Our article in this journal some 15 years ago focussed on the role of serotonin (5-HT) autoreceptors in the mechanism of action of antidepressant drugs. Specifically in this regard, the results were summarised of rat microdialysis studies carried out to examine: (a) the relative importance of 5-HT1A and 5-HT1B autoreceptors, including (b) possible regional variation, and (c) potential changes in autoreceptor responsiveness following chronic selective serotonin reuptake inhibitor administration. In the present reflection piece, I recap some of the key findings against a brief background and provide an account of their bearing within the context of subsequent endeavours in the antidepressant drug research and development field. I conclude by shortly commenting on selected topics relevant to novel, interesting advances and avenues for future research.
ArtigasF (1993) 5-HT and antidepressants: new views from microdialysis studies. Trends Pharmacol Sci14: 262.
3.
ArtigasFPerezVAlvarezE (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry51: 248–251.
4.
BetryCEtievantAPehrsonA. (2015) Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. Prog Neuropsychopharmacol Biol Psychiatry58: 38–46.
5.
BeyerCECremersTI (2008) Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin?Eur J Pharmacol580: 350–354.
6.
BlierPBergeronR (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol15: 217–222.
7.
BlierPde MontignyCChaputY (1987) Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression. J Clin Psychopharmacol7: 24S–35S.
8.
BooijLVan der DoesAJRiedelWJ (2003) Monoamine depletion in psychiatric and healthy populations: review. Mol Psychiatry8: 951–973.
9.
BoothmanLJMitchellSNSharpT (2006) Investigation of the SSRI augmentation properties of 5-HT2 receptor antagonists using in vivo microdialysis. Neuropharmacology50: 726–732.
10.
CalizoLHAkanwaAMaX. (2011) Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence. Neuropharmacology61: 524–543.
11.
CarlssonAWongDT (1997) Correction: a note on the discovery of selective serotonin reuptake inhibitors. Life Sci61: 1203.
12.
CliffordEMGartsideSEUmbersV. (1998) Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo. Br J Pharmacol124: 206–212.
13.
CremersTIde BoerPLiaoY. (2000) Augmentation with a 5-HT1A, but not a 5-HT1B receptor antagonist critically depends on the dose of citalopram. Eur J Pharmacol397: 63–74.
14.
CremersTIGiorgettiMBoskerFJ. (2004) Inactivation of 5-HT2C receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology29: 1782–1789.
15.
CremersTIReaKBoskerFJ. (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology32: 1550–1557.
16.
DawsonLA (2013) The discovery and development of vilazodone for the treatment of depression: a novel antidepressant or simply another SSRI?Expert Opin Drug Discov8: 1529–1539.
17.
DawsonLABromidgeSM (2008) 5-HT1 receptor augmentation strategies as enhanced efficacy: therapeutics for psychiatric disorders. Curr Top Med Chem8: 1008–1023.
18.
de GrooteLKlompmakersAAOlivierB. (2003a) An evaluation of the effect of NAS-181, a new selective 5-HT1B receptor antagonist, on extracellular 5-HT levels in rat frontal cortex. Naunyn Schmiedebergs Arch Pharmacol367: 89–94.
19.
de GrooteLKlompmakersAAOlivierB. (2003b) Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade. Psychopharmacology (Berl)167: 153–158.
20.
FriedEINesseRM (2015) Depression sum-scores don’t add up: why analyzing specific depression symptoms is essential. BMC Med13: 72.
21.
FriedEIBoschlooLvan BorkuloCD. (2015) Commentary: “Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression”. Front Psychiatry6: 117.
22.
GigliucciVO’DowdGCaseyS. (2013) Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology (Berl)228: 157–166.
23.
GobertARivetJMCistarelliL. (1997) Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935. J Neurochem68: 1159–1163.
24.
HajosMAllersKAJenningsK. (2007) Neurochemical identification of stereotypic burst-firing neurons in the rat dorsal raphe nucleus using juxtacellular labelling methods. Eur J Neurosci25: 119–126.
25.
HatzenbuhlerNTEvrardDAHarrisonBL. (2006) Synthesis and biological evaluation of novel compounds within a class of 3-aminochroman derivatives with dual 5-HT1A receptor and serotonin transporter affinity. J Med Chem49: 4785–4789.
26.
HieronymusFEmilssonJFNilssonS. (2015) Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Mol Psychiatry. Epub ahead of print 28April2015. DOI: 10.1038/mp.2015.53.
27.
HillegaartV (1991) Functional topography of brain serotonergic pathways in the rat. Acta Physiol Scand Suppl598: 1–54.
28.
HirschfeldRM (2000) History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry61 (Suppl 6): 4–6.
29.
HjorthS (1992a) Functional differences between ascending 5 HT systems. In: BradleyPBHandleySLCooperSJ. (eds) Serotonin, CNS Receptors and Brain Function. Oxford: Pergamon Press, pp. 203–218.
30.
HjorthS (1992b) (–)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol222: 121–127.
31.
HjorthS (1993) Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study. J Neurochem60: 776–779.
32.
HjorthS (1998a) In vivo rat brain microdialysis studies of the new 5-HT1A receptor antagonist robalzotan. Eur Neuropsychopharmacol8 (Suppl 2):S175 (P.171.113).
33.
HjorthS (1998b) In vivo rat brain microdialysis studies of the novel, selective 5 HT1B receptor antagonist NAS 181. Soc Neurosci Abstr24: 1109 (# 1438.1113).
34.
HjorthSCarlssonA (1986) Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors?Eur J Pharmacol129: 131–138.
35.
HjorthSSharpT (1991) Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis. Life Sci48: 1779–1786.
36.
HjorthSSharpT (1993) In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol. J Pharmacol Exp Ther265: 707–712.
37.
HjorthSBengtssonHJKullbergA. (2000) Serotonin autoreceptor function and antidepressant drug action. J Psychopharmacol14: 177–185.
38.
HjorthSWestlinDBengtssonHJ (1997) WAY100635-induced augmentation of the 5-HT-elevating action of citalopram: relative importance of the dose of the 5-HT1A (auto)receptor blocker versus that of the 5-HT reuptake inhibitor. Neuropharmacology36: 461–465.
39.
HughesZADawsonLA (2004) Differential autoreceptor control of extracellular 5-HT in guinea pig and rat: species and regional differences. Psychopharmacology (Berl)172: 87–93.
40.
HughesZAStarrKRScottCM. (2007) Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B. Psychopharmacology (Berl)192: 121–133.
41.
JainRChenDEdwardsJ. (2014) Early and sustained improvement with vilazodone in adult patients with major depressive disorder: post hoc analyses of two phase III trials. Curr Med Res Opin30: 263–270.
42.
KaufmanJDeLorenzoCChoudhuryS. (2016) The 5-HT1A receptor in major depressive disorder. Eur Neuropsychopharmacol26: 397–410.
LamersFBursteinMHeJP. (2012) Structure of major depressive disorder in adolescents and adults in the US general population. Br J Psychiatry201: 143–150.
45.
LiXMPerryKWWongDT (1999) Difference in the in vivo influence of serotonin1A autoreceptors on serotonin release in prefrontal cortex and dorsal hippocampus of the same rat treated with fluoxetine. Chin J Physiol42: 53–59.
46.
MarekGJCarpenterLLMcDougleCJ. (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology28: 402–412.
47.
MatzenLvan AmsterdamCRautenbergW. (2000) 5-HT reuptake inhibitors with 5-HT1B/1D antagonistic activity: a new approach toward efficient antidepressants. J Med Chem43: 1149–1157.
48.
MillanMJ (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther110: 135–370.
49.
MillanMJ (2014) On ‘polypharmacy’ and multi-target agents, complementary strategies for improving the treatment of depression: a comparative appraisal. Int J Neuropsychopharmacol17: 1009–1037.
50.
MolliverME (1987) Serotonergic neuronal systems: what their anatomic organization tells us about function. J Clin Psychopharmacol7: 3S–23S.
51.
MurroughJWNeumeisterA (2011) The serotonin 1B receptor: a new target for depression therapeutics?Biol Psychiatry69: 714–715.
52.
NuttDJ (2009) Beyond psychoanaleptics – can we improve antidepressant drug nomenclature?J Psychopharmacol23: 343–345.
53.
OficialdeguiAMMartinezJPerezS. (2000) Design, synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives as potential antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor antagonism. Farmaco55: 345–353.
54.
OstroffRBNelsonJC (1999) Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry60: 256–259.
55.
PehrsonALSanchezC (2015) Altered gamma-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des Devel Ther9: 603–624.
56.
PerezMPauwelsPJPallard-SigogneauI. (1998) Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors. Bioorg Med Chem Lett8: 3423–3428.
57.
PortellaMJde Diego-AdelinoJBallesterosJ. (2011) 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 Psychiatry72: 962–969.
58.
RomeroLArtigasF (1997) Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors. J Neurochem68: 2593–2603.
59.
RuheHGMasonNSScheneAH (2007) Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry12: 331–359.
60.
SanchezCAsinKEArtigasF (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther145: 43–57.
61.
ScattonBRouquierLBonventoG. (1991) Autoreceptor-mediated control of serotonin release in the rat brain in vivo. In: LangerSZGalzinAMCostentinJ (eds) Presynaptic Receptors and Neuronal Transporters. Oxford: Pergamon Press, pp. 75–78.
62.
ScorzaMCLlado-PelfortLOllerS. (2012) Preclinical and clinical characterization of the selective 5-HT1A receptor antagonist DU-125530 for antidepressant treatment. Br J Pharmacol167: 1021–1034.
63.
ScottCSoffinEMHillM. (2006) SB-649915, a novel, potent 5-HT1A and 5-HT1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue. Eur J Pharmacol536: 54–61.
64.
SegraveRNathanPJ (2005) Pindolol augmentation of selective serotonin reuptake inhibitors: accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression. Hum Psychopharmacol20: 163–174.
65.
SharpTBoothmanLRaleyJ. (2007) Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci28: 629–636.
66.
SharpTUmbersVGartsideSE (1997) Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo. Br J Pharmacol121: 941–946.
StahlSM (2013) Mechanism of action of ketamine. CNS Spectr18: 171–174.
69.
TakeuchiKKohnTJHonigschmidtNA. (2006) Advancestoward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5. Bioorg Med Chem Lett16: 2347–2351.
70.
ThaseME (2008) Are SNRIs more effective than SSRIs? A review of the current state of the controversy. Psychopharmacol Bull41: 58–85.
71.
VandermaelenCPAghajanianGK (1983) Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices. Brain Res289: 109–119.
72.
WalshBTSeidmanSNSyskoR. (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA287: 1840–1847.
73.
WatsonJMDawsonLA (2007) Characterization of the potent 5-HT1A/B receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy. CNS Drug Rev13: 206–223.
74.
WenXJWangLMLiuZL. (2014) Meta-analysis on the efficacy and tolerability of the augmentation of antidepressants with atypical antipsychotics in patients with major depressive disorder. Braz J Med Biol Res47: 605–616.
75.
WhaleRTeraoTCowenP. (2010) Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review. J Psychopharmacol24: 513–520.
76.
XuYHackettMCarterG. (2015) Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. Epub ahead of print 17November2015. DOI: 10.1093/ijnp/pyv124.
77.
YamanakaHYokoyamaCMizumaH. (2014) A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. Transl Psychiatry4: e342.
78.
YbemaCUndénFThorbergSO. (2003) Lack of anti-depressant efficacy of the selective 5-HT1A receptor antagonist NAD-299. Results from an 8-week placebo and paroxetine-controlled study. Eur Neuropsychopharmacol13 (Suppl 4): S189.
