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01-09-2013 | Leading Article

Serotonin 5-HT_1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research

Authors: Pau Celada, Analía Bortolozzi, Francesc Artigas

Published in: CNS Drugs | Issue 9/2013

Abstract

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-HT_1A receptor (5-HT_1A-R) function and the role of pre- and postsynaptic 5-HT_1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT_1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT_1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT_1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT_1A-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-HT_1A-Rs, thus reducing the effectiveness of the 5-HT_1A 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-HT_1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT_1A-Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT_1A-R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT_1A-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-HT_1A autoreceptors. Postsynaptic 5-HT_1A-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-HT_1A-Rs in binding assays, clozapine displays functional agonist properties at this receptor type in vivo. The stimulation of 5-HT_1A-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-HT_1A-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-HT_1A-Rs, together with full agonist properties at presynaptic 5-HT_1A autoreceptors, as well as their gastrointestinal side effects. The partial 5-HT_1A-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-HT_1A-R agonists with selectivity for postsynaptic 5-HT_1A-Rs may open new perspectives in the field.

Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21:718–79.PubMed

Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.PubMed

Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet. 1997;349:1498–504.PubMed

Ustun TB, Ayuso-Mateos JL, Chatterji S, et al. Global burden of depressive disorders in the year 2000. Br J Psychiatry. 2004;184:386–92.PubMed

Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.PubMed

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.PubMed

Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166:152–63.PubMed

Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31–41.PubMed

Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13:1102–7.PubMed

10.

Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.PubMed

11.

Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev. 1992;72:165–229.PubMed

12.

Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–152.PubMed

13.

Adell A, Celada P, Abellan MT, et al. Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei. Brain Res Brain Res Rev. 2002;39:154–80.PubMed

14.

Smythies J, Section V. Serotonin system. Int Rev Neurobiol. 2005;64:217–68.PubMed

15.

Oleskevich S, Descarries L. Quantified distribution of the serotonin innervation in adult rat hippocampus. Neuroscience. 1990;34:19–33.PubMed

16.

Beaudet A, Descarries L. The monoamine innervation of rat cerebral cortex: synaptic and nonsynaptic axon terminals. Neuroscience. 1978;3:851–60.PubMed

17.

Innis RB, Aghajanian GK. Pertussis toxin blocks 5-HT1A and GABAB receptor-mediated inhibition of serotonergic neurons. Eur J Pharmacol. 1987;143:195–204.PubMed

18.

Sprouse JS, Aghajanian GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987;1:3–9.PubMed

19.

Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse. 1987;1:470–80.PubMed

20.

Adell A, Artigas F. Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study. Naunyn Schmiedebergs Arch Pharmacol. 1991;343:237–44.PubMed

21.

Artigas F, Romero L, de Montigny C, et al. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci. 1996;19:378–83.PubMed

22.

Romero L, Artigas F. Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors. J Neurochem. 1997;68:2593–603.PubMed

23.

Celada P, Puig MV, Casanovas JM, et al. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci. 2001;21:9917–29.PubMed

24.

Ferres-Coy A, Santana N, Castane A et al. Acute 5-HT(1A) autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions. Psychopharmacology (Berl). 2012;225:61–74.

25.

Casanovas JM, Berton O, Celada P, et al. In vivo actions of the selective 5-HT1A receptor agonist BAY x 3702 on serotonergic cell firing and release. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:248–54.PubMed

26.

Sharp T, Bramwell SR, Grahame-Smith DG. 5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis. Br J Pharmacol. 1989;96:283–90.PubMed

27.

Adell A, Carceller A, Artigas F. In vivo brain dialysis study of the somatodendritic release of serotonin in the Raphe nuclei of the rat: effects of 8-hydroxy-2-(di-n-propylamino)tetralin. J Neurochem. 1993;60:1673–81.PubMed

28.

Gobert A, Lejeune F, Rivet JM, et al. Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats. J Pharmacol Exp Ther. 1995;273:1032–46.PubMed

29.

Casanovas JM, Lesourd M, Artigas F. The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain. Br J Pharmacol. 1997;122:733–41.PubMed

30.

Casanovas JM, Artigas F. Differential effects of ipsapirone on 5-hydroxytryptamine release in the dorsal and median raphe neuronal pathways. J Neurochem. 1996;67:1945–52.PubMed

31.

Hamon M, Nelson DL, Herbet A, et al. Multiple receptors for serotonin in the rat brain. Adv Biochem Psychopharmacol. 1980;21:223–33.PubMed

32.

Kia HK, Brisorgueil MJ, Hamon M, et al. Ultrastructural localization of 5-hydroxytryptamine1A receptors in the rat brain. J Neurosci Res. 1996;46:697–708.PubMed

33.

Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci. 1992;12:440–53.PubMed

34.

Pazos A, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res. 1985;346:205–30.PubMed

35.

Martinez D, Hwang D, Mawlawi O, et al. Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology. 2001;24:209–29.PubMed

36.

Sargent PA, Kjaer KH, Bench CJ, et al. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57:174–80.PubMed

37.

Santana N, Bortolozzi A, Serrats J, et al. Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2004;14:1100–9.PubMed

38.

de Almeida J, Mengod G. Serotonin 1A receptors in human and monkey prefrontal cortex are mainly expressed in pyramidal neurons and in a GABAergic interneuron subpopulation: implications for schizophrenia and its treatment. J Neurochem. 2008;107:488–96.PubMed

39.

Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167–202.PubMed

40.

Groenewegen HJ, Uylings HB. The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog Brain Res. 2000;126:3–28.PubMed

41.

Diaz-Mataix L, Scorza MC, Bortolozzi A, et al. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J Neurosci. 2005;25:10831–43.PubMed

42.

Astier B, Lambas SL, Souliere F, et al. In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity. Eur J Pharmacol. 2003;459:17–26.PubMed

43.

Hajos-Korcsok E, Sharp T. 8-OH-DPAT-induced release of hippocampal noradrenaline in vivo: evidence for a role of both 5-HT1A and dopamine D1 receptors. Eur J Pharmacol. 1996;314:285–91.PubMed

44.

Amargos-Bosch M, Bortolozzi A, Puig MV, et al. Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb Cortex. 2004;14:281–99.PubMed

45.

Warden MR, Selimbeyoglu A, Mirzabekov JJ, et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012;492:428–32.PubMed

46.

Andrade R, Malenka RC, Nicoll RA. A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science. 1986;234:1261–5.PubMed

47.

Rauly-Lestienne I, Lestienne F, Ailhaud MC, et al. Competitive interaction of 5-HT(1A) receptors with G-protein subtypes in CHO cells demonstrated by RNA interference. Cell Signal. 2011;23:58–64.PubMed

48.

Raymond JR, Mukhin YV, Gettys TW, et al. The recombinant 5-HT1A receptor: G protein coupling and signalling pathways. Br J Pharmacol. 1999;127:1751–64.PubMed

49.

Polter AM, Li X. 5-HT1A receptor-regulated signal transduction pathways in brain. Cell Signal. 2010;22:1406–12.PubMedCentralPubMed

50.

Puig MV, Artigas F, Celada P. Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. Cereb Cortex. 2005;15:1–14.PubMed

51.

Araneda R, Andrade R. 5-Hydroxytryptamine2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience. 1991;40:399–412.PubMed

52.

Ashby CR Jr, Edwards E, Wang RY. Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: an iontophoretic study. Synapse. 1994;17:173–81.PubMed

53.

Albert PR, Zhou QY, Van Tol HH, et al. Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene. J Biol Chem. 1990;265:5825–32.PubMed

54.

Albert PR, Francois BL. Modifying 5-HT1A Receptor Gene Expression as a New Target for Antidepressant Therapy. Front Neurosci. 2010;4:35.PubMedCentralPubMed

55.

Lemonde S, Turecki G, Bakish D, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci. 2003;23:8788–99.PubMed

56.

Kishi T, Yoshimura R, Fukuo Y, et al. The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2013;263:105–18.PubMed

57.

Czesak M, Le Francois B, Millar AM, et al. Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice. J Biol Chem. 2012;287:6615–27.PubMed

58.

Parsey RV, Ogden RT, Miller JM, et al. Higher serotonin 1A binding in a second major depression cohort: modeling and reference region considerations. Biol Psychiatry. 2010;68:170–8.PubMedCentralPubMed

59.

Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994;15:220–6.PubMed

60.

Hervas I, Vilaro MT, Romero L, et al. Desensitization of 5-HT(1A) autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635. Neuropsychopharmacology. 2001;24:11–20.PubMed

61.

Riad M, Zimmer L, Rbah L, et al. Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat. J Neurosci. 2004;24:5420–6.PubMed

62.

Sprouse JS, Aghajanian GK. Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology. 1988;27:707–15.PubMed

63.

Newman-Tancredi A, Martel JC, Assie MB, et al. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. Br J Pharmacol. 2009;156:338–53.PubMed

64.

Llado-Pelfort L, Assie MB, Newman-Tancredi A, et al. Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors. Br J Pharmacol. 2010;160:1929–40.PubMed

65.

Hajos M, Hajos-Korcsok E, Sharp T. Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat. Br J Pharmacol. 1999;126:1741–50.PubMed

66.

Borsini F, Ceci A, Bietti G, et al. BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol. 1995;352:283–90.PubMed

67.

Diaz-Mataix L, Artigas F, Celada P. Activation of pyramidal cells in rat medial prefrontal cortex projecting to ventral tegmental area by a 5-HT1A receptor agonist. Eur Neuropsychopharmacol. 2006;16:288–96.PubMed

68.

Llado-Pelfort L, Assie MB, Newman-Tancredi A, et al. In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat. Psychopharmacology (Berl). 2012;221:261–72.

69.

Llado-Pelfort L, Santana N, Ghisi V, et al. 5-HT1A receptor agonists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. Cereb Cortex. 2012;22:1487–97.PubMed

70.

Stockmeier CA, Shapiro LA, Dilley GE, et al. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci. 1998;18:7394–401.PubMed

71.

Neff CD, Abkevich V, Packer JC, et al. Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Mol Psychiatry. 2009;14:621–30.PubMed

72.

Artigas F, Perez V, Alvarez E. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry. 1994;51:248–51.PubMed

73.

Artigas F, Celada P, Laruelle M, et al. How does pindolol improve antidepressant action? Trends Pharmacol Sci. 2001;22:224–8.PubMed

74.

Perez V, Gilaberte I, Faries D, et al. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet. 1997;349:1594–7.PubMed

75.

Portella MJ, Diego-Adelino J, Ballesteros J, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry. 2011;72:962–9.PubMed

76.

Whale R, Terao T, Cowen P, et al. Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review. J Psychopharmacol. 2010;24:513–20.PubMed

77.

Bel N, Artigas F. Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse. 1993;15:243–5.PubMed

78.

Richardson-Jones JW, Craige CP, Guiard BP, et al. 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron. 2010;65:40–52.PubMedCentralPubMed

79.

Bortolozzi A, Castane A, Semakova J, et al. Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry. 2012;17:612–23.PubMed

80.

Page ME, Cryan JF, Sullivan A, et al. Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist. J Pharmacol Exp Ther. 2002;302:1220–7.PubMed

81.

Mork A, Pehrson A, Brennum LT, et al. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012;340:666–75.PubMed

82.

Haddjeri N, Blier P, de Montigny C. Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci. 1998;18:10150–6.PubMed

83.

Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry. 2003;53:193–203.PubMed

84.

Richardson-Jones JW, Craige CP, Nguyen TH, et al. Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. J Neurosci. 2011;31:6008–18.PubMedCentralPubMed

85.

Martin P, Beninger RJ, Hamon M, et al. Antidepressant-like action of 8-OH-DPAT, a 5-HT1A agonist, in the learned helplessness paradigm: evidence for a postsynaptic mechanism. Behav Brain Res. 1990;38:135–44.PubMed

86.

Carr GV, Lucki I. The role of serotonin receptor subtypes in treating depression: a review of animal studies. Psychopharmacology (Berl). 2011;213:265–87.

87.

Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev. 2005;29:547–69.PubMed

88.

Jacobs BL, van Praag H, Gage FH. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry. 2000;5:262–9.PubMed

89.

Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.PubMed

90.

Savitz J, Lucki I, Drevets WC. 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol. 2009;88:17–31.PubMedCentralPubMed

91.

Bhagwagar Z, Rabiner EA, Sargent PA, et al. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry. 2004;9:386–92.PubMed

92.

Ramboz S, Oosting R, Amara DA, et al. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci USA. 1998;95:14476–81.PubMed

93.

Heisler LK, Chu HM, Brennan TJ, et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci USA. 1998;95:15049–54.PubMed

94.

Mayorga AJ, Dalvi A, Page ME, et al. Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J Pharmacol Exp Ther. 2001;298:1101–7.PubMed

95.

Banasr M, Hery M, Printemps R, et al. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology. 2004;29:450–60.PubMed

96.

Scorza M, Llado-Pelfort L, Oller S, et al. Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment. Br J Pharmacol. 2012;167:1021–34.PubMed

97.

Lucas G, Rymar VV, Du J, et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron. 2007;55:712–25.PubMed

98.

Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther. 2013;137:119–31.PubMed

99.

Heiser JF, Wilcox CS. Serotonin 5-HT1A receptor agonists as antidepressants - Pharmacology rationale and evidence for efficacy. Cns Drugs. 1998;10:343–53.

100.

Stahl SM, Kaiser L, Roeschen J, et al. Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder: support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants. Int J Neuropsychopharmacol. 1998;1:11–8.PubMed

101.

Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243–52.PubMed

102.

Ansseau M, Pitchot W, Moreno AG, et al. Pilot-study of flesinoxan, a 5-Ht1A agonist, in major depression—effects on sleep rem latency and body-temperature. Human Psychopharmacol Clin Exp. 1993;8:279–83.

103.

Ayd FJ Jr. Lexicon of psychiatry, neurology, and the neuroscience. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2000.

104.

Newman-Tancredi A. Biased agonism at serotonin 5-HT1A receptors: preferential postsynaptic activity for improved therapy of CNS disorders. Neuropsychiatry. 2011;1:149–64.

105.

Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006. CD006115.

106.

Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clonazepam with paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. J Clin Psychiatry. 2004;65:244–8.PubMed

107.

Pollack MH, Simon NM, Zalta AK, et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 2006;59:211–5.PubMed

108.

Holmes A, Heilig M, Rupniak NM, et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci. 2003;24:580–8.PubMed

109.

Stein DJ, Seedat S. Unresolved questions about treatment-resistant anxiety disorders. CNS Spectr. 2004;9:715.PubMed

110.

Champoux M, Bennett A, Shannon C, et al. Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol Psychiatry. 2002;7:1058–63.PubMed

111.

Francis D, Diorio J, Liu D, et al. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science. 1999;286:1155–8.PubMed

112.

Francis DD, Szegda K, Campbell G, et al. Epigenetic sources of behavioral differences in mice. Nat Neurosci. 2003;6:445–6.PubMed

113.

Kalinichev M, Easterling KW, Plotsky PM, et al. Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharmacol Biochem Behav. 2002;73:131–40.PubMed

114.

Liu D, Diorio J, Day JC, et al. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci. 2000;3:799–806.PubMed

115.

Gleason G, Liu B, Bruening S, et al. The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci USA. 2010;107:7592–7.PubMed

116.

Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–31.PubMed

117.

Greenberg BD, Li Q, Lucas FR, et al. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet. 2000;96:202–16.PubMed

118.

Auerbach J, Geller V, Lezer S, et al. Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. Mol Psychiatry. 1999;4:369–73.PubMed

119.

Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–9.PubMed

120.

Neumeister A, Bain E, Nugent AC, et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. 2004;24:589–91.PubMed

121.

Nash JR, Sargent PA, Rabiner EA, et al. Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry. 2008;193:229–34.PubMed

122.

Lesch KP, Aulakh CS, Wolozin BL, et al. Serotonin (5-HT) receptor, 5-HT transporter and G protein-effector expression: implications for depression. Pharmacol Toxicol. 1992;71(Suppl 1):49–60.PubMed

123.

Lanzenberger RR, Mitterhauser M, Spindelegger C, et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry. 2007;61:1081–9.PubMed

124.

Lopez JF, Chalmers DT, Little KY, et al. A.E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry. 1998;43:547–73.PubMed

125.

Tauscher J, Bagby RM, Javanmard M, et al. Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers. Am J Psychiatry. 2001;158:1326–8.PubMed

126.

Sullivan GM, Oquendo MA, Simpson N, et al. Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety. Biol Psychiatry. 2005;58:947–54.PubMed

127.

Finn DA, Rutledge-Gorman MT, Crabbe JC. Genetic animal models of anxiety. Neurogenetics. 2003;4:109–35.PubMed

128.

Holmes A. Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci Biobehav Rev. 2001;25:261–73.PubMed

129.

Parks CL, Robinson PS, Sibille E, et al. Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci USA. 1998;95:10734–9.PubMed

130.

Lo IL, Gross C. Alpha-Ca²⁺/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice. J Neurosci. 2008;28:6250–7.

131.

Millan MJ. The neurobiology and control of anxious states. Prog Neurobiol. 2003;70:83–244.PubMed

132.

Gross C, Zhuang X, Stark K, et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature. 2002;416:396–400.PubMed

133.

Kusserow H, Davies B, Hortnagl H, et al. Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors. Brain Res Mol Brain Res. 2004;129:104–16.PubMed

134.

Bannerman DM, Rawlins JN, McHugh SB, et al. Regional dissociations within the hippocampus–memory and anxiety. Neurosci Biobehav Rev. 2004;28:273–83.PubMed

135.

Deacon RM, Bannerman DM, Rawlins JN. Anxiolytic effects of cytotoxic hippocampal lesions in rats. Behav Neurosci. 2002;116:494–7.PubMed

136.

Kjelstrup KG, Tuvnes FA, Steffenach HA, et al. Reduced fear expression after lesions of the ventral hippocampus. Proc Natl Acad Sci USA. 2002;99:10825–30.PubMed

137.

Sarnyai Z, Sibille EL, Pavlides C, et al. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc Natl Acad Sci USA. 2000;97:14731–6.PubMed

138.

Sibille E, Pavlides C, Benke D, et al. Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci. 2000;20:2758–65.PubMed

139.

Gordon JA, Lacefield CO, Kentros CG, et al. State-dependent alterations in hippocampal oscillations in serotonin 1A receptor-deficient mice. J Neurosci. 2005;25:6509–19.PubMed

140.

Adhikari A, Topiwala MA, Gordon JA. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron. 2010;65:257–69.PubMedCentralPubMed

141.

Malizia AL, Cunningham VJ, Bell CJ, et al. Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55:715–20.PubMed

142.

Bremner JD, Innis RB, White T, et al. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry. 2000;47:96–106.PubMed

143.

Bystritsky A, Pontillo D, Powers M, et al. Functional MRI changes during panic anticipation and imagery exposure. Neuroreport. 2001;12:3953–7.PubMed

144.

Dilger S, Straube T, Mentzel HJ, et al. Brain activation to phobia-related pictures in spider phobic humans: an event-related functional magnetic resonance imaging study. Neurosci Lett. 2003;348:29–32.PubMed

145.

Shah AA, Treit D. Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests. Brain Res. 2003;969:183–94.PubMed

146.

Singewald N, Salchner P, Sharp T. Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry. 2003;53:275–83.PubMed

147.

Bailey SJ, Toth M. Variability in the benzodiazepine response of serotonin 5-HT1A receptor null mice displaying anxiety-like phenotype: evidence for genetic modifiers in the 5-HT-mediated regulation of GABA(A) receptors. J Neurosci. 2004;24:6343–51.PubMed

148.

Bruening S, Oh E, Hetzenauer A, et al. The anxiety-like phenotype of 5-HT receptor null mice is associated with genetic background-specific perturbations in the prefrontal cortex GABA-glutamate system. J Neurochem. 2006;99:892–9.PubMed

149.

Burnet PWJ, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology. 1996;15:442–55.PubMed

150.

Burnet PWJ, Eastwood SL, Harrison PJ. [H-3]WAY-100635 for 5-HT1A receptor autoradiography in human brain: A comparison with [H-3]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int. 1997;30:565–74.PubMed

151.

Sumiyoshi T, Stockmeier CA, Overholser JC, et al. Serotonin(1A) receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res. 1996;708:209–14.PubMed

152.

Simpson MD, Lubman DI, Slater P, et al. Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT(1A) receptors in ventral prefrontal cortex in schizophrenia. Biol Psychiatry. 1996;39:919–28.PubMed

153.

Kasper S, Tauscher J, Willeit M, et al. Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette’s disorder—implications for psychopharmacology. World J Biol Psychiatry. 2002;3:133–46.PubMed

154.

Tauscher J, Kapur S, Verhoeff NPLG, et al. Brain serotonin 5-HT1A receptor binding in schizophrenia measured by positron emission tomography and [C-11]WAY-100635. Arch Gen Psychiatry. 2002;59:514–20.PubMed

155.

Yasuno F, Suhara T, Ichimiya T, et al. Decreased 5-HT1A receptor binding in amygdala of schizophrenia. Biol Psychiatry. 2004;55:439–44.PubMed

156.

Moessner R, Schuhmacher A, Kuehn KU, et al. Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet Genomics. 2009;19:91–4.

157.

Choi YK, Snigdha S, Shahid M, et al. Subchronic effects of phencyclidine on dopamine and serotonin receptors: implications for schizophrenia. J Mol Neurosci. 2009;38:227–35.PubMed

158.

Horiguchi M, Meltzer HY. The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats. Psychopharmacology (Berl). 2012;221:205–15.

159.

Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60:553–64.PubMed

160.

Leucht S, Wahlbeck K, Hamann J, et al. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361:1581–9.PubMed

161.

Farde L, Nordstrom AL, Wiesel FA, et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–44.PubMed

162.

Nordstrom AL, Farde L, Nyberg S, et al. D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry. 1995;152:1444–9.PubMed

163.

Artigas F. The prefrontal cortex: a target for antipsychotic drugs. Acta Psychiatr Scand. 2010;121:11–21.PubMed

164.

Vazquez-Borsetti P, Cortes R, Artigas F. Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex. 2009;19:1678–86.PubMed

165.

Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153:466–76.PubMed

166.

Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3:353–9.PubMed

167.

Rollema H, Lu Y, Schmidt AW, et al. Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Eur J Pharmacol. 1997;338:R3–5.PubMed

168.

Rollema H, Lu Y, Schmidt AW, et al. 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry. 2000;48:229–37.PubMed

169.

Millan MJ. Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J Pharmacol Exp Ther. 2000;295:853–61.PubMed

170.

Bortolozzi A, Masana M, Diaz-Mataix L, et al. Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors. Int J Neuropsychopharmacol. 2010;13:1299–314.PubMed

171.

Bantick RA, Deakin JFW, Grasby PM. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol. 2001;15:37–46.PubMed

172.

Meltzer HY, Sumiyoshi T. Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia? Behav Brain Res. 2008;195:98–102.PubMed

173.

Sumiyoshi T, Matsui M, Nohara S, et al. Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry. 2001;158:1722–5.PubMed

174.

Sumiyoshi T, Park S, Jayathilake K, et al. Effect of buspirone, a serotonin(1A) partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2007;95:158–68.PubMed

175.

Meneses A, Perez-Garcia G. 5-HT(1A) receptors and memory. Neurosci Biobehav Rev. 2007;31:705–27.PubMed

176.

Depoortere R, Auclair A, Bardin L, et al. F15063, a compound with D-2/D-3 antagonist, 5-HT1A agonist and D-4 partial agonist properties: (III) activity in models of cognition and negative symptoms. Br J Pharmacol. 2007;151:266–77.PubMed

177.

Depoortere R, Auclair AL, Bardin L, et al. F15599, a preferential post-synaptic 5-HT1A receptor agonist: Activity in models of cognition in comparison with reference 5-HT1A receptor agonists. Eur Neuropsychopharmacol. 2010;20:641–54.PubMed

178.

Ogren SO, Eriksson TM, Elvander-Tottie E, et al. The role of 5-HT1A receptors in learning and memory. Behav Brain Res. 2008;195:54–77.PubMed

179.

Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995;376:572–5.PubMed

180.

Sakai N, Tanaka C. Inhibitory modulation of long-term potentiation via the 5-HT1A receptor in slices of the rat hippocampal dentate gyrus. Brain Res. 1993;613:326–30.PubMed

181.

Mori K, Togashi H, Kojima T, et al. Different effects of anxiolytic agents, diazepam and 5-HT(1A) agonist tandospirone, on hippocampal long-term potentiation in vivo. Pharmacol Biochem Behav. 2001;69:367–72.PubMed

182.

Sanberg CD, Jones FL, Do VH, et al. 5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments. Learn Mem. 2006;13:52–62.PubMed

183.

Tachibana K, Matsumoto M, Togashi H, et al. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors. Neurosci Lett. 2004;357:91–4.PubMed

184.

Huang CC, Liang YC, Hsu KS. A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci. 1999;19:9728–38.PubMed

185.

Kojima T, Matsumoto M, Togashi H, et al. Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors. Brain Res. 2003;959:165–8.PubMed

186.

Winstanley CA, Dalley JW, Theobald DE, et al. Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats. Psychopharmacology (Berl). 2003;170:320–31.

187.

Yasuno F, Suhara T, Nakayama T, et al. Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory. Am J Psychiatry. 2003;160:334–40.PubMed

188.

Invernizzi RW, Cervo L, Samanin R. 8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis. Neuropharmacology. 1988;27:515–8.PubMed

189.

Goff DC, Midha KK, Brotman AW, et al. An open trial of buspirone added to neuroleptics in schizophrenic-patients. J Clin Psychopharmacol. 1991;11:193–7.PubMed

190.

Piskulic D, Olver JS, Maruff P, et al. Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist. Hum Psychopharmacol. 2009;24:437–46.PubMed

191.

Sirota P, Epstein B, Benatov R, et al. An open study of buspirone augmentation of neuroleptics in patients with schizophrenia. J Clin Psychopharmacol. 2001;21:454–5.PubMed

192.

Newman-Tancredi A, Chaput C, Verriele L, et al. Clozapine is a partial agonist at cloned, human serotonin 5-HT1A receptors. Neuropharmacology. 1996;35:119–21.PubMed

193.

Chou YH, Halldin C, Farde L. Occupancy of 5-HT1A receptors by clozapine in the primate brain: a PET study. Psychopharmacology. 2003;166:234–40.PubMed

194.

Assie MB, Cosi C, Koek W. 5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine. Eur J Pharmacol. 1997;334:141–7.PubMed

195.

Heusler P, Newman-Tancredi A, Loock T, et al. Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells. Eur J Pharmacol. 2008;581:37–46.PubMed

196.

Ichikawa J, Ishii H, Bonaccorso S, et al. 5-HT2A and D-2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:1521–31.PubMed

197.

Bortolozzi A, Diaz-Mataix L, Toth M, et al. In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacology (Berl). 2007;191:745–58.PubMed

198.

Newman-Tancredi A, Kleven MS. Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. Psychopharmacology (Berl). 2011;216:451–73.

199.

Lacivita E, Leopoldo M, Berardi F, et al. 5-HT1A receptor, an old target for new therapeutic agents. Curr Top Med Chem. 2008;8:1024–34.PubMed

200.

Takei A, Hamada T, Yabe I, et al. Treatment of cerebellar ataxia with 5-HT1A agonist. Cerebellum. 2005;4:211–5.PubMed

201.

Ohno Y. Therapeutic role of 5-HT1A receptors in the treatment of schizophrenia and Parkinson’s disease. CNS Neurosci Ther. 2011;17:58–65.PubMed

202.

Maurel JL, Autin JM, Funes P, et al. High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity. J Med Chem. 2007;50:5024–33.PubMed

Title: Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research
Authors: Pau Celada
Analía Bortolozzi
Francesc Artigas
Publication date: 01-09-2013
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 9/2013
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.1007/s40263-013-0071-0

Keynote webinar | Spotlight on medication adherence

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Serotonin 5-HT_1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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