Advertisement

BRAIN SEROTONIN RELEASE IS REDUCED IN PATIENTS WITH DEPRESSION: A [11C]Cimbi-36 PET STUDY WITH A D-AMPHETAMINE CHALLENGE.

      Abstract

      INTRODUCTION

      The “serotonin hypothesis” of depression proposes that a diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We have recently demonstrated that the 5-HT2A receptor (5-HR2A-R) agonist PET radioligand, [11C]Cimbi-36, is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge (
      • Erritzoe D.
      • Ashok A.H.
      • Searle G.E.
      • Colasanti A.
      • Turton S.
      • Lewis Y.
      • et al.
      Serotonin release measured in the human brain: a PET study with [(11)C]CIMBI-36 and d-amphetamine challenge.
      ). Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity (SRC) in patients undergoing a major depressive episode (MDE) to that of non-depressed healthy controls (HC).

      METHODS

      Seventeen antidepressant-free patients with MDE (14m/3f, 44±13 y.o., HAM-D: 21±4 (16-30)) and 20 HC (17m/3f, 32±9 y.o.), underwent 90 min dynamic [11C]Cimbi-36 PET before (PET-1) and 3 hours after (PET-2) a 0.5mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A-R non-displaceable binding was calculated from kinetic analysis using the multilinear analysis-1 (MA1) approach with the cerebellum as the reference region.

      RESULTS

      Following d-amphetamine administration, frontal BPND was significantly reduced in the HC group (1.04±0.31 vs 0.87±0.24 , p < 0.001) but not in MDE (0.97 ± 0.25 vs 0.92 ± 0.22, ns). ΔBPND of the MDE group was significantly lower than that of the HC (HC: 15±14% vs MDE: 6.5±20%, p=0.038).

      CONCLUSIONS

      This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating a reduced 5-HT release capacity in patients undergoing a major depressive episode.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Erritzoe D.
        • Ashok A.H.
        • Searle G.E.
        • Colasanti A.
        • Turton S.
        • Lewis Y.
        • et al.
        Serotonin release measured in the human brain: a PET study with [(11)C]CIMBI-36 and d-amphetamine challenge.
        Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2020; 45: 804-810
        • Global Burden of Disease Study C
        Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2015; 386: 743-800
        • Gartlehner G.
        • Hansen R.A.
        • Morgan L.C.
        • Thaler K.
        • Lux L.
        • Van Noord M.
        • et al.
        Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.
        Annals of internal medicine. 2011; 155: 772-785
        • Gaynes B.N.
        • Warden D.
        • Trivedi M.H.
        • Wisniewski S.R.
        • Fava M.
        • Rush A.J.
        What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression.
        Psychiatric services. 2009; 60: 1439-1445
        • Delgado P.L.
        Monoamine depletion studies: implications for antidepressant discontinuation syndrome.
        The Journal of clinical psychiatry. 2006; 67: 22-26
        • Shaw D.M.
        • Camps F.E.
        • Eccleston E.G.
        5-Hydroxytryptamine in the hind-brain of depressive suicides.
        The British journal of psychiatry : the journal of mental science. 1967; 113: 1407-1411
        • Cowen P.J.
        • Browning M.
        What has serotonin to do with depression?.
        World psychiatry : official journal of the World Psychiatric Association. 2015; 14: 158-160
        • Artigas F.
        • Nutt D.J.
        • Shelton R.
        Mechanism of action of antidepressants.
        Psychopharmacol Bull. 2002; 36: 123-132
        • Shopsin B.
        • Gershon S.
        • Goldstein M.
        • Friedman E.
        • Wilk S.
        Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients.
        Psychopharmacology communications. 1975; 1: 239-249
        • Shopsin B.
        • Friedman E.
        • Gershon S.
        Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients.
        Archives of general psychiatry. 1976; 33: 811-819
        • Smith K.A.
        • Fairburn C.G.
        • Cowen P.J.
        Relapse of depression after rapid depletion of tryptophan.
        Lancet. 1997; 349: 915-919
        • Delgado P.L.
        • Miller H.L.
        • Salomon R.M.
        • Licinio J.
        • Krystal J.H.
        • Moreno F.A.
        • et al.
        Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action.
        Biological psychiatry. 1999; 46: 212-220
        • Ruhe H.G.
        • Mason N.S.
        • Schene A.H.
        Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies.
        Molecular psychiatry. 2007; 12: 331-359
        • Dan R.
        • Ruzicka F.
        • Bezdicek O.
        • Ruzicka E.
        • Roth J.
        • Vymazal J.
        • et al.
        Separate neural representations of depression, anxiety and apathy in Parkinson's disease.
        Scientific reports. 2017; 712164
        • Pagano G.
        • Niccolini F.
        • Fusar-Poli P.
        • Politis M.
        Serotonin transporter in Parkinson's disease: A meta-analysis of positron emission tomography studies.
        Annals of neurology. 2017; 81: 171-180
        • Braak H.
        • Del Tredici K.
        • Rub U.
        • de Vos R.A.
        • Jansen Steur E.N.
        • Braak E.
        Staging of brain pathology related to sporadic Parkinson's disease.
        Neurobiology of aging. 2003; 24: 197-211
        • Jorgensen L.M.
        • Henriksen T.
        • Mardosiene S.
        • Keller S.H.
        • Stenbaek D.S.
        • Hansen H.D.
        • et al.
        Parkinson patients have a presynaptic serotonergic deficit: A dynamic deep brain stimulation PET study.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021; 41: 1954-1963
        • Moncrieff J.
        • Cooper R.E.
        • Stockmann T.
        • Amendola S.
        • Hengartner M.P.
        • Horowitz M.A.
        The serotonin theory of depression: a systematic umbrella review of the evidence.
        Molecular psychiatry. 2022;
        • Jorgensen L.M.
        • Weikop P.
        • Villadsen J.
        • Visnapuu T.
        • Ettrup A.
        • Hansen H.D.
        • et al.
        Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016;
        • Finnema S.J.
        • Scheinin M.
        • Shahid M.
        • Lehto J.
        • Borroni E.
        • Bang-Andersen B.
        • et al.
        Application of cross-species PET imaging to assess neurotransmitter release in brain.
        Psychopharmacology. 2015; 232: 4129-4157
        • Shotbolt P.
        • Tziortzi A.C.
        • Searle G.E.
        • Colasanti A.
        • van der Aart J.
        • Abanades S.
        • et al.
        Within-subject comparison of [(11)C]-(+)-PHNO and [(11)C]raclopride sensitivity to acute amphetamine challenge in healthy humans.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2012; 32: 127-136
      1. Erritzoe D. CA, Searle G., Lewis Y., Passchier J., Azeem S., Beaver J., Nutt D., Knudsen G., Gunn R., Rabiner E. (2017): Serotonin release measured in the human brain: A PET study with [11C]Cimbi-36 and d-amphetamine challenge. BrainPET 2017. Berlin, Germany.

        • Heal D.J.
        • Cheetham S.C.
        • Prow M.R.
        • Martin K.F.
        • Buckett W.R.
        A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents.
        British journal of pharmacology. 1998; 125: 301-308
        • Kuczenski R.
        • Segal D.S.
        • Cho A.K.
        • Melega W.
        Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 1995; 15: 1308-1317
        • Yang K.C.
        • Takano A.
        • Halldin C.
        • Farde L.
        • Finnema S.J.
        Serotonin concentration enhancers at clinically relevant doses reduce [(11)C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain.
        Translational psychiatry. 2018; 8: 132
        • Kehr J.
        • Ichinose F.
        • Yoshitake S.
        • Goiny M.
        • Sievertsson T.
        • Nyberg F.
        • et al.
        Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats.
        British journal of pharmacology. 2011; 164: 1949-1958
        • Nejati V.
        • Majdi R.
        • Salehinejad M.A.
        • Nitsche M.A.
        The role of dorsolateral and ventromedial prefrontal cortex in the processing of emotional dimensions.
        Scientific reports. 2021; 11: 1971
        • Pizzagalli D.A.
        • Roberts A.C.
        Prefrontal cortex and depression.
        Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2022; 47: 225-246
        • Hamilton M.
        Development of a rating scale for primary depressive illness.
        Br J Soc Clin Psychol. 1967; 6: 278-296
        • Ichise M.
        • Toyama H.
        • Innis R.B.
        • Carson R.E.
        Strategies to improve neuroreceptor parameter estimation by linear regression analysis.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2002; 22: 1271-1281
        • Tukey J.W.
        Some thoughts on clinical trials, especially problems of multiplicity.
        Science. 1977; 198: 679-684
        • Beliveau V.
        • Ganz M.
        • Feng L.
        • Ozenne B.
        • Hojgaard L.
        • Fisher P.M.
        • et al.
        A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2017; 37: 120-128
        • Ettrup A.
        • Svarer C.
        • McMahon B.
        • da Cunha-Bang S.
        • Lehel S.
        • Moller K.
        • et al.
        Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: Test-retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin.
        NeuroImage. 2016; 130: 167-174
        • Toll L.
        • Berzetei-Gurske I.P.
        • Polgar W.E.
        • Brandt S.R.
        • Adapa I.D.
        • Rodriguez L.
        • et al.
        Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications.
        NIDA research monograph. 1998; 178: 440-466
        • Tyacke R.J.
        • Nutt D.J.
        Optimising PET approaches to measuring 5-HT release in human brain.
        Synapse. 2015; 69: 505-511
        • Ettrup A.
        • Hansen M.
        • Santini M.A.
        • Paine J.
        • Gillings N.
        • Palner M.
        • et al.
        Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers.
        European journal of nuclear medicine and molecular imaging. 2011; 38: 681-693
      2. Johnson S, Stockmeier CA, Meyer JH, Austin MC, Albert PR, Wang J, et al. (2011): The reduction of R1, a novel repressor protein for monoamine oxidase A, in major depressive disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 36:2139-2148.

        • Meyer J.H.
        • Wilson A.A.
        • Sagrati S.
        • Miler L.
        • Rusjan P.
        • Bloomfield P.M.
        • et al.
        Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence.
        Archives of general psychiatry. 2009; 66: 1304-1312
        • Meyer J.H.
        • Ginovart N.
        • Boovariwala A.
        • Sagrati S.
        • Hussey D.
        • Garcia A.
        • et al.
        Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression.
        Archives of general psychiatry. 2006; 63: 1209-1216
        • Savitz J.B.
        • Drevets W.C.
        Neuroreceptor imaging in depression.
        Neurobiology of disease. 2013; 52: 49-65
        • Fukui M.
        • Rodriguiz R.M.
        • Zhou J.
        • Jiang S.X.
        • Phillips L.E.
        • Caron M.G.
        • et al.
        Vmat2 heterozygous mutant mice display a depressive-like phenotype.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007; 27: 10520-10529
        • Taylor T.N.
        • Caudle W.M.
        • Shepherd K.R.
        • Noorian A.
        • Jackson C.R.
        • Iuvone P.M.
        • et al.
        Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009; 29: 8103-8113
        • Narboux-Neme N.
        • Sagne C.
        • Doly S.
        • Diaz S.L.
        • Martin C.B.
        • Angenard G.
        • et al.
        Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences.
        Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2011; 36: 2538-2550
        • Drevets W.C.
        • Thase M.E.
        • Moses-Kolko E.L.
        • Price J.
        • Frank E.
        • Kupfer D.J.
        • et al.
        Serotonin-1A receptor imaging in recurrent depression: replication and literature review.
        Nuclear medicine and biology. 2007; 34: 865-877
        • Bhagwagar Z.
        • Rabiner E.A.
        • Sargent P.A.
        • Grasby P.M.
        • Cowen P.J.
        Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.
        Molecular psychiatry. 2004; 9: 386-392
        • Sullivan G.M.
        • Ogden R.T.
        • Oquendo M.A.
        • Kumar J.S.
        • Simpson N.
        • Huang Y.Y.
        • et al.
        Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression.
        Biological psychiatry. 2009; 66: 223-230
        • Ballanger B.
        • Klinger H.
        • Eche J.
        • Lerond J.
        • Vallet A.E.
        • Le Bars D.
        • et al.
        Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease.
        Movement disorders : official journal of the Movement Disorder Society. 2012; 27: 84-89
        • Erritzoe D.
        • Holst K.
        • Frokjaer V.G.
        • Licht C.L.
        • Kalbitzer J.
        • Nielsen F.A.
        • et al.
        A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010; 30: 3391-3397
        • Meyer J.H.
        • McMain S.
        • Kennedy S.H.
        • Korman L.
        • Brown G.M.
        • DaSilva J.N.
        • et al.
        Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm.
        The American journal of psychiatry. 2003; 160: 90-99
        • Bhagwagar Z.
        • Hinz R.
        • Taylor M.
        • Fancy S.
        • Cowen P.
        • Grasby P.
        Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907.
        The American journal of psychiatry. 2006; 163: 1580-1587
        • Biver F.
        • Wikler D.
        • Lotstra F.
        • Damhaut P.
        • Goldman S.
        • Mendlewicz J.
        Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex.
        The British journal of psychiatry : the journal of mental science. 1997; 171: 444-448
        • Attar-Levy D.
        • Martinot J.L.
        • Blin J.
        • Dao-Castellana M.H.
        • Crouzel C.
        • Mazoyer B.
        • et al.
        The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.
        Biological psychiatry. 1999; 45: 180-186
        • Yatham L.N.
        • Liddle P.F.
        • Shiah I.S.
        • Scarrow G.
        • Lam R.W.
        • Adam M.J.
        • et al.
        Brain serotonin2 receptors in major depression: a positron emission tomography study.
        Archives of general psychiatry. 2000; 57: 850-858
        • Mintun M.A.
        • Sheline Y.I.
        • Moerlein S.M.
        • Vlassenko A.G.
        • Huang Y.
        • Snyder A.Z.
        Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography.
        Biological psychiatry. 2004; 55: 217-224
        • Messa C.
        • Colombo C.
        • Moresco R.M.
        • Gobbo C.
        • Galli L.
        • Lucignani G.
        • et al.
        5-HT(2A) receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study.
        Psychopharmacology. 2003; 167: 72-78
        • Meyer J.H.
        • Kapur S.
        • Houle S.
        • DaSilva J.
        • Owczarek B.
        • Brown G.M.
        • et al.
        Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.
        The American journal of psychiatry. 1999; 156: 1029-1034
        • Frokjaer V.G.
        • Mortensen E.L.
        • Nielsen F.A.
        • Haugbol S.
        • Pinborg L.H.
        • Adams K.H.
        • et al.
        Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder.
        Biological psychiatry. 2008; 63: 569-576
        • Frokjaer V.G.
        • Vinberg M.
        • Erritzoe D.
        • Baare W.
        • Holst K.K.
        • Mortensen E.L.
        • et al.
        Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding.
        Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2010; 35: 1129-1137
        • Elmenhorst D.
        • Kroll T.
        • Matusch A.
        • Bauer A.
        Sleep deprivation increases cerebral serotonin 2A receptor binding in humans.
        Sleep. 2012; 35: 1615-1623
        • Soloff P.H.
        • Price J.C.
        • Mason N.S.
        • Becker C.
        • Meltzer C.C.
        Gender, personality, and serotonin-2A receptor binding in healthy subjects.
        Psychiatry research. 2010; 181: 77-84
        • Meyer J.H.
        • Kapur S.
        • Eisfeld B.
        • Brown G.M.
        • Houle S.
        • DaSilva J.
        • et al.
        The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.
        The American journal of psychiatry. 2001; 158: 78-85
        • Samama P.
        • Cotecchia S.
        • Costa T.
        • Lefkowitz R.J.
        A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
        The Journal of biological chemistry. 1993; 268: 4625-4636
        • Roberts D.J.
        • Strange P.G.
        Mechanisms of inverse agonist action at D2 dopamine receptors.
        British journal of pharmacology. 2005; 145: 34-42
        • Narendran R.
        • Slifstein M.
        • Guillin O.
        • Hwang Y.
        • Hwang D.R.
        • Scher E.
        • et al.
        Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo.
        Synapse. 2006; 60: 485-495
        • Cumming P.
        • Wong D.F.
        • Gillings N.
        • Hilton J.
        • Scheffel U.
        • Gjedde A.
        Specific binding of [(11)C]raclopride and N-[(3)H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2002; 22: 596-604
        • Leonhardt S.
        • Gorospe E.
        • Hoffman B.J.
        • Teitler M.
        Molecular pharmacological differences in the interaction of serotonin with 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors.
        Molecular pharmacology. 1992; 42: 328-335
        • Teitler M.
        • Leonhardt S.
        • Weisberg E.L.
        • Hoffman B.J.
        4-[125I]iodo-(2,5-dimethoxy)phenylisopropylamine and [3H]ketanserin labeling of 5-hydroxytryptamine2 (5HT2) receptors in mammalian cells transfected with a rat 5HT2 cDNA: evidence for multiple states and not multiple 5HT2 receptor subtypes.
        Molecular pharmacology. 1990; 38: 594-598
        • Egan C.
        • Grinde E.
        • Dupre A.
        • Roth B.L.
        • Hake M.
        • Teitler M.
        • et al.
        Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors.
        Synapse. 2000; 35: 144-150