Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia

Abstract

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.

Contrasting Effects of Increased and Decreased Dopamine Transmission on Latent Inhibition in Ovariectomized Rats and Their Modulation by 17β-Estradiol: An Animal Model of Menopausal Psychosis?

“…Moreover, LI disruption in amphetamine-treated OVX rats is more resistant to APDs because in the previous study, clozapine was effective at the 5 mg/kg dose. These results support our previous conclusion that OVX-induced loss of estrogen reduces the potency of APDs, and further indicate that loss of estrogen coupled with hyperdopaminergia aggravates the loss of APDs efficacy so that not only typical but also atypical APDs, which are considered more effective antipsychotics in general (Horacek et al, 2006;Stone and Pilowsky, 2006) and in women in particular (de Leon et al, 2004), lose their efficacy. Failure of APDs to restore disrupted LI, and in particular the different efficacies of haloperidol and clozapine, in OVX rats, are of particular interest given that in male rats, reversal by both classes of APDs has characterized to date all known instances of LI disruption, be they induced by pharmacological (Barak and Weiner, 2007;Russig et al, 2003), brain lesion (Coutureau et al, 1999;Weiner et al, 1996a), neurodevelopmental (Zuckerman et al, 2003), or parametric (Killcross et al, 1994b;Shadach et al, 1999;Weiner et al, 1996b) manipulations.…”

“…Women have a more favorable illness course during the reproductive years, characterized by later onset of symptoms, lower symptom severity, and better response to antipsychotic drug (APD) treatment (Agius et al, 2009;Angermeyer and Kuhn, 1988;Hafner, 2003;Hafner et al, 1989;Iacono and Beiser, 1992;Lindamer et al, 1997;Mortimer, 2007;Pregelj, 2009;Riecher-Rossler and Hafner, 2000;Salem and Kring, 1998;Seeman, 1982Seeman, , 1986Szymanski et al, 1995;Tamminga, 1997). In contrast, menopause is associated with increased vulnerability to illness, elevated symptom severity, and reduced response to treatment (Horacek et al, 2006;Kulkarni et al, 1996Kulkarni et al, , 2008bLane et al, 1999;Salokangas, 1995;Saugstad, 1989;Seeman and Lang, 1990). Increased symptom severity and reduced treatment response are associated also with low-estrogen phases of the menstrual cycle (Ereshefsky et al, 1991;Farina et al, 1981;Lane et al, 1999;Salokangas, 1995;Seeman, 1989;Simpson et al, 1990;Tamminga, 1997).…”

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

“…Accumulated evidence suggests that D 2 R is the common target for all of current antipsychotics (Kapur et al, 1999, Kapur and Mamo, 2003, Seeman, 2011. On the other hand, it has been proposed that a relatively higher 5-HT 2A R affinity compared to the D 2 R is the mechanism underlying the therapeutic effects of SGAs (Meltzer et al, 2003, Horacek et al, 2006, Kuroki et al, 2008, Meltzer and Massey, 2011. Serotonin neurons are located in the raphe nuclei which broadly project to various brain regions and exert their actions via various types of 5-HT receptors (Millan et al, 2008).…”

“…Furthermore, the blockade of 5-HT 2A R by olanzapine could contribute to the 5-HTergic modulation on the nigrostriatal, mesolimbic or mesocortical dopaminergic pathways which affects dopaminergic output in the NAc, CPu, PFC and Cg (Van Oekelen et al, 2003, Horacek et al, 2006 and D 2 R mediated neurotransmission (Meltzer and Massey, 2011).…”

Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity

“…On the other hand, mice heterozygous for NRG-1 display abnormal prepulse inhibition of the startle response, a behavioral abnormality that is also found in schizophrenic patients and that can be alleviated by treatment with the antipsychotic clozapine, 4 that primarily targets D2-type dopamine receptors. 5,6 This prompted us to investigate a possible involvement of the dopamine system in mediating NRG-1-induced depotentiation.…”