Возможные механизмы антидепрессивного действия антипсихотиков второго поколения

Although the exact mechanism of SGAs for MDD has not yet been clearly elucidated, several plausible underlying mechanisms are listed as follows: modulation of crucial neurotransmitter receptors and transporters such as dopamine, serotonin and noreinephrine resulting in net effect of enhancement of such neurotransmitters' transmission, effects on sleep, alteration of various hormones (ACTH, sex hormones, etc.), modification of immune functions including modulation of inflammation process (cytokines, etc.), antioxidation process and modulation of neurotrophic factors (BDNF, etc).[13]

Specifically, the main pharmacological rationale of SGAs as an antidepressant augmentation would be based on their effects on monoamine transporters or receptors of crucial neurotransmitters such as serotonin, norepinephrine and dopamine, which are also the main target of contemporary antidepressants. The partial agonism at D2 and/or D3 receptors may increase dopamine neurotransmission at the prefrontal cortex. The increase in the dopamine concentration in the prefrontal cortex may be also indirectly related to the antidepressive effect of 5-HT1A receptor agonist.[14,15] The antidepressant effect may also be mediated by 5-HT1A partial agonism and/or antagonism at 5-HT2A receptors.[16–18] Although, still controversial, the antidepressant effect of 5-HT1A receptor agonists may be predominantly mediated by postsynaptic 5-HT1A receptors, while the anxiolytic effect would be mainly associated with presynptic 5-HT1A receptors.[19] The antagonism of the 5-HT2C receptors has been also found to be involved in increased dopamine and norepinephrine transmission.[20] It is also well known that high affinity at the α2-adrenergic receptor may enhance the release of norepinephrine.[21] Unlike any other SGAs, ziprasidone was reported to block synaptic serotonin, norepinephrine and dopamine reuptake in vitro.[22,23] Evidence indicates that both 5-HT6 agonists and antagonists may evoke identical responses in animal models of MDD, although the possible mechanisms of these effects seem to be diverse and are not clearly understood. The augmented effects were notable by combining antidepressants with a selective 5-HT6 receptor antagonist.[24] There is also a considerable amount of evidence supporting a role for the 5-HT7 receptor in MDD. The blockade of the 5-HT7 receptor led to antidepressant-like effects in animal models of MDD. It should be also worthy to mention that augmentation of 5-HT7 receptor antagonists with antidepressants was remarkable in animal models of MDD.[25]

Another mechanism involving in the action of SGAs should be the alteration of the glutamate receptor activity, and thus restoring normal glutamatergic neurotransmission and reducing the chances of excitotoxicity.[26] Some SGA treatment may also cause a decrease in plasma adrenocorticotropic hormone concentration and a normalization of HPA-axis dynamics.[27] An impaired neuroprotection has also been implicated in the pathophysiology of MDD.[28,29] Interestingly, activation of the 5-HT1A receptors was shown to be neuroprotective against various brain insults such as N-methyl-daspartic acid.[30] Some SGAs have also demonstrated such neuroprotective effects indicating a potential role in the protection against excitotoxicity in vivo.[30]

Overall 5-HT2A antagonism should be a commonly shared biological relevance for most of the SGAs as a potential mechanism of their antidepressant effect. Interactive effects with the dopaminergic system may be more distinct with the action mechanism of amisulpride and aripiprazole, while norepinephrine- and/or serotonin-reuptake inhibition should be the unique case with quetiapine or ziprasidone.[31] Each antipsychotic has a distinct profile of affinities towards different neurotransmitter receptors, which should be associated mainly with mediation of antidepressant-like effects.

Second-generation Antipsychotics in the Treatment of Major Depressive Disorder