Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The 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.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors. Balancing presynaptic and postsynaptic D(2) receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors. Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (e.g. by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors. In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, 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 abnormalities and affect the core pathophysiological substrates for schizophrenia.

Prague Psychiatric Centre Prague Czech Republic

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J Clin Psychiatry. 1997;58 Suppl 10:22-7 PubMed

Prog Brain Res. 2004;146:151-65 PubMed

Psychopharmacology (Berl). 1997 Mar;130(2):152-8 PubMed

Synapse. 1994 Nov;18(3):241-60 PubMed

Am J Psychiatry. 1996 Apr;153(4):466-76 PubMed

Brain Res. 2005 Nov 23;1063(1):32-9 PubMed

Br J Pharmacol. 1998 Aug;124(7):1550-6 PubMed

Schizophr Bull. 1993;19(1):119-40 PubMed

Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):735-40 PubMed

Pharmacopsychiatry. 2000 Sep;33 Suppl 1:34-42 PubMed

Eur Arch Psychiatry Clin Neurosci. 1994;244(5):272-7 PubMed

Eur J Pharmacol. 2004 Oct 11;502(1-2):109-16 PubMed

J Neurosci Res. 2003 Jan 1;71(1):127-31 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1113-23 PubMed

Eur J Pharmacol. 1990 Feb 13;176(3):371-4 PubMed

Synapse. 2001 Mar 15;39(4):297-304 PubMed

J Neurosci. 2000 Jun 1;20(11):4011-20 PubMed

Am J Psychiatry. 2001 Mar;158(3):360-9 PubMed

Eur J Pharmacol. 2002 Apr 26;441(3):137-40 PubMed

Neurosci Lett. 2004 Feb 12;356(2):135-9 PubMed

Neurosci Lett. 1999 Feb 26;262(1):1-4 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1091-9 PubMed

J Nucl Med. 1996 Jul;37(7):1122-7 PubMed

Neuropsychopharmacology. 2002 Sep;27(3):430-41 PubMed

Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134B(1):76-8 PubMed

Arch Gen Psychiatry. 1997 Jun;54(6):567-72 PubMed

J Clin Psychopharmacol. 1997 Oct;17(5):377-89 PubMed

Neuropsychopharmacology. 1997 Sep;17(3):162-74 PubMed

Neuropsychopharmacology. 1996 Feb;14(2):87-96 PubMed

Arch Gen Psychiatry. 2003 Jan;60(1):69-77 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1101-11 PubMed

J Neural Transm (Vienna). 1998;105(2-3):317-27 PubMed

Trends Pharmacol Sci. 1994 Jul;15(7):264-70 PubMed

Psychopharmacology (Berl). 1988;94(1):1-7 PubMed

CNS Drugs. 2004;18(9):597-616 PubMed

Biol Psychiatry. 1991 Jan 15;29(2):159-75 PubMed

Lancet. 2003 May 10;361(9369):1581-9 PubMed

Psychopharmacology (Berl). 2000 Jan;148(1):22-3 PubMed

Int J Neuropsychopharmacol. 2000 Mar;3(1):13-25 PubMed

Arch Gen Psychiatry. 1995 Oct;52(10):805-18; discussion 819-20 PubMed

J Pharmacol Exp Ther. 1999 Feb;288(2):774-81 PubMed

J Psychopharmacol. 1997;11(1):24-5 PubMed

Brain Res. 1988 Sep 20;460(2):398-401 PubMed

Brain Res Bull. 2000 Jan 1;51(1):75-81 PubMed

J Psychiatry Neurosci. 2003 Jul;28(4):275-84 PubMed

Arch Gen Psychiatry. 2003 Jun;60(6):553-64 PubMed

Br J Pharmacol. 2000 Mar;129(5):1028-34 PubMed

Pharmacopsychiatry. 1998 Jul;31 Suppl 2:92-103 PubMed

Psychopharmacology (Berl). 1995 Oct;121(3):317-22 PubMed

Neuropsychopharmacology. 2002 Oct;27(4):672-83 PubMed

Brain Res. 2004 Jan 2;995(1):14-22 PubMed

Pharmacol Ther. 2003 Feb;97(2):153-79 PubMed

Br J Pharmacol. 1999 Feb;126(3):572-4 PubMed

Neuropharmacology. 2000 Sep;39(12):2318-28 PubMed

J Clin Pharmacol. 2001 Jul;41(S7):64S-71S PubMed

Arch Gen Psychiatry. 2000 Jan;57(1):65-73 PubMed

J Pharmacol Exp Ther. 1989 Oct;251(1):238-46 PubMed

J Psychopharmacol. 1997;11(2):123-31 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 1992;16(6):797-832 PubMed

Pol J Pharmacol. 2003 Mar-Apr;55(2):133-54 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1159-72 PubMed

Psychopharmacology (Berl). 2005 Apr;179(1):30-53 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1125-43 PubMed

Schizophr Res. 1999 Nov 30;40(2):87-99 PubMed

Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301 PubMed

J Neurosci Res. 2003 Jun 1;72(5):622-8 PubMed

Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 5;133B(1):97-100 PubMed

Brain Res. 2002 Nov 1;954(1):11-20 PubMed

J Pharmacol Exp Ther. 1994 Nov;271(2):1058-66 PubMed

Science. 2000 Mar 17;287(5460):2020-2 PubMed

Biol Psychiatry. 2004 Oct 15;56(8):570-80 PubMed

Psychopharmacology (Berl). 2004 Jun;174(1):54-64 PubMed

Int Clin Psychopharmacol. 1997 May;12 Suppl 2:S29-36 PubMed

Mol Pharmacol. 2001 Nov;60(5):1020-30 PubMed

Lancet. 1995 Feb 18;345(8947):456-7 PubMed

J Neurosci. 1985 Sep;5(9):2539-44 PubMed

Neuropsychopharmacology. 2004 Jul;29(7):1230-8 PubMed

J Neurochem. 2001 Mar;76(5):1521-31 PubMed

J Neural Transm (Vienna). 2004 Jan;111(1):91-100 PubMed

Brain Res. 2001 Jan 5;888(1):51-59 PubMed

Eur J Pharmacol. 1994 Jul 21;260(1):79-83 PubMed

Neuropharmacology. 1998 Jul;37(7):953-5 PubMed

Eur J Pharmacol. 2000 Aug 18;402(1-2):39-44 PubMed

Am J Psychiatry. 2003 Aug;160(8):1413-20 PubMed

Biol Psychiatry. 2001 Dec 1;50(11):825-44 PubMed

Br J Psychiatry. 2002 Sep;181:254-5; author reply 255 PubMed

Brain Res Bull. 2001 Nov 15;56(5):441-51 PubMed

Science. 1991 Feb 22;251(4996):947-50 PubMed

J Neurosci. 1997 Apr 15;17(8):2785-95 PubMed

J Psychiatry Neurosci. 2000 Mar;25(2):161-6 PubMed

Psychoneuroendocrinology. 2003 Jan;28 Suppl 1:9-26 PubMed

Can J Psychiatry. 2002 Feb;47(1):27-38 PubMed

J Psychiatry Neurosci. 1998 Mar;23(2):93-4 PubMed

Clin Neuropharmacol. 1992;15 Suppl 1 Pt A:468A-469A PubMed

Neuropsychopharmacology. 1996 Feb;14(2):105-110 PubMed

Neuroreport. 2004 Sep 15;15(13):2109-12 PubMed

Biol Psychiatry. 2001 Nov 15;50(10):729-42 PubMed

Psychiatry Res. 1991 Nov;40(3):157-66 PubMed

Exp Neurol. 1993 Aug;122(2):244-52 PubMed

Arch Gen Psychiatry. 2003 Jul;60(7):681-90 PubMed

Neuropsychopharmacology. 2004 Jun;29(6):1063-9 PubMed

J Neural Transm (Vienna). 1998;105(6-7):749-67 PubMed

Neuropsychopharmacology. 2003 Aug;28(8):1400-11 PubMed

Schizophr Res. 1999 Jan 4;35(1):51-68 PubMed

Dev Psychopathol. 2000 Summer;12(3):501-27 PubMed

Am J Psychiatry. 2004 Feb;161(2 Suppl):1-56 PubMed

Arch Gen Psychiatry. 2003 May;60(5):443-56 PubMed

Arch Gen Psychiatry. 1974 Jul;31(1):58-61 PubMed

Psychol Rev. 1992 Jan;99(1):45-77 PubMed

Drugs. 2004;64(7):701-23 PubMed

Arch Gen Psychiatry. 2005 Apr;62(4):361-70 PubMed

Synapse. 1997 Sep;27(1):79-82 PubMed

Compr Psychiatry. 1995 Mar-Apr;36(2):83-105 PubMed

J Neurosci Res. 2000 Jun 15;60(6):783-94 PubMed

Psychopharmacol Bull. 1989;25(3):390-2 PubMed

Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):11-26 PubMed

Am J Psychiatry. 1994 Oct;151(10):1430-6 PubMed

Lancet. 1995 Sep 23;346(8978):820-5 PubMed

Br J Psychiatry. 2001 Dec;179:503-8 PubMed

J Neurosci Res. 2002 Jul 1;69(1):72-9 PubMed

Nature. 1991 Apr 18;350(6319):610-4 PubMed

Psychopharmacology (Berl). 1994 Feb;114(1):31-8 PubMed

Trends Pharmacol Sci. 2001 May;22(5):229-32 PubMed

Synapse. 2000 Jun 1;36(3):205-21 PubMed

Curr Opin Neurobiol. 2002 Apr;12(2):223-9 PubMed

Biol Psychiatry. 1999 Nov 1;46(9):1181-91 PubMed

Naunyn Schmiedebergs Arch Pharmacol. 1999 Apr;359(4):280-7 PubMed

Brain Res. 2002 Aug 30;947(2):157-65 PubMed

Lancet. 2003 Sep 6;362(9386):798-805 PubMed

J Neural Transm (Vienna). 1998;105(4-5):365-96 PubMed

Eur Neuropsychopharmacol. 1995;5 Suppl:25-30 PubMed

CNS Drugs. 2004;18(4):251-67 PubMed

Curr Opin Investig Drugs. 2002 Jan;3(1):113-20 PubMed

Neuroscience. 1992;46(2):315-28 PubMed

Am J Psychiatry. 1999 Feb;156(2):286-93 PubMed

J Clin Psychiatry. 1994 Sep;55 Suppl B:53-6 PubMed

Eur J Pharmacol. 2004 Jan 1;483(1):45-53 PubMed

Arch Gen Psychiatry. 1994 Mar;51(3):199-214 PubMed

CNS Drugs. 2004;18(13):933-56 PubMed

Arch Gen Psychiatry. 2003 Oct;60(10):974-7 PubMed

Prog Neuropsychopharmacol Biol Psychiatry. 1996 May;20(4):659-71 PubMed

J Neural Transm (Vienna). 1997;104(8-9):867-74 PubMed

Am J Psychiatry. 2002 Feb;159(2):180-90 PubMed

Psychopharmacology (Berl). 2002 Jun;162(1):55-62 PubMed

Prog Neurobiol. 2001 Feb;63(3):241-320 PubMed

Brain Res. 2000 May 12;864(2):176-85 PubMed

Neuropsychopharmacology. 1992 Dec;7(4):261-84 PubMed

Gen Pharmacol. 1988;19(1):55-60 PubMed

BMJ. 2000 Dec 2;321(7273):1371-6 PubMed

Cochrane Database Syst Rev. 2000;(2):CD000966 PubMed

J Pharmacol Exp Ther. 2002 Jul;302(1):381-9 PubMed

Eur J Pharmacol. 1999 Mar 12;369(1):133-43 PubMed

J Pharmacol Exp Ther. 1997 Apr;281(1):582-8 PubMed

Curr Drug Targets CNS Neurol Disord. 2004 Jun;3(3):217-25 PubMed

Life Sci. 1993;52(5-6):441-8 PubMed

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Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy?

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Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing-study on P300 and mismatch negativity in healthy volunteers

Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task