Psychiatric disorders represent a large economic burden in modern societies. 
However, pharmacological treatments are still far from optimal. Drugs used in 
the treatment of major depressive disorder (MDD) and anxiety disorders 
(selective serotonin [5-HT] reuptake inhibitors [SSRIs] and 
serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological 
refinements of first-generation tricyclic drugs, discovered by serendipity, and 
show low efficacy and slowness of onset. Moreover, antipsychotic drugs are 
partly effective in positive symptoms of schizophrenia, yet they poorly treat 
negative symptoms and cognitive deficits. The present article reviews the 
neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of 
pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic 
disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas 
appears beneficial for the therapeutic action of antidepressant drugs. However, 
presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with 
high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood 
disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the 
indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron 
activity and terminal 5-HT release, thus opposing the elevation of extracellular 
5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. 
Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus 
reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative 
feedback. The prevention of this process by the non-selective partial agonist 
pindolol accelerates clinical antidepressant effects. Two new antidepressant 
drugs, vilazodone (marketed in the USA) and vortioxetine (in development) 
incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several 
studies with transgenic mice have also established the respective role of pre- 
and postsynaptic 5-HT1A-Rs in MDD and anxiety. In agreement with pharmacological 
studies, presynaptic and postsynaptic 5-HT1A-R activation appears necessary for 
anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental 
roles for 5-HT1A-Rs are also involved. Likewise, the use of small interference 
RNA has enabled the showing of robust antidepressant-like effects in mice after 
selective knock-down of 5-HT1A autoreceptors. Postsynaptic 5-HT1A-Rs in the 
prefrontal cortex (PFC) also appear important for the superior clinical effects 
of clozapine and other second-generation (atypical) antipsychotic drugs in the 
treatment of schizophrenia and related psychotic disorders. Despite showing a 
moderate in vitro affinity for 5-HT1A-Rs in binding assays, clozapine displays 
functional agonist properties at this receptor type in vivo. The stimulation of 
5-HT1A-Rs in the PFC leads to the distal activation of the mesocortical pathway 
and to an increased dopamine release in PFC, an effect likely involved in the 
clinical actions of clozapine in negative symptoms and cognitive deficits in 
schizophrenia. The anxiolytic/antidepressant properties of 5-HT1A-R agonists in 
preclinical tests raised expectations enormously. However, these agents have 
achieved little clinical success, possibly due to their partial agonist 
character at postsynaptic 5-HT1A-Rs, together with full agonist properties at 
presynaptic 5-HT1A autoreceptors, as well as their gastrointestinal side 
effects. The partial 5-HT1A-R agonists buspirone, gepirone, and tandospirone are 
marketed as anxiolytic drugs, and buspirone is also used as an augmentation 
strategy in MDD. The development of new 5-HT1A-R agonists with selectivity for 
postsynaptic 5-HT1A-Rs may open new perspectives in the field.