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CNS Drugs 2006; 20 (5): 389-409REVIEW ARTICLE 1172-7047/06/0005-0389/$39.95/0 2006 Adis Data Information BV. All rights reserved.

Mechanism of Action of AtypicalAntipsychotic Drugs and theNeurobiology of Schizophrenia

Jiri Horacek,1,2,3

Vera Bubenikova-Valesova,1

Milan Kopecek,1,2

Tomas Palenicek,1,2,3

Colleen Dockery,1,2 Pavel Mohr1,2 and Cyril H oschl1,2,3

1 Prague Psychiatric Centre, Prague, Czech Republic

2 Centre of Neuropsychiatric Studies, Prague, Czech Republic

3 3rd Medical Faculty of Charles University, Prague, Czech Republic

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

1. Classification of Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

2. Clinical Effect of Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

3. Mechanisms of Action of the Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

3.1 Dopaminergic Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3933.1.1 Dopamine D2 Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

3.1.2 D1 R e c e p t o r B l o c k a d e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 9 3

3.1.3 D4 R e c e p t o r B l o c k a d e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 9 4

3.1.4 Blockade of D2/D3 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.1.5 Rapid Dissociation from D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.1.6 Partial Agonism of D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.2 Serotonergic Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

3.2.1 Serotonin 5-HT2A Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

3.2.2 5-HT2C Receptor Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3.2.3 Agonism of 5-HT1A Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3.3 Combined Modulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

3.3.1 Blockade of 5-HT2A and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

3.3.2 Blockade of 5-HT2C and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

3.3.3 Agonism of 5-HT1A and Blockade of D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

3.3.4 D2 Antagonism and Interaction with Muscarinic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 399

3.3.5 Blockade of -Adrenergic and D2 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

4. The Neurobiology of Schizophrenia and the Effects of Atypical Antipsychotics . . . . . . . . . . . . . . . . . 400

4.1 Neuroplastic Effect of Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia.AbstractThe mechanisms underlying the effectiveness and adverse effects of these drugs

are, to date, not sufficiently explained. This article summarises the hypothetical

mechanisms of action of atypical antipsychotics with respect to the neurobiology

of schizophrenia.


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390 Horacek et al.

When considering treatment models for schizophrenia, the role of dopamine

receptor blockade and modulation remains dominant. The optimal occupancy of

dopamine D2 receptors seems to be crucial to balancing efficacy and adverse

effects transient D2 receptor antagonism (such as that attained with, for example,

quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while

permanent D2 receptor antagonism (as is caused by conventional antipsychotics)

increases the risk of adverse effects such as extrapyramidal symptoms. Partial D2receptor agonism (induced by aripiprazole) offers the possibility of maintaining

optimal blockade and function of D2 receptors. Balancing presynaptic and post-

synaptic D2 receptor antagonism (e.g. induced by amisulpride) is another mecha-

nism that can, through increased release of endogenous dopamine in the striatum,

protect against excessive blockade of D2 receptors.

Serotonergic modulation is associated with a beneficial increase in striatal

dopamine release. Effects on the negative and cognitive symptoms of schizophre-

nia relate to dopamine release in the prefrontal cortex; this can be modulated by

combined D2 and serotonin 5-HT2A receptor antagonism (e.g. by olanzapine and

risperidone), partial D2 receptor antagonism or the preferential blockade of

inhibitory dopamine autoreceptors.

In the context of the neurodevelopmental disconnection hypothesis of schizo-

phrenia, atypical antipsychotics (in contrast to conventional antipsychotics)

induce neuronal plasticity and synaptic remodelling, not only in the striatum but

also in other brain areas such as the prefrontal cortex and hippocampus. This

mechanism may normalise glutamatergic dysfunction and structural abnormalitiesand affect the core pathophysiological substrates for schizophrenia.

The development of antipsychotics represents effect only compensates for this deficit at a sympto-

one of the most important successes of applied matologic level, remains unanswered.neuroscience. In most patients, antipsychotic drugs

Newer (atypical) antipsychotic drugs offer notbring a significant improvement in psychotic symp-

only a better therapeutic tool but, because of theirtoms and better health and quality of life. However,

stratified effect on the finer dimensions of psychoticwhile antipsychotic drugs provide a basic therapeu-symptoms, they also provide deeper insight into thetic tool for the treatment of schizophrenia and other

pathophysiology of schizophrenia itself. While thepsychotic conditions, their effectiveness is associat-majority of models explaining the effects of antipsy-ed with a series of unresolved questions. It is not

clear, for example, which neurobiological mecha- chotic drugs indicate that these drugs modulate vari-nism (beyond dopamine D2 receptor antagonism) is ous monoaminergic systems, novel theories ofthe final therapeutic target responsible for the bene- schizophrenic pathophysiology are predominantlyficial effect on distorted information processing in

focused on different levels of cortical and cortico-schizophrenia and for subsequent elimination or re-

subcortical disconnection. This article surveys con-duction of psychotic symptoms. Also, the principal

temporary concepts and hypotheses of the effects ofquestion of whether the effectiveness of antipsy-antipsychotic drugs and the neurobiological basis ofchotic drugs represents a causal intervention intoschizophrenia with respect to the integration of thesethe pathophysiological chain of events leading to

aspects.psychotic information processing or whether their

2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (5)


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Mechanism of Atypical Antipsychotics 391

1. Classification of positive symptoms and the superiority of atypicalsAtypical Antipsychotics on negative and affective symptoms, cognitive dys-

function and aggression.[5] Furthermore, during theThe original classification of antipsychotics ac-

course of illness, atypical antipsychotics are associ-cording to their chemical structure (phenothiazines,

ated with the following benefits:[2,4]thioxanthenes, butyrophenones, perathiepines and

higher rate of responders;diphenylpiperidines) and prevailing sedative or efficiency in patients with refractory disease;antipsychotic (incisiveness) potential is still relevant lower risk of suicides;for the conventional (typical) antipsychotic agents. better functional capacity;The classification of atypical antipsychotics is improved quality of life;linked essentially to their pharmacodynamic proper-

ties, which reflect their affinities for specific recep- favourable pharmacoeconomic profile.tors. Atypical antipsychotics with a high selectivity They also have a more favourable adverse effectfor serotonin 5-HT2A receptors and dopamine D2 profile, being associated with a lower risk of EPSreceptors (and also 1-adrenoceptors) are called se- and tardive dyskinesias, hyperprolactinaemia, mor-rotonin-dopamine antagonists (SDA). Drugs show- phological changes in the CNS and noncompliance,ing an affinity for 5-HT2A, D2 and receptors of other as well as better overall tolerability.[5] However,systems (cholinergic, histaminergic, 5-HT1A, 5- atypical antipsychotics, as a class, are associatedHT2C and others) are designated as multi-acting with their own unique adverse effects; their meta-receptor-targeted antipsychotics (MARTA).[1] bolic adverse effects, for example, are currently ofDrugs that preferentially block D2 and D3 subtypes great interest to clinicians.[6]

of the D2-like receptors are classified as combined Nevertheless, based on study findings and grow-

D2/D3 receptor antagonists. A final class of atypical ing empirical evidence, atypical antipsychotics areantipsychotics are the partial dopamine receptor ag- becoming the first-line treatment of schizophrenia.onists. Table I provides a summary of the typical Thus far, there has been a general consensus thatrepresentatives of each class. atypical antipsychotics are effective and reliable in

the treatment of schizophrenia, and similar in their2. Clinical Effect of

efficacy,[7,8] although clozapine appears to be moreAtypical Antipsychotics

effective than other atypicals.[9]

Conventional antipsychotics are characterised by Interestingly, two recent meta-analyses of pub-

undesirable effects, such as extrapyramidal symp- lished clinical trials have suggested that atypicals

toms (EPS), hyperprolactinaemia and neuroleptic are no better than conventional antipsychotics,

malignant syndrome, which are specific to the group which stimulated great controversy. First, Geddes et

as a whole and associated typically with high doses. al.[10] concluded that when the dosage of conven-

From the clinical point of view, atypical antipsy- tional antipsychotics used in the published studies,chotic drugs can be differentiated from conventional which appeared to be higher than that recommended

antipsychotics by their effectiveness, influence on (haloperidol 12 mg/day or equivalent), is con-

behaviour and increased safety.[4] trolled for, the difference between the two groups of

The clinical efficacy of atypical antipsychotics drugs in terms of efficacy and overall tolerability

has been tested in numerous double-blind, disappears. Second, in a systematic review and

randomised, controlled trials in which the newer meta-analysis of studies that used low-potency con-

agents have been compared with both placebo and ventional antipsychotics, Leucht et al.[11] found that

conventional antipsychotics in schizophrenia and atypicals were moderately more efficacious and,

other psychotic disorders. Study results have invari- with the exception of clozapine, equally as prone as

ably confirmed the comparable effects of atypical low-potency conventional drugs to induce EPS.

and conventional antipsychotics in the control of However, the conclusions of Geddes et al.[10] and



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2006AdisDataInformationBV.Allrightsreserved.

CNSDrugs2006;20(5)

Table I. Pharmacodynamic characteristics and classification of selected antipsychotics and clinical criteria characterising atypical antipsychotics

Antipsychotic Classification Criteria for Receptor affinity (Ki)a

atypical D2 D2 5-HT2A 5-HT2A/D2 5-HT1A 5-HT2C 2 1 H

antipsychotic[2] dissociation

(koff)b

Amisulpride D2/D3 0EPS (?), 1.3 0.02 2000 1538


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3.1.1 Dopamine D2 Receptor BlockadeLeucht et al.[11] have been rebuffed by other authors.D2 receptor blockade in the brain is a generalFor example, Davis et al.,[12] in their meta-analysis

pharmacodynamic property of all antipsychotics,of 124 trials, found that the effect of the dosage ofand without it a drug will not show any antipsychot-the comparator is an artifact; analysing haloperidol-ic properties.[17] With conventional antipsychotics,equivalent dosages of conventional antipsychoticsthe level of D2 receptor blockade is directly relateddid not affect the results. The authors also found thatto the antipsychotic effect, but with atypical agentssome atypicals (clozapine, amisulpride, olanzapinethe situation is more complicated. Currently, theand risperidone) were significantly more efficaciousconcept of a therapeutic window of the percentagethan conventional drugs; some atypicals also pro-

of D2 receptors blocked is being evaluated by aduced a better functional recovery and were more series of neuroimaging studies in relation to treat-cost effective. Olanzapine and risperidone werement efficacy and development of EPS. It has beenslightly superior to conventional antipsychotics withrepeatedly confirmed that D2 receptor occupanciesrespect to positive symptoms and moderately supe->80% are, in most cases, associated with EPS.[18-23]rior with respect to negative and cognitive symp-A lower striatal D2 receptor occupancy mediated bytoms, mood and impulse control/excitement.lower affinity for D2 receptors (table I) or by in-Based on information from current meta-analy-creased extracellular dopamine release (see sectionsses, it seems that the atypical antipsychotics are a3.2 and 3.3) would explain the clinical characteris-heterogeneous group in terms of effectiveness andtics of atypical antipsychotics.adverse effects, and that in addition to their superior

antipsychotic effects, some of the drugs cause an3.1.2 D1 Receptor BlockadeEPS rate similar to that of a placebo.[12,13]

D1 receptor blockade was once considered a key

3. Mechanisms of Action of the mechanism for atypical antipsychotics, particularlyAtypical Antipsychotics in light of the very high D1 receptor antagonistic

activity of clozapine. The affinity of clozapine forThe hypothetical mechanisms of action of atypi-

D1 receptors is even higher than that for D2 recep-cal antipsychotics are hereinafter classified into

tors.[4] D1 receptors are the principal dopamine re-dopaminergic, serotonergic and combined modula-

ceptors in the prefrontal cortex, and an effect ontion effects. Since the atypical antipsychotics share

these receptors is usually linked to therapeutic ef-several pharmacodynamic mechanisms which are

fects on the negative[24] and cognitive symptoms ofoften intermingled, the classification is largely moti-

schizophrenia.[25] From a development/hierarchyvated by the quest to develop a comprehensive over-

point of view, the D1 receptors of the prefrontalview. Subsequently, within the context of the

cortex may influence the lower levels of the nervousneurodevelopment theory of schizophrenia, the

system[26] associated with positive symptoms (relat-neuroplastic effect of antipsychotics is also impor-

ed to the temporal or limbic regions), and maytant.explain the efficacy of clozapine in patients with

treatment-resistant symptoms.[27] D1 receptors inter-3.1 Dopaminergic Modulationact with D2 receptors at the cellular level and, thus,

Dopamine is a neuromodulator acting in the brain D1 receptor antagonism may directly influence

by means of two basic groups of receptors. The D1 schizophrenia at the level of D2 receptor modula-

and D5 receptors have similar structures and intra- tion.[28,29] However, the fact that atypical antipsy-

cellular signalling mechanisms (increased levels of chotic drugs other than clozapine lack affinity for D1cyclic adenosine monophosphate [cAMP]) and are receptors[2] and that pure D1 receptor antagonists

termed D1-like receptors. The D2, D3 and D4 re- have not shown any pronounced antipsychotic po-

ceptors reduce cAMP levels and are termed D2-like tential does not support the role of D1 receptors in

receptors.[14-16] antipsychotic drug efficacy.[30,31] The role of D1



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394 Horacek et al.

receptors therefore appears to be important for the tex. The increased level of dopamine in the

delicate coordination of other receptor modulations prefrontal cortex is responsible for the effects on

(see sections 3.3 and 4).[32,33] negative and cognitive symptoms.[42,43]

3.1.3 D4 Receptor Blockade 3.1.5 Rapid Dissociation from D 2 Receptors

D4 receptor blockade was also considered as a Rapid dissociation from D2 receptors (fast

possible mechanism by which clozapine is effective OFF) is one explanation for the improved EPS

in treating schizophrenia. Clozapine shows a higher profile of atypical antipsychotics, and one that is

affinity for the D4 compared with the D2 subtype of also consistent with the theory of a lower affinity for

the D2-like receptors. On the other hand, conven- D2 receptors for these drugs. The baseline occupa-

tional antipsychotics show approximately equal af- tion of D2 receptors by endogenous dopamine isfinity for D4 and D2 receptors. Furthermore, in within the range of 2540%,[44] and antipsychotics

laboratory animals, the rate of induction of catalepsy compete with endogenous dopamine for binding to

(a model of EPS) decreases in relation to the increas- D2 receptors. The drugs with faster dissociation

ing D4 receptor affinity of the drug.[34] The increase (k off) from D2 receptors can more effectively reach

of dopamine output into the basal ganglia and the equilibrium between association (kon) and koffin

prefrontal cortex induced by D4 receptor antagonists the dynamic process of binding to the receptor

may explain the lower risk of EPS and the therapeu- against a background of ongoing endogenous

tic influence on cognitive symptoms with these dopamine binding and release. At an equilibrium

agents.[35] In connection with D4 receptor antago- state, a drug with a faster dissociation, such as

nism, it is also interesting that in schizophrenia, the clozapine, can go on and off the receptor 100 times

D4 receptors are over-expressed.[36,37] However, more frequently than haloperidol. By this mecha-

drugs selectively influencing only D4 receptors have nism, clozapine (and other antipsychotics with rapidnot shown themselves to be therapeutically effec- dissociation; see table I) can more effectively inter-

tive.[38] fere with or attenuate the phasic release of endoge-

nous dopamine than drugs with slow koff, even at anIn summary, D4 receptor antagonism should be

equal level of receptor occupancy.[45] Rapid dissoci-considered only as supplementary to D2 receptoration from D2 receptors is, according to proponentsblockade for a therapeutic effect.

of this idea, necessary for a more robust antipsychot-3.1.4 Blockade of D2/D3 Receptors

ic effect, but insufficient for induction of EPS andThe properties of the substituted benzamides

hyperprolactinaemia.[3,4,45] The mechanism of rapid(sulpiride, remoxipride and especially amisulpride)

dissociation is especially useful for explaining thecan be understood only if the D2 and D3 subtypes of

properties of quetiapine and clozapine (table I), butthe D2-like receptors are distinguished. These drugs

the properties of other atypical antipsychotic drugshave a higher affinity for D3 than D2 receptors.[39]

with low EPS risk but lacking rapid koff (e.g.

D3 receptors are localised in the limbic cortex, and ziprasidone, aripiprazole, amisulpride and ser-preferential blockage of these receptors offers re-

tindole) are not explained by such reasoning.gionally selective antidopaminergic activity, result-

The development of the rapid dissociation con-ing in an accentuated effect on positive symp-

cept may be considered a supplement to the D2toms.[40,41] The atypical features of amisulpride

receptor occupancy therapeutic window theory, oneand other substituted benzamides may also result

which adds a temporal aspect to explaining how thefrom the pro-dopaminergic effect mediated by

drug exerts its effect on the receptor.blocking of presynaptic D2 autoreceptors. Blockade

3.1.6 Partial Agonism of D2 Receptorsof these presynaptic inhibitory D2 receptors leads to

increased dopamine output into the striatum (reduc- Partial agonism of D2 receptors is one of the

tion of EPS), maintaining a high rate of D3/D2 newest models for explaining the properties of atyp-

receptor blockade in the thalamus and temporal cor- ical antipsychotics.[46] Partial agonism means that



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when binding to the receptor, the drug blocks the Furthermore, the dopaminergic effect of aripipra-

zole, and therefore the ratio between its agonistic/effects of the extracellular physiologically active

antagonistic effects, is dependent on the type andsubstance (e.g. dopamine), while at the same havingfunction of the respective neuronal populations.[54]an agonistic effect on this receptor. The partial agon-This effect also mediates its functional (and anatom-ism model has been successfully applied within theical) selectivity on various dopaminergic pathways.framework of the development of aripiprazole.In addition, antagonism of 5-HT2A receptors (withAripiprazole is a drug showing, in clinical practice,only a slight intrinsic agonistic activity) allowsthe characteristics of an atypical antipsychotic witharipiprazole to manifest 5-HT2A/D2 receptor antag-a low risk of EPS.[46] However, when administered

onistic properties as well.in therapeutic doses, aripiprazole occupies aboutAn interesting possibility is suggested by the95% of the striatal D2 receptors, which does not

long-term influence of partial agonists on D2 recep-correspond to a low incidence of EPS.[47,48] In thetor availability. Agonists of D2 receptors causecase of aripiprazole, the concept of rapid dissocia-downregulation (internalisation) of receptors.[55]

tion cannot be applied because this drug shows oneThere is still the unanswered question of whether a

of the highest D2 receptor affinities and its koff for 3040% agonistic effect, as seen with aipiprazole, isD2 receptors is even lower than that of many con- sufficient for internalisation of D2 receptors (yield-ventional antipsychotic drugs (table I). ing a long-term positive therapeutic effect).

Although the partial agonism of D2 receptors3.2 Serotonergic Modulationexhibited by aripiprazole is the drugs most fre-

quently mentioned attribute, in order to explain theFrom the historical point of view, interest in

incongruity between the low potency of EPS withserotonergic modulation for the treatment of schizo-aripiprazole and its high degree of D2 receptor phrenia arose from the finding that 5-HT2A receptor

blockade, its effects on other monoaminergic recep- agonists (e.g. lysergic acid diethylamide [LSD]) aretors should not be overlooked. Aripiprazole is a strong psychedelic drugs that can elicit psychoticpartial agonist of a series of receptors that are in- symptoms.[2,56]

volved in antipsychotic effects, namely 5-HT1A, 5-3.2.1 Serotonin 5-HT2A Receptor BlockadeHT2C, D2, D3, D4 and, to a much lesser extent, 5-Experience with LSD suggests that 5-HT2A re-HT2A receptors.[48-51] In fact, at D3, D4, 5-HT1A and

ceptor blockade might be a promising method of5-HT2C receptors, aripiprazole shows 4080% the

treating schizophrenia. However, a heuristic prob-activity of a full agonist. At D2 receptors, the ago-

lem remains: the phenomenology of the psychoticnistic activity of aripiprazole reaches about 30%

symptoms caused by 5-HT2 receptor agonists differs(maximum 40%) of the effects of dopamine as an

substantially from the symptoms of schizophrenicendogenous ligand; on 5-HT2A receptors, however,

psychoses.[57,58]

it shows a weak 5% agonistic activity. At therapeu- On the other hand, the anatomical localisation oftic dosages (1530 mg/day), aripiprazole thus occu- 5-HT2A receptors supports their possible role inpies 95% of striatal D2 receptors and if we subtract antipsychotic effects. 5-HT2A receptors are local-about 30% of the intrinsic agonistic activity there is ised on hippocampal and cortical pyramidal cells, asapproximately a 65% blockade of D2 receptor activ- well as on GABA neurons. The highest density of 5-ity, a level analogous to the optimum therapeutic HT2A receptors is in the fifth neocortex layer wherewindow for most antipsychotics.[52] Partial D2 re- the inputs of various cortical and subcortical brainceptor agonism by aripiprazole at the level of the areas are integrated (and computed).[59,60] This facttubero-infundibular dopaminergic projection is re- makes 5-HT2A receptor blockade an extraordinarily

sponsible for its prolactin-neutral or prolactin-re- interesting area, given the aetiopathogenesis of

ducing effect.[53] schizophrenia.



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396 Horacek et al.

Because agonism at 5-HT2A receptors induces midbrain nuclei and brain stem. These receptors

depolarisation of pyramidal cells, it has been specu- have somato-dentritic localisation and, in cortical

lated that 5-HT2A receptor blockade is responsible areas, appear to be mostly expressed on pyramidal

for normalisation of pyramidal cell activity, which (glutamatergic) cells. It has also been suggested that

leads to the therapeutic effect of atypical antipsy- 5-HT2C receptors control monoaminergic and cho-

chotics.[61] The psychomimetic effect of glutamate linergic neurons. In the substantia nigra, 5-HT2CNMDA receptor antagonists may be blocked by receptors are co-localised with GABA, indicating

selective antagonists of 5-HT2A receptors,[61] but the that 5-HT2C receptors yield indirect control of

antipsychotic potential of pure 5-HT2A receptor an- dopaminergic transmission.[69] Consequently, the

tagonists has not been convincingly proven.[62,63]

blockade of 5-HT2C receptors on GABA cells in thesubstantia nigra would potentiate the D2 receptor-5-HT2A receptors are also localised on dopamin-

mediated tonic inhibitory control of the three neu-ergic neurons in the substantia nigra and ventral

ronal striato-pallido-talamo-cortical projection,[67]tegmentum, as well as on their terminals.[64] 5-HT2Awith protective effect against EPS. In this regard,receptor antagonism may modulate the activity of

administration of a 5-HT2C receptor antagonist maydopamine neurons differentially in nigrostriatal,

increase dopamine levels in the nucleus accumbensmesolimbic and mesocortical projections.[65] The

and prefrontal cortex.[70]fundamental interaction of 5-HT2A and D2 receptor

antagonism is discussed in section 3.3.1. Because of the increase in limbic dopamine

levels induced by 5-HT2C receptor antagonism, thisThe activity of the striato-pallidal GABA neu-

effect on these receptors is not sufficient for anrons is also regulated by 5-HT2A receptors.[66] D2antipsychotic effect. Moreover, systematic adminis-receptors regulate, in a tonic inhibitory manner, the

tration of an antagonist of 5-HT2C receptors (SB-indirect three neuronal GABAergic inhibitory pro-242084) activates mesolimbic dopamine neuronaljection to the thalamus and cortex. The administra-

function in an animal model of schizophrenia-liketion of D2 receptor antagonists leads to dis-inhibi-behaviour (induced by a noncompetitive NMDAtion of this projection with facilitation of inhibitory

receptor antagonist) and is associated with worsen-effects on locomotion and subsequent EPS.[67]

ing of hyperlocomotion and a deficit in informationTherefore, the antagonism of 5-HT2A receptors lo-

processing.[71]cated at pallidal GABA cells would counteract the

inhibition of movement. This mechanism may ex-3.2.3 Agonism of 5-HT1A Receptorsplain the reduced risk of EPS seen with atypicalAgonism of 5-HT1A receptors is considered aantipsychotics. The role of 5-HT2A receptor antago-

possible mechanism associated with the activity ofnism in the pharmacological profile of atypical an-some atypical antipsychotic drugs.[65] The onlytipsychotics may also be supported by the fact that,antipsychotics that manifest 5-HT1A receptor agon-conversely, SSRIs may induce EPS.[68]

ism are aripiprazole, clozapine, quetiapine,3.2.2 5-HT2C Receptor Blockade ziprasidone and risperidone. 5-HT1A receptor block-

ade (with WAY100635) prevents the increase in5-HT2C receptor blockade has received relatively

dopamine in the prefrontal cortex induced by theselittle attention in studies of antipsychotics. Binding

drugs, even with olanzapine[72] which does not ex-affinity for the 5-HT2C receptor does not distinguish

press 5-HT1A receptor affinity. Therefore, it seemsconventional from atypical antipsychotics (table I).

that these receptors play an important role in theSome atypicals (clozapine and risperidone), but also

action of atypical antipsychotics, irrespective ofsome conventional antipsychotics (chlorpromazine,

whether they are directly agonised by the drug (seemesoridazine, loxapine and fluphenazine) have high

section 3.3.3).affinities for 5-HT2C receptors. 5-HT2C receptors

have been found in cortical areas and in the hippo- Generally, it may be concluded that a simple

campus, striatum, septal nuclei, thalamic nuclei, effect at serotonergic receptors is probably not suffi-



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cient for an antipsychotic effect in schizophrenia.

More promising seems to be the assumption that

serotonergic activity takes part in the antipsychotic

effect in combination with D2 receptor blockade,

and possibly with other systems as well.

3.3 Combined Modulations

3.3.1 Blockade of 5-HT2A and D2 Receptors

Blockade of 5-HT2A and D2 receptors was, in1989, first labelled a pharmacodynamic mechanism

that differentiated conventional from atypical

antipsychotics.[73,74] Meltzer et al.[73,74] defined atyp-

ical antipsychotic drugs as drugs showing a higher

affinity for 5-HT2A receptors than for D2 receptors

and a lower affinity for D2 receptors than was seen

with conventional antipsychotics. These two criteria

enabled these investigators and other authors[2] to

classify the antipsychotics in two groups and con-

firmed, in most cases, their ability to predict the

clinical properties of antipsychotic drugs with re-

spect to the affinity constants for 5-HT2A and D2

receptors.For the nigrostriatal dopaminergic pathway, a

model was suggested in which blockade of 5-HT2Areceptors leads to increased output of dopaminergic

neurons into the striatum. Such increased extracellu-

lar activity of dopamine in the striatum displaces

the antipsychotic drug from its binding to D2 recep-

0100 frequency

100200 frequency200300 frequency


10/21

398 Horacek et al.

(figures 2e and f). The interaction between both

systems in mesolimbic projections would explain

this effect. These findings indicate the role of other

serotonergic receptors such as 5-HT1A and 5-HT2Cin the action of atypical antipsychotics (see sections

3.3.2 and 3.3.3).

From the point of view of understanding the

mechanism of atypical antipsychotics, it is impor-

tant that, for their long-term administration, adap-

tive changes in the serotonergic system occur in thesame direction as in the case of an acute blockade.

Long-term administration leads to a reduced

downregulation (internalisation) of 5-HT2A recep-

tors.[86,87]

The concept of 5-HT2A/D2 receptor antagonism

has led to the development of several new, efficient

drugs and some progress in understanding the func-

tioning of antipsychotics. However, the 5-HT2A/D2model does not explain the effects of all atypical

antipsychotics, such as aripiprazole and amisul-

pride, for which pharmacodynamic criteria (5-

HT2A/D2) are not consistent with clinical criteria

(see sections 3.1.4 and 3.1.6). These exceptions shift

our attention from the pharmacodynamic level to a

physiological approach (such as measuring the ex-

tracellular concentrations of monoamines), which

brings us closer to the pathophysiological substrate

of schizophrenic disorder.

3.3.2 Blockade of 5-HT2C and D2 Receptors

Blockade of 5-HT2C and D2 receptors represents

a third possible serotonergic effect of antipsy-

chotics.[65] Because 5-HT2C receptors regulate the

tonic inhibition of dopaminergic output using sero-

tonin from the ventral tegmentum, antagonism ofthese receptors may cause an effect analogous to 5-

HT2A receptor blockade.[88,89] There is some evi-

dence that a combination of 5-HT2A and 5-HT2Creceptor blockade is more efficient than 5-HT2A

0100 frequency

100200 frequency

200300 frequency


11/21


HT2C receptor antagonism in combination with ripheral regions of the open field), hypothetically

dopamine receptor blockade should therefore in- because of facilitation of limbic dopamine release.

crease the safety of the drugs.[91] 5-HT2 receptor antagonism, contrary to the 5-HT2A/

D2 receptor antagonism concept, facilitated the in-5-HT2C receptors also play a role in food intake

hibitory effect of haloperidol in this experimentaland are involved in weight gain, which is an adversesetting (figures 2e and f).[80-83] The more sophisticat-effect of some atypical antipsychotics. Recent re-

ed (in terms of the combination of different receptorports indicate that 759C/T polymorphism of the 5-

targets) the interaction between serotonin andHT2C receptor gene is associated with weight gain

dopamine, the more important it seems to be inin schizophrenic patients treated with olanzapine

influencing the optimal orchestration of an antipsy-and clozapine.[92,93]

chotic effect.

3.3.3 Agonism of 5-HT1A and Blockade of

D2 Receptors 3.3.4 D2 Antagonism and Interaction with

Agonism of 5-HT1A and blockade of D2 recep- Muscarinic Receptors

tors represents another possible combination which, Some atypical antipsychotics, such as olanzapinefrom a theoretical point of view, complies with the and clozapine, have a marked affinity for choliner-

5-HT2A/D2 hypothesis. To a certain extent, 5-HT2A gic muscarinic receptors (M1 and M4). These recep-and 5-HT1A receptors show functionally opposite tors are predominately expressed in the frontal and

effects.[65] Thus, like 5-HT2A receptor antagonists, limbic areas of the brain and have extensive interac-5-HT1A receptor agonists increase dopamine output tions with dopaminergic neurons.[96,97] On the other

in the neocortex and striatum.[72] However, the hand, risperidone, haloperidol, ziprasidone and que-5-HT1A receptor agonist buspirone also increases tiapine do not have high affinities for muscarinic

extracellular dopamine levels, even in the limbic receptors, and direct interaction with muscarinicarea (nucleus accumbens).[94] Therefore, it is likely receptors is not important in their pharmacology.[97]

the role of 5-HT1A receptor agonism is more impor- The main effect of antimuscarinics is to antagonisetant for influencing negative and cognitive symp- antipsychotic-induced EPS, and the affinity of

toms than positive symptoms. Also, the ratio be- antipsychotics for muscarinic receptors has beentween the influence of postsynaptic and presynaptic shown to be inversely correlated with their propensi-

5-HT1A receptors may play an important role; bi- ty for causing EPS.[98] In contrast to the effect in-

modal dependence based on this ratio cannot be duced by antagonism of muscarinic receptors, atypi-

excluded.[81] cal antipsychotics also increase extracellular levels

Experimental data from our laboratory prove that of acetylcholine in the prefrontal cortex, striatum

a decrease in serotonergic activity (tryptophan de- and nucleus accumbens. Conventional antipsychot-

pletion) is essential for normalisation of locomotor ics such as haloperidol and thioridazine, on the other

activity in combination with D2 receptor antagonism hand, do not increase acetylcholine levels in thein an animal model of schizophrenia induced by prefrontal cortex, but they do increase acetylcholine

short-term administration of the NMDA receptor levels in the nucleus accumbens and striatum.[99]

antagonist dizolcipine (MK-801) [figure 1].[79] Ad- The effect of antipsychotics on acetylcholine levels

ministration of a specific 5-HT2A receptor antago- could be due to an interaction between the dopamin-

nist or 5-HT1A receptor agonist in combination with ergic and acetylcholinergic systems. There are some

haloperidol did not show such a beneficial effect findings that agonists of muscarinic receptors have

(figure 2). Interestingly, 5-HT1A receptor agonism antipsychotic features and act as dopamine receptor

(figures 2c and d) or 5-HT2C receptor antagonism antagonists.[97] Taken together, the antimuscarinic

(figure 2g) prolonged the hypolocomotion induced activity of clozapine and olanzapine could be hypo-

by haloperidol, but strongly affected the spatial thetically responsible for the effect on positive and

characteristics of the behaviour (preferences for pe- cognitive symptoms.



12/21

400 Horacek et al.

There are no data indicating that antipsychotics simultaneous increased density in pyramidal neu-

bind at nicotinic receptors. However, the effect of rons, supports the fact that the morphological sub-

agonists of the 7 subunit of the nicotinic receptor in strate of the disorder consists of a reduced number of

improving perceptual disturbances and cognitive neuronal fibres and synapses, rather than a reduced

deficit in schizophrenia was recently described.[100] number of neurons. The absence of gliosis in the

brains of patients with schizophrenia contradicts the3.3.5 Blockade of-Adrenergic and D2 Receptors

theory of a degenerative/inflammatory process andAtypical antipsychotics are, with some excep-

also supports the neurodevelopmental aetiology oftions (e.g. benzamides), relatively strong antago-

the morphological findings in schizophrenia.[111,112]nists of1-adrenoceptors. In atypical antipsychotic

In addition, the abnormalities are even present priorfunction, the role of1-adrenoceptor antagonism isto onset of the disease.[26]

supported by findings which demonstrate thatThe theory of glutamatergic dysfunction in schiz-prazosin (an 1-adrenoceptor antagonist) adminis-

ophrenia is also supported by the fact that phencycli-tered simultaneously with haloperidol reduces thedine and other antagonists of glutamatergic NMDArisk of EPS and leads to higher haloperidol bindingreceptors may, from the phenomenological point ofto limbic D2 receptors.[101,102] This phenomenonview, model the schizophrenic symptoms in healthymay be explained by the fact that blockade of1-ad-persons better than serotonergic psychotomimeticrenoceptors leads to inhibition of serotonin neuronsdrugs (e.g. LSD; see section 3.2), and may aggravatein the raphe nuclei and thus may induce an effector exacerbate psychosis in patients with schizophre-similar to that of 5-HT2 receptor blockade by 5-HT2/nia.[57]D2 receptor antagonists.[103]

In addition, 2-adrenoceptor antagonism by Novel and very promising findings in schizo-

some atypical antipsychotics may play a role in phrenia implicate the pathology of myelin. Morpho-atypical properties. Research in animals confirms logic and neurocytochemical evidence, myelin-re-that yohimbine, MK-912 and other antagonists of lated gene abnormalities and abnormalities in the2-adrenoceptors reduce the cataleptic effect of oligodendroglia demonstrated in the brains of pa-haloperidol.[104] tients with schizophrenia support changes in white

matter as an alternative mechanism for disconnec-4. The Neurobiology of tion.[113,114]Schizophrenia and the Effects

The target structures for all antipsychotics areof Atypical Antipsychoticsprimarily the monoaminergic receptors associated

In the last decade, a new theory of schizophrenia with G-proteins. Using the above-mentioned mech-

has been proposed. According to this theory, schizo- anisms of direct/indirect modulation, antipsychotic

phrenia develops as a result of a disconnection of the drugs change the behaviour (excitability) of pyrami-

distributed networks of pyramidal neurons, which dal cells. Such an effect might be considered com-represent the principal substrate for information pensatory. From a theoretical perspective of infor-

processing.[105] mation processing, they may, by means of shifting

the signal/noise ratio, partially normalise the activityThere is much evidence to indicate dysfunction

of the pyramidal cells altered by neuro-develop-in the connectivity of glutamatergic neurons in

ment.[115-117] Such a mechanism would be topo-schizophrenia. For example, reductions in the densi-

graphically selective; blockade of D2 receptors inty of prefrontal cortex pyramidal cell dendrites, the

the medio-temporal cortex and striatum is associat-number of glutamatergic synaptosomes and the ex-

ed with remission of positive symptoms. Moreover,pression of messenger RNA (mRNA) for the synap-

typical and atypical antipsychotics affect the gluta-tic density marker synaptophysin are found at post-

matergic system directly as partial agonists at themortem in patients who had schizophrenia.[106-110]

NMDA receptor-associated glycine recognitionThe reduced brain volume in schizophrenia, with the



13/21


site[118] and indirectly by the blockade of glycine and In the case of haloperidol, induction of synaptic

glutamate transporters at the synaptic level.[119] By plasticity has been particularly well documented in

this mechanism, deficient glutamatergic signalling the striatum,[122-124] where the highest concentration

would be potentiated. of D2 receptors exists. This is indirectly supported

by volumetric studies that have found extension ofThis explanation is supported by the finding thatthe basal ganglia after haloperidol treatment.[125-127]the glutamate co-agonist glycine and its derivatives

The increase in basal ganglia volume is reversible(D-serine, D-cycloserine), as well as inhibitors of

after therapy is discontinued or after switching toglycine reuptake, potentiate the clinical effect of

clozapine, which has significantly lower D2 receptorconventional antipsychotics.[119]

affinity.[125,128]

Dopaminergic activity in the prefrontal cortex ismediated more by D1 receptors than D2 recep- The neuroplastic changes are based on the cAMPtors.[14,33,120] The negative symptoms of schizophre- increase after the D2 receptors are blocked. cAMPnia and reduced performance in cognitive functions activates protein kinase A (PKA), which phospho-associated with the disorder may hypothetically be rylates (reinforces) NMDA and other receptors.influenced by antipsychotics that increase dopamin- PKA also activates transcription factors, which reg-ergic activity in the prefrontal cortex. This assump- ulate the expression of genes of neuronal growthtion has been confirmed in animal studies that evalu- factors.[127,129] A regionally stratified increase inated the effect of atypical antipsychotics on neurotrophin nerve growth factor (NGF) was report-dopamine levels in the frontal cortex.[121] This hy- ed after administration of antipsychotics.[122] Thepothesis is not fully consistent with the expected increase in NGF is mediated by D2 receptor block-positive therapeutic role of D1 receptor blockade, ade; it is also increased by conventional antipsy-which is particularly notable for clozapine (see sec-

chotics.[123,124]

tion 3.1.2). This situation confirms the complexityIt has been shown that haloperidol treatment in

of the problem and may be explained by the differ-rats upregulates binding of NMDA receptors in the

ent functions of the tonic and phasic effect ofparietal and frontal cortices,[130,131] and an increase

dopamine in the neocortex.[116]in this binding level probably results from an in-

crease in the maximal density of NMDA recep-

4.1 Neuroplastic Effect of Antipsychotics tors.[118] There is evidence that antipsychotics

change the expression of NMDA and non-NMDA

receptors in different brain structures.[119] However,Neuroplasticity refers to the ability of the ner-findings related to the effect of antipsychotics on thevous system to adapt to environmental changes, andmRNA level of glutamate receptor subunits are in-includes both synaptic plasticity (remodelling of theconsistent and depend on the antipsychotics usedsynapses and development of new neuronal connec-and the duration of treatment.[132]

tions) and neurogenesis (development of new neu-rons). Antipsychotic drugs appear to induce restruc- The expression of the neuronal growth factor

turing of neuronal networks by inducing neuroplas- brain-derived neurotrophic factor (BDNF) is also

tic changes. This effect contributes to a more influenced by antipsychotics. However, the effects

substantial description of the interaction between of the respective antipsychotics on this neurotrophin

antipsychotics and the neurodevelopmentally al- differ significantly from each other. After chronic

tered function and structure of the brain in patients administration of haloperidol and risperidone, re-

with schizophrenia. In addition, it can explain the duced production of mRNA for BDNF was found in

delayed onset of the antipsychotic effect, suggesting the hippocampus and the frontal and orbital cortical

a remodelling of neuronal structures and circuits is regions in rats.[133,134] On the other hand, after chron-

required for this effect rather than exclusively recep- ic administration of olanzapine, increased expres-

tor blockade or changes in neurotransmitter levels. sion of BDNF in CA1 and CA3 of the hippocampus



14/21

402 Horacek et al.

Substantia nigra

VTA

Str.

Neocortex

Thalamus

GPHippocampus

and LS

Hypophysis

Facilitated release of dopamine

mediated by blockade of 5-HT2A,

5-HT2C, D4 and presynaptic D2 receptors

or by agonism of 5-HT1A receptors

D1 receptor antagonism (?)

Induction of neuroplasticity

Improvement of negative and

cognitive symptoms:

Lower D2 receptor occupancy

Increased release of dopamine

mediated by blockade of 5-HT2A,

5-HT2C, D4 and presynaptic D2receptors or by agonism of 5-HT1Areceptors

Partial D2 receptor agonism

5-HT2A receptor-mediated modulation

of GABA interneurons

Fast dissociation from D2 receptor

Lower neurotoxicity due to lower

blockade of D2 receptor

Lower risk of EPS:

D1 receptor-mediated

suppression of D2 receptor

Affinity for D3 receptors

The possibility of higher D2receptor blockade mediated by

decreased binding to striatal D2receptors (see striatum)

5-HT2A receptor-mediated decrease

of dopamine release to LS

Greater effectivity on positive

symptoms:

Lower D2 receptor affinity

Increased dopamine release (?)

Partial D2 receptor agonism

Fast dissociation from D2 receptor

Lower risk of

hyperprolactinaemia:

Fig. 3. Schematic illustration of the hypothetical mechanisms of action of atypical antipsychotics. Solid arrows show the main neuronal

circuits involved in the pathophysiology of schizophrenia. The reciprocal pathways connect the neocortex with the hippocampus, mediotem-

poral structures and limbic system (LS). The second circuit represents connections between the cortex, striatum (Str.), globus pallidus (GP),

thalamus and back to the cortex. Dashed lines symbolise dopaminergic projections from the ventral tegmental area (VTA) to the neocortex

and limbic areas. The nigrostriatal projection connects the substantia nigra with striatal GABAergic interneurons. The tuberoinfundibular

projection from the hypothalamus to the adenohypophysis regulates prolactin release (modified from Konradi and Heckers[95]). EPS =

extrapyramidal syndrome.

area and in the dentate gyrus was found.[135] In From the point of view of the glutamatergic

addition, olanzapine is able to normalise a haloper- theory of schizophrenia, there is a very interesting

idol-induced decrease in the levels of BDNF.[136] observation that dizocilpine, a noncompetitive an-

tagonist of NMDA receptors, reduces BDNF ex-The neurotrophic or protective effect of atypicalpression.[139] In an animal model, coadministration

antipsychotics was also recently proven in humans of dizocilpine with haloperidol amplifies this reduc-by promising results from a magnetic resonancetion; olanzapine, on the other hand, normalises theimaging study. Patients with first-episode psychosisdizocilpine-induced decrease in expression ofwere treated by haloperidol or olanzapine and fol-BDNF.[140] When considering the effects of atypicallowed-up for up to 2 years. A significantly lowerantipsychotics, it is noteworthy that 5-HT2A recep-whole brain grey matter volume reduction wastor antagonism itself leads to a higher production offound after olanzapine treatment compared with af-BDNF,[134,141,142] and that, conversely, D2 receptorter haloperidol treatment. A lower reduction in greyantagonism reduces BDNF.[143] This explains thematter volume was detected in the frontal, temporal

BDNF-stimulating effect of olanzapine. Risper-and parietal cortical regions after 24 weeks, al-

idone is also a strong 5-HT2A receptor antagonist,though after 104 weeks this effect was apparent only

in the parietal cortex.[137,138] but because of its very high affinity for D2 receptors,



15/21


its D2 receptor-mediated suppression of BDNF may more towards a causal therapeutic influence on the

assumed causes of schizophrenic psychosis.prevail. Therefore, the effect of risperidone is simi-

lar to that of haloperidol and thus BDNF is reduced. The current hot topic concerning the neuroplas-

This speculation is supported by the finding that for tic effects of antipsychotics is whether antipsychot-

very low doses of risperidone, when the 5-HT2A ics may, like antidepressant drugs,[154] induce

receptor blockade prevails over the unsaturated D2 neurogenesis (development of new neurons). It has

receptor blockade, risperidone loses its BDNF-re- been demonstrated that in the gerbil hippocampus,

short-term haloperidol treatment can induce mitoticducing effect or does not change the BDNF lev-

activity.[155] But for the evaluation of the clinicalel.[144]

relevance of neurogenesis, chronic treatment isQuetiapine has also been shown to have an effectmore pertinent. It has been shown that 34 weeks ofon BDNF. Quetiapine blocks the stress-induced re-treatment with clozapine,[156] quetiapine[157] andduction of BDNF[145] and induces the expression ofolanzapine,[158] but not with haloperidol, induces anBDNF and another trophic factor (fibroblast growthincrease in the number of cells positive forfactor-2) when coadministered with dizocilpine,[146]bromodeoxyuridine (a marker of DNA synthesis) inand is probably similar in this respect to olanzapine.the rat dentate gyrus and (olanzapine only) in the

Both phosphorylation of NMDA receptors and prefrontal cortex.[159] However, the further study[160]induction of growth factors (NGF and BDNF) play a did not detect any change in the total number ofrole in the development of new synapses or their newly dividing cells in the dentate gyrus after sub-remodelling;[95] in this way, antipsychotic drugs chronic haloperidol or clozapine treatment, and evenmay therapeutically influence the deficit of in the studies with positive results, the newly gener-neurodevelopment linked with the reduction of syn- ated neurons did not survive for many weeks follow-aptic connections.[145] This mechanism, however, ing bromodeoxyuridine administration.[156,159]can lead to neurotoxic damage in the case of

The idea that atypical antipsychotics could in-haloperidol,[138,147] caused by extensive facilitation

duce neurogenesis is attractive with respect to theof NMDA receptors and excessive influx of calcium

cognitive and emotional clinical effects of theseinto neurons.[95] The macroscopic results consist of a

drugs,[161] but the results are inconclusive and thereduction in the size of the basal ganglia and devel-

survival and physiological influence of newly divid-opment of tardive dyskinesia.[148,149]

ing cells in antipsychotic-treated adult individualsTherefore, according to current knowledge, some remains unresolved.

atypical antipsychotics (unlike haloperidol) increase

not only NGF but also BDNF. It is probable that 5. Conclusioninduction of neuroplastic changes by atypical

A summary of the hypothetical mechanisms ofantipsychotics occurs not only in the striatum but

action of atypical antipsychotics with respect to theiralso in other areas involved with the neurobiology ofinteractions and anatomical specificity is shown inschizophrenia.[95] This assumption may be sup-

figure 3 and table II.ported by the fact that, at present, early gene expres-

sion in the prefrontal cortex and other brain areas is The arguments supporting the key role of

primarily induced by atypical antipsychotics with a dopaminergic receptor blockade as the mechanism

simultaneous lower rate of gene expression changes of action of antipsychotics still unequivocally pre-

in the striatum compared with the conventional an- vail. However, the optimum orchestration of

tipsychotics.[150-153] This may explain the superior dopaminergic modulation during antipsychotic ther-

therapeutic effect of atypicals on the more subtle apy depends on adequate D2 receptor blockade, the

dimensions of psychopathology (negative, cognitive intensity and duration of the effect, and also on the

or possibly emotional symptoms). Influencing syn- regional distribution of the dopaminergic effect.

aptic plasticity shifts therapy with antipsychotics Serotonergic modulation through 5-HT2A, 5-HT1A



16/21

404 Horacek et al.

Table II. Hypothetical mechanisms involved in the action of atypical antipsychotics

Dopaminergic modulation

Blockade of D2 receptors: shared by all antipsychotics, optimal blockade is within 6575% of D2 receptors, leads to effectiveness with

preserved safety (EPS and hyperprolactinaemia)

Blockade of D1 receptors: D1 are localised in PFC, leads to therapeutic effect on negative and cognitive symptoms. D1 receptors

modulate activity of D2 receptors (potentiation of efficiency). D1 antagonism alone does not exert an antipsychotic effect

Blockade of D4 receptors: decreases catalepsy and induces dopamine release in the basal ganglia and PFC. D4 antagonism alone

does not exert an antipsychotic effect

Blockade of D2/D3 receptors: preferential antagonism of inhibitory D2 autoreceptors; increased striatal (lower risk of EPS) and

neocortical dopamine release (cognitive and negative symptoms). Blockade of D3 receptors in temporal cortex, leads to stereoselectivity

and efficacy on positive symptoms without induction of EPS

Rapid dissociation from D2 receptors (fast OFF): shorter duration of the drug binding to the D2 receptor is sufficient for anantipsychotic action but insufficient to induce EPS and hyperprolactinaemia (quetiapine and clozapine)

Partial D2 agonism: with aripiprazole, 3040% of intrinsic D2 receptor agonism in connection with high D2 blockade exerts an

antipsychotic effect with a low risk of EPS and hyperprolactinaemia

Serotonergic modulation

Blockade of 5-HT2A receptors: 5-HT2A receptors integrate cortical and subcortical inputs. Antagonism of 5-HT2A receptors blocks the

effect of NMDA antagonists and induces striatal and neocortical dopamine release

5-HT1A receptor agonism: induces dopamine release into the striatum and neocortex (analogous to 5-HT2A receptor blockade) and also

into limbic structures

Blockade of 5-HT2C receptors: induces neocortical dopamine release

Modulation of 5-HT2A, 5-HT1A and 5-HT2C receptors alone does not have an antipsychotic effect

Combined modulations

Blockade of 5-HT2A and D2 receptors: higher affinity for 5-HT2A receptors than for D2 receptors, leads to lower risk for EPS (SDA and

MARTA antipsychotics). 5-HT2A/D2 receptor antagonism increases dopamine release to the PFC and striatum (improvement in negative

and cognitive symptoms and lower EPS). Also valid for partial dopamine receptor agonism with 5-HT 2A antagonism (aripiprazole)

5-HT1A receptor agonism and blockade of D2 receptors: increases dopamine release to the PFC, striatum and limbic structures

Blockade of 5-HT2C receptors and blockade of D2 receptors: analogous to 5-HT2A receptor blockade or its facilitation

Blockade of -adrenoceptors and D2 receptors: 1-adrenoceptor antagonism decreases activity of serotonin projections, and in

combination with D2 receptor blockade would mimic/simulate 5-HT2A/D2 receptor antagonism. Similarly with 2-adrenoceptor

antagonism

Blockade of D2 receptors and interaction with muscarinic receptors: lower risk of EPS and probable pro-cognitive effect (acetylcholine

stimulation) [?]

Induction of neuroplasticity

Phosphorylation of receptors, potentiation of glutamate/glycine and induction of neuronal growth factors (NGF and BDNF):

reinforcement of NMDA receptor activity and development of new synapses or their remodelling

BDNF = brain-derived neurotrophic factor; EPS = extrapyramidal syndrome; MARTA = multi-acting receptor targeted antipsychotics; NGF =

nerve growth factor; PFC = prefrontal cortex; SDA = serotonin-dopamine antagonists.

and 5-HT2C receptors may accommodate the aim of patients treated with atypical antipsychotics in com-

higher dopamine output in the striatum and parison to patients treated with haloperidol but with

prefrontal cortex (figure 3). These mechanisms are the same occupancy of D2-like receptors in the

consistent with the proposed anatomically selective temporal cortex.[164,165] This theory has been im-

effect of atypical antipsychotics.[162,163] The concept peached by other authors, who suggest that it is the

of regional selectivity assumes that blockade of result of a methodological error caused by a non-

D2-like receptors in the limbic areas (temporal cor- equipotent dosage comparison between convention-

tex, thalamus) reduces positive symptoms with a al and atypical antipsychotics.[166,167] The effect on

minimal blockade of striatal D2 receptors, thereby negative and cognitive symptoms is induced by

minimising the incidence of EPS. This theory is dopamine output into the prefrontal cortex. In this

supported by neuroimaging studies, which found a area, dopamine may optimise information process-

lower occupancy of striatal D2-like receptors in ing or possibly compensate for information process-



17/21


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