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Possible dose–side effect relationship of antipsychotic drugs: relevance to cognitive function in schizophrenia Expert Rev. Clin. Pharmacol. 1(6), 791–802 (2008)

Tomiki Sumiyoshi Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama, 930-0194, Japan Tel.: +81 76 434 7323 Fax: +81 76 434 5030 tomikisumiyoshi840@ hotmail.com

Management of adverse events is a major concern of clinicians who use antipsychotic drugs. The incidence of motor side effects is dose dependent. Atypical antipsychotic drugs are less likely to induce neurologic side effects compared with typical (conventional) antipsychotics, such as haloperidol. Some recent, large-scale studies have shown that the incidence of metabolic side effects often associated with atypical agents does not differ among typical and atypical antipsychotics. Cognitive function, such as verbal learning memory, working memory, executive function, verbal fluency and attention/information processing, is the most influential determinant of outcome in patients with schizophrenia. Atypical antipsychotic drugs have been shown to be more efficacious in treating cognitive disturbances of schizophrenia compared with typical antipsychotic drugs. Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes, such as the 5-HT1A receptor, are considered to mediate the ability of antipsychotic drugs to enhance cognition. On the other hand, treatment with some atypical agents, such as risperidone, may deteriorate working memory in some people with early-stage schizophrenia. The paradoxical side effects of these antipsychotic drugs in terms of cognition may be attributable to dose, duration of treatment and type of cognitive domain. Further research will add to the worldwide endeavor to develop more effective psychotropic drugs accompanied with minimal side effects, for the improvement of cognition, adherence and long-term outcome in patients with schizophrenia or other major psychiatric illnesses. Keywords : 5-HT1A receptor • atypical antipsychotic drug • cognition • dose dependence • extrapyramidal sign • schizophrenia • serotonin receptor • typical antipsychotic drug

Since the discovery of chlorpromazine in the early 1950s, antipsychotic drugs have provided the most reliable and efficacious tools in the treatment of major psychiatric disorders, such as schizophrenia, schizoaffective disorders, mood disorders, substance abuse and dementias [1–3] . The dopamine (DA) hypothesis of schizophrenia was postulated based on evidence from laboratory and clinical data indicating that DA supersensitivity in some of the subcortical brain regions (e.g., the striatum and nucleus accumbens) constitutes a neurochemical basis for positive psychotic symptoms (e.g., delusions and hallucinations) [4–6] . Postmortem [7,8] and PET [9] studies have elicited upregulation of DA-D2 family receptor subtypes in the brain of subjects with schizophrenia, providing clinical evidence supporting the DA hypothesis. In animals, dysregulation of DA-related behaviors, including www.expert-reviews.com

10.1586/17512433.1.6.791

enhanced locomotor activity and stereo­t ypy, as well as disrupted prepulse inhibition, have been thought to reflect psychosis-related symptoms  [5,6,10] . Recently, the DA hypothesis has evolved to the concept that the high-affinity states of D2 receptors, or D2high, may play a major role in the development of psychosis [5,6] . Consistent with this hypothesis, Seeman et  al. provided the first demonstration of a linear relationship between clinical potencies of antipsychotic drugs and their affinity for D2 receptors in the brain [11,12] (see [13] for a review). This finding shaped the subsequent course of antipsychotic development. In fact, almost all of the antipsychotic drugs currently marketed for clinical use possess D2 antagonist actions, irrespective of chemical class, (e.g.,  phenothiazines, thioxanthenes, butyro­p henones, diphenylbutylpiperidines,

© 2008 Expert Reviews Ltd

ISSN 1751-2433

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Clocapramine

Mosapramine

Zotepine

Tiospirone

RMI-81582

Clozapine

Pimozide

Haloperidol

-Log(ED50[5-HT2A]/ED50[D2])

demonstrate antipsychotic activity compared with first-generation antipsychotics, such as chlor­promazine, haloperidol 3 and perphenazine [16] . This ‘5-HT2A /D2 5-HT2A dominant 2 hypothesis’ has contributed to the development of most of the current generation 1 of atypical antipsychotic agents, including risperidone, olanzapine, quetiapine, zip0 rasidone, melperone and perospirone, all -1 DA2 of which have a higher affinity for 5-HT2A dominant than for D2 receptors [16,27–31] . -2 Receptor binding profiles of several of the FGAs SGAs Others representative typical and atypical antipsychotic drugs, including those currently Figure 1. In vivo serotonin-5-HT2A /dopamine-D2 receptor occupancy ratios of used for first-line treatment of schizophreantipsychotic drugs. SGAs show relatively high serotonin-5-HT2A /dopamine-D2 receptor occupancy ratios in vivo, compared with the FGAs. [3H]-ketanserin and nia, can be seen in Figure 2. With the excep[3H]-YM-09151-2 were used to label 5-HT2A and D2 receptors, respectively. tion of the typical antipsychotic haloperiFGA: First-generation antipsychotic; SGA: Second-generation antipsychotic. dol that mainly blocks D2 receptors, these Based on [26] . compounds possess variable affinities for benzamides, dibenzodiazepines and benzisoxazoles) [2,3] . Some 5-HT1A , 5-HT2A , 5-HT6 and 5-HT 7, as of the novel agents (e.g., aripiprazole and bifeprunox) have been well as nor­adrenalin, histamine and muscarinic acetylcholine shown to act as partial D2 agonists, capable of opposing exces- receptors [31] . These pharmacological properties are thought to sive activation of receptors in the target sites (e.g., limbic areas) mediate both unique efficacy (e.g., mood and cognition) and a while maintaining modest stimulation of other sites (e.g., stria- series of side effects, as discussed later. tum and frontal cortex) [14] . Another landmark hypothesis for the etiology of schizo- Side effects of antipsychotics phrenia and action of antipsychotic drugs concerns the neuro­ Treatment with antipsychotic drugs, whether typical or atypical transmitter serotonin (5-hydroxytryptamine [5-HT]). This agents, is associated with various adverse effects, including acute concept is based on clinical observations that indole compounds EPS (dystonia, parkinsonism and akathisia), chronic EPS (tardive (e.g.,  N,N-dimethyltryptamine, mescaline, psilocybin and dyskinesia), neuroleptic malignant syndrome, weight gain, glucose lysergic acid diethylamide) are hallucinogenic, and is also sup- intolerance (diabetes mellitus [DM]), metabolic syndrome and ported by biological evidence that 5-HT1A , 5-HT 2A , 5-HT 2C , 5-HT 3 , 5-HT6 and Table 1. Side-effect profiles of antipsychotic drugs. 5-HT 7 genes and receptors play potential Drug Daily EPS TD HyperWeight Glucose roles in psychosis, cognition and mood dose (mg) prolactinemia gain intolerance [15–17] . Specifically, postmortem studies First-generation antipsychotics have demonstrated decreased 5-HT 2A ++ ++ + ++ ++ receptor density and mRNA expression, Chlorpromazine 50–450 as well as increased 5-HT1A receptor den- Haloperidol 3–6 +++ ++ ++ + + sity, in the cerebral cortex of subjects with Perphenazine 6–48 ++/+++ ++ + ++ ++ schizophrenia [18–20] . Meltzer et al. reported the first data Second-generation antipsychotics 150–600 ± ± ± +++ +++ demonstrating that a relatively high affin- Clozapine ity for the 5-HT2A receptor compared with Risperidone 2–6 ±~+ + ++ + + the affinity for the D2 receptor provides Olanzapine 10–20 ±~+ + ± +++ +++ a basis for the difference between ‘atypi150–750 ± + ± + ++ cal’ and ‘typical’ antipsychotic agents [21] , Quetiapine which was confirmed by subsequent stud- Ziprasidone 80–200 ±~+ + ± ± ± ies using experimental in vivo paradigms Amisulpride 50–800 ±~+ + ++ + + (F igur e  1) [22–26] . Here, atypical antipsyAripiprazole 6–30 ±~+ + ± ± ± chotic drugs, or so-called second-genera12–48 ±~+ NA ± ± ± tion antipsychotics, with clozapine as the Perospirone prototype compound, are defined as an Blonanserin 8–24 ±~+ NA ± ± + agent causing low incidence of extrapy- EPS: Extrapyramidal signs; NA: Information not available; TD: Tardive dyskinesia. ramidal symptoms (EPS) at doses that Data from [1,3,31,35]. Expert Rev. Clin. Pharmacol. 1(6), (2008)

Side effects, cognition & antipsychotics

Blonanserin

Quetiapine

Risperidone

Olanzapine

Aripiprazole

Haloperidol

Lurasidone

Review

Perospirone

Clozapine

D1 D2L 5-HT2A 5-HT1A 5-HT6 5-HT7 α2c α1a H1 M1

Figure 2. Pie charts of receptor affinity of antipsychotic drugs. Affinity ratios for various neurotransmitter receptors are shown; the sum of inverse of Ki values for these receptors is supposed to be 100% for each agent. Graphs for clozapine and lurasidone were based on independent experimental procedures from the rest of the compounds. 5-HT: 5-hydroxytryptamine (serotonin); D: Dopamine. Data are quoted and modified from [31,107,108] .

elevation of plasma prolactin levels [1–3,32,33] . Several of these side effects are known to be related to distinct pharmacological profiles of the antipsychotic agents. For example, parkinsonisms, tardive dyskinesia, neuroleptic malignant syndrome and hyperprolactinemia are considered to be a result of acute or chronic blockade of DA receptors, while histamine-H1 and 5-HT2C receptors may contribute to antipsychotic-induced weight gain [1–3,32,33] . A summary of side effect-inducing potentials of widely used antipsychotic drugs is shown in Table 1. By definition, typical antipsychotic drugs (first-generation antipsychotics) are prone to induce EPS; whereas atypical compounds are less likely to cause EPS and tardive dyskinesia, but some atypicals are more frequently associated with metabolic side effects, such as DM and weight gain. However, recent large-scale studies, particularly the Clinical www.expert-reviews.com

Antipsychotic Trials of Intervention Effectiveness (CATIE) [34] and the European First Episode Schizophrenia Trial (EUFEST)  [35] , did not find a significant difference in the incidence of the development of antipsychotic-induced DM among typical and atypical antipsychotic drugs. The CATIE (Phase I) and EUFEST studies were multicenter, active-control, randomized trials that were designed to compare the effectiveness of atypical and typical antipsychotic drugs [34,35] . The side-effect profiles of antipsychotic drugs, as revealed in these studies, are summarized in Table 2 . Olanzapine, quetiapine and ziprasidone were tested as atypical antipsychotic drugs in both trials, while the EUFEST study used amisulpiride instead of risperidone, which was included in the CATIE study. The most substantial difference between the two studies was the type of typical antipsychotic 793

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Table 2. Comparison of side-effect potentials among antipsychotic drugs in the CATIE and EUFEST studies. Variable

CATIE (2005, Phase I)

EUFEST (2008)

Subjects

Chronic schizophrenia

First-episode schizophrenia

Antipsychotics tested

OLZ, QTP, RPD, ZIP, PER

OLZ, QTP, ZIP, AMI, HPD

Treatment discontinuation due to side effects

RPD had the lowest rate

OLZ and QTP showed better tolerability than HPD

Neurologic side effects

No between drug differences in EPS, akathisia or movement disorders

HPD showed the greatest incidence of parkinsonism

Weight changes

OLZ showed the greatest weight gain

OLZ showed the greatest weight gain

Blood glucose

No between drug differences in blood glucose change

No between drug differences in blood glucose change

Other metabolic effects

OLZ elevated blood levels of cholesterol and triglycerides

No between-drug differences in cholesterol and triglycerides

pPRL

Only RPD elevated pPRL levels Only AMI elevated pPRL levels

AMI: Amysulpiride; CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness; EUFEST: European First Episode Schizophrenia Trial; EPS: Extrapyramidal symptoms; HPD: Haloperidol; OLZ: Olanzapine; PER: Perphenazine; pPRL: Plasma prolactin; QTP: Quetiapine; RPD: Risperidone; ZIP: Ziprasidone.

drug as a comparator, such as perphenazine, a low-potency drug, in the CATIE study versus haloperidol, a high-potency and one of the most commonly used typical drugs, in the EUFEST study. Risperidone was found to show the lowest treatment discontinuation rate due to side effects overall in the CATIE study, while olanzapine and quetiapine were superior to haloperidol in the EUFEST study. It is noteworthy that the incidence of neurologic side effects, such as EPS and akathisia, did not differ between atypical drugs across the two studies, while the typical compound haloperidol elicited the greatest incidence of parkinsonism. Olanzapine yielded the greatest degree of weight gain, whereas it did not differ from other atypical or typical antipsychotic drugs in terms of the DM-inducing potential (Table 2) [34,35] . This may not be in agreement with the traditional notion that patients taking olanzapine have an increased risk of developing DM than those taking typical antipsychotics [36] , but indeed confirms the results of head-to-head comparisons of the incidence of DM between clozapine, olanzapine, risperidone and quetiapine [32,33] . These studies provided the first data showing that olanzapine did not differentiate from risperidone with regard to the risk of developing DM, similar to the result of a retrospective study  [37] . Only the CATIE study reports a significant difference in the incidence of plasma lipid elevation between olanzapine and other atypical or typical drugs. On the other hand, risperidone and amisulpiride showed the greatest risk of plasma prolactin elevation in the respective studies (Table 2) [34,35] . Side-effect incidence & dose of antipsychotic drugs

It has been reported that neurologic side effects are, in general, dependent on dose of antipsychotic drugs, whereas the development of DM and weight gain has been shown not to be affected 794

by dose [2,38–40] . Corrected QT interval (QTc) prolongation is associated with typical antipsychotic drugs (e.g., chlorpromazine, thioridazine and mesoridazine), as well atypical drugs (e.g., ziprasidone) and is dose dependent [2] . Sedation is often observed for antipsychotic drugs with histamine-H1 receptor-blocking actions, such as chlorpromazine [2] . PET studies have revealed that more than 80% of D2 receptor occupancy in the striatum is associated with emergence of EPS in patients with schizophrenia [41,42] . As shown in Figure 3, an animal study showed a dose–D2 occupancy relationship for typical (haloperidol) and atypical (risperidone and aripiprazole) antipsychotic drugs [43] . Aripiprazole did not elicit catalepsy even when its D2 occupancy exceeded 80% (Figure 3) , which may be attributable to D2 partial agonism action of this compound [43] . In fact, no significant differences between aripiprazole and placebo were identified on EPS at any clinical dose [44] .

Disturbances of cognitive function in schizophrenia

Several domains of cognition, such as verbal learning memory, attention and vigilance, executive function, verbal fluency and working memory, are impaired in patients with schizophrenia [45–47] . There is a large consensus that cognitive function, as specified earlier, is a major determinant of outcome in schizophrenia [28] . It should be noted that, among the cognitive domains, verbal memory is one of the best predictors of outcome in schizophrenia [48,49] . We have reported recently that Japanese patients with schizophrenia also elicit an impaired performance on tests of various cognitive domains that is two standard deviations below the normative level on average (Figure 4) [50,51] . These data provide compelling evidence supporting the hypothesis that cognitive deficits in schizophrenia, reported mainly from English-speaking countries, are universal, particularly for performance on the verbal fluency tasks [52–55] . Cognitive enhancement by antipsychotic drugs

In the treatment of schizophrenia, atypical antipsychotic drugs constitute the first-choice medication for cognitive enhancement and prevention of relapse [1,29,56,57] . The mechanisms by which these agents enhance cognitive function include enhancement of dopaminergic and cholinergic output in the cortex and hippo­ campus [58–62] , which is linked to the 5-HT2A /D2 antagonist property, as discussed previously [21,22,26] . An overview of several of the clinical trials conducted in the last 5  years to determine the effect of atypical antipsychotic drugs on key domains of cognition in schizophrenia is shown in Table 3 [28,29,63–70] . Specifically, we reported ziprasidone [28] and perospirone [27] , which have agonist actions at 5-HT1A receptors, Expert Rev. Clin. Pharmacol. 1(6), (2008)

Side effects, cognition & antipsychotics

75% animals cataleptic

86% animals cataleptic

Review

0% animals cataleptic

100.0

D2 occupancy (%)

80.0

60.0

40.0

20.0

0.0 0.025 0.05

0.1

0.5

1

0.05

Haloperidol (mg/kg)

0.1

0.25

0.5

Risperidone (mg/kg)

1

2

0.3

1

3

10

30

Aripiprazole (mg/kg)

Figure 3. D2 receptor occupancy and catalepsy-inducing potentials of antipsychotic drugs. Red symbols represent data from animals that elicited catalepsy. Reprinted with permission from Macmillan Publishers Ltd (Neuropsychopharmacology) [43] © 2006.

alleviate impaired memory organization (e.g., irregular association of category members) [54] . As the deficit of this particular aspect of cognition is also alleviated by tandospirone, a selective 5-HT1A partial agonist [71,72] , stimulation of 5-HT1A receptors is thought to enhance cognitive abilities related to frontal lobe function [73,74] . There is an argument that some of the cognitive benefits (e.g., improvement in verbal learning memory) of atypical antipsychotic drugs might be due to practice effects as a result of repeated assessments [75] . However, this possibility is questionable in view of abundant evidence that patients treated with atypical antipsychotic drugs, such as olanzapine and perospirone, still show significant improvement in verbal learning memory, as measured by standardized alternate forms of word memory tests [68,69,74] . Dose-dependent effect of antipsychotic drugs on cognition in schizophrenia

The cognitive benefits of antipsychotic drugs in schizophrenia depend on various factors, such as type of antipsychotic (typical or atypical), cognitive domain, stage of schizophrenia (first episode patients or chronic patients) and dose. For example, risperidone has been considered to be effective in alleviating working www.expert-reviews.com

memory [76] , while relatively short-term treatment with clozapine was associated with deterioration of this cognitive domain both in neuroleptic-resistant [77] and -responsive [78] patients. However, recent studies have reported risperidone specifically worsens working memory in first-episode schizophrenia  [79,80] , suggesting a need for caution in the choice of medication for the treatment of early-stage schizophrenia [81] . While information regarding the dose–effect relationship for cognitive enhancement by antipsychotic drugs may be relatively scarce, a recent meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics successfully answered several critical questions [82] . Thus, Woodward et al. found first, that overall cognitive performance improves while on haloperidol, and second that studies using a low dose of haloperidol (10 mg) (Figure 5) [82] . These findings provide a valid challenge against the suggestion that the cognitive improvements observed with atypical antipsychotics reflect an avoidance of a deleterious effect of haloperidol on cognitive function that might be dose related [82] . 795

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with 5-HT1A agonist properties may protect against excitotoxic insults that may be 0 responsible for progression to psychosis [88] . -0.5 Using in vivo microdialysis methods, we reported that the 5-HT1A partial agonist -1 Composite Motor Attention/ score tandospirone increased extracellular confunction -1.5 processing centrations of the energy substrate lactate speed -2 Verbal Working in the prefrontal cortex [89] , a brain region Verbal Executive fluency memory -2.5 memory governing higher cognitive functions, function -3 such as social cognition [90] . The advan1 tage of 5-HT1A receptor stimulation for Schizophrenia reducing excitotoxic burden in the brain Normal 0.5 and improving cognition, as revealed by 0 these basic studies, is consistent with our clinical observations that tandospirone -0.5 and buspirone, 5-HT1A partial agonists, -1 enhance cognitive performance in patients with schizo­phrenia treated with typical or -1.5 atypical anti­psychotic drugs [71–73,91] . -2 There is a strong consensus for the up­regulation of 5-HT1A receptors in the -2.5 brains of subjects with schizophrenia [19,92] . -3 The augmented tonic stimulation of post­ synaptic 5-HT1A receptors, as a result of the increased number of these receptors, may be a reason for impaired cognitive function in patients with schizophrenia. Activation of presynaptic 5-HT1A autoreceptors by lowFigure 4. Cognitive performance in schizophrenia as assessed by standardized dose tandospirone, by means of inhibition neuropsychological battery. Patients with schizophrenia show a decline in cognitive of 5-HT neuronal activity, would produce function, (e.g., verbal memory, verbal fluency, attention and executive function). (A) Cognitive performance in schizophrenia as measured by the Brief Assessment of a greater degree of decrease in the stimuCognition in Schizophrenia – Japanese Version (based on [50] ). lation of postsynaptic 5-HT1A receptors (B) Cognitive performance in schizophrenia as measured by the Toyama in patients with schizophrenia compared Psychopharmacological Study Battery (based on [51] ). with psychiatrically normal subjects. Thus, low-dose tandospirone improved memory Expert commentary function in patients with schizophrenia [71,72,91,92] but not in norAs mentioned earlier, treatment with atypical antipsychotic mal subjects (Figure 6) [92,93] . Additional discussions of this issue drugs has been shown to be associated with improvement in vari- have been reported [92,94] . Further studies are needed to determine ous types of cognitive function in patients with schizophrenia the role of the 5-HT1A receptor to improve cognitive function in [27,29,56,83–86] . However, the effect size of the cognitive benefit of schizophrenia [94] . atypical agents has been found to be small to moderate in a recent Other investigators have reported that buspirone may be efficameta-analysis [86,87] . For example, the ability of the atypical drugs cious in the treatment of tardive dyskinesia [95] but not acute akathto improve attention/vigilance (effect size 0.12) was less than isia [96] . Our preliminary analysis suggests buspirone 30 mg/day their ability to improve learning and memory (0.24) or verbal added to treatment with atypical antipsychotic drugs, such as olanfluency (0.16) [87] . Therefore, efforts to identify additional means zapine and risperidone, produced limited change in these neuroto improve cognition in schizophrenia, especially attention/vigi- logic signs in a randomly assigned double-blind placebo‑controlled lance and executive function, another domain of cognition that study [Sumiyoshi T et al., Unpublished Data] . is relatively unresponsive to atypical agents, are needed. Findings from basic research indicate that clozapine, ziprasi- Five-year view done and aripiprazole, which are partial agonists at 5-HT1A recep- Increasing attention and efforts are now directed to the develtors, decreased kainic acid (an excitotoxin)-induced striatal lesion opment of pharmacotherapy to intervene into the early stage volumes, an effect reversed by pretreatment with WAY100635, a of psychosis [81] . Preventive treatment with risperidone [97] or 5-HT1A receptor antagonist [88] . By contrast, haloperidol, which olanzapine [98] has been shown to reduce the risk of transition to is devoid of 5-HT1A agonist properties, did not show such an psychosis in subjects with prodromal symptoms of schizophreeffect. These results suggest that some atypical antipsychotics nia. However, attention should be paid to evidence that these 796

Script

Sentence memory

Verbal learning

Backward digit span

Forward digit span

Ball search

Zoo map

Temporal judgement

Rule shift

Z-score

Z-score

Normative level

Expert Rev. Clin. Pharmacol. 1(6), (2008)

Side effects, cognition & antipsychotics

Review

Table 3. Effect of antipsychotic drugs on cognition in schizophrenia. Study

Test drugs

Dose (mg/day)

Findings

Ref.

Harvey et al. (2003)

Olanzapine Risperidone

5–20 2–6

Both drugs equally improved attention, verbal memory, executive function, working memory and verbal fluency

[63]

Keefe et al. (2004)

Olanzapine Haloperidol

9.6 4.6

Both drugs improved verbal memory and working memory. Attention and executive function were alleviated by olanzapine and haloperidol, respectively

[64]

Bellack et al. (2004)

Clozapine Risperidone

500 6

Neither drug was effective for enhancing executive function

[65]

Sumiyoshi et al. (2006)

Olanzapine Ziprasidone

8 83.5

Both drugs improved semantic memory organization as measured by the Category Fluency Task

[28]

Keefe et al. (2007). CATIE study

Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone

7.5–30 8–32 200–800 1.5–6 40–160

All drugs elicited small improvement in a composite score of speed, reasoning, working memory, verbal memory and vigilance after 2 months of treatment. There was no difference among the drugs

[66]

Keefe et al. (2007). Early psychosis study

Olanzapine Quetiapine Risperidone

2.5–20 100–800 0.5–4

All drugs produced modest improvement in cognition as assessed by the CATIE battery and the BACS

[67]

Higuchi et al. (2008)

Olanzapine

9.1

Enhancement of verbal memory by olanzapine was associated with improvement of P300 activity in the left superior temporal gyrus

[68]

BACS: Brief Assessment of Cognition in Schizophrenia; CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness.

www.expert-reviews.com

Grooved pegboard

Finger tapping

Verbal fluency

VLLd

VLLi

WCST

Trials B

Digit symbol

Trials A

ES relative to baseline

compounds, particularly risperidone, may be associated with that combine antagonism or partial agonism at dopamine D2-like deterioration of working memory in patients with first-episode receptors with agonism at serotonin 5-HT1A receptors [14] . Thus, psychosis [79,80] . Moreover, as discussed earlier, atypical antipsy- preclinical and clinical studies of novel antipsychotics with 5-HT1A chotic drugs in general have metabolic side effects, (e.g., increased agonist actions (e.g., bifeprunox, SLV313, SSR181507 and lurasiincidence of DM and weight gain) [32,33] , underscoring the need done) are currently in progress [14,104–106] . Optimizing the balance for risk–benefit considerations before using these drugs to inter- of actions on various neurotransmitter systems may be beneficial vene with people who do not elicit overt psychotic symptoms [81,99,100] . In spite of strenuous efforts to identify 0.6 pharmacotherapy to tackle cognitive disturHaloperidol dose bances of schizophrenia [101] , there are sev0.4 10 mg respond than others. In particular, impairment of executive function, as measured by 0.2 the Wisconsin Card Sorting Test, is treatable only by a limited number of antipsychotics, 0 such as melperone [29] , which, similar to clozapine, is one of the prototypical atypical antipsychotic drugs [30,102] . As to attention/ -0.2 vigilance, a recent study of the effect of blonanserin, a novel antipsychotic drug (Figure 2) and risperidone as a comparator found the ability of blonanserin to specifically ameliorate attention/information processing in Figure 5. Cognitive changes with haloperidol in clinical trials of atypical patients with schizophrenia [103] . antipsychotic drugs. Meta-analysis of within-group change on several Prompted by our discovery that 5-HT1A neuropsychological tests with haloperidol from atypical versus haloperidol randomized receptors are promising targets in the manclinical trials. agement of cognitive disturbances of schizoES: Effect size; VLLi: Verbal Learning List–Immediate Recall; VLLd: Verbal Learning List–Delayed Recall. WCST: Wisconsin Card Sorting Test. phrenia [72–74,91,92], research is now focused on Redrawn with permission from [82,87] . developing ‘third-generation’ antipsychotics 797

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Control subjects

5-HT1A receptors 5-HT neuron

Stimulation by 5-HT1A partial agonists

Cortical neuron

Inhibitory outputs

Cortical neuron

Inhibitory outputs

5-HT1A receptors

Schizophrenia

5-HT1A receptors 5-HT neuron

Stimulation by 5-HT1A partial agonists

5-HT1A receptors (upregulation)

Cognitive improvement Expert Rev. Clin. Pharmacol. © Future Science Group (2008)

Figure 6. Mechanism for the ability of 5-HT1A agonism to enhance cognitive function in subjects with schizophrenia. There is a strong consensus for the upregulation of 5-HT1A receptors in the brains of subjects with schizophrenia. The augmented tonic stimulation of postsynaptic 5-HT1A receptors, as a result of the increased number of these receptors, may be a reason for impaired cognitive function in patients with schizophrenia. Activation of presynaptic 5-HT1A autoreceptors by low-dose 5-HT1A partial agonists, by means of inhibition of 5-HT neuronal activity, would produce a greater degree of decrease in the stimulation of postsynaptic 5-HT1A receptors in patients with schizophrenia compared with psychiatrically normal subjects. Thus, low-dose 5-HT1A agonists improve memory function in patients with schizophrenia but not in normal subjects. 5-HT: 5-hydroxytryptamine. Redrawn from [92] .

for the purpose of the development of a series of pharmacotherapies that are both efficacious and accompanied with minimal incidence of adverse effects. Acknowledgements

The author is grateful to Drs Seiya Miyamoto, Neil Woodward and Adrian Newman-Tancredi for insightful comments and discussions.

Financial & competing interests disclosure

Support was received from Dainippon Sumitomo Pharmaceuticals and Yoshitomi-yakuhin Co Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Atypical antipsychotic drugs are less prone to induce extrapyramidal side effects than typical antipsychotics. • Distinct pharmacologic profiles, especially actions on 5-hydroxytryptamine (5-HT) receptor subtypes, may contribute to the advantage of atypical antipsychotics in terms of adverse effects. • Incidence of metabolic side effects (e.g., diabetes mellitus) is not likely to differ among atypical antipsychotic drugs. • Cognitive function is a major determinant of outcome in schizophrenia. • Atypical antipsychotic drugs are generally superior to typical drugs with regard to enhancing cognition. • The advantage of atypical agents for alleviating impaired cognitive function in schizophrenia may be related to actions on 5-HT receptors. • 5-HT1A receptors are one of the most promising targets for the development of novel antipsychotics.

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References

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Sumiyoshi T, Seeman P, Uehara T, Itoh H, Tsunoda M, Kurachi M. Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia. Brain Res. Mol. Brain Res. 140(1–2), 116–119 (2005).

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Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188(4194), 1217–1219 (1975).

Papers of special note have been highlighted as: • of interest •• of considerable interest 1

2

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Meltzer HY, Sumiyoshi T. Les nouveaux antipsychotiques; perspective clinique. In: Medicaments Antipsychotiques: Evolution ou Revolution? Olie J-P, Dalery J, Azorin J-M (Eds). Paris, France 63–90 (2001). Sadock BJ, Sadock VA, Sussman N. Kaplan & Sadock’s Pocket Handbook of Psychiatric Drug Treatment (4th Edition). Lippincott Williams & Wilkins, Inc., PA, USA (2006). Miyamoto S, Merrill DB, Lieberman JA et al. Antipsychotic drugs. In: Psychiatry (3rd Edition). Tasman A, Kay J, Lieberman JA, First MB, Maj M (Eds). John Wiley & Sons, Ltd, Chichester, UK 2161–2201 (2008).

•

Excellent up-to-date summary of antipsychotic treatment.

4

van Rossum JM. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch. Int. Pharmacodyn. Ther. 160(2), 492–494 (1966).

•

First paper on the dopamine– antipsychotic relationship.

5

Seeman P, Weinshenker D, Quirion R et al. Dopamine supersensitivity correlates with D2high states, implying many paths to psychosis. Proc. Natl Acad. Sci. USA 102(9), 3513–3518 (2005).

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Provides a novel hypothesis for the contribution of dopamine receptors in the development of psychosis.

6

Seeman P, Schwarz J, Chen JF et al. Psychosis pathways converge via D2high dopamine receptors. Synapse 60(4), 319–346 (2006).

7

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Seeman P, Guan H-C, Van Tol HHM. Dopamine D4 receptors elevated in schizophrenia. Nature 365, 441–445 (1993). Sumiyoshi T, Stockmeier CA, Overholser JC, Thompson PA, Meltzer HY. Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate of subjects with schizophrenia or major depression. Brain Res. 681, 109–116 (1995). Wong DF, Wagner HN, Tune LE et al. Positron emission tomography reveals elevated D2-dopamine receptors in drug-naive schizophrenia. Science 234, 1558–1563 (1986).

www.expert-reviews.com

21

Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/ dopamine receptors. Nature 261(5562), 717–719 (1976).

13

Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin. Ther. Targets 10(4), 515–531 (2006).

14

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Newman-Tancredi A, Cussac D, Depoortere R. Neuropharmacological profile of bifeprunox: merits and limitations in comparison with other third-generation antipsychotics. Curr. Opin. Investig. Drugs 8(7), 539–554 (2007). Excellent review on serotonin receptors and the directions of the antipsychotic development.

15

Meltzer HY. The significance of serotonin for neuropsychiatric disorders. J. Clin. Psychiatry 52, 70–72 (1991).

16

Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27(7), 1159–1172 (2003).

17

Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology (8th Edition). Oxford University Press, Oxford, UK (2003).

18

Hashimoto T, Kitamura N, Kajimoto Y et al. Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia. Psychopharmacology 112, S35–S39 (1993).

19

Sumiyoshi T, Stockmeier CA, Overholser JC, Dilley GE, Meltzer HY. Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res. 708, 209–214 (1996).

20

Burnet PW, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15(5), 442–455 (1996).

Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 251(1), 238–246 (1989).

•• Landmark paper on the serotonin/ dopamine hypothesis of atypical antipsychotic drugs. 22

Stockmeier CA, DiCarlo JJ, Zhang Y, Thompson P, Meltzer HY. Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J. Pharmacol. Exp. Ther. 266(3), 1374–1384 (1993).

23

Sumiyoshi T, Kido H, Sakamoto H et al. Time course of dopamine1, 2 and serotonin2 receptor binding of antipsychotics in vivo. Pharmacol. Biochem. Behav. 49(1), 165–169 (1994).

24

Sumiyoshi T, Kido H, Sakamoto H et al. In vivo dopamine-D2 and serotonin-5-HT2 receptor binding study of risperidone and haloperidol. Pharmacol. Biochem. Behav. 47(3), 553–557 (1994).

25

Sumiyoshi T, Kido H, Sakamoto H et al. Time course of dopamine-D2 and serotonin5-HT2 receptor occupancy rates by haloperidol and clozapine in vivo. Jpn. J. Psychiatry Neurol. 47(1), 131–137 (1993).

26

Sumiyoshi T, Suzuki K, Sakamoto H et al. Atypicality of several antipsychotics on the basis of in vivo dopamine-D2 and serotonin5HT2 receptor occupancy. Neuropsychopharmacology 12(1), 57–64 (1995).

27

Araki T, Yamasue H, Sumiyoshi T et al. Perospirone in the treatment of schizophrenia: effect on verbal memory organization. Prog. Neuropsychopharmacol. Biol. Psychiatry 30(2), 204–208 (2006).

28

Sumiyoshi C, Sumiyoshi T, Roy A, Jayathilake K, Meltzer HY. Atypical antipsychotic drugs and organization of long-term semantic memory: multidimensional scaling and cluster analyses of category fluency performance in schizophrenia. Int. J. Neuropsychopharmacol. 9(6), 677–683 (2006).

29

Sumiyoshi T, Jayathilake K, Meltzer HY. The effect of melperone, an atypical antipsychotic drug, on cognitive function in schizophrenia. Schizophr. Res. 59(1), 7–16 (2003).

30

Sumiyoshi T, Jayathilake K, Meltzer HY. A comparison of two doses of melperone, an atypical antipsychotic drug, in the treatment of schizophrenia. Schizophr. Res. 62(1–2), 65–72 (2003).

•• Landmark paper reporting the role of dopamine D2 receptor-blocking effects in antipsychotic actions. 12

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31

Murasaki M, Nishikawa H, Ishibashi T. Dopamine-serotonin antagonist: receptor binding profile of a novel antipsychotic blonanserin. Jpn. J. Clin. Psychopharmacol. 11, 845–854 (2008).

32

Sumiyoshi T, Roy A, Anil AE, Jayathilake K, Ertugrul A, Meltzer HY. A comparison of incidence of diabetes mellitus between atypical antipsychotic drugs: a survey for clozapine, risperidone, olanzapine, and quetiapine. J. Clin. Psychopharmacol. 24(3), 345–348 (2004).

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Sumiyoshi T, Roy A, Jayathilake K, Meltzer HY. The effect of hypertension and obesity on the development of diabetes mellitus in patients treated with atypical antipsychotic drugs. J. Clin. Psychopharmacol. 24(4), 452–454 (2004). Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353(12), 1209–1223 (2005).

41

Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Arch. Gen. Psychiatry 49, 538–544 (1992).

52

Sumiyoshi C, Matsui M, Sumiyoshi T, Yamashita I, Sumiyoshi S, Kurachi M. Semantic structure in schizophrenia as assessed by the category fluency test: effect of verbal intelligence and age of onset. Psychiatry Res. 105(3), 187–199 (2001).

42

Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am. J. Psychiatry 157(4), 514–520 (2000).

53

Sumiyoshi C, Sumiyoshi T, Matsui M et al. Effect of orthography on the verbal fluency performance in schizophrenia: examination using Japanese patients. Schizophr. Res. 69(1), 15–22 (2004).

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43

Natesan S, Reckless GE, Nobrega JN, Fletcher PJ, Kapur S. Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models. Neuropsychopharmacology 31(9), 1854–1863 (2006).

Sumiyoshi C, Sumiyoshi T, Nohara S et al. Disorganization of semantic memory underlies alogia in schizophrenia: an analysis of verbal fluency performance in Japanese subjects. Schizophr. Res. 74(1), 91–100 (2005).

55

Sumiyoshi C, Ertugrul A, Anil Yagcioglu AE. Semantic memory deficits based on category fluency performance in schizophrenia: similar impairment patterns of semantic organization across Turkish and Japanese patients. Psychiatry Res. (2009) (In Press).

56

Meltzer HY, Sumiyoshi T. Atypical antipsychotic drugs improve cognition in schizophrenia. Biol. Psychiatry 53(3), 265–267 (2003).

57

Sumiyoshi T, Meltzer HY. Relapse in schizophrenia. In: Psychiatry Highlights 2001–02. Lader M (Ed.). Health Press, Oxford, UK 27–35 (2002).

58

Chung YC, Li Z, Dai J, Meltzer HY, Ichikawa J. Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res. 1023(1), 54–63 (2004).

59

Ichikawa J, Dai J, O’Laughlin IA, Fowler WL, Meltzer HY. Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26(3), 325–339 (2002).

60

Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J. Neurochem. 76(5), 1521–1531 (2001).

61

Kuroki H, Meltzer HY, Ichikawa J. Effect of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontalcortex and nucleus accumbens. J. Pharmacol. Exp. Ther. 288, 774–781 (1998).

44

Marder SR, McQuade RD, Stock E et al. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr. Res. 61, 123–136 (2003).

45

Mohamed S, Paulsen JS, O’Leary D, Arndt S, Andreasen N. Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Arch. Gen. Psychiatry 56, 749–754 (1999).

•• First paper reporting the original data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. 35

Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 371(9618), 1085–1097 (2008).

•• First paper reporting the original data from the European First Episode Schizophrenia Trial (EUFEST) study. 36

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Koro CE, Fedder DO, L’Italien GJ et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case–control study. BMJ 325(7358), 243 (2002). Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am. J. Psychiatry 159(4), 561–566 (2002). Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine treatment: weight change and weightrelated health factors in schizophrenia. J. Clin. Psychiatry 62(2), 92–100 (2001). Koller EA, Doraiswamy PM. Olanzapine‑associated diabetes mellitus. Pharmacotherapy 22(7), 841–852 (2002). Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol. Psychiatry 44(8), 778–783 (1998).

800

46

47

Keefe RS, Eesley CE, Poe MP. Defining a cognitive function decrement in schizophrenia. Biol. Psychiatry 57(6), 688–691 (2005). Nieuwenstein MR, Aleman A, de Haan EH. Relationship between symptom dimensions and neurocognitive functioning in schizophrenia: a meta-analysis of WCST and CPT studies. J. Psychiatr. Res. 35(2), 119–125 (2001).

48

Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153(3), 321–330 (1996).

49

McGurk SR, Meltzer HY. The role of cognition in vocational functioning in schizophrenia. Schizophr. Res. 45(3), 175–184 (2000).

50

Kaneda Y, Sumiyoshi T, Keefe R, Ishimoto Y, Numata S, Ohmori T. Brief assessment of cognition in schizophrenia: validation of the Japanese version. Psychiatry Clin. Neurosci. 61(6), 602–609 (2007).

51

Matsui M, Sumiyoshi T, Arai H, Higuchi Y, Kurachi M. Cognitive functioning related to quality of life in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 32(1), 280–287 (2008).

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Side effects, cognition & antipsychotics

62

Parada MA, Hernandez L, Puig de Parada M, Rada P, Murzi E. Selective action of acute systemic clozapine on acetylcholine release in the rat prefrontal cortex by reference to the nucleus accumbens and striatum. J. Pharmacol. Exp. Ther. 281, 582–588 (1997).

63

Harvey PD, Green MF, McGurk SR, Meltzer HY. Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale, double-blind, randomized study. Psychopharmacology (Berl.) 169(3–4), 404–411 (2003).

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Keefe RS, Seidman LJ, Christensen BK et al. Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am. J. Psychiatry 161(6), 985–995 (2004). Bellack AS, Schooler NR, Marder SR, Kane JM, Brown CH, Yang Y. Do clozapine and risperidone affect social competence and problem solving? Am. J. Psychiatry 161(2), 364–367 (2004). Keefe RS, Bilder RM, Davis SM et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry 64(6), 633–647 (2007).

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Excellent study reporting the effect of antipsychotic drugs on cognition based on the CATIE trials.

67

Keefe RS, Sweeney JA, Gu H et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am. J. Psychiatry 164(7), 1061–1071 (2007).

68

Higuchi Y, Sumiyoshi T, Kawasaki Y, Matsui M, Arai H, Kurachi M. Electrophysiological basis for the ability of olanzapine to improve verbal memory and functional outcome in patients with schizophrenia: a LORETA analysis of P300. Schizophr. Res. 101(1–3), 320–330 (2008).

•

Reports a neurophysiological basis for the ability of antipsychotics to improve cognition, based on neuroimaging techniques.

69

Sumiyoshi T, Higuchi Y, Kawasaki Y et al. Electrical brain activity and response to olanzapine in schizophrenia: a study with LORETA images of P300. Prog. Neuropsychopharmacol. Biol. Psychiatry 30(7), 1299–1303 (2006).

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Review

70

Sumiyoshi T, Roy A, Kim CH et al. Prediction of changes in memory performance by plasma homovanillic acid levels in clozapine-treated patients with schizophrenia. Psychopharmacology (Berl.) 177(1–2), 79–83 (2004).

80

Reilly JL, Harris MS, Khine TT, Keshavan MS, Sweeney JA. Antipsychotic drugs exacerbate impairment on a working memory task in first-episode schizophrenia. Biol. Psychiatry 62(7), 818–821 (2007).

71

Sumiyoshi T, Matsui M, Yamashita I et al. The effect of tandospirone, a serotonin1A agonist, on memory function in schizophrenia. Biol. Psychiatry 49(10), 861–868 (2001).

81

72

Sumiyoshi T, Matsui M, Yamashita I et al. Effect of adjunctive treatment with serotonin-1A agonist tandospirone on memory functions in schizophrenia. J. Clin. Psychopharmacol. 20(3), 386–388 (2000).

Sumiyoshi T, Kawasaki Y, Suzuki M, Higuchi Y, Kurachi M. Neurocognitive assessment and pharmacotherapy towards prevention of schizophrenia: what can we learn from first episode psychosis? Clin. Psychopharmacol. Neurosci. 6(2), 57–64 (2008).

82

Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebocontrolled study. Schizophr. Res. 95(1–3), 158–168 (2007).

Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects. Schizophr. Res. 89(1–3), 211–224 (2007).

•

Excellent work investigating the effect of antipsychotic dose on cognitive function in schizophrenia.

83

Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 25(2), 233–255 (1999).

84

Harvey PD, Keefe RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am. J. Psychiatry 158(2), 176–184 (2001).

85

Keefe RSE, Silva SG, Perkins DO, Lieberman JA. The effect of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr. Bull. 25, 201–222 (1999).

86

Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int. J. Neuropsychopharmacol. 8(3), 457–472 (2005).

87

Woodward ND. A meta-analysis of neuropsychological change with second generation antipsychotics in schizophrenia. Presented at: 24th CINP Congress. Chicago, IL, USA 12 July 2006

88

Cosi C, Waget A, Rollet K, Tesori V, Newman-Tancredi A. Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation. Brain Res. 1043(1–2), 32–41 (2005).

89

Uehara T, Sumiyoshi T, Matsuoka T, Itoh H, Kurachi M. Role of 5-HT1A receptors in the modulation of stressinduced lactate metabolism in the medial

73

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Sumiyoshi T, Higuchi Y, Ito T et al. Effect of perospirone on P300 electrophysiological activity and social cognition in schizophrenia: a three-dimensional analysis with sLORETA. Psychiatry Res. Neuroimag. (2009) (In Press). Goldberg TE, Goldman RS, Burdick KE et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch. Gen. Psychiatry 64, 1115–1122 (2007). Green MF, Marshall BD Jr, Wirshing WC et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am. J. Psychiatry 154, 799–804 (1997). Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY. Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol. Psychiatry 34, 702–712 (1993).

•• First report on the ability of the atypical antipsychotic drug clozapine to improve cognitive function in schizophrenia. 78

Lee MA, Jayathilake K, Meltzer HY. A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr. Res. 37, 1–11 (1999).

79

Reilly JL, Harris MS, Keshavan MS, Sweeney JA. Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch. Gen. Psychiatry 63(11), 1189–1197 (2006).

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Sumiyoshi

prefrontal cortex and basolateral amygdala. Psychopharmacology (Berl.) 186(2), 218–225 (2006). 90

Sumiyoshi T, Matsui M, Itoh H et al. Essential polyunsaturated fatty acids and social cognition in schizophrenia. Psychiatry Res. 157(1–3), 87–93 (2008).

91

Sumiyoshi T, Matsui M, Nohara S et al. Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am. J. Psychiatry 158(10), 1722–1725 (2001).

•

Reports on the ability of serotonin1A partial agonists to improve key domains of cognition in schizophrenia.

92

Sumiyoshi T, Meltzer HY. Serotonin 1A receptors in memory function. Am. J. Psychiatry 161(8), 1505 (2004).

93

Yasuno F, Suhara T, Nakayama T et al. Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory. Am. J. Psychiatry 160(2), 334–340 (2003).

94

Meltzer HY, Sumiyoshi T. Does stimulation of 5-HT1A receptors improve cognition in schizophrenia? Behav. Brain Res. 195(1), 98–102 (2008),

95

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Moss LE, Neppe VM, Drevets WC. Buspirone in the treatment of tardive dyskinesia. J. Clin. Psychopharmacol. 13(3), 204–209 (1993). Poyurovsky M, Weizman A. Serotonergic agents in the treatment of acute neurolepticinduced akathisia: open-label study of buspirone and mianserin. Int. Clin. Psychopharmacol. 12(5), 263–268 (1997). McGorry PD, Yung AR, Phillips LJ et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch. Gen. Psychiatry 59(10), 921–928 (2002).

802

98

McGlashan TH, Zipursky RB, Perkins D et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am. J. Psychiatry 163(5), 790–799 (2006).

99

Sumiyoshi T. Neurocognitive assessment and pharmacotherapy: towards prevention of psychosis. First episode psychosis: integrating neurobiological and psychosocial determinants of outcome Presented at: 62nd Annual Meeting of Society of Biological Psychiatry. San Diego, CA, USA, 17–19 May 2007.

100

Sumiyoshi T, Kawasaki Y, Higuchi Y, Matsui M, Suzuki M, Kurachi M. Neurocognitive assessment and pharmacotherapy: towards prevention of psychosis. First episode psychosis: integrating neurobiological and psychosocial determinants of outcome. Presented at: 2nd International Congress of Biological Psychiatry. Santiago, Chile, 17–21 April 2007.

101

Hagan JJ, Jones DN. Predicting drug efficacy for cognitive deficits in schizophrenia. Schizophr. Bull. 31(4), 830–853 (2005).

102

Meltzer HY, Sumiyoshi T, Jayathilake K. Melperone in the treatment of neuroleptic-resistant schizophrenia. Psychiatry Res. 105(3), 201–209 (2001).

103

Miyake N, Miyamoto S, Takeuchi A et al. Effect of new-generation antipsychotic blonanserin on cognitive impairment in schizophrenia: a randomized, doubleblind comparison with risperidone. Jpn. J. Clin. Psychopharmacol. 11, 315–326 (2008).

104

Newman-Tancredi A, Assie MB, Leduc N, Ormiere AM, Danty N, Cosi C. Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A

receptors: affinity, efficacy and potential implications for treatment of schizophrenia. Int. J. Neuropsychopharmacol. 8(3), 341–356 (2005). 105

Enomoto T, Ishibashi T, Tokuda K, Ishiyama T, Toma S, Ito A. Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats. Behav. Brain Res. 186(2), 197–207 (2008).

106

Ishiyama T, Tokuda K, Ishibashi T, Ito A, Toma S, Ohno Y. Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur. J. Pharmacol. 572(2–3), 160–170 (2007).

107

Goldstein JM. Atypical antipsychotic drugs: beyond acute psychosis, new directions. Expert Opin. Emerg. Drugs 4(1), 127–151 (1999).

108

Ishibashi T, Horisawa T, Yabuuchi K, Tagashira R, Ohno Y. Receptor binding characteristics of SM-13496, a novel atypical antipsychotic agent. Soc. Neurosci. Abstr. 894, 7 (2002).

Affiliation •

Tomiki Sumiyoshi Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan and Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama, 930-0194, Japan Tel.: +81 76 434 7323 Fax: +81 76 434 5030 [email protected]

Expert Rev. Clin. Pharmacol. 1(6), (2008)