappreciable antipsychotic activity was ob-served although it had precognitive effects inanimal models. A clinical study of the D1 re-ceptor antagonist 49 (NNC-01-0687) reportedefficacy on the negative symptoms of schizo-phrenia. Compound 50, with a half-life of 37h,was reported to produce significant receptordesensitization following a single dose, whiletid dosingwith51maintainedactivity for up to

NHHO

HOH

H

51, A-86929

HO

HOCl

NH

H

48, SKF-812197

HO

HO50, A-7763

ONH2

SNHO

O2N

O

49, NNC-01-687


30 days of treatment. For some antipsychoticagents with more complex pharmacologicalprofile, D1 receptor modulation plays an im-portant role. For example, zuclopenthixol (52)is a D2/D1 antagonist while asenapine (53) is aD1/D2/5-HT2A antagonist [303].

52, Zuclopenthixol

S

N

NOH

53, Asenapine

O

Cl

N

CH3

Whereas nearly all antipsychotic agentsare D2 receptor antagonists to some degree,selective dopamine D3 receptor antagonistshave attracted much attention in the area ofschizophrenia during the last dec-ade [304–307]. Selective dopamine D3 recep-tor antagonists are anticipated to have re-duced EPS liability compared to D2 receptorantagonists. Recent examples include tetra-hydrobenzazepine 54, arylalkylpiperazine 55and benzazepinone 56.

8.2. Serotonin Receptor SubtypeApproaches

Seven distinct families of serotonin receptors(5-HT) have been identified (5-HT1–5-HT7),

and at least 15 subpopulations have beencloned to date [308]. Among the known sub-types, both 5-HT2C and 5-HT6 are implicatedto have a relationship to schizpphrenia inaddition to 5-HT1A and 5-HT2A as we dis-cussed before.

Unlike 5-HT2A and 5-HT2B receptor sub-types, the 5-HT2C receptor is distributed al-most exclusively in the brain. 5-HT2C has nowbeen established as a potential target fortreating schizpphrenia [302,309,310] in addi-tional to anxiety, depression, and obesity. Theteracyclic indoline 57 (WAY-163909) is a po-tent and selective 5-HT2C agonist with a Ki of10.5 nM (EC50¼ 8nM) while for 5-HT2A its Ki

is 485nMand for 5-HT2B itsKi is 212nM[311].57 also worked in several antipsychotic ani-mal models including rat conditioned avoid-ance (ID50¼ 1.3mg/kg), mouse PCP-inducedhyperactivity (0.1mg/kg), and MK-801-in-duced disruption of prepulse inhibition (MED5.4mg/kg). Encouragingly, it did not showcataleptic potential in mouse. A full 5-HT2C

agonist, VER-2692 (58), was active in vivo at3mg/kg dose in a feeding model [312]. Thesepositive results suggest that 5-HT2C receptoragonists could be atypical neuroleptics.

HN

O

NO

N

CH3

N

CH3O2S

54

OH

H3C CH3

CH3

CH3

HNO

55

N

OO

N

N

NN

CH3

CH3CH3

H3C

56

N

HN

57, WAT-163909

N

NH2

58, VER-2692

STRATEGIES FOR DRUG DISCOVERY 41

Meanwhile, the 5-HT6 receptor, identifiedin the 1990s, has recently emerged as anattractive target for the treatment of schizo-phrenia. The 5-HT6 receptor exhibits only36–41% transmembrane homology with 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT2A, and5-HT2C receptors. The 5-HT6 receptor was thefirst cloned 5-HT receptor shown to be coupledpositively to activation of adenylate cyclase,similar to 5-HT4 and 5-HT7 [313]. A number ofantipsychotic agents, typical and atypical, aswell as antidepressants, have been shown tobind at rat 5-HT6 receptors with low nanomo-lar affinity. Since the 5-HT6 receptor has beenknown for a decade, several 5-HT6 receptoranatagonists have been advanced to the clinicfor the treatment of CNS diseases. Indolyl-sulfonate LY-483518 (59) is a potent (Ki¼ 1.3nM) and selective 5-HT6 receptor antago-nist [314]. It is now in phase II clinical trialsfor the treatment of cognitive impairmentassociated with schizphrenia. Thiephene-sul-fonamide 60 (SB-271046), also a potent(Ki¼ 1.3 nM) and selective 5-HT6 receptor an-tagonist, is currently in phase I clinical trialsfor the treatment of schizophrenia andAlzheimer’s disease [315].

8.3. Glutamatergic Agents

L-Glutamate (61) is a major excitatory neuro-transmitter in the mammalian central ner-vous system and plays a fundamental role inthe control of motor function, cognition, andmood. The physiological and pathophysiologi-cal effects of glutamate are mediated throughtwo receptor families: metabolic and ionotro-pic. Themetabotropic (G-protein-coupled) glu-tamate receptors are responsible for mediat-ing slow metabolic response whereas the io-notropic (ligand-gated ion channel) glutamatereceptors mediate the fast synaptic responseto extracellular L-glutamate. The ionotropicglutamate receptors are further divided intothree subclasses according to their molecularand pharmacological differences and arenamed after the agonists that were originallyidentified to selectively activate them: NMDA(62,N-methyl-D-aspartate), AMPA (63, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-pro-pionic acid), and kainate (64, 2-carboxy-3-car-boxymethyl-4-isopenylpyrrolidine). mGluRs,NMDA, and AMPA receptors have emergedas promising therapeutic targets for a varietyof clinical indications including schizophre-nia, depression, and Alzeimer’s disease.

N

59, LY-483518

S

60, SB-271046

Cl

N

OSF

F

O

O SO

O

O

NH

N NH

HO OH

O

NH2

O

61, (S)-Glutamic acid 62, NMDA

HOO

O

NHH3C

OH

63, AMPAO

N

OH

H3C

H2N

O

HO

NH

OOH

OH

O

64, Kainic acid


8.3.1. mGluR The mGluRs belong to the fa-mily of GPCRs and eight subtypes of mGluRshave been identified. Based on sequencehomology, pharmacological selectivity andprimary G-protein coupling, mGluRs havebeen divided into three groups: group ImGluRs include mGluR1 and mGluR5, bothof which are coupled to Gq/11 to activate phos-pholipase C (PLC); group II mGluRs (mGluR2

andmGluR3) and group III mGluRs (mGluR4,mGluR6, mGluR7 and mGluR8) are coupled toGi/o and associated effectors such as ion chan-nels or adenylyl cyclase. The mGluRs providea mechanism by which glutamate can modu-late activity at the same synapses at which itelicits fast excitatory synaptic responses. Be-cause of the ubiquitous distribution of gluta-matergic synapses, mGluRs participate in awide variety of functions in theCNS [316,317].Recent genetic data suggests genetic associa-tions between the schizophrenia and the me-tabotropic glutamate receptors, most notablewith themGLuR3 receptor [32,33]. In contrastto ligand-gated ion-channels (NMDA, AMPA,and kainite receptors), which are responsiblefor fast excitory transmission, mGluRs have amoremodulatory role, contributing to the fine-tuning of synaptic efficacy and control of theaccuracy and sharpness of transmission.

In early clinical studiesmGluR2/3 agonistshave shown promise. Administration of a pro-drug of the mGluR2/3 agonist that mimicsglutamate, 65 (LY404039) was shown to havepositive clinical effects over placebo and com-parable effect to olanzapine (4) [34]. The cor-responding methionine prodrug 66(LY2140023), had increased oral bioavailabil-ity. In phase II clinical trials, 66 relievedschizophrenia patients’ positive and negativesymptoms to a greater extent than a placebo.In addition, the compound did not causeweight gain, a common side effect of severalestablished schizophrenia drugs. The phase IItrial results validated the idea that normal-izing glutamate neurotransmission might al-leviate some of the negative symptoms.

SO O

HO2C

H

HCO2H

HN O

H2N SCH3

66, LY-2140023

SO O

HO2C

H

HCO2H

NH2

65, LY-404039

On the other hand, mGluR5 is expressedubiquitously in the mammalian CNS and isprimarily localized postsynaptically, althoughit also displays some presynaptic localization.Activation of mGluR5 elicits slow synapticresponses and modulates neuronal excitabil-ity through downstream signaling pathways.Previous studies have led to the hypothesisthat mGluR5-selective ligands may have po-tential utility as novel therapeutic agents formultiple psychiatric or neurological disordersincluding schizophrenia [319,320]. Therefore,mGluR5 positive allosteric modulators repre-sent an exciting approach for the treatment ofschizophrenia. Three distinct series ofmGluR5 positive allosteric modulators exist.The first is difluorobenzaldazine (DFB, 67),the second series is N-[4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl]-2-hydroxybenzamide (CPPHA, 68) and thethird is 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB, 69). Compound 67was the first mGluR5 positive allosteric mod-ulators identified. It does not activatemGluR5

when added alone, but increases the sensitiv-ity of mGluR5 to orthosteric agonists, andthereby shifts the concentration–responsecurve of orthosteric agonists to the left. It ishighly selective for mGluR5 and has littleactivity at other mGluR subtypes. The discov-ery of 67 provided a major breakthrough indemonstrating the possibility of developingmGluR5-selective positive allosteric modula-tors. However, the poor potency, efficacy andsolubility of this compound prevented itsfurther study in native tissue prepara-tions [316,317]. The validity of the mGluR5-selective positive allosteric modulators needsto be further demonstrated by molecules withsuperior potency, efficacy and pharmacoki-netic profiles.


8.3.2. NMDA Receptor In Section 2.2.2, wedescribed experimental data linking the iono-tropic glutamate receptor (NMDA receptor)with the core symptoms of schizophre-nia [17,18]. PCP can induce all three types ofschizophrenia symptoms and works by block-ing theNMDAreceptor. TheNMDAhypofunc-tion may result from decreased glutamatelevels in the brain. However, glutamate levelshave been shown to be unaltered in schizo-phrenic patients [19,20]. In addition to gluta-mate, NMDA receptor activation requires thecofactor glycine and blockade of this glycinesite inhibits NMDA function. Other findingswould support the hypotheses that decreasedNMDA function, due to a kynurenic acid (70)-mediated blockade of the glycine site of theNMDA receptor contributes to the pathologyof schizophrenia. In addition to kynurenicacid,NMDA function can be inhibited by otherendogenousNMDAantagonists. For example,activity and binding of glutamate carboxypep-tidease, the enzyme that breaks down NAAG(71) to NAA and glutamate, is reduced inschizophrenic patients [26,27], an effect un-likely mediated by changes in mRNA [28].This is of relevance since NAAG antagonizesNMDA receptor function [29,30]. These datasupport a hypothesis that hypofunction of theNMDA receptor may result from endogenous,orthosteric, or allosteric inhibitors of NMDAreceptor function.

N CO2H

OH

70, Kynurenic acid

CO2H

HN CO2H

NH

CO2H

O

O

71, N-Acetyl-aspartyl glutamate

When given in combination with antipsy-chotic drugs, positive modulators of glycine/D-serine site of the NMDA receptor such as D-

serine, glycine, and D-alanine significantlyimprove symptoms in patients with schizo-phrenia [318]. As orthosteric NMDA agonistsresult in neurotoxicity, targeting the allostericsite of the NMDA receptor would thereforeenhance NMDA responses to glutamate with-out direct activation [31]. This is a more in-direct way to target glutamate neurotrans-mission—blocking a glycine transporterknown as GlyT1. Normally, GlyT1 decreasesthe concentration of glycine in synapses, theinterneuron structures through which neuro-chemical messages propagate from neuron toneuron. Glycine, together with glutamate, isrequired to activate the NMDA receptor,which mediates glutamate signaling in thebrain. A drug that blocks GlyT1 would allowhigher concentrations of glycine to remain inthe synapse and could aid in normalizing glu-tamate signaling in patients. Sarcosine (72), aGlyT1 antagonist, was more effective at redu-cing both positive and negative symptomsthan was direct activation of the glycine/D-serine site of the NMDA receptor by D-ser-ine [319].

72, Sarcosine

NH

CO2H

O

Among the newer GlyT1 inhibitors, thereare glycine and sarcosine (72) derivatives suchas 73 (ALX-5407) and 74 [320]. There are alsopotent and selective nonamino-acid-contain-ing GlyT1 inhibitors such as 75 (SSR504734),76, and 77 (DCCCyB). Sulfone 77was derivedfrom a HTS hit through methodical SAR toincrease the GlyT1 selectivity as well as todecrease the liability of the P-glycoproteintransporter. Its phase I clinical trial has beenrecently completed.

NN

FF

67, DFB

N HN

Cl

OO

O

68, CPPHA

NN

HN

O CN

69, CDPPB


8.3.3. AMPA Receptor Ligands showingcompetitive antagonistic action at the AMPAtype of Glu receptors were first reported in1988, and the systemically active 2,3-dihy-droxy-6-nitro-7-sulphamoyl-benzo[f]quinoxa-line (78, NBQX)was first shown to have usefultherapeutic effects in animal models of neu-rological disease in 1990. Since then, the qui-noxaline template has represented the back-bone of various competitive AMPA receptorantagonists belonging to different classeswhich had been developed in order to increasepotency, selectivity and water solubility, butalso to prolong the in vivo action [321].

Unfortunately, direct activation of AMPAreceptors carries the risk of producing sei-

zures, excitotoxicity and a loss of efficacy dueto desensitization. However, the discovery ofpositive allosteric modulators (PAMs) offers amechanism for enhancing receptor activitywhile avoiding these issues [322]. There aretwomajor structural classes of AMPApositiveallosteric modulators [302,323].

The benzamide series were the first class ofAMPA positive allosteric modulators to beinvestigated when aniracetam (79) was foundto potentiate AMPA receptor-mediated trans-mission in the hippocampus.

The second major class of AMPA positiveallosteric modulators are the benzothiadia-

NH

HN

H2NO2S

O

O

O2N

78, NBQX

N

O

O

O

79, aniracetam

N

O O

80, CX-516

N

N

N

O O

81, CX-614

O

O O

NOH

O

O

F73, ALX-5407

NOH

O

74Cl

Cl

S

NH

O

O O

Cl

Cl

77, DCCCyB

Cl

CF3

HN ONH

75, SSR504734 76

NN

NH

HO

O


zines derived from cyclothiazide (82). 82 ishighly selective for flipoforms, givinga twofold(EC2�) petentiation value of the AMPA cur-rent at a concentration of 1.6mM. S-18986 (83,EC2�¼ 60mM) is in phase I clinical trials forthe treatment of cognitive deficits. Benzothia-diazine 84 (EC2�¼ 8.8mM) with even higherpotency than 83 has also been reported.

Additional AMPA positive allosteric mod-ulators may be represented by the sulfona-mides 85–87.

8.4. Histamine H3 Receptor

Antagonists of the histamine H1 andH2 recep-tors have been successful as blockbuster drugsfor treating allergic conditions and gastric ul-cers, respectively. The histamine H3 receptorwas discovered pharmacologically in 1983 andgenetically identified in 1999. Signalingthrough the H3 receptor activates G proteinsthat inhibit adenylate cyclase activity and re-duce intracellular cAMP levels. In the CNS,the H3 receptor is localized on the presynapticmembrane as an autoreceptor and negativelyregulates the release and synthesis of hista-mine. In addition, the H3 receptor is known to

modulate the release of other neurotransmit-ters such as norepinephrine, dopamine, acet-ylcholine, serotonin, andGABA.Becauseof theeffects of H3 signaling on multiple neuronaltransmitters, it has been suggested that H3

antagonists/inverse agonists could be effectivetherapeutics for several CNS-related disor-ders. For instance, the potent and selective

histamine H3 receptor inverse agonist 88(BF2.649) suppressed the excessive daytimesleep of narcoleptic patients [324].

O N

Cl

88, BF2.649, hH3 (IC50) 12 ± 3 nM

Several histamine H3 receptor antagonistshave been advanced into clinicaltrials [325–327]. 89 (ABT-239), a potent his-tamine H3 receptor antagonist, was effectiveat a low dose (0.1mg/kg s.c.) in a repeat trialinhibitory avoidance task in SHR pups, amodel involving aspects of attention, impul-sivity and learning that is thought to be re-

CH3 HN

SO2

CH3

CH3

NH

O2S

H3C 85, LY-451395

NHO2S

CH3

CH3

HN

SO2

H3C86

NSO2

CH3

S

87

NH

NH

O2S

H

H

H2NO2S

Cl

82, cyclothiazide

N

NH

O2S

H

83, S-18986

N

NH

O2S

84CH3


lated to characteristics of ADHD. Compound89 was active in a social recognition model ofshort-termmemory in aged and adult rats andin the water maze model, demonstrating ef-fects on different aspects of cognitive impair-ment. Furthemore, 89 was also active in theprepulse inhibition startle model, a model ofsensory gating proposed to be related to schi-zophrenia [325]. Unfortunately, despite itsimpressive in vivo profile for cognition en-hancement, the development of 89was halteddue to cardiovascular liabilities. It inhibits[3H]-dofetilide binding to thehERGpotassiumchannel with aKi of 195nM. Its liabilities alsoinclude a high c logP of 5.2, which is believedto contribute to the high brain partitioning (B/P> 34) and high plasma protein binding. An-otherpotenthistamineH3 receptor antagonist90 (GSK189254) was in phase I clinical trialsfor the treatment of dementia. Thepotential ofH3 antagonists/inverse agonists as antipsy-chotics still needs to be validated in clinicaltrials.

8.5. Neuronal Nicotinic AcetylcholineReceptor

Smoking is three times higher for schizophre-nics than that in the general population andnicotine can produce modest transient im-provements in cognitive and sensory deficits.Meanwhile, neuronal nicotinic acetylcholinereceptors (nAChRs) are involved inavariety ofattention and cognitive processes. nAChRsare Ca2þ -permeable, ligand-gated ion chan-nels that modulate synaptic transmission ofkey regions of the central nervous systemsinvolved in learning and memory [302].

The highly selective a4b2 nAChR agonist91 (isproniciline, TC-1734) is active in severalanimal models indictive of cogniotive en-hancement. In phase I clinical trials, 91 waswell tolerated and demonstrated linear phar-

macokinetics [328]. Another selective a4b2

agonist 92 (ABT-089) underwent phase I clin-ical trials and was reported to have an excel-lent pharmacokinetic profile in humans, goodcardiovascular and gastrointestinal tolerabil-ity, and positive signs of cognitive effects asmeasured by decrease in reaction time.

91, Ispronicline

N

OH3C

CH3

HN

CH3

CH3 N

O

H3C

NH

92, ABT-089

Positive allostericmodulators of subtypea7

neuronal nicotinic acetylcholine receptor re-present an important therapeutic potential.Positive allosteric modulators increase theprobability of channel opening, while decreasethe inherent agonist potential for receptordesensitization [302]. The selectivea7 nAChRpositive allosteric modulator 93 is in phase II

clinical trials and several other positive allos-teric modulators 94, 95, and 96 are in phase Iclinical trials [306].

N

OBr

NO N

HN

N

O

O

94, TC-561993, SSR180711

N O

NH

ON

95, PHA-543613

N O

NH

O

96, PHA-709829

N

O

N

H3CNC

89, ABT-239, hH3 (IC50) 0.63 ± 0.24 nM

NHN

H3CO

ON

90, GSK189254, hH3 (IC50) 0.55 ± 0.07 nM


8.6. Neurokinin3 (NK3) ReceptorAntagonists

Antagonists of the neurokinin-1 receptor(NK1r) and NK2r have been extensively ex-plored for both peripheral indications (e.g.,urinary incontinence, asthma) and central in-dications (e.g., pain, depression). Recently,neurokinin receptor expression was system-

atically compared in rodent, primate, and hu-man brain. These studies verified the pre-sence of NK3r in primate brain although atexceptionally low levels compared with NK1r.NK3 receptors are present on dopamine neu-rons in the A9 and A10 groups and modulatedopamine release and cholinergic tone. Over-all, support for NK3r as a critical mediator inthe human CNS remains equivocal based onexpression and localization studies. However,two clinical studies disclosed two structurallyunrelatedNK3r antagonists that are reportedto be well tolerated and show antipsychoticefficacy. These reports have acceleratedfurther exploration of NK3r antagonists andheightened speculation about the potential forsuch antagonists to be a new generation ofantipsychotics [329].

In animal models, the NK3r antagonist 97(SSR146977) prevented NK3r agonist-in-duced release of Ach, 5-HT, and DA. At200mg/day, 97 (osanetant), an NK3r antago-nist, showed antipsychotic efficacy similar tohaloperidol (3). But unlike haloperidol (3),Compound 97 is devoid of EPS and weightgain. It was discontinued in August 2005 pos-sibly because it failed to show dependent re-

lated efficacy [306]. Another selective NK3rantagonist 98 (talnetant) was active in phaseII trials for schizophrenia. In a study involving236 patients over 6 weeks, 98 showed signifi-cant antipsychotic effects in 40% of patients at200mg. Furthemore, it was better toleratedthan resperidone (6) with reduced prolactinelevation, decreased tetesterone reduction, noweight gain, no QTC effects and no EPS [329].

8.7. PDE Inhibitors

Phosphodiesterase (PDE) inhibitors such assildenafil, tadalafil and vardenafil as PDE5inhibitors have had distinctive clinical benefitand notable commercial success for the treat-ment of erectile dysfunction.

PDEs are a class of key enzymes within theintracellular signal transduction cascade thatfollow activation of many types of membrane-bound receptors. PDEs degrade cyclic adeno-sine mono phosphate (cAMP) and/or cyclicguanosine mono phosphate (cGMP) by hydro-lysis of phosphodiester bonds. Twenty-onegenes are currently known to encode at least11 different PDE families (PDE1–PDE11).Modifying the rate of cyclic nucleotide forma-tion or degradation via PDEs will change theactivation state of related pathways. There-fore, PDE inhibitors can prolong or enhancethe effects of physiological processesmediatedby cAMP or cGMP. It is noteworthy that PDEsare the most important means of inactivatingintracellular cAMP in the brain, suggestingthat PDE inhibitors present a potentiallypowerful means to manipulate second mes-

97, OsanetantNK3r K i = 1.2 nMNK2r K i = 40 nMNK1r K i = 774 nM

98, TalnetantNK3r K i = 1.0 nMNK2r K i = 144 nMNK1r K i = > 10 µM

N

Cl

Cl

O

N

N

O

N

OH

O NH


sengers involved in learning, memory, andmood.

PDE4 is a cGMP-specific phosphodiester-ase that is widely distributed in humans. Inanimal models (acoustic startle and PPI), thePDE4 inhibitor 99 (rolipram) appears to havea pharmacological profile similar to that ofsome newer antipsychotics that claim to re-duce motor side effect liability at therapeuticdoses. However, 99 produces nausea and em-esis at doses that overlap the therapeuticrange, suggesting that more selective agentsmay be needed [330]. Another PDE4 inhibitorMEM1414 is in clinical trials for potential usein treating Alzheimer’s disease [331]. In miceand rats, cognitive improvements were ob-served at doses as low as 1mg/kg i.p. PhaseII clinical trials for MEM1414 were initiatedin 2006.

PDE10 is a dual substrate cyclic nucleotidephosphodiesterase (cAMP and cGMP) thathas preferential expression in the spiny neu-rons of the striatum, aportion of the brain thatis believed to have impaired regulation inschizophrenia. Inhibiting PDE10 in rodentsleads to increases in cyclic nucleotides in thestriatum and a behavioral antipsychotic phe-notype. In mice, 100 (papaverine), a PDE10Ainhibitor, is associated with increased cGMPlevels in the striatumand increasedphosphor-ylation of CREB, which are both crucial forstriatal function [332]. Interestingly, 100 wasalso found to reduce deficits caused by chronicphencyclidine treatment, a recognized animalmodel for schizophrenia. The findings led tointense interest in exploring this approach forschizophrenia treatment. Another PDE10Aselective inhibitor 101 (PF-2545920) was ef-fective at treating schizophrenia symptoms inanimals. Phase I clinical trials with 101 were

completed and it nowhas entered into phase IItrials [333]. This compound will help deter-minewhetherPDE10A inhibitors are effectiveagainst schizophrenia.

8.8. Cannabinoids

The association between cannabinoids andpsychosis has been long recognized. Cannabi-noids can induce acute transient psychoticsymptoms or an acute psychosis in a smallportion of individuals. Similar to smoking andlung cancer, it is more likely that cannabisexposure is a component cause that interactswith other factors, for example, genetic risk, to“cause” schizophrenia. There is also tantaliz-ing evidence frompostmortem, neurochemicaland genetic studies suggesting CB1 receptordysfunction (endogenous hypothesis) in schi-zophrenia that warrants further investiga-

tion [334]. The central cannabinoid (CB1) re-ceptor is a G protein-coupled receptor that iswidely distributed in the central nervous sys-tem and several peripheral tissues.

Apotent and selectiveCB1 receptor antago-nist 102 (rimonabant) was approved in Eur-ope for obesity and is currently suspended forneurological andpsychiatric side effects. Com-pound 102 was shown to reduce stimulant-induced hyperactivity [335]. Compound 103(AVE-1625) is a highly potent, selective an-tagonist for the CB1 receptor withKi values of0.16–0.44nM. At 1–3mg/kg, AVE-1625 signif-icantly improves the performance of rodentsinworkingmemory tasks [336].104 (SLV-319)319 is a potent and selective CB1 receptorantagonist with Ki values of 7.8 and 7943nMfor CB1 and peripheral cannabinoid (CB2),respectively [337]. 104 is less lipophilic (logP5.1) and therefore more water soluble thanother known CB1 receptor ligands.

O

OCH3

NH

O

99, rolipram 100, papaverine

NN

H

CH3

O

O

H3CN

N CH3

N

ON

101, PF-2545920


In summary, many targets exist for thetreatment of schizophrenia beyond the tradi-tional dopamine/serotonin receptor mechan-ism.Hopefully, some of thesemechanismswillprovide novel antipsychotics that are as effi-cacious as the existing antipsychotics but yetdevoid of the side effects associated with themsuch as EPS and weight gain.

REFERENCES

1. Diagnostic and Statistical Manual of MentalDisorders. 4th ed. Text Rev. Washington, DC:American Psychiatric Association; 2000.

2. Green MF, Nuechterlein KH, Gold JM,Barch DM, Cohen J, Essock S, Fenton WS,Frese F, Goldberg TE, Heaton RK, Keefe RS,Kern RS, Kraemer H, Stover E, WeinbergerDR, Zalcman S, Marder SR Biol Psychiatry2004;56:301–307.

3. Courvoisier S. J Clin Exp Psychopathol1956;17:25–37.

4. O’Keeffe R, Sharman DF, Vogt M. Br J Phar-macol 1970;38:287–304.

5. Van Rossum JM. Arch Int Pharmacodyn Ther1966;160:492–494.

6. SeemanP, LeeT. Science 1975;188:1217–1219.

7. Creese I, Burt DR, Snyder SH. Science1976;30:481–483.

8. Cross AJ, Crow TJ, Owen F. Psychopharma-cology 1981;74:122–124.

9. Wong DF, Wagner HN, Jr, Tune LE, DannalsRF, Pearlson GD, Links JM, Tamminga CA,Broussolle EP, Ravert HT, Wilson AA, ToungJK, Malat J, Williams JA, O’Tuama LA,Snyder SH, Kuhar MJ, Gjedde A. Science1986;234:1558–1563.

10. Farde L, Wiesel FA, Stone-Elander S, HalldinC, Nordstr€omAL, Hall H, Sedvall G. Arch GenPsychiatry 1990;47:213–219.

11. Hietala J, Syv€alahti E, Vuorio K, Na�gren K,

LehikoinenP,RuotsalainenU,R€akk€ol€ainenV,Lehtinen V, Wegelius U. Arch Gen Psychiatry1994;51:116–123.

12. Nordstr€omAL,FardeL,ErikssonL,HalldinC.Psychiatry Res 1995;61:67–83.

13. LaruelleM,Abi-DarghamA,VanDyckCH,GilR, D’Souza CD, Erdos J, McCance E, Rosen-blatt W, Fingado C, Zoghbi SS, Baldwin RM,Seibyl JP, Krystal JH, Charney DS, Innis RB.PNAS 1996;93:9235–9240.

14. Bannon JM, Roth RH. Pharmacol Rev1983;35:53–68.

15. Davis KL, Kanh RS, Ko G, Davidson M. Am JPsychiatry 1991;148:1474–1486.

16. Luby ED, Cohen BD, Rosenbaum G, GottliebJS, Kelley AMA Arch Neurol Psychiatry1959;81:363–369.

17. Javitt DC, Zukin SR. Am J Psychiatry1991;148:1301–1308.

18. Olney JW, Farber NB. Arch Gen Psychiatry1995;52:998–1007.

19. Perry TL. Neurosci Lett. 1982;28:81–85.

20. Korpi ER, Kaufmann CA, Marnela KM, Wein-berger DR. Psychiatry Res 1987;20:337–45.

21. SchwarczR, RassoulpourA,WuHQ,Medoff D,Tamminga CA, Roberts RC. Biol Psychiatry2001;50:521–530.

22. Erhardt S, Schwieler L, Engberg G. Adv ExpMed Biol 2003;527:155–165.

23. Nilsson LK, LinderholmKR, Engberg G, Paul-son L, Blennow K, Lindstr€om LH, Nordin C,Karanti A, Persson P, Erhardt S. SchizophrRes 2005;80:315–322.

N N

CH3

ClCl

Cl

O

NH

N

102, rimonabant

NN

Cl

NNH

H3C SO

O

Cl103, AVE-1625

NOF

N

NN

O

HO

H3C

104, (SLV-319)


24. ParsonsCG,DanyszW,QuackG,HartmannS,Lorenz B, Wollenburg C, Baran L, Przegalins-ki E, KostowskiW, Krzascik P, Chizh B, Head-ley PM. J Pharmacol Exp Ther1997;283:1264–1275.

25. ErhardtS, SchwielerL,EmanuelssonC,GeyerM. Biol Psychiatry 2004;56:255–260.

26. TasiG,PassaniLA,SlusherBS,CarterR,BaerL, Kleinman JE, Coyle JT. Arch Gen Psychia-try 1995;52:829–836.

27. Guilarte TR, Hammoud DA, McGlothan JL,Caffo BS, Foss CA, Kozikowski AP, PomperMG. Schizophr Res 2008;99:324–332.

28. Ghose S, Weickert CS, Colvin SM, Coyle JT,Herman MM, Hyde TM, Kleinman JE. Neu-ropsychopharmacology 2004;29:117–125.

29. Grunze HC, Rainnie DG, Hasselmo ME, Bar-kai E, Hearn EF, McCarley RW, Greene RW. JNeurosci. 1996 16:2034–2043.

30. Bergeron R, Imamura Y, Frangioni JV,Greene RW, Coyle JT. J Neurochem.2007;100:346–357.

31. CoyleJT.CellMolNeurobiol 2006;26:365–384.

32. Fujii Y, Shibata H, Kikuta R, Makino C,Tani A, Hirata N, Shibata A, Ninomiya H,Tashiro N, Fukumaki Y. Psychiatr Genet2003;13:71–76.

33. Egan MF, Straub RE, Goldberg TE, Yakub I,Callicott JH, Hariri AR, Mattay VS, BertolinoA, Hyde TM, Shannon-Weickert C, Akil M,Crook J, Vakkalanka RK, Balkissoon R, GibbsRA, Kleinman JE, Weinberger DR. Proc NatlAcad Sci 2004;101:12604–12609.

34. Patil ST, Zhang L,Martenyi F, Lowe SL, Jack-son KA, Andreev BV, Avedisova AS, Barden-stein LM,Gurovich IY,MorozovaMA,MosolovSN,NeznanovNG, ReznikAM, SmulevichAB,Tochilov VA, Johnson BG, Monn JA, SchoeppDD. Nat Med 2007;13:1102–1107.

35. Sesack SR, Hawrylak VA, Melchitzky DS,Lewis DA. Cereb Cortex 1998;8:614–622.

36. Melchitzky DS, Lewis DA. Cereb Cortex2003;13:452–460.

37. Volk DW, Austin MC, Pierri JN, Sampson AR,Lewis DA. Arch Gen Psychiatry 2000;57:237–245.

38. Volk D, Austin M, Pierri J, Sampson A, LewisD. Am J Psychiatry 2001;158:256–265.

39. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, GraysonDR, Impagna-tiello F, Pandey G, Pesold C, Sharma R,Uzunov D, Costa E. Arch Gen Psychiatry2000;57:1061–1069.

40. Schleimer SB, Hinton T, Dixon G, JohnstonGA. Neuropsychobiology 2004;50:226–230.

41. Guidotti A, Auta J,Davis JM,DongE,GraysonDR, Veldic M, Zhang X, Costa E. Psychophar-macology 2005;180:191–205.

42. Meltzer HY, Li Z, Kaneda Y, Ichikawa J.Prog Neuropsychopharmacol Biol Psychiatry2003;27:1159–1172.

43. D�ıaz-Mataix L, Scorza MC, Bortolozzi A, TothM, Celada P, Artigas F. J Neurosci2005;25:10831–10843.

44. Sumiyoshi T, Park S, Jayathilake K, Roy A,Ertugrul A, Meltzer HY. Schizophr Res2007;95:158–168.

45. Reynolds GP, Arranz B, Templeman LA,Fertuzinhos S, San L. Am J Psychiatry2006;163:1826–1829.

46. Jakab RL, Goldman-Rakic PS. Proc Natl AcadSci 1998;20:735–740.

47. Willine DL, Deutch AY, Roth BL. Synapse1997;27:79–82.

48. Arranz B, Rosel P, San L, Ram�ırez N, DueñasRM, Salavert J, Centeno M, Del Moral E.Psychiatry Res 2007;153:103–109.

49. Levin ED, McClernon FJ, Rezvani AH. Psy-chopharmacology 2006;184:523–539.

50. Levin ED, Wilson W, Rose JE, McEvoy J.Neuropsychopharmacology 1996;15:429–36.

51. FreedmanR,HallM,AdlerLE,LeonardS.BiolPsychiatry 1995;38:22–33.

52. Durany N, Z€ochling R, Boissl KW, Paulus W,Ransmayr G, Tatschner T, Danielczyk W, Jel-linger K, Deckert J, Riederer P. Neurosci Lett2000;287:109–112.

53. Guan ZZ, Zhang X, Blennow K, Nordberg A.Neuroreport 1999;10:1779–1782.

54. Olincy A, Harris JG, Johnson LL, Pender V,Kongs S, Allensworth D, Ellis J, Zerbe GO,Leonard S, Stevens KE, Stevens JO, MartinL, Adler LE, Soti F, Kem WR, Freedman R.Arch Gen Psychiatry 2006;63:630–638.

55. Yamamoto K, Hornykiewicz O. Prog Neurop-sychopharmacol Biol Psychiatry 2004;28:913–922.

56. Binder EB, Kinkead B, Owens MJ, NemeroffCB. Biol Psychiatry 2001;50:856–72.

57. Arinami T. J Hum Genet 2006;51:1037–1045.

58. Allen NC, Bagade S, McQueen MB, IoannidisJP, Kavvoura FK, Khoury MJ, Tanzi RE, Ber-tram L. Nat Genet 2008;40:827–834.

59. Dayalu P, Chou KL. Expert Opin Pharmac-other 2008;9:1451–1462.

REFERENCES 51

60. Kapur S, Zipursky R, Jones C, Remington G,Houle S. Am J Psychiatry 2000;157:514–520.

61. Lieberman JA, Stroup TS, McEvoy JP, SwartzMS, Rosenheck RA, Perkins DO, Keefe RS,Davis SM, Davis CE, Lebowitz BD, Severe J,Hsiao JK. Clinical Antipsychotic Trials of In-tervention Effectiveness (CATIE) Investiga-tors. N Engl J Med 2005;353:1209–1223.

62. Strawn JR, Keck PE, Jr, Caroff SN. Am JPsychiatry 2007;164:870–876.

63. Mackin P. Cardiac Hum Psychopharmacol2008; (Suppl) 1: 3–14.

64. Drici MD, Priori S. Pharmacoepidemiol DrugSaf 2007;16:882–890.

65. Watanabe A, Shibata I, Kato T. PsychiatryClin Neurosci 2004;58:268–273.

66. Haddad PM, Sharma SG. CNS Drugs2007;21:911–936.

67. Stroup TS, Lieberman JA, McEvoy JP, SwartzMS, Davis SM, Rosenheck RA, Perkins DO,Keefe RS, Davis CE, Severe J, Hsiao JK. Am JPsychiatry 2006;163:611–622.

68. Lambert BL, Cunningham FE, Miller DR, Da-lack GW, Hur K. Am J Epidemiol2006;164:672–681.

69. Haddad PM, Dursun SM. Hum Psychophar-macol 2008;Supp 1: 15–26.

70. Clozapine package inset. Teva Pharmaceudi-cals Ind. Ltd; Jerusalem, Israel.

71. WallaceM. Int Clin Psychopharmacol 2001;16(Suppl) 1: S21–24.

72. Haddad PM, Wieck A. Drugs2004;64:2291–2314.

73. Atasoy N, Erdogan A, Yalug I, Ozturk U,Konuk N, Atik L, Ustundag Y. Prog Neurop-sychopharmacol Biol Psychiatr 2007;31:1255–1260.

74. Erdogan A, Atasoy N, Akkurt H, Ozturk D,Karaahmet E, Yalug I, Yalug K, Ankarali H,Balcioglu I. Prog Neuropsychopharmacol BiolPsychiatry 2008;32:849–857.

75. Kane JM,Leucht S, CarpenterD,Docherty JP.J Clin Psychiatry 2003;64:5–19.

76. Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor JJ, Jr, Okasha A, Singh B, Stein DJ, OlieJP, Fleischhacker WW, Moeller HJ. Section ofPharmacopsychiatry, World Psychiatric Asso-ciation. Schizophr Res 2008;100:20–38.

77. Jones PB, Barnes TR,Davies L, DunnG, LloydH, Hayhurst KP, Murray RM, Markwick A,Lewis SW. Arch Gen Psychiatry2006;63:1079–1087.

78. Van Ree JM, Elands J, Kir�aly I, Wolterink G.Eur J Pharmacol 1989;166:441–452.

79. Gold LH, Swerdlow NR, Koob GF. Behav Neu-rosci 1988;102:544–552.

80. Jones GH, Robbins TW. Pharmacol BiochemBehav 1992;43:887–895.

81. Costall B, Naylor RJ, Nohria V. Eur J Phar-macol 1978;50:39–50.

82. Arnt J. Eur J Pharmacol 1983;90:47–55.

83. Nordquist RE, Risterucci C, Moreau JL, VonKienlin M, K€unnecke B, Maco M, Freichel C,Riemer C, Spooren W. Neuropharmacology2008;54:405–446.

84. Chiodo LA, Bunney BS. J Neurosci1983;3:1607–1619.

85. Akhtar M, Uma Devi P, Ali A, Pillai KK, Vo-hora D. Fundam Clin Pharmacol2006;20:373–378.

86. Skuza G, Rogóz Z. Pharmacol Rep2006;58:626–635.

87. Siuciak JA, Chapin DS, McCarthy SA, Gua-nowsky V, Brown J, Chiang P, Marala R, Pat-terson T, Seymour PA, Swick A, Iredale PA.Neuropharmacology 2007;52:279–590.

88. JentschJD,RothRH.Neuropsychopharmacol-ogy 1999;20:201–225.

89. Stefani MR, Moghaddam B. Ann NY Acad Sci2003;1003;464–467.

90. Rodefer JS, Nguyen TN, Karlsson JJ, ArntJ. Neuropsychopharmacology. 2008;33:2657–2666.

91. Noda Y, Yamada K, Furukawa H, NabeshimaT. Br J Pharmacol 1995;116:2531–2537.

92. Noda Y, Kamei H, Mamiya T, Furukawa H,Nabeshima T. Neuropsychopharmacology2000;23:375–387.

93. Porsolt RD, Le Pichon M, Jalfre M. Nature1977;266:730–732.

94. Sams-Doss F. Behav Pharmacol 1998;7:3–23.

95. Lahti AC, Koffel B, LaPorte D, Tamminga CA.Neuropsychopharmacology 1995;13:9–19.

96. Malhotra AK, Adler CM, Kennison SD, ElmanI, Pickar D, Breier A. Biol Psychiatry1997;42:664–668.

97. Braff D, Stone C, Callaway E, Geyer M, GlickI, Bali L. Psychophysiology 1978;15:339–343.

98. Kumari V, Sharma T. Psychopharmacology2002;162:97–101.

99. Lubow RE. Schizophr Bull 2005;31:139–153.

100. Gray NS, Pickering AD, Hemsley DR,Dawling S, Gray JA. Psychopharmacology1992;107:425–430.


101. Swerdlow NR, Stephany N, Wasserman LC,Talledo J, SharpR, Auerbach PP. Psychophar-macology 2003;169:314–320.

102. Baruch I, Hemsley DR, Gray JA. J Nerv MentDiscov 1988;176:598–606.

103. Gray NS, Pilowsky LS, Gray JA, Kerwin RW.Schizophr Res 1995;17:95–107.

104. Weiner I, Lubow RE, Feldon J. Psychophar-macology 1984;83:194–199.

105. Aguado L, San Antonio A, P�erez L, del Valle R,Gómez J. BehavNeural Biol 1994;61:271–281.

106. Turgeon SM, Auerbach EA, Duncan-SmithMK, George JR, Graves WW. Pharmacol Bio-chem Behav 2000;66:533–539.

107. Weiner I, Feldon J. J Pharmacol BiochemBehav 1992;42:625–631.

108. Weiner I. Psychopharmacology 2003;169:257–297.

109. Wadenberg ML, Hicks PB. Neurosci BiobehavRev 1999;23:851–862.

110. Moore NA, Tye NC, Axton MS, Risius FC. JPharmacol Exp Ther 1992;262:545–551.

111. Seeger TF, Seymour PA, Schmidt AW, ZornSH, Schulz DW, Lebel LA, McLean S, Gua-nowskyV, HowardHR, Lowe JA, 3rd, Heym J.J Pharmacol Exp Ther 1995;275:101–113.

112. NatesanS,RecklessGE,Nobrega JN,FletcherPJ, Kapur S. Neuropsychopharmacology2006:31:1854–1863.

113. Takano A, Suhara T, Maeda J, Ando K, Okau-chi T, Obayashi S, Nakayama T, Kapur S.Psychiatry Clin Neurosci 2004;58:330–332.

114. Wadenberg ML, Kapur S, Soliman A, Jones C,Vaccarino F. Psychopharmacology 2000;150:422–429.

115. O’Tuathaigh CM, Babovic D, O’MearaG, Clifford JJ, Croke DT, Waddington JL.Neurosci Biobehav Rev 2007;31:60–78.

116. Benson MA, Newey SE, Martin-Rendon E,Hawkes R, Blake DJ. J Biol Chem 2001;276:24232–24241.

117. Straub RE, Jiang Y,MacLean CJ, Ma Y,WebbBT, Myakishev MV, Harris-Kerr C, WormleyB, Sadek H, Kadambi B, Cesare AJ, Gibber-manA,WangX, O’Neill FA,WalshD, KendlerKS. Am J Hum Genet 2002;71:337–348.

118. Talbot K, EidemWL, Tinsley CL, BensonMA,ThompsonEW,SmithRJ,HahnCG, Siegel SJ,Trojanowski JQ, Gur RE, Blake DJ, ArnoldAE. J Clin Invest 2004;113:1353–1363.

119. Hattori S, Murotani T, Matsuzaki S, IshizukaT, Kumamoto N, Takeda M, Tohyama M, Ya-

matodaniA,KunugiH,HashimotoR.BiochemBiophys Res Commun. 2008;22:298–302.

120. StClairD,BlackwoodD,MuirW,CarothersA,Walker M, Spowart G, Gosden C, Evans HJ.Lancet 1990;336:13–16.

121. Millar JK, Wilson-Annan JC, Anderson S,Christie S, Taylor MS, Semple CA, Devon RS,Clair DM, Muir WJ, Blackwood DH, PorteousDJ. Hum Mol Genet 2000;22:1415–1423.

122. Sachs NA, Sawa A, Holmes SE, Ross CA, De-Lisi LE, Margolis RL. Mol Psychiatry2005;10:758–764.

123. Li W, Zhou Y, Jentsch JD, Brown RA, Tian X,EhningerD,HennahW,PeltonenL,L€onnqvistJ, Huttunen MO, Kaprio J, Trachtenberg JT,Silva AJ, Cannon TD. Proc Natl Acad Sci USA2007;13:18280–18285.

124. Clapcote SJ, Lipina TV, Millar JK, Mackie S,Christie S, Ogawa F, Lerch JP, Trimble K,Uchiyama M, Sakuraba Y, Kaneda H, Shir-oishiT,HouslayMD,HenkelmanRM,SledJG,Gondo Y, Porteous DJ, Roder JC. Neuron2007;54:387–402.

125. Gogos JA, Gerber DJ. Trends Pharmacol Sci2006;27:226–233.

126. Costa E, Dong E, Grayson DR, Guidotti A,Ruzicka W, Veldic M. Epigenetics2007;2:29–36.

127. van der Stelt O, Belger A. Schizophr Bull2007;33:955–970.

128. Jensen O, Kaiser J, Lachaux JP. Trends Neu-rosci 2007;30:317–324.

129. Kwon JS, O’Donnell BF, Wallenstein GV,GreeneRW,HirayasuY,Nestor PG,HasselmoME, Potts GF, Shenton ME, McCarley RW.Arch Gen Psychiatry 1999;56:1001–1005.

130. Gallinat J, Winterer G, Herrmann CS,Senkowski D. Clin Neurophysiol 2004;115:1863–1874.

131. Hajós M, Hoffmann WE, Kocsis B. Biol Psy-chiatry 2008;63:1075–1083.

132. Ellenbroek B, Cools AR. Life Sci 1988;42:1205–1213.

133. Prinssen EP, Ellenbroek BA, Stamatovic B,Cools AR. Brain Res 1995;673:283–289.

134. Turrone P, Remington G, Nobrega JN. Neu-rosci Biobehav Rev 2002;26:361–380.

135. Gao XM, Sakai K, Tamminga CA. Neuropsy-chopharmacology 1998;19:428–433.

136. Rourke C, Starr KR, Reavill C, Fenwick S,Deadman K, Jones DN. Psychopharmacology2006;184:107–114.

REFERENCES 53

137. Kalinichev M, Rourke C, Daniels AJ, GrizzleMK, Britt CS, Ignar DM, Jones DN. Psycho-pharmacology 2005;182:220–231.

138. The FDA website: http://www.centerwatch.com/patient/drugs/DRUGLIST.html.

139. Li JJ, Johnson DS, Sliskovic DR, Roth BD.Contemporary Drug Synthesis. Hoboken, NJ:Wiley & Sons; 2004. p 89–111.

140. Li JJ. Laughing Gas, Viagra, and Lipitor, TheHuman Stories behind the Drugs We Use. NewYork, NY: Oxford University Press; 2006. p150–158.

141. De Oliveira IR, Juruena MF. J Clin PharmTherap 2006;31:523–534.

142. KramerM, SimpsonG,Maciulis V, Kushner S,Vijapurkar U, Lim P, Eerdekens M. J Clin.Psychopharm 2007;27:6–14.

143. Seeman P, Corbett R, Nam D, Van Tol HHM.Jpn J Pharmacol 1996;71:187–204.

144. Seeman P, Corbett R, Nam D, Van Tol HHM.Neuropsychopharmacol 1997;16:93–110.

145. Seeman P. Can J Psychiatry 2002;47:27–38.

146. Miyamoto S, Duncan GE, Marx CE, Lieber-man JA. Mol Psychiatry 2005;10:79–104.

147. Meltzer HY, Matsubara S, Lee JC. J Pharma-col Exp Therap 1989;251:238–246.

148. Lee T, Tang SW. Psychiatry Res 1984;12:277–285.

149. Kiss B, Bitter I. Structural Analogues of Clo-zapine. In: Fischer J, Ganellin CR, editors.Analogue-Based Drug Discovery. Weinheim,Germany: Wiley-VCH; 2006. p 297–313.

150. Wilk S, Stanley M. Eu J Pharmacol 1977;41:65–726.

151. Meltzer HY, Fibiger HC. Neuropsychophar-macol 1976;14:83–85.

152. Bhana N, Foster RH, Olney R, Plosker GL.Drugs 2001;61:111–161.

153. Gunasekara NS, Spencer CM. CNS Drugs1998;9:325–340.

154. Goldstein JM. Drugs Today 1999;35:193–210.

155. Nemeroff CB, Kinkead B, Goldstein J. J ClinPsychiatry 2002;63 (Suppl 13): 5–11.

156. ApiquianR, FresanA,UlloaR-E, de la Fuente-Sandoval C, Herrera-Estrella M, Vazquez A,Nicolini H, Kapur S. Neuropsychopharmacol2005;30:72236–72244.

157. Lydiard RB, Gelenberg AJ. Pharmacotherapy1981;1:163–178.

158. Liegeois JFF, Rogister FA, Bruhwyler J, Da-mas J, Nguyen TP, Inarejos MO, ChleideEMG,Mercier MGA, Delarge JE. J Med Chem1984;37:519–525.

159. Seminara G, Trassari V, Prestifilippo N, Chia-vetta R. Calandra Minerva Psichiatrica1993;34:95–99.

160. VelascoA,LeridaMT,MayoR,Perez-AccinoC,Alamo C. Gen Pharmacol 1998;30:521–524.

161. Smits RA, Lim HD, Stegink B, Bakker RA, DeEsch IJP, Leurs R. J Med Chem2006;49:4512–4516.

162. Eichenberger E. Arzneimittel-Forschung1984;34:5110–113.

163. Andersen PH, Braestrup C. J Neurochem1986;47:1822–1831.

164. Farber NB, Foster J, Duhan NL, Olney JW.Schizophrenia Res 1996;21:33–37.

165. Arnt J, Skarsfeldt T. Neuropsychopharmacol1998;18:63–101.

166. Janssen PAJ, Niemegeers CJE, Awouters F,Schellekens KHL,Megens AAHP,Meert TF. JPharmacol Exp Ther 1988;244:685–693.

167. Buckley PF. Drugs Today 2000;36:583–589.

168. Schmidt AW, Lebel LA, Howard HR, Zorn SH.Eur J Pharmacol 2001;425:197–201.

169. Murdoch DK, Gillian M. CNS Drugs 2006;20:233–255.

170. Herrick-Davis K, Grinde E, Teitler M. J Phar-macolExpTherapeutics 2000;295(1): 226–232.

171. Hietala J, Kuoppam€aki M, Majasuo H, Palvi-maki E-P, Laakso A, Syvalahti E. Psychophar-macol 2001;157(2): 180–187.

172. Kasper S, Tauscher J, K€ufferle B, Barnas C,HesselmannB,AsenbaumS,Podreka I,BruckeT. Psychopharmacol 1998;136:367–373.

173. PilowskyLS,O’Connell PN, et al. Psychophar-macol 1997;130:152–158.

174. Baldessarini R, Tarazi F. Goodman andGilman’s the Pharacological Basis of Thera-peutics. McGraw Hill: New York; 2006.

175. Caccia S. Curr Opin Investig Drugs2002;3:1073.

176. Mathews M, Muzina DJ. Cleve Clin J Med2007;74:597.

177. Mauri MC, Volonteri LS, Colasanti A, Fioren-tini A, De Gaspari IF, Bareggi SR. Clin Phar-macokinet 2007;46:359.

178. Murray M. J Pharm Pharmacol 2006;58:871.

179. Caccia S. Clin Pharmacokinet 2000;38:393.

180. DeVane C, Markowitz J. Metabolic DrugInteractions. Philadelphia: LippincottWilliams & Wilkins; 2000. p 245.

181. Hubbard JW, Midha KK, Hawes EM, McKayG,Marder SR, AravagiriM,Korchinski ED.BrJ Psychiatry (Suppl) 1993;19.


182. Urichuk L, Prior TI, Dursun S, Baker G. CurrDrug Metab 2008;9:410.

183. Conley RR, Kelly DL. Psychopharmacol Bull2007;40:77.

184. Meyer J. CNS Spectr 2007;12:6.

185. Obach RS, Walsky RL. J Clin Psychopharma-col 2005;25:605.

186. Prior TI, Baker GB. J Psychiatry Neurosci2003;28:99.

187. Shin JG, Soukhova N, Flockhart DA. DrugMetab Dispos 1999;27:1078.

188. Spina E, de Leon J. Basic Clin PharmacolToxicol 2007;100:4.

189. DeVaneCL.AmJHealthSyst Pharm1995;52:S15.

190. Dahl SG, Strandjord RE. Clin Pharmacol Ther1977;21:437.

191. Yeung PK, Hubbard JW, Korchinski ED, Mid-ha KK. Eur J Clin Pharmacol 1993;45:563.

192. Cashman JR, Yang Z, Yang L, Wrighton SA.Drug Metab Dispos 1993;21:492.

193. Green DE, Forrest IS. Can Psychiatr Assoc J1966;11:299.

194. Yoshii K, Kobayashi K, Tsumuji M, Tani M,Shimada N, Chiba K. Life Sci 2000;67:175.

195. Muralidharan G, Cooper JK, Hawes EM,Korchinski ED, Midha KK. Eur J Clin Phar-macol 1996;50:121.

196. Yamamoto T, Suzuki A, Kohno Y. Xenobiotica2003;33:823.

197. Ravic M, Warrington S, Boyce M, Dunn K,Johnston A. Br J Clin Pharmacol 2004;58(Suppl1): 34.

198. von Bahr C, Movin G, Nordin C, Liden A,Hammarlund-Udenaes M, Hedberg A, RingH, Sjoqvist F. Clin Pharmacol Ther1991;49:234.

199. Cohen BM, Lipinski JF, Waternaux C. Psy-chopharmacology 1989;97:481.

200. Lin G, Hawes EM, McKay G, Korchinski ED,Midha KK. Xenobiotica 1993;23:1059.

201. Wojcikowski J, Maurel P, Daniel WA. DrugMetab Dispos 2006;34:471.

202. Carrillo JA, Ramos SI, Herraiz AG, Llerena A,Agundez JA, Berecz R, Duran M, Benitez J.J Clin Psychopharmacol 1999;19:494.

203. Jann MW, Ereshefsky L, Saklad SR. ClinPharmacokinet 1985;10:315.

204. Koytchev R, Alken RG, McKay G, Katzarov T.Eur J Clin Pharmacol 1996;51:183.

205. Marder SR, Midha KK, Van Putten T, Arava-giri M, Hawes EM, Hubbard JW, McKay G,Mintz J. Br J Psychiatry 1991;158:658.

206. MidhaKK,HubbardJW,MarderSR,MarshallBD, Van Putten T. J Psychiatry Neurosci1994;19:254.

207. Ereshefsky L, Jann MW, Saklad SR, DavisCM, Richards AL, Burch NR. Biol Psychiatry1985;20:329.

208. Goff DC, Midha KK, Sarid-Segal O, HubbardJW, Amico E. Psychopharmacology 1995;117:417.

209. Dahl-Puustinen ML, Liden A, Alm C, NordinC, Bertilsson L. Clin Pharmacol Ther1989;46:78.

210. Hansen LB, Elley J, Christensen TR, LarsenNE, Naestoft J, Hvidberg EF. Br J Clin Phar-macol 1979;7:75.

211. OzdemirV,NaranjoCA,HerrmannN,ReedK,Sellers EM, Kalow W. Clin Pharmacol Ther1997;62:334.

212. Olesen OV, Linnet K. Br J Clin Pharmacol2000;50:563.

213. Midha KK, Hawes EM, Hubbard JW, Korch-inski ED, McKay G. Psychopharmacology1988;95:333.

214. Aravagiri M, Hawes EM, Midha KK. J Phar-macol Exp Ther 1986;237:615.

215. Uchaipichat V, Mackenzie PI, Elliot DJ,Miners JO. Drug Metab Dispos 2006;34:449.

216. Guthrie SK, Hariharan M, Kumar AA, BaderG, Tandon R. J Clin Pharm Ther 1997;22:221.

217. Hobbs DC, Welch WM, Short MJ, Moody WA,Van der Velde CD. Clin Pharmacol Ther1974;16:473.

218. Hobbs DC. J Pharm Sci 1968;57:105.

219. Weissman A. Adv Biochem Psychopharmacol1974;9:471.

220. Ereshefsky L, Saklad SR, Watanabe MD,Davis CM, JannMW. J Clin Psychopharmacol1991;11:296.

221. Heel RC, Brogden RN, Speight TM, Avery GS.Drugs 1978;15:198.

222. Cheung SW, Tang SW, Remington G. J Chro-matogr 1991;564:213.

223. Luo H, Hawes EM, McKay G, Korchinski ED,Midha KK. Xenobiotica 1995;25:291.

224. Froemming JS, Lam YW, Jann MW, DavisCM. Clin Pharmacokinet 1989;17:396.

225. Kudo S, Ishizaki T. Clin Pharmacokinet1999;37:435.

226. Avent KM, DeVoss JJ, Gillam EM. Chem ResToxicol 2006;19:914.

REFERENCES 55

227. Kalgutkar AS, Taylor TJ, VenkatakrishnanK,Isin EM. Drug Metab Dispos 2003;31:243.

228. Shin JG, Kane K, Flockhart DA. Br J ClinPharmacol 2001;51:45.

229. Gate. http://www.Gatepharma.Com/orap/script_info.html; 2008.

230. Desta Z, KerbuschT, FlockhartDA.Clin Phar-macol Ther 1999;65:10.

231. McCreadie RG, Heykants JJ, Chalmers A,Anderson AM. Br J Clin Pharmacol1979;7:533.

232. Pinder RM, Brogden RN, Swayer R, SpeightTM, Spencer R, Avery GS. Drugs 1976;12:1.

233. Sallee FR, Pollock BG, Stiller RL, Stull S,Everett G, Perel JM. J Clin Pharmacol1987;27:776.

234. Desta Z, Kerbusch T, Soukhova N, Richard E,Ko JW, Flockhart DA. J Pharmacol Exp Ther1998;285:428.

235. Desta Z, Soukhova N, Flockhart DA. J ClinPsychopharmacol 2002;22:162.

236. Endo. http://www.Endo.Com/pdf/moban_pack_insert.Pdf.

237. OwenRR, Jr,ColeJO. JClinPsychopharmacol1989;9:268.

238. Peper M. J Clin Psychiatry 1985;46:26.

239. Zetin M, Cramer M, Garber D, Plon L, Paul-shock M, Hoffman HE, Schary WL. Clin Ther1985;7:169.

240. Novartis. http://www.Pharma.Us.Novartis.Com/product/pi/pdf/clozaril.Pdf; 2008.

241. Choc MG, Lehr RG, Hsuan F, Honigfeld G,Smith HT, Borison R, Volavka J. Pharm Res1987;4:402.

242. Fitton A, Heel RC. Drugs 1990;40:722.

243. JannMW, Grimsley SR, Gray EC, ChangWH.Clin Pharmacokinet 1993;24:161.

244. Marder S, Wirshing D. Textbook of psycho-pharmacology. Washington, DC: AmericanPsychiatric Publishing; 2004. p 443.

245. Chetty M, Murray M. Curr Drug Metab2007;8:307.

246. Lilly E. http://pi.Lilly.Com/us/zyprexa-pi.Pdf;2008.

247. Callaghan JT, Bergstrom RF, Ptak LR, Beas-ley CM. Clin Pharmacokinet 1999;37:177.

248. Kassahun K, Mattiuz E, Nyhart E, Jr, Ober-meyer B, Gillespie T,Murphy A, Goodwin RM,Tupper D, Callaghan JT, Lemberger L. DrugMetab Dispos 1997;25:81.

249. Markowitz JS, Devane CL, Liston HL,Boulton DW, Risch SC. Clin Pharmacol Ther2002;71:30.

250. Schulz S, Olson S, Kotlyar M. Textbook ofPsychopharmacology.Washington, DC: Amer-ican Psychiatric Publising; 2004. p 457.

251. LinnetK.HumPsychopharmacol 2002;17:233.

252. Ring BJ, Catlow J, Lindsay TJ, Gillespie T,Roskos LK, Cerimele BJ, Swanson SP, Ham-manMA,Wrighton SA. J Pharmacol Exp Ther1996;276:658.

253. Zeneca A. http://www1.Astrazeneca-us.Com/pi/seroquel.Pdf; 2008.

254. DeVane CL, Nemeroff CB. Clin Pharmacoki-net 2001;40:509.

255. Goren JL, Levin GM. Pharmacotherapy1998;18:1183.

256. Grimm SW, Richtand NM, Winter HR, StamsKR,ReeleSB.Br JClinPharmacol 2006;61:58.

257. Keating GM, Robinson DM. Drugs2007;67:1077.

258. Gunasekara N, Spencer C. CNS Drugs1998;9:325.

259. Lieberman J. Textbook of Psychopharmacol-ogy. Washington, DC: American PsychiatricPublishing; 2004. p 473.

260. Astella. http://www.E-search.Ne.Jp/�jpr/pdf/astellas52.Pdf; 2008.

261. Noda K, Suzuki A, Okui M, Noguchi H,Nishiura M, Nishiura N. Arzneimittel-forschung 1979;29:1595.

262. OtaniK,KondoT,KanekoS,HiranoT,MiharaK, Fukushima Y. Human Psychopharmacol-ogy 1992;7:331.

263. Prakash A, Lamb H. CNS Drugs 1998;9:153.

264. Tanaka O. Nihon Shinkei Seishin YakurigakuZasshi 1996;16:49.

265. Shiraga T, Kaneko H, Iwasaki K, Tozuka Z,Suzuki A, Hata T. Xenobiotica 1999;29:217.

266. Kondo T, Tanaka O, Otani K, Mihara K,Tokinaga N, Kaneko S, Chiba K, Ishizaki T.Psychopharmacology 1996;127:311.

267. Janssen. 2008.

268. Goff D. Textbook of Psychopharmacology.Washington, DC: American Psychiatric Pub-lishing; 2004. p 495.

269. Heykants J, HuangML,MannensG,Meulder-mans W, Snoeck E, Van Beijsterveldt L, VanPeer A, Woestenborghs R. J Clin Psychiatry1994;55 (Suppl): 13.

270. Huang ML, Van Peer A, Woestenborghs R,De Coster R, Heykants J, Jansen AA, Zylicz


Z, VisscherHW, Jonkman JH. Clin PharmacolTher 1993;54:257.

271. Mannens G, Huang ML, Meuldermans W,Hendrickx J, Woestenborghs R, Heykants J.Drug Metab Dispos 1993;21:1134.

272. Spina E, Avenoso A, Scordo MG, Ancione M,Madia A, Gatti G, Perucca E. J Clin Psycho-pharmacol 2002;22:419.

273. Scordo MG, Spina E, Facciola G, Avenoso A,Johansson I, Dahl ML. Psychopharmacology1999;147:300.

274. Spina E, Avenoso A, Facciola G, Salemi M,Scordo MG, Giacobello T, Madia AG, PeruccaE. Ther Drug Monit 2000;22:481.

275. ZhuHJ,Wang JS,Markowitz JS, Donovan JL,Gibson BB, DeVaneCL. Neuropsychopharma-cology 2007;32:757.

276. Janssen. http://www.Invega.Com/invega/shared/pi/invega.Pdf#zoom¼100; 2008.

277. Dolder C, NelsonM, Deyo Z. Am JHealth SystPharm 2008;65:403.

278. Vermeir M, Naessens I, Remmerie B, Man-nens G, Hendrickx J, Sterkens P, Talluri K,Boom S, EerdekensM, van Osselaer N, CletonA. Drug Metab Dispos 2008;36:769.

279. Pfizer. http://www.Pfizer.Com/files/products/uspi_geodon.Pdf; 2008.

280. Daniel D, Copeland L, Tamminga C. Textbookof psychopharmacology. Washington, DC:American Psychiatric Publishing; 2004. p 507.

281. Stimmel GL, Gutierrez MA, Lee V. Clin Ther2002;24:21.

282. PrakashC,KamelA,CuiD,WhalenRD,MiceliJJ, Tweedie D. Br J Clin Pharmacol 2000; 49(Suppl 1): 35S.

283. Miceli JJ, Anziano RJ, Robarge L, Hansen RA,Laurent A. Br J Clin Pharmacol 2000; 49(Suppl 1): 65S.

284. Wilner KD, Demattos SB, Anziano RJ, Apsel-off G, Gerber N. Br J Clin Pharmacol 2000; 49(Suppl 1): 43S.

285. Sumitomo. http://www.E-search.Ne.Jp/�jpr/pdf/sumito12.Pdf; 2008.

286. Masui T, Kusumi I, Takahashi Y, Koyama T.Prog Neuropsychopharmacol Biol Psychiatry2006;30:1330.

287. Masui T, Kusumi I, Takahashi Y, Koyama T.Ther Drug Monit 2006;28:73.

288. Onrust SV, McClellan K. CNS Drugs2001;15:329.

289. Yasui-Furukori N, Furukori H, Nakagami T,Saito M, Inoue Y, Kaneko S, Tateishi T. TherDrug Monit 2004;26:361.

290. Kitamura A, Mizuno Y, Natsui K, Yabuki M,Komuro S, Kanamaru H. Biopharm Drug Dis-pos 2005;26:59.

291. Squibb B-M. http://packageinserts.Bms.Com/pi/pi_abilify.Pdf; 2008.

292. Lieberman J. Textbook of psychopharmacol-ogy. Washington, DC: American PsychiatricPublishing; 2004. p 487.

293. MallikaarjunS,SalazarDE,BramerSL. JClinPharmacol 2004;44:179.

294. Swainston Harrison T, Perry CM. Drugs2004;64:1715.

295. EMEA. http://www.Emea.Europa.Eu/pdfs/hu-man/referral/sertindole/285202en.Pdf; 2008.

296. Ereshefsky L. J Clin Psychiatry 1996;57(Suppl11): 12.

297. Murdoch D, Keating GM. CNS Drugs2006;20:233.

298. Wong SL, Cao G, Mack RJ, Granneman GR.Clin Pharmacol Ther 1997;62:157.

299. Aventis S. http://www.Medicines.Ie/emc/in-dustry/; 2008.

300. Rosenzweig P, Canal M, Patat A, BergougnanL, Zieleniuk I, Bianchetti G.HumPsychophar-macol 2002;17:1.

301. Schaus JM, Bymaster FP. AnnRepMedChem1998;33:1–10.

302. Rogers BN, Schmidt CJ. Ann Rep Med Chem2006;41:3–21.

303. Nikam SS, Awasthi AK. Curr Opin InvestigDrugs 2008;9:37–46.

304. Micheli F, Heidbreder C. ExpOpin Therap Pat2008;18:821–840.

305. Strange PG. Trends Pharm Sci 2008;29:314–321.

306. Marino MJ, Knutsen LJS, Williams M. J MedChem 2008;51:1077–1107

307. Rowley M, Bristow LJ, Hutson PH. J MedChem 2001;44:477–501.

308. Childers WE, Jr, Robichaud AJ. Ann RepMedChem 2005;40:17–33.

309. Roth BL, Shapiro DA. Exp Opin Therap Tar-gets 2001;5:685–695.

310. FitzgeraldLW,EnnisMD.AnnRepMedChem2006;37:21–30.

311. Dunlop J, Sabb AL, Mazandarani H, Zhang J,KalgaonkerS,ShukhinaE,Sukoff S,VogelRL,Stack G, Schechter L, Harrison BL, Rosenz-weig-Lipson S. J Pharmacol Exp Ther2005;313:862–869.

312. Adams DR, Bentley JM, Benwell KR, Bicker-dike MJ, Bodkin CD, Cliffe IA, Dourish CT,

REFERENCES 57

George AR, Kennett GA, Knight AR, MalcolmCS,MansellHL,MisraA,QuirkK,RoffeyJRA,Vickers SP. Bioorg Med Chem Lett2006;16:677–680.

313. Holenz J, Pauwels PJ, Diaz JL, Merce R, Cod-ony X, Buschmann H. Drug Discov Today2006;11:283–299.

314. Filla SA, Flaugh ME, Gillig JR, Heinz LJ,Krushinski JH, Jr, Liu B, Pineiro-Nunez MM,Schaus JM, Ward JS.WO patent 2002060871.

315. BromidgeSM,BrownAM,ClarkeSE,DodgsonK, Gager T, Grassam HL, Jeffrey PM, JoinerGF, King FD, Middlemiss DN, Moss SF, New-manH,RileyG, RoutledgeC,WymanP. JMedChem 1999;42:202–205.

316. ChenY,ConnPJ.DrugsFut. 2008;33: 355–360.

317. GaspariniF,BilbeG,Gomez-MancillaB,Spoo-ren W. Curr Opin Drug Discov Dev.2008;11:655–665.

318. KristiansenLV,Huerta I, BeneytoM,Meador-Woodruff JH. Cur Opin Pharm 2007;7:48–55.

319. Lane HY, Chang YC, Liu YC, Chiu CC, TsaiGE. Arch Gen Psychiatry 2005;62:1196–1204.

320. Lechner SM, Sandra M. Curr Opin Pharm2006;6:75–81.

321. Catarzi D, Colotta V, Varano F. Med Res Rev2007;27:239–278.

322. Staubi U, Rogers G, Lynch G. Proc Natl AcadSci USA 1994;91:777–781.

323. Morrow JA, Maclean JKF, Jamieson C. CurrOpin Drug Discov Dev 2006;9:571–579.

324. Nagase T, Mizutani T, Sekino E, Ishikawa S,Ito S, Mitobe Y, Miyamoto Y, Yoshimoto R,Tanaka T, Ishihara A, Takenaga N, Tokita S,Sato N. J Med Chem 2008;51: nnnn–nnn.

325. Hudkins RL, Raddatz R. Ann Rep Med Chem2007;42:49–62.

326. Berlin M, Boyce CW. Exp Opin Therap Pat2007;17:675–687.

327. Celanire S,WijtmansM, Talaga P, Leurs R, deEsch IJP. Drug Discov Today2005;10:1613–1627.

328. BreiningSR,MazurovAA,MillerCH.AnnRepMed Chem 2005;40:3–16.

329. Albert JS, Potts W. Exp Opin Therap Pat2006;16:925–937.

330. Halene TB, Siegel SJ. Drug Discov Today2007;12:870–878.

331. Siuciak JA, et al. Neuropharmacol.2006;51:386–396.

332. Brandon NJ, Rottela DP. Ann Rep Med Chem2008;42:3–12.

333. Verhoest PR.Abstracts of Papers, 236th ACSNational Meeting, Philadelphia, PA; 2008 Au-gust 17–21; 2008; MEDI-219.

334. D’Souza DC. Int Rev Neurobiol 2007;78:289–326.

335. PonceletM, BarnouinMC, Breliere JC, Le FurG, Soubrie P. Neuropharmacol 1999;144:144–150.

336. Borowsky B, Stevens R, Mark B, et al. Neuro-pharmacol 2005;30:S77–S142.

337. Lange JHM, Coolen HKAC, van StuivenbergHH, Dijksman JAR, Herrmans AHJ, RonkenE, Keizer HG, McCreary AC, Veerman W,Wals HC, Stork B, Vereer PC, den Hartog AP,de Jong NMJ, Adolfs TJP, Hoogendoorn J,Kruse CG. J Med Chem 2004;47:627–643.


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