LAUSR

The introduction of atypical, i.e. second generation, antipsychotics (AAPs) since the discovery of clozapine, has been a big step in schizophrenia treatment. They are ‘atypical’ as their clinical profile differs from typical (first-generation) antipsychotics. All AAPs share dopamine and serotonin receptor antagonism (except for amisulpride, which preferentially binds to dopamine D2/D3 receptors). Besides antagonism to the dopamine D2 receptor, the AAPs also block other dopamine receptors such as D1, D3, or D4 [1]. The serotonergic system modulates a broad spectrum of the central nervous system functions through 5-HT binding to 5-HT receptors. The overwhelming majority of research has focused on 5-HT2A receptors antagonism. However, a variety of 5-HT receptors, such as 5-HT2A/2C, 5-HT1A, 5-HT3, 5-HT6, and 5-HT7 receptors, may contribute to the mechanisms of action of ‘atypicality’ [2]. For example, we have data indicating that 5-HT3 receptor antagonists (ondansentron) as adjunctive therapy can improve negative symptoms in schizophrenia [3]. Other molecular targets are also relevant for further AAPs characterization. Some AAPs act at adrenergic alpha 1/2, histamine (especially H1) and muscarinic receptors. Targeting glutamatergic neurotransmission may be also involved. Clinical characteristics of individual AAPs can be predicted according to their molecular profile [1]. The AAPs can be divided into four subgroups: firstly, compounds belonging to substituted benzamides that able to modulate dopaminergic neurons selectively and specifically. The first was sulpiride, which has been replaced in the clinic by amisulpride (synthesized 1978), a selective D2/D3 receptor antagonist. Secondly, a subgroup commonly called serotonin/dopamine antagonists. Risperidone (introduced in 1993), the first representative of this subgroup, has a relatively potent antagonism of 5HT2A receptors and relatively weaker antagonism of D2 receptors. Risperidone shows also high affinity for alfa adrenergic receptors. Thirdly, a subgroup of AAPs called multi-target AAPs has also certain affinity for other receptors (histamine, muscarinic); this profile may explain their higher propensity for metabolic side effects. Among these, clozapine has a unique position as the first prototypic AAP. It was developed in 1961, followed by the second representative of this subgroup olanzapine much later (1996). Clozapine remains the most effective antipsychotic. Its effect is mediated not only through dopamine receptors but also serotonergic, noradrenergic, and glutamatergic receptors. In addition to its effect in treatment-resistant schizophrenia, clozapine has shown a decrease of suicidality and substance use in patients with schizophrenia. Clozapine is also a suitable treatment option for psychoses associated with Parkinson diseases, and tardive dyskinesia [4]. Most recently, AAPs with novel dopamine D2/3 receptor partial agonist pharmacology have been advanced as ‘thirdgeneration’ antipsychotics. Also, the mode of action of partial dopamine receptor agonists involves serotonin receptor antagonism as well. These mechanisms allowed AAPs to bring significant relief to many patients not only in terms of hospitalization and reduction of symptoms severity but also in terms of safety [5]. The AAPs have become the drugs of choice not only in patients during their first psychotic break but they are also indicated for maintenance treatment. AAPs are prescribed also for affective disorders (depression and mania), and difficult-totreat behavioral problems in gerontoand pedopsychiatry. Historically, several lines of evidence support the hypothesis that serotonin system abnormalities play an important role in the pathogenesis and treatment of schizophrenia. The role of serotonin alterations in the pathophysiology of schizophrenia has long been suspected in view of the psychotogenic effects of serotonergic agonists and the therapeutic effects of 5 HT2 antagonists [2]. The current neurochemical hypothesis of schizophrenia is focusing on neurotransmitters (dopamine, serotonin, glutamate). The serotonin hypothesis attributes an important role to the hyperactivation of 5-HT2A receptors on glutamate neurons [5]. A close anatomical and functional relationship between 5-HT2A receptors and glutamatergic excitability supports the hypothesis that even 5-HT2A receptor antagonism alone could improve schizophrenia-like (psychotic) symptoms in disorders where dopaminergic antagonism is undesirable [6]. Following this idea, pimavanserin, a selective 5-HT2A receptor inverse