Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders


Abstract

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.

Keywords: adenosine; atypical antipsychotics; dopamine; histamine; mechanism of action; norepinephrine; receptor pharmacology; serotonin; trace amines.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Receptor-binding profile of antipsychotic drugs. Typical antipsychotics (A) act almost exclusively as blockers of dopamine-2 (D2) receptors. All contemporary atypical antipsychotic drugs (B) are characterized by serotonin-2A (5-HT2A) antagonistic property, comparable to or even higher than their D2 blocking potential. Some atypical antipsychotics are also potent serotonin-1A (5-HT1A; aripiprazole), serotonin-1C (5-HT1C; clozapine, olanzapine, risperidone), histamine-1 (H1; olanzapine, quetiapine) and α1-(aripiprazole, clozapine, olanzapine, paliperidone, quetiapine) and α2-adrenergic (clozapine, olanzapine, paliperidone, quetiapine, risperidone) receptor blockers. Future drugs with dual antipsychotic and antidepressant therapeutic potential (C) may also target trace amine-associated receptor-1 (TAAR1), as well as histamine-3 (H1) and adenosine-2A (A2A) receptors.
Figure 2
Figure 2
Serotonergic augmentation of the selective serotonin reuptake inhibitors (SSRI) escitalopram response by the atypical antipsychotic drug paliperidone. Effect of the subchronic (a) and chronic (b) risperidone or paliperidone, alone or in combination with escitalopram, on the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN). The animals were implanted with minipumps containing the vehicle or escitalopram (10 mg/kg/day) for two or fourteen days and received the subcutaneous vehicle, risperidone or paliperidone injections (1 mg/kg each). After two days, there was a significant effect of escitalopram (Fdf1243 = 26.16, p < 0.001), risperidone and paliperidone (Fdf2243 = 3.99, p < 0.05), and escitalopram?×?risperidone/paliperidone interaction (Fdf2243 = 3.93, p < 0.05). After fourteen days, there was a significant effect of risperidone and paliperidone (Fdf2221 = 6.61, p < 0.01). The number of neurons recorded in each group is provided within the histograms. ** p < 0.01 and *** p < 0.001 in comparison with control animals. From Dremencov et al. 2007 [38]. Reused by permission of Springer Nature.
Figure 3
Figure 3
Noradrenergic augmentation of the SSRI escitalopram response by the atypical antipsychotic drug risperidone. The animals were implanted with minipumps containing vehicle or escitalopram (10 mg/kg/day; the main treatment) for two days and were subcutaneously (s.c.) co-treated with vehicle, risperidone (1 mg/kg/day), SB 242084 (0.5 mg/kg/day), haloperidol (0.1 mg/kg/day), M100907 (0.5 mg/kg/day), or idazoxan (1 mg/kg/day; co-treatments) for two days. Two-way ANOVA showed a significant effect of the main treatment (Fdf1486 = 5.41, p < 0.05), of the co-treatment (Fdf5486 = 17.18, p < 0.001), and treatment × co-treatment interaction (Fdf5486 = 11.07, p < 0.001). * p < 0.01, in comparison with control animals and # p < 0.05, in comparison with animals administered escitalopram alone, Bonferroni post hoc test. The number of neurons recorded in each group is provided within the histograms. From Dremencov et al. 2007 [61]. Reused by permission of Elsevier.
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