Advertisement

Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action

Open AccessPublished:May 14, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.05.008

      Abstract

      Neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), have been associated with depression and antidepressant drug action. A variety of preclinical and clinical studies have implicated impaired BDNF signaling through its receptor TrkB (neurotrophic receptor tyrosine kinase 2) in the pathophysiology of mood disorders, but many of the initial findings have not been fully supported by more recent meta-analyses, and more both basic and clinical research is needed. In contrast, increased expression and signaling of BDNF has been repeatedly implicated in the mechanisms of both typical and rapid-acting antidepressant drugs, and recent findings have started to elucidate the mechanisms through which antidepressants regulate BDNF signaling. BDNF is a critical regulator of various types of neuronal plasticities in the brain, and plasticity has increasingly been connected with antidepressant action. Although some equivocal data exist, the hypothesis of a connection between neurotrophic factors and neuronal plasticity with mood disorders and antidepressant action has recently been further strengthened by converging evidence from a variety of more recent data reviewed here.

      Keywords

      Several lines of evidence link BDNF (brain-derived neurotrophic factor) and its receptor TrkB (neurotrophic receptor tyrosine kinase 2) with mood disorders and antidepressant effects [reviewed in (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ,
      • Bjorkholm C.
      • Monteggia L.M.
      BDNF—a key transducer of antidepressant effects.
      ,
      • Castrén E.
      • Kojima M.
      Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.
      ,
      • Hing B.
      • Sathyaputri L.
      • Potash J.B.
      A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder.
      )]. Duman’s group (
      • Nibuya M.
      • Morinobu S.
      • Duman R.S.
      Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
      ,
      • Duman R.S.
      • Heninger G.R.
      • Nestler E.J.
      A molecular and cellular theory of depression.
      ) was the first to discover a connection between BDNF, depression, and antidepressant action. They first showed that BDNF levels are increased by electroconvulsive treatment in rats and that antidepressants also increase BDNF expression in the hippocampus and cortex (
      • Nibuya M.
      • Morinobu S.
      • Duman R.S.
      Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
      ), a finding that has subsequently been confirmed by several groups (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ). The work of the Duman laboratory has been a major contributor to the field ever since (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ,
      • Duman R.S.
      • Deyama S.
      • Fogaca M.V.
      Role of BDNF in the pathophysiology and treatment of depression: Activity dependent effects distinguish rapid acting antidepressants.
      ). We review here the role of BDNF signaling in mood disorders and the antidepressant effects. While there is a large amount of convergent evidence suggesting reduced BDNF signaling in mood disorders, not all evidence supports this conclusion, and a reduction in BDNF signaling is not specific to mood disorders. On the other hand, the evidence for the critical role for BDNF signaling in the antidepressant responses is convincing and has recently been further strengthened.
      BDNF is a critical mediator of activity-dependent neuronal plasticity in the brain (
      • Park H.
      • Poo M.M.
      Neurotrophin regulation of neural circuit development and function.
      ,
      • Zagrebelsky M.
      • Korte M.
      Form follows function: BDNF and its involvement in sculpting the function and structure of synapses.
      ). It has a major impact on neuronal morphology and physiology, increasing neurite sprouting and synapse stabilization and promoting long-term potentiation (
      • Zagrebelsky M.
      • Korte M.
      Form follows function: BDNF and its involvement in sculpting the function and structure of synapses.
      ). Synthesis and release of BDNF are regulated by neuronal activity, which is consistent with the role of BDNF as a major mediator of activity-dependent neuronal plasticity. Recent data suggest that BDNF may also be linked to spontaneous, activity-independent transmission. The blockade of postsynaptic NMDA receptors involved in spontaneous transmission can rapidly increase BDNF protein translation, which can produce an increase in synaptic potentiation that resembles homeostatic scaling. This connection between spontaneous transmission and BDNF that triggers a novel form of plasticity has been linked to the rapid antidepressant action of ketamine (
      • Autry A.E.
      • Adachi M.
      • Nosyreva E.
      • Na E.S.
      • Los M.F.
      • Cheng P.F.
      • et al.
      NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
      ,
      • Nosyreva E.
      • Szabla K.
      • Autry A.E.
      • Ryazanov A.G.
      • Monteggia L.M.
      • Kavalali E.T.
      Acute suppression of spontaneous neurotransmission drives synaptic potentiation.
      ,
      • Gideons E.S.
      • Kavalali E.T.
      • Monteggia L.M.
      Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses.
      ,
      • Kavalali E.T.
      • Monteggia L.M.
      Targeting homeostatic synaptic plasticity for treatment of mood disorders.
      ).

      BDNF-TrkB Signaling in Mood Disorders

      BDNF signaling has been implicated in the pathophysiology of mood disorders in humans. Levels of BDNF messenger RNA (mRNA) and protein have been found to be reduced in postmortem samples taken from brains of depressed patients (
      • Dwivedi Y.
      Involvement of brain-derived neurotrophic factor in late-life depression.
      ), in particular in the hippocampus (
      • Dunham J.S.
      • Deakin J.F.
      • Miyajima F.
      • Payton A.
      • Toro C.T.
      Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains.
      ,
      • Ray M.T.
      • Weickert C.S.
      • Wyatt E.
      • Webster M.J.
      Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders.
      ,
      • Ray M.T.
      • Shannon Weickert C.
      • Webster M.J.
      Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders.
      ) and amygdala (
      • Guilloux J.P.
      • Douillard-Guilloux G.
      • Kota R.
      • Wang X.
      • Gardier A.M.
      • Martinowich K.
      • et al.
      Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression.
      ). BDNF levels have also consistently been found to be reduced in brain samples of people who died as a result of suicide (
      • Dwivedi Y.
      • Rizavi H.S.
      • Conley R.R.
      • Roberts R.C.
      • Tamminga C.A.
      • Pandey G.N.
      Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.
      ,
      • Dwivedi Y.
      • Rizavi H.S.
      • Zhang H.
      • Mondal A.C.
      • Roberts R.C.
      • Conley R.R.
      • et al.
      Neurotrophin receptor activation and expression in human postmortem brain: Effect of suicide.
      ,
      • Chen B.
      • Dowlatshahi D.
      • MacQueen G.M.
      • Wang J.F.
      • Young L.T.
      Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
      ,
      • Youssef M.M.
      • Underwood M.D.
      • Huang Y.Y.
      • Hsiung S.C.
      • Liu Y.
      • Simpson N.R.
      • et al.
      Association of BDNF Val66Met polymorphism and brain BDNF levels with major depression and suicide.
      ,
      • Pandey G.N.
      • Ren X.
      • Rizavi H.S.
      • Conley R.R.
      • Roberts R.C.
      • Dwivedi Y.
      Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims.
      ,
      • Dwivedi Y.
      Brain-derived neurotrophic factor: Role in depression and suicide.
      ). Conversely, antidepressant treatment increases BDNF expression in brains of depressed patients (
      • Chen B.
      • Dowlatshahi D.
      • MacQueen G.M.
      • Wang J.F.
      • Young L.T.
      Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
      ). However, the numbers of examined cases are generally low, and reduction in BDNF is not specific to mood disorders, as similar reductions have been observed in other neuropsychiatric disorders, such as schizophrenia and dementia (
      • Carlino D.
      • De Vanna M.
      • Tongiorgi E.
      Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions.
      ,
      • Michalski B.
      • Corrada M.M.
      • Kawas C.H.
      • Fahnestock M.
      Brain-derived neurotrophic factor and TrkB expression in the “oldest-old,” the 90+ Study: Correlation with cognitive status and levels of soluble amyloid-beta.
      ).
      DNA methylation of BDNF gene promoters has been shown to be increased in peripheral blood mononuclear cells of depressed patients (
      • Roy B.
      • Shelton R.C.
      • Dwivedi Y.
      DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation.
      ,
      • Kim J.M.
      • Kang H.J.
      • Bae K.Y.
      • Kim S.W.
      • Shin I.S.
      • Kim H.R.
      • et al.
      Association of BDNF promoter methylation and genotype with suicidal ideation in elderly Koreans.
      ,
      • Schroter K.
      • Brum M.
      • Brunkhorst-Kanaan N.
      • Tole F.
      • Ziegler C.
      • Domschke K.
      • et al.
      Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder.
      ), which is consistent with a reduction in BDNF expression. A similar increase in BDNF promoter methylation has also been observed in brain samples from people who died by suicide (
      • Keller S.
      • Sarchiapone M.
      • Zarrilli F.
      • Videtic A.
      • Ferraro A.
      • Carli V.
      • et al.
      Increased BDNF promoter methylation in the Wernicke area of suicide subjects.
      ), suggesting dysregulation of BDNF expression. This suggests that the findings in blood cells may perhaps be extrapolated to neuronal tissue, although this requires further investigation.
      In addition to BDNF, levels of TrkB and TrkB mRNA have also been found to be decreased in postmortem samples of depressed patients (
      • Dwivedi Y.
      • Rizavi H.S.
      • Conley R.R.
      • Roberts R.C.
      • Tamminga C.A.
      • Pandey G.N.
      Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.
      ,
      • Tripp A.
      • Oh H.
      • Guilloux J.P.
      • Martinowich K.
      • Lewis D.A.
      • Sibille E.
      Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.
      ), and genetic variants in the TrkB gene NTRK2 are associated with suicide attempts (
      • Kohli M.A.
      • Salyakina D.
      • Pfennig A.
      • Lucae S.
      • Horstmann S.
      • Menke A.
      • et al.
      Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.
      ). Furthermore, the activated, phosphorylated forms of TrkB have been found to be decreased in brain samples from depressed patients (
      • Dwivedi Y.
      • Rizavi H.S.
      • Zhang H.
      • Mondal A.C.
      • Roberts R.C.
      • Conley R.R.
      • et al.
      Neurotrophin receptor activation and expression in human postmortem brain: Effect of suicide.
      ).

       Genetic Association Between BDNF and Depression

      Valine is the predominant amino acid at position 66 of BNDF, but 25% to 50% of individuals in different populations have methionine at this position (Val66Met) (
      • Egan M.F.
      • Kojima M.
      • Callicott J.H.
      • Goldberg T.E.
      • Kolachana B.S.
      • Bertolino A.
      • et al.
      The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.
      ,
      • Shimizu E.
      • Hashimoto K.
      • Iyo M.
      Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: The possibility to explain ethnic mental traits.
      ). Mechanistically, this polymorphism influences intracellular BDNF trafficking and activity-dependent BDNF release (
      • Egan M.F.
      • Kojima M.
      • Callicott J.H.
      • Goldberg T.E.
      • Kolachana B.S.
      • Bertolino A.
      • et al.
      The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.
      ,
      • Chen Z.Y.
      • Jing D.
      • Bath K.G.
      • Ieraci A.
      • Khan T.
      • Siao C.J.
      • et al.
      Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
      ), and the Met allele has been shown to impair dendritic transportation of BDNF mRNA (
      • Baj G.
      • Carlino D.
      • Gardossi L.
      • Tongiorgi E.
      Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: A model of impaired dendritic mRNA trafficking.
      ). As the activity-dependent synaptic release of BDNF is critical for its action on certain types of neuronal plasticity, Met66BDNF might impede plasticity. Early studies suggested that the Met allele might be a risk factor for a number of neuropsychiatric disorders (
      • Bath K.G.
      • Lee F.S.
      Variant BDNF (Val66Met) impact on brain structure and function.
      ). However, subsequent larger studies failed to replicate these effects, and the latest meta-analyses do not support the role of BDNF Val66Met polymorphism in mood disorders (
      • Gyekis J.P.
      • Yu W.
      • Dong S.
      • Wang H.
      • Qian J.
      • Kota P.
      • et al.
      No association of genetic variants in BDNF with major depression: A meta- and gene-based analysis.
      ,
      • Li M.
      • Chang H.
      • Xiao X.
      BDNF Val66Met polymorphism and bipolar disorder in European populations: A risk association in case-control, family-based and GWAS studies.
      ) [reviewed in (
      • Hing B.
      • Sathyaputri L.
      • Potash J.B.
      A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder.
      )], with perhaps an exception of increased risk of depression in male Met-carriers (
      • Verhagen M.
      • van der Meij A.
      • van Deurzen P.A.
      • Janzing J.G.
      • Arias-Vasquez A.
      • Buitelaar J.K.
      • et al.
      Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: Effects of gender and ethnicity.
      ). In addition to Val66Met, several other single nucleotide polymorphisms have been detected in the human BDNF gene, and initial studies associated some of them with depression (
      • Hing B.
      • Sathyaputri L.
      • Potash J.B.
      A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder.
      ,
      • Licinio J.
      • Dong C.
      • Wong M.L.
      Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response.
      ,
      • Hing B.
      • Davidson S.
      • Lear M.
      • Breen G.
      • Quinn J.
      • McGuffin P.
      • et al.
      A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
      ,
      • Juhasz G.
      • Dunham J.S.
      • McKie S.
      • Thomas E.
      • Downey D.
      • Chase D.
      • et al.
      The CREB1-BDNF-NTRK2 pathway in depression: Multiple gene-cognition-environment interactions.
      ). However, also here, meta-analyses have not supported the initial findings (
      • Hing B.
      • Sathyaputri L.
      • Potash J.B.
      A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder.
      ,
      • Gyekis J.P.
      • Yu W.
      • Dong S.
      • Wang H.
      • Qian J.
      • Kota P.
      • et al.
      No association of genetic variants in BDNF with major depression: A meta- and gene-based analysis.
      ).
      There is evidence that Val66Met polymorphism might modulate the effects of early life adversity (
      • Kaufman J.
      • Yang B.Z.
      • Douglas-Palumberi H.
      • Grasso D.
      • Lipschitz D.
      • Houshyar S.
      • et al.
      Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children.
      ,
      • Aguilera M.
      • Arias B.
      • Wichers M.
      • Barrantes-Vidal N.
      • Moya J.
      • Villa H.
      • et al.
      Early adversity and 5-HTT/BDNF genes: New evidence of gene-environment interactions on depressive symptoms in a general population.
      ,
      • Frodl T.
      • Skokauskas N.
      • Frey E.M.
      • Morris D.
      • M. Gill M
      • Carballedo A.
      BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields.
      ,
      • Carballedo A.
      • Morris D.
      • Zill P.
      • Fahey C.
      • Reinhold E.
      • Meisenzahl E.
      • et al.
      Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.
      ) or chronic stress on depression in adulthood (
      • Hosang G.M.
      • Shiles C.
      • Tansey K.E.
      • McGuffin P.
      • Uher R.
      Interaction between stress and the BDNF Val66Met polymorphism in depression: A systematic review and meta-analysis.
      ). Indeed, a recent meta-analysis that examined the interaction between the Val66Met polymorphism and stressful life events or childhood adversity in more than 20,000 participants in 31 independent studies concluded that Met carriers have significantly higher risk of developing depression when exposed to stress either during childhood or in adulthood (
      • Zhao M.
      • Chen L.
      • Yang J.
      • Han D.
      • Fang D.
      • Qiu X.
      • et al.
      BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.
      ).
      Activity-dependent BDNF release is suggested to be important for the antidepressant response. Consistently, behavioral as well as plasticity-related responses to antidepressants were lost in a mouse model of Val66Met polymorphism (
      • Chen Z.Y.
      • Jing D.
      • Bath K.G.
      • Ieraci A.
      • Khan T.
      • Siao C.J.
      • et al.
      Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
      ,
      • Bath K.G.
      • Jing D.Q.
      • Dincheva I.
      • Neeb C.C.
      • Pattwell S.S.
      • Chao M.V.
      • et al.
      BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity.
      ). Furthermore, increased spine formation in responses to ketamine and its metabolite (2R,6R)-hydroxynorketamine were lost in these mice (
      • Liu R.J.
      • Lee F.S.
      • Li X.Y.
      • Bambico F.
      • Duman R.S.
      • Aghajanian G.K.
      Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex.
      ,
      • Fukumoto K.
      • Fogaca M.V.
      • Liu R.J.
      • Duman C.
      • Kato T.
      • Li X.Y.
      • et al.
      Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.
      ). However, similar loss has not been observed in human studies, and the Met allele, if anything, improves the response to antidepressants (
      • Yan T.
      • Wang L.
      • Kuang W.
      • Xu J.
      • Li S.
      • Chen J.
      • et al.
      Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: A systematic review and meta-analysis.
      ,
      • Choi M.J.
      • Kang R.H.
      • Lim S.W.
      • Oh K.S.
      • Lee M.S.
      Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder.
      ,
      • Colle R.
      • Deflesselle E.
      • Martin S.
      • David D.J.
      • Hardy P.
      • Taranu A.
      • et al.
      BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients.
      ,
      • Domschke K.
      • Lawford B.
      • Laje G.
      • Berger K.
      • Young R.
      • Morris P.
      • et al.
      Brain-derived neurotrophic factor (BDNF) gene: No major impact on antidepressant treatment response.
      ), and patients heterozygous for Val66Met appear to show a better response to antidepressants than patients homozygous for either the Val or the Met allele (
      • Niitsu T.
      • Fabbri C.
      • Bentini F.
      • Serretti A.
      Pharmacogenetics in major depression: A comprehensive meta-analysis.
      ).

       Serum BDNF and Mood Disorders

      Levels of BDNF are high in human serum; however, levels in plasma and cerebrospinal fluid are orders of magnitude lower (
      • Yamamoto H.
      • Gurney M.E.
      Human platelets contain brain-derived neurotrophic factor.
      ,
      • Radka S.F.
      • Holst P.A.
      • Fritsche M.
      • Altar C.A.
      Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay.
      ,
      • Serra-Millas M.
      Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation.
      ,
      • Korhonen L.
      • Riikonen R.
      • Nawa H.
      • Lindholm D.
      Brain derived neurotrophic factor is increased in cerebrospinal fluid of children suffering from asphyxia.
      ). More than 90% of BDNF found in blood is contained in platelets (
      • Yamamoto H.
      • Gurney M.E.
      Human platelets contain brain-derived neurotrophic factor.
      ,
      • Radka S.F.
      • Holst P.A.
      • Fritsche M.
      • Altar C.A.
      Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay.
      ,
      • Naegelin Y.
      • Dingsdale H.
      • Sauberli K.
      • Schadelin S.
      • Kappos L.
      • Barde Y.A.
      Measuring and validating the levels of brain-derived neurotrophic factor in human serum.
      ,
      • Lommatzsch M.
      • Zingler D.
      • Schuhbaeck K.
      • Schloetcke K.
      • Zingler C.
      • Schuff-Werner P.
      • et al.
      The impact of age, weight and gender on BDNF levels in human platelets and plasma.
      ,
      • Fujimura H.
      • Altar C.A.
      • Chen R.
      • Nakamura T.
      • Nakahashi T.
      • Kambayashi J.
      • et al.
      Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation.
      ). Although it has been suggested that circulating BDNF could be derived from brain (
      • Seifert T.
      • Brassard P.
      • Wissenberg M.
      • Rasmussen P.
      • Nordby P.
      • Stallknecht B.
      • et al.
      Endurance training enhances BDNF release from the human brain.
      ), it is by now clear that serum BDNF is derived from blood platelets that release it on platelet activation (
      • Yamamoto H.
      • Gurney M.E.
      Human platelets contain brain-derived neurotrophic factor.
      ,
      • Radka S.F.
      • Holst P.A.
      • Fritsche M.
      • Altar C.A.
      Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay.
      ,
      • Naegelin Y.
      • Dingsdale H.
      • Sauberli K.
      • Schadelin S.
      • Kappos L.
      • Barde Y.A.
      Measuring and validating the levels of brain-derived neurotrophic factor in human serum.
      ). Within platelets, BDNF is contained within the alpha granules and in the cytoplasm (
      • Serra-Millas M.
      Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation.
      ,
      • Tamura S.
      • Suzuki H.
      • Hirowatari Y.
      • Hatase M.
      • Nagasawa A.
      • Matsuno K.
      • et al.
      Release reaction of brain-derived neurotrophic factor (BDNF) through PAR1 activation and its two distinct pools in human platelets.
      ), and on stimulation, less than half of BDNF within platelets is released, probably representing the alpha-granule pool. Platelet BDNF is derived from megakaryocytes that transport BDNF into newly formed platelets (
      • Tamura S.
      • Nagasawa A.
      • Masuda Y.
      • Tsunematsu T.
      • Hayasaka K.
      • Matsuno K.
      • et al.
      BDNF, produced by a TPO-stimulated megakaryocytic cell line, regulates autocrine proliferation.
      ,
      • Chacón-Fernández P.
      • Säuberli K.
      • Colzani M.
      • Moreau T.
      • Ghevaert C.
      • Barde Y.A.
      Brain-derived neurotrophic factor in megakaryocytes.
      ). Whether platelets also take up BDNF from plasma is unclear; platelets do not express BDNF receptors, but uptake of labeled BDNF into platelets has been reported (
      • Fujimura H.
      • Altar C.A.
      • Chen R.
      • Nakamura T.
      • Nakahashi T.
      • Kambayashi J.
      • et al.
      Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation.
      ). Interestingly, mouse megakaryocytes do not synthesize BDNF, and, consequently, BDNF levels in mouse serum and plasma are very low, below detection limit (
      • Chacón-Fernández P.
      • Säuberli K.
      • Colzani M.
      • Moreau T.
      • Ghevaert C.
      • Barde Y.A.
      Brain-derived neurotrophic factor in megakaryocytes.
      ), which speaks against uptake from plasma as a significant source of platelet BDNF.
      Several studies have observed that serum or plasma BDNF levels are abnormally low in depressed patients (
      • Karege F.
      • Perret G.
      • Bondolfi G.
      • Schwald M.
      • Bertschy G.
      • Aubry J.M.
      Decreased serum brain-derived neurotrophic factor levels in major depressed patients.
      ) and that the levels increase back to baseline after successful treatment with antidepressants (
      • Shimizu E.
      • Hashimoto K.
      • Okamura N.
      • Koike K.
      • Komatsu N.
      • Kumakiri C.
      • et al.
      Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.
      ,
      • Sen S.
      • Duman R.
      • Sanacora G.
      Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications.
      ,
      • Karege F.
      • Bondolfi G.
      • Gervasoni N.
      • Schwald M.
      • Aubry J.M.
      • Bertschy G.
      Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.
      ,
      • Bocchio-Chiavetto L.
      • Bagnardi V.
      • Zanardini R.
      • Molteni R.
      • Nielsen M.G.
      • Placentino A.
      • et al.
      Serum and plasma BDNF levels in major depression: A replication study and meta-analyses.
      ,
      • Gonul A.S.
      • Akdeniz F.
      • Taneli F.
      • Donat O.
      • Eker C.
      • Vahip S.
      Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients.
      ,
      • Piccinni A.
      • Marazziti D.
      • Catena M.
      • Domenici L.
      • Del Debbio A.
      • Bianchi C.
      • et al.
      Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments.
      ,
      • Matrisciano F.
      • Bonaccorso S.
      • Ricciardi A.
      • Scaccianoce S.
      • Panaccione I.
      • Wang L.
      • et al.
      Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine.
      ,
      • Yoshimura R.
      • Mitoma M.
      • Sugita A.
      • Hori H.
      • Okamoto T.
      • Umene W.
      • et al.
      Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients.
      ,
      • Hellweg R.
      • Ziegenhorn A.
      • Heuser I.
      • Deuschle M.
      Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.
      ,
      • Molendijk M.L.
      • Bus B.A.
      • Spinhoven P.
      • Penninx B.W.
      • Kenis G.
      • Prickaerts J.
      • et al.
      Serum levels of brain-derived neurotrophic factor in major depressive disorder: State-trait issues, clinical features and pharmacological treatment.
      ) or electroconvulsive treatment (
      • Bocchio-Chiavetto L.
      • Zanardini R.
      • Bortolomasi M.
      • Abate M.
      • Segala M.
      • Giacopuzzi M.
      • et al.
      Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients.
      ,
      • Rocha R.B.
      • Dondossola E.R.
      • Grande A.J.
      • Colonetti T.
      • Ceretta L.B.
      • Passos I.C.
      • et al.
      Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: A meta-analysis study.
      ), but not after repetitive transcranial magnetic stimulation or vagus nerve stimulation (
      • Lang U.E.
      • Bajbouj M.
      • Gallinat J.
      • Hellweg R.
      Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation.
      ). Although a recent meta-analysis found reduced effect sizes in more recent studies, reduction in serum BDNF remained highly significant in untreated depressed patients compared with successfully treated patients or healthy individuals (
      • Molendijk M.L.
      • Spinhoven P.
      • Polak M.
      • Bus B.A.
      • Penninx B.W.
      • Elzinga B.M.
      Serum BDNF concentrations as peripheral manifestations of depression: Evidence from a systematic review and meta-analyses on 179 associations (N=9484).
      ). Unfortunately, high interindividual and intraindividual variation in serum BDNF levels (
      • Polacchini A.
      • Metelli G.
      • Francavilla R.
      • Baj G.
      • Florean M.
      • Mascaretti L.G.
      • et al.
      A method for reproducible measurements of serum BDNF: Comparison of the performance of six commercial assays.
      ) prevents its use as a diagnostic marker for depression. However, as serum levels of proBDNF are not reduced in depressed patients while those of mature BDNF are (
      • Yoshida T.
      • Ishikawa M.
      • Niitsu T.
      • Nakazato M.
      • Watanabe H.
      • Shiraishi T.
      • et al.
      Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder.
      ), a ratio between mature BDNF and proBDNF has been suggested as a biomarker for bipolar disorder (
      • Sodersten K.
      • Palsson E.
      • Ishima T.
      • Funa K.
      • Landen M.
      • Hashimoto K.
      • et al.
      Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: A study of two independent cohorts.
      ) and for discriminating between bipolar and major depressive disorder with reasonable sensitivity (
      • Zhao G.
      • Zhang C.
      • Chen J.
      • Su Y.
      • Zhou R.
      • Wang F.
      • et al.
      Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression.
      ). Notably, a decrease in serum BDNF levels is not specific to depression: serum BDNF levels have been reported to be decreased also in schizophrenia (
      • Toyooka K.
      • Asama K.
      • Watanabe Y.
      • Muratake T.
      • Takahashi M.
      • Someya T.
      • et al.
      Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients.
      ,
      • Fernandes B.S.
      • Steiner J.
      • Berk M.
      • Molendijk M.L.
      • Gonzalez-Pinto A.
      • Turck C.W.
      • et al.
      Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: Meta-analysis and implications.
      ,
      • Kimhy D.
      • Vakhrusheva J.
      • Bartels M.N.
      • Armstrong H.F.
      • Ballon J.S.
      • Khan S.
      • et al.
      The impact of aerobic exercise on brain-derived neurotrophic factor and neurocognition in individuals with schizophrenia: A single-blind, randomized clinical trial.
      ) and in autism (
      • Hashimoto K.
      • Iwata Y.
      • Nakamura K.
      • Tsujii M.
      • Tsuchiya K.J.
      • Sekine Y.
      • et al.
      Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism.
      ,
      • Katoh-Semba R.
      • Wakako R.
      • Komori T.
      • Shigemi H.
      • Miyazaki N.
      • Ito H.
      • et al.
      Age-related changes in BDNF protein levels in human serum: Differences between autism cases and normal controls.
      ).
      While serum BDNF levels were low in patients with depression and schizophrenia, whole-blood BDNF levels were not different between patients and control subjects (
      • Karege F.
      • Bondolfi G.
      • Gervasoni N.
      • Schwald M.
      • Aubry J.M.
      • Bertschy G.
      Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.
      ,
      • Toyooka K.
      • Asama K.
      • Watanabe Y.
      • Muratake T.
      • Takahashi M.
      • Someya T.
      • et al.
      Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients.
      ). Therefore, the difference between patients and control subjects is not in the amount of BDNF in platelets, but in the ability of platelets to release it. Authors have proposed that instead of serum BDNF levels, a ratio between BDNF in serum and whole blood, which represents BDNF release from platelets, should be reported (
      • Karege F.
      • Bondolfi G.
      • Gervasoni N.
      • Schwald M.
      • Aubry J.M.
      • Bertschy G.
      Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.
      ). Interestingly, serotonin is concentrated into platelets through the serotonin transporter, the target of serotonin-selective antidepressants (selective serotonin reuptake inhibitors), and, as is the case for BDNF, serotonin release is reduced in depressed patients (
      • Serra-Millas M.
      Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation.
      ,
      • Tuomisto J.
      • Tukiainen E.
      Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients.
      ), suggesting a link between BDNF and serotonin release. Molecular pathways that regulate vesicular release in the brain and in platelets share many components (
      • Blair P.
      • Flaumenhaft R.
      Platelet alpha-granules: Basic biology and clinical correlates.
      ). It is therefore possible that reduced release from platelets could reflect compromised BDNF release also in the brain.
      Susceptibility to depression can be influenced by genetic, epigenetic, and environmental risk factors. Stressful life events may contribute to an individual’s developing depression, while some individuals display resilience. In preclinical models, stress paradigms are often used to model depression-related behavior. However, the type and duration of stress can produce a range of effects on the hypothalamic-pituitary-adrenal axis, metabolism, and epigenetic and genetic effects as well as behavior. Stress has been shown to decrease BDNF expression in many brain regions, but increased expression has also been observed in certain brain regions depending on the type and duration of stress. Given the complexity of the relationship between stress and neurotrophins, the reader is referred to articles in this special issue focusing on stress and its role in the transcriptome by Girgenti et al. (
      • Girgenti M.J.
      • Pothula S.
      • Newton S.S.
      Stress and its impact on the transcriptome.
      ) and the neurobiology of stress by Ploski and Vaidya (
      • Ploski J.E.
      • Vaidya V.A.
      The neurocircuitry of posttraumatic stress disorder and major depression: Insights into overlapping and distinct circuit dysfunction—A tribute to Ron Duman.
      ).
      Taken together, while several studies indicate abnormal expression and function of BDNF in depressed patients and a return to normal on recovery, many other studies, including genetic association studies, have failed to show a consistent relationship between BDNF and mood disorders. Therefore, a causal role for BDNF in depression remains equivocal.

      BDNF Expression and TrkB Signaling Are Required for Antidepressant Drug Action

      Given the evidence that BDNF signaling may be reduced in depression, the finding that antidepressant drugs increase BDNF levels has generated interest. Duman’s laboratory was the first to find that electroconvulsive treatment as well as tricyclic and selective serotonin reuptake inhibitor antidepressants increase BDNF expression in rodent brain (
      • Nibuya M.
      • Morinobu S.
      • Duman R.S.
      Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
      ,
      • Duman R.S.
      • Heninger G.R.
      • Nestler E.J.
      A molecular and cellular theory of depression.
      ), which has been confirmed in numerous studies [reviewed in (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ,
      • Castrén E.
      • Kojima M.
      Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.
      ,
      • Autry A.E.
      • Monteggia L.M.
      Brain-derived neurotrophic factor and neuropsychiatric disorders.
      )]. Antidepressant-induced increase in BDNF levels has also been observed in human postmortem brain samples (
      • Chen B.
      • Dowlatshahi D.
      • MacQueen G.M.
      • Wang J.F.
      • Young L.T.
      Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
      ) as well as in serum of depressed patients (see above).
      BDNF levels are increased quickly after electroconvulsive treatment, but only after several days of continuous antidepressant treatment (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ,
      • Nibuya M.
      • Morinobu S.
      • Duman R.S.
      Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
      ). However, antidepressants activated TrkB autophosphorylation and downstream signaling within an hour after treatment in mice (
      • Saarelainen T.
      • Hendolin P.
      • Lucas G.
      • Koponen E.
      • Sairanen M.
      • MacDonald E.
      • et al.
      Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.
      ,
      • Rantamäki T.
      • Hendolin P.
      • Kankaanpaa A.
      • Mijatovic J.
      • Piepponen P.
      • Domenici E.
      • et al.
      Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-C gamma signaling pathways in mouse brain.
      ), indicating that antidepressants may initially promote BDNF release and TrkB signaling and that the increase in BDNF expression takes place only later, but it has been unclear how antidepressants activate TrkB. A recent study demonstrated that antidepressants belonging to different classes, such as fluoxetine, imipramine, and ketamine, directly bind to TrkB (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ). Dimerized TrkB transmembrane domains cross each other in the transmembrane domain and create a pocket for antidepressants. Antidepressant binding stabilizes TrkB in synaptic membranes and promotes BDNF-mediated TrkB signaling (Figure 1) (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ). The affinity of antidepressants to TrkB is much lower than their affinity to the serotonin transporter, but antidepressants accumulate in brain, and concentrations needed for TrkB binding are achieved in human brain after several weeks of treatment (
      • Karson C.N.
      • Newton J.E.
      • Livingston R.
      • Jolly J.B.
      • Cooper T.B.
      • Sprigg J.
      • et al.
      Human brain fluoxetine concentrations.
      ), which might contribute to the slow action onset of typical antidepressants. These findings suggest a provocative hypothesis that the primary site of action of antidepressants is direct binding to TrkB instead of monoamine transporters and other classical targets.
      Figure thumbnail gr1
      Figure 1Direct binding of antidepressants to TrkB (neurotrophic receptor tyrosine kinase 2). (A) Two TrkB receptors cross each other within the transmembrane region, creating a binding site for fluoxetine (inset, blue) at the outer opening of the crossed dimer of TrkB. Image courtesy of M. Girych and G. Enkavi. (B) The configuration of TrkB dimers is dependent on membrane thickness, which is regulated by cholesterol concentration. (Left panel) In moderate cholesterol concentrations, the configuration is favorable for signaling. (Right panel) At high cholesterol concentrations, such as in synaptic membranes, the crossed dimers assume a more parallel orientation, which is not compatible with signaling, and the residence time of TrkB in these membranes is short. Binding of fluoxetine (Flx) acts as a wedge that maintains the crossed transmembrane domain orientation that is compatible with signaling, which increases a probability of BDNF (brain-derived neurotrophic factor) binding and signaling. (C) Allosteric activation of BDNF signaling by antidepressants. (Left panel) Antidepressants (ADs) promote TrkB translocation to and retention at the plasma membrane. (Right panel) BDNF (B) released from presynaptic and postsynaptic sites of active synapses efficiently signal through TrkB at the cell surface, but TrkB receptors in inactive synapses remain silent because no BDNF is released.
      BDNF signaling through TrkB is required for the behavioral effects of antidepressants (
      • Saarelainen T.
      • Hendolin P.
      • Lucas G.
      • Koponen E.
      • Sairanen M.
      • MacDonald E.
      • et al.
      Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.
      ,
      • Monteggia L.M.
      • Barrot M.
      • Powell C.M.
      • Berton O.
      • Galanis V.
      • Gemelli T.
      • et al.
      Essential role of brain-derived neurotrophic factor in adult hippocampal function.
      ), and several studies have investigated the brain regions and cell types where BDNF-TrkB signaling mediates antidepressant effects. Adachi et al. (
      • Adachi M.
      • Barrot M.
      • Autry A.E.
      • Theobald D.
      • Monteggia L.M.
      Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy.
      ) found that deletion of BDNF from the dentate gyrus cells of mice inhibits the effects of antidepressants in behavioral paradigms. Similarly, deletion of TrkB from the progenitor cells of dentate granule neurons, but not from the mature granule neurons, prevents the effects of antidepressants on the forced swim test as well as on induced neurogenesis (
      • Li Y.
      • Luikart B.W.
      • Birnbaum S.
      • Chen J.
      • Kwon C.H.
      • Kernie S.G.
      • et al.
      TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment.
      ), suggesting that TrkB in the progenitor cells is the target of BDNF released from the dentate granule neurons. Cortical interneurons have been implicated as the target for both typical (
      • Guirado R.
      • Perez-Rando M.
      • Sanchez-Matarredona D.
      • Castrén E.
      • Nacher J.
      Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons.
      ) and fast-acting (
      • Gerhard D.M.
      • Pothula S.
      • Liu R.J.
      • Wu M.
      • Li X.Y.
      • Girgenti M.J.
      • et al.
      GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions.
      ,
      • Wohleb E.S.
      • Wu M.
      • Gerhard D.M.
      • Taylor S.R.
      • Picciotto M.R.
      • Alreja M.
      • et al.
      GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.
      ,
      • Yang C.
      • Shirayama Y.
      • Zhang J.C.
      • Ren Q.
      • Yao W.
      • Ma M.
      • et al.
      R-ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects.
      ) antidepressants, especially parvalbumin-containing interneurons and perineuronal nets that encase them (
      • Ohira K.
      • Takeuchi R.
      • Iwanaga T.
      • Miyakawa T.
      Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice.
      ,
      • Sagi Y.
      • Medrihan L.
      • George K.
      • Barney M.
      • McCabe K.A.
      • Greengard P.
      Emergence of 5-HT5A signaling in parvalbumin neurons mediates delayed antidepressant action.
      ,
      • Donegan J.J.
      • Lodge D.J.
      Hippocampal perineuronal nets are required for the sustained antidepressant effect of ketamine.
      ,
      • Umemori J.
      • Winkel F.
      • Castren E.
      • Karpova N.N.
      Distinct effects of perinatal exposure to fluoxetine or methylmercury on parvalbumin and perineuronal nets, the markers of critical periods in brain development.
      ,
      • Pozzi L.
      • Pollak Dorocic I.
      • Wang X.
      • Carlen M.
      • Meletis K.
      Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.
      ,

      Winkel F, Ryazantseva M, Voigt MB, Didio G, Lilja A, Pou ML, et al. (In press): Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulates intrinsic states to orchestrate cortical plasticity. Mol Psychiatry.

      ,
      • Lesnikova A.
      • Casarotto P.C.
      • Fred S.M.
      • Voipio M.
      • Winkel F.
      • Steinzeig A.
      • et al.
      Chondroitinase and antidepressants promote plasticity by releasing TRKB from dephosphorylating control of PTPσ in parvalbumin neurons.
      ), but somatostatin-containing neurons have also been implicated in the antidepressant action (
      • Gerhard D.M.
      • Pothula S.
      • Liu R.J.
      • Wu M.
      • Li X.Y.
      • Girgenti M.J.
      • et al.
      GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions.
      ,
      • Carceller H.
      • Perez-Rando M.
      • Castren E.
      • Nacher J.
      • Guirado R.
      Effects of the antidepressant fluoxetine on the somatostatin interneurons in the basolateral amygdala.
      ). Finally, BDNF infused into the midbrain produced an antidepressant effect in rats (
      • Siuciak J.A.
      • Lewis D.R.
      • Wiegand S.J.
      • Lindsay R.M.
      Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).
      ), suggesting that this effect may be mediated through monoaminergic neurons. In a recent study using an adeno-associated virus approach to inject Cre recombinase into the dorsal raphe, either BDNF or TrkB was deleted in adult mice. The deletion of BDNF did not impact antidepressant responses in behavioral paradigms, but the loss of TrkB resulted in an attenuated response to antidepressants (
      • Adachi M.
      • Autry A.E.
      • Mahgoub M.
      • Suzuki K.
      • Monteggia L.M.
      TrkB signaling in dorsal raphe nucleus is essential for antidepressant efficacy and normal aggression behavior.
      ), revealing a critical role for TrkB in the dorsal raphe in conventional antidepressant action and suggesting a noncell autonomous role for BDNF in the dorsal raphe in conventional antidepressant action. However, direct deletion of TrkB in serotonergic neurons did not prevent the antidepressant-like effects of fluoxetine (
      • Sahu M.P.
      • Pazos-Boubeta Y.
      • Steinzeig A.
      • Kaurinkoski K.
      • Palmisano M.
      • Borowecki O.
      • et al.
      Depletion of TrkB receptors from adult serotonergic neurons increases brain serotonin levels, enhances energy metabolism and impairs learning and memory.
      ), suggesting that the target for BDNF may be nonserotonergic neurons in the raphe nuclei. Taken together, these data suggest that BDNF-TrkB signaling through several different neuronal systems can mediate different effects of antidepressant drugs.

       Typical Antidepressants Increase Other Growth Factors

      While numerous studies have linked BDNF to antidepressant action, VEGF (vascular endothelial growth factor) and its tyrosine kinase receptor, Flk1 (fetal liver kinase 1), have also been suggested to play a critical role, although with more limited findings. VEGF is a growth factor that is important in hippocampal neurogenesis (
      • Cao L.
      • Jiao X.
      • Zuzga D.S.
      • Liu Y.
      • Fong D.M.
      • Young D.
      • et al.
      VEGF links hippocampal activity with neurogenesis, learning and memory.
      ), although it is unclear if this is how it contributes to antidepressant action. Similar to BDNF, VEGF expression is increased by electroconvulsive and conventional antidepressant treatment (
      • Greene J.
      • Banasr M.
      • Lee B.
      • Warner-Schmidt J.
      • Duman R.S.
      Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: Pharmacological and cellular characterization.
      ). Conversely, pharmacological approaches that block VEGF-Flk1 signaling block the behavioral effects of conventional antidepressants, suggesting a crucial role in antidepressant-like action (
      • Greene J.
      • Banasr M.
      • Lee B.
      • Warner-Schmidt J.
      • Duman R.S.
      Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: Pharmacological and cellular characterization.
      ,
      • Warner-Schmidt J.L.
      • Duman R.S.
      VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.
      ,
      • Kiuchi T.
      • Lee H.
      • Mikami T.
      Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice.
      ). Curiously, the antidepressant-like effects of BDNF and VEGF appear mutually dependent on each other (
      • Deyama S.
      • Bang E.
      • Kato T.
      • Li X.Y.
      • Duman R.S.
      Neurotrophic and antidepressant actions of brain-derived neurotrophic factor require vascular endothelial growth factor.
      ). While additional studies are necessary to delineate the mechanistic role of VEGF in antidepressant drug action, nevertheless these data further strengthen the importance of neurotrophic factors in antidepressant action.

       Rapid Antidepressants Require BDNF

      The rather unexpected finding that ketamine, an NMDA receptor antagonist, produces rapid antidepressant action provides an opportunity to delineate intracellular signaling involved in the behavioral effects. Three main hypotheses have been put forth to explain the mechanism of action of ketamine. The first is often referred to as the disinhibition hypothesis. In this model, ketamine is postulated to block NMDA receptors on inhibitory neurons, which increases extracellular glutamate levels and activates AMPA receptors. This in turn causes the release of BDNF, which triggers downstream effects, such as activation of mTOR (mechanistic target of rapamycin), and ultimately synaptogenesis (
      • Gerhard D.M.
      • Pothula S.
      • Liu R.J.
      • Wu M.
      • Li X.Y.
      • Girgenti M.J.
      • et al.
      GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions.
      ,
      • Widman A.J.
      • McMahon L.L.
      Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy.
      ,
      • Fuchs T.
      • Jefferson S.J.
      • Hooper A.
      • Yee P.H.
      • Maguire J.
      • Luscher B.
      Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.
      ,
      • Pothula S.
      • Kato T.
      • Liu R.-J.
      • Wu M.
      • Gerhard D.
      • Shinohara R.
      • et al.
      Cell-type specific modulation of NMDA receptors triggers antidepressant actions [published online ahead of print Jun 2].
      ,
      • Picard N.
      • Takesian A.E.
      • Fagiolini M.
      • Hensch T.K.
      NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity.
      ). In support of this hypothesis, it was shown that blocking mTOR with an infusion of rapamycin, an mTOR inhibitor, in the cortex blocked ketamine’s antidepressant-like effects and synaptogenesis (
      • Li N.
      • Lee B.
      • Liu R.J.
      • Banasr M.
      • Dwyer J.M.
      • Iwata M.
      • et al.
      mTOR-Dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
      ). These studies suggested that mTOR was required for rapid antidepressant action and that compounds that promote mTOR activation may have therapeutic potential as rapid antidepressants. However, a separate group demonstrated that administration of rapamycin via intraperitoneal injection, to better mimic potential clinical approaches, did not prevent ketamine’s rapid antidepressant action (
      • Autry A.E.
      • Adachi M.
      • Nosyreva E.
      • Na E.S.
      • Los M.F.
      • Cheng P.F.
      • et al.
      NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
      ). More recently, a small clinical study administered rapamycin intravenously to patients and found that it did not block ketamine’s rapid antidepressant action but rather may augment the long-term effects (
      • Abdallah C.G.
      • Averill L.A.
      • Gueorguieva R.
      • Goktas S.
      • Purohit P.
      • Ranganathan M.
      • et al.
      Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.
      ). These clinical data call into question the necessity of mTOR in the rapid antidepressant action of ketamine.
      The second hypothesis focuses on how ketamine works through intracellular signaling to produce the antidepressant effects and identifies a novel form of synaptic plasticity strongly correlated with the behavioral action. Ketamine, via blockade of NMDA receptors, blocks calcium entry through these receptors, which results in the inhibition of the calcium/calmodulin-dependent kinase eEF2K (eukaryotic elongation factor 2 kinase), dephosphorylation of its sole target, eEF2 (eukaryotic elongation factor 2), and a resulting rapid increase in protein synthesis of BDNF as well as other synaptic proteins (
      • Autry A.E.
      • Adachi M.
      • Nosyreva E.
      • Na E.S.
      • Los M.F.
      • Cheng P.F.
      • et al.
      NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
      ). This study showed that loss of BDNF or TrkB in broad forebrain regions blocked ketamine’s antidepressant action, demonstrating a requirement for BDNF-TrkB signaling in the rapid antidepressant-like effects in animal models. Anisomycin, a protein synthesis inhibitor, was also shown to block ketamine’s rapid antidepressant action, thus demonstrating a key role for protein translation that was due to eEF2K in the fast-acting behavioral effects. Ketamine, in an eEF2K-dependent manner, was also shown to trigger the insertion of AMPA receptors that resulted in an expected effect on synaptic plasticity, namely, synaptic potentiation at hippocampal Schaffer collateral inputs to CA1 synapses (
      • Autry A.E.
      • Adachi M.
      • Nosyreva E.
      • Na E.S.
      • Los M.F.
      • Cheng P.F.
      • et al.
      NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
      ,
      • Nosyreva E.
      • Szabla K.
      • Autry A.E.
      • Ryazanov A.G.
      • Monteggia L.M.
      • Kavalali E.T.
      Acute suppression of spontaneous neurotransmission drives synaptic potentiation.
      ). The notion that an NMDA receptor antagonist produces an augmentation of synaptic responses at CA3-CA1 synapses is at first perplexing, as data over the past 2 decades have shown that brief applications of NMDA receptor antagonists on hippocampal slices results in no detectable synaptic effects. However, when ketamine is perfused for 30 minutes on a hippocampal slice, similar to the time of the ketamine infusion, and then washed out, a robust augmentation of field excitatory postsynaptic potentials is observed at CA3-CA1 synapses. This augmentation is observed by blocking NMDA receptors, suggesting that it is due to a form of homeostatic, non-Hebbian type of plasticity (
      • Kavalali E.T.
      • Monteggia L.M.
      Targeting homeostatic synaptic plasticity for treatment of mood disorders.
      ). This form of homeostatic synaptic plasticity is closely associated with ketamine’s antidepressant effects in that deletion of eEF2K inhibits ketamine’s antidepressant-like action and the augmented synaptic potentiation. Deletion of BDNF also blocks ketamine’s antidepressant-like effects as well as the synaptic potentiation. This body of work has built a crucial link between synaptic transmission and antidepressant action. The identification of the engagement of homeostatic plasticity by ketamine provides an avenue to an understanding of how ketamine may compensate circuit dysfunction or activate dormant mechanisms of patients with depression that are not evoked under normal physiological circumstances.
      A third hypothesis for how ketamine exerts antidepressant effects suggests direct binding to the TrkB receptor. As described above, typical antidepressants were found to directly bind to a site formed by two transmembrane domains of TrkB within the plasma membrane, which promotes the synaptic localization TrkB, thereby increasing the probability of BDNF binding to TrkB and activating it (Figure 1) (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ). Unexpectedly, ketamine and esketamine displace fluoxetine from this binding site with an affinity that is in the same range as the affinity of ketamine to NMDA receptors, suggesting that they, too, bind to this same site on TrkB. This study also reported that the Y433F mutation of the TrkB receptor blocks the binding and antidepressant-like effects of typical antidepressants as well as those of ketamine (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ). This TrkB receptor mutation also blocked ketamine’s effects on surface localization of AMPA receptors, indicating that increased AMPA signaling is a downstream effect of TrkB activation (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ). Moreover, (2R,6R)-hydroxynorketamine, the ketamine metabolite reported to be NMDA receptor–independent (
      • Zanos P.
      • Moaddel R.
      • Morris P.J.
      • Georgiou P.
      • Fischell J.
      • Elmer G.I.
      • et al.
      NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
      ) [but see (
      • Suzuki K.
      • Nosyreva E.
      • Hunt K.W.
      • Kavalali E.T.
      • Monteggia L.M.
      Effects of a ketamine metabolite on synaptic NMDAR function.
      )], directly binds to TrkB with an affinity comparable to that of ketamine, but clearly higher than its affinity to NMDA receptor, and this binding is lost in the Y433F TrkB mutants. Collectively, these data suggest that direct binding to TrkB may be a common mechanism of action for typical as well as rapid-acting antidepressants (
      • Casarotto P.C.
      • Girych M.
      • Fred S.M.
      • Kovaleva V.
      • Moliner R.
      • Enkavi G.
      • et al.
      Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
      ).
      It is intriguing that these three main hypotheses on the rapid antidepressant effects of ketamine all involve a critical role for BDNF and/or TrkB signaling. In support of this premise, deletion of BDNF or TrkB in broad forebrain regions of mice blocks ketamine’s antidepressant-like behavioral effects as well as the hippocampal synaptic potentiation that has been suggested as a key correlate of rapid antidepressant action (
      • Nosyreva E.
      • Szabla K.
      • Autry A.E.
      • Ryazanov A.G.
      • Monteggia L.M.
      • Kavalali E.T.
      Acute suppression of spontaneous neurotransmission drives synaptic potentiation.
      ,
      • Nosyreva E.
      • Autry A.E.
      • Kavalali E.T.
      • Monteggia L.M.
      Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade.
      ). Other studies have also reported a key role for BDNF in the antidepressant action of ketamine (
      • Zhou W.
      • Wang N.
      • Yang C.
      • Li X.M.
      • Zhou Z.Q.
      • Yang J.J.
      Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.
      ,
      • Yang C.
      • Hu Y.M.
      • Zhou Z.Q.
      • Zhang G.F.
      • Yang J.J.
      Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.
      ). In addition, BDNF signaling has been implicated in the effects of other anesthetic agents with putative antidepressant effects (
      • Antila H.
      • Ryazantseva M.
      • Popova D.
      • Sipila P.
      • Guirado R.
      • Kohtala S.
      • et al.
      Isoflurane produces antidepressant effects and induces TrkB signaling in rodents.
      ,
      • Rantamaki T.
      • Kohtala S.
      Encoding, consolidation, and renormalization in depression: Synaptic homeostasis, plasticity, and sleep integrate rapid antidepressant effects.
      ). Moreover, knock-in mice expressing the BDNF Val66Met polymorphism, which have impaired BDNF mRNA trafficking to dendrites, do not show antidepressant-like responses to ketamine (
      • Liu R.J.
      • Lee F.S.
      • Li X.Y.
      • Bambico F.
      • Duman R.S.
      • Aghajanian G.K.
      Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex.
      ). However, studies examining ketamine action in patients with a Met allele compared with individuals with the Val/Val allele have yielded conflicting data. An initial study examined ketamine response in depressed patients and reported an increase in the likelihood of response in individuals with the BDNF Val/Val allele compared with patients with a Met allele (
      • Laje G.
      • Lally N.
      • Mathews D.
      • Brutsche N.
      • Chemerinski A.
      • Akula N.
      • et al.
      Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients.
      ). However, a larger study did not find any difference in ketamine response between depressed patients with the Val/Val allele and patients the Met allele (
      • Su T.P.
      • Chen M.H.
      • Li C.T.
      • Lin W.C.
      • Hong C.J.
      • Gueorguieva R.
      • et al.
      Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression.
      ). While more research is necessary to elucidate the role of BDNF signaling in the antidepressant response of patients, it will also be important to identify the full scope of genetic determinants that influence antidepressant responsiveness.
      We have focused on the three main hypotheses of ketamine action; however, others have been proposed that were not discussed owing to space limitations. While there is still much work to be done to understand ketamine’s mechanism of action, the current models provide testable hypotheses that will hopefully contribute to the development of faster-acting antidepressants without the associated side effects. One key consideration when comparing studies is the dose of ketamine administered, which can often vary widely and provide conflicting data. Preclinical work has shown that a low dose of ketamine produces an antidepressant-like response, while increasing doses curtail antidepressant responses, intracellular signaling, and the synaptic potentiation in the hippocampus (
      • Kim J.W.
      • Monteggia L.M.
      Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways.
      ). Another key issue to consider is that ketamine’s antidepressant effects are not mimicked by the closely related NMDA receptor antagonist memantine (
      • Lenze E.J.
      • Skidmore E.R.
      • Begley A.E.
      • Newcomer J.W.
      • Butters M.A.
      • Whyte E.M.
      Memantine for late-life depression and apathy after a disabling medical event: A 12-week, double-blind placebo-controlled pilot study.
      ,
      • Ferguson J.M.
      • Shingleton R.N.
      An open-label, flexible-dose study of memantine in major depressive disorder.
      ,
      • Zarate C.A.J.
      • Singh J.B.
      • Quiroz J.A.
      • De Jesus G.
      • Denicoff K.K.
      • Luckenbaugh D.A.
      • et al.
      A double-blind, placebo-controlled study of memantine in the treatment of major depression.
      ). The second model described above can explain why ketamine exerts antidepressant effects while memantine cannot (
      • Gideons E.S.
      • Kavalali E.T.
      • Monteggia L.M.
      Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses.
      ). Therefore, alternative proposals should also include memantine as a negative control. Work over the next several years will hopefully provide critical insight into rapid antidepressant action as well as whether these effects can be extended.

      Conclusions

      Twenty-five years have passed since Duman’s group (
      • Duman R.S.
      • Monteggia L.M.
      A neurotrophic model for stress-related mood disorders.
      ,
      • Nibuya M.
      • Morinobu S.
      • Duman R.S.
      Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
      ,
      • Duman R.S.
      • Heninger G.R.
      • Nestler E.J.
      A molecular and cellular theory of depression.
      ) proposed the connection between neurotrophic factors, mood disorders, and the antidepressant effect. Since then, converging data from a variety of preclinical and clinical studies implicate impaired BDNF signaling through TrkB in the pathophysiology of mood disorders, although especially genetic evidence has recently not supported this notion, and deficiencies in BDNF signaling are not specific to mood disorders. However, there is solid evidence to indicate that increased expression and signaling of BDNF is critical in the mechanisms of both typical and rapid-acting antidepressant drugs. As BDNF is a critical mediator of various types of synaptic plasticity, these data suggest that restricted plasticity may underlie depression and that promotion of plasticity enhances mood recovery. As plastic networks need experience-dependent activity to guide their selection (
      • Kavalali E.T.
      • Monteggia L.M.
      Targeting homeostatic synaptic plasticity for treatment of mood disorders.
      ,
      • Maya Vetencourt J.F.
      • Sale A.
      • Viegi A.
      • Baroncelli L.
      • De Pasquale R.
      • O’Leary O.F.
      • et al.
      The antidepressant fluoxetine restores plasticity in the adult visual cortex.
      ,
      • Castrén E.
      Neuronal network plasticity and recovery from depression.
      ), these data suggest a new paradigm for the treatment of mood disorders, where pharmacological and psychological approaches are closely intertwined, emphasizing the need for the active participation of the patient in successful antidepressant drug treatment.

      Acknowledgments and Disclosures

      This work was supported by the European Research Council Advanced Grant (Grant No. 322742 –iPLASTICITY [to Castrén laboratory]), Academy of Finland (Grant Nos. 294710 , 327192 , and 307416 [to Castrén laboratory]), Sigrid Jusélius Foundation (to Castrén laboratory), Jane and Aatos Erkko Foundation (to Castrén laboratory), and National Institutes of Health (Grant Nos. MH070727 and MH081060 [to Monteggia laboratory]).
      EC has received a speaker fee from Janssen Cilag. LM has received a speaker fee from Concert Pharmaceuticals and Acadia and is on the Scientific Advisory Board of Gilgamesh.

      References

        • Duman R.S.
        • Monteggia L.M.
        A neurotrophic model for stress-related mood disorders.
        Biol Psychiatry. 2006; 59: 1116-1127
        • Bjorkholm C.
        • Monteggia L.M.
        BDNF—a key transducer of antidepressant effects.
        Neuropharmacology. 2016; 102: 72-79
        • Castrén E.
        • Kojima M.
        Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.
        Neurobiol Dis. 2017; 97: 119-126
        • Hing B.
        • Sathyaputri L.
        • Potash J.B.
        A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder.
        Am J Med Genet B Neuropsychiatr Genet. 2018; 177: 143-167
        • Nibuya M.
        • Morinobu S.
        • Duman R.S.
        Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
        J Neurosci. 1995; 15: 7539-7547
        • Duman R.S.
        • Heninger G.R.
        • Nestler E.J.
        A molecular and cellular theory of depression.
        Arch Gen Psychiatry. 1997; 54: 597-606
        • Duman R.S.
        • Deyama S.
        • Fogaca M.V.
        Role of BDNF in the pathophysiology and treatment of depression: Activity dependent effects distinguish rapid acting antidepressants.
        Eur J Neurosci. 2021; 53: 126-139
        • Park H.
        • Poo M.M.
        Neurotrophin regulation of neural circuit development and function.
        Nat Rev Neurosci. 2013; 14: 7-23
        • Zagrebelsky M.
        • Korte M.
        Form follows function: BDNF and its involvement in sculpting the function and structure of synapses.
        Neuropharmacology. 2014; 76: 628-638
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Nosyreva E.
        • Szabla K.
        • Autry A.E.
        • Ryazanov A.G.
        • Monteggia L.M.
        • Kavalali E.T.
        Acute suppression of spontaneous neurotransmission drives synaptic potentiation.
        J Neurosci. 2013; 33: 6990-7002
        • Gideons E.S.
        • Kavalali E.T.
        • Monteggia L.M.
        Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses.
        Proc Natl Acad Sci U S A. 2014; 111: 8649-8654
        • Kavalali E.T.
        • Monteggia L.M.
        Targeting homeostatic synaptic plasticity for treatment of mood disorders.
        Neuron. 2020; 106: 715-726
        • Dwivedi Y.
        Involvement of brain-derived neurotrophic factor in late-life depression.
        Am J Geriatr Psychiatry. 2013; 21: 433-449
        • Dunham J.S.
        • Deakin J.F.
        • Miyajima F.
        • Payton A.
        • Toro C.T.
        Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains.
        J Psychiatr Res. 2009; 43: 1175-1184
        • Ray M.T.
        • Weickert C.S.
        • Wyatt E.
        • Webster M.J.
        Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders.
        J Psychiatry Neurosci. 2011; 36: 195-203
        • Ray M.T.
        • Shannon Weickert C.
        • Webster M.J.
        Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders.
        Transl Psychiatry. 2014; 4: e389
        • Guilloux J.P.
        • Douillard-Guilloux G.
        • Kota R.
        • Wang X.
        • Gardier A.M.
        • Martinowich K.
        • et al.
        Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression.
        Mol Psychiatry. 2012; 17: 1130-1142
        • Dwivedi Y.
        • Rizavi H.S.
        • Conley R.R.
        • Roberts R.C.
        • Tamminga C.A.
        • Pandey G.N.
        Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.
        Arch Gen Psychiatry. 2003; 60: 804-815
        • Dwivedi Y.
        • Rizavi H.S.
        • Zhang H.
        • Mondal A.C.
        • Roberts R.C.
        • Conley R.R.
        • et al.
        Neurotrophin receptor activation and expression in human postmortem brain: Effect of suicide.
        Biol Psychiatry. 2009; 65: 319-328
        • Chen B.
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
        Biol Psychiatry. 2001; 50: 260-265
        • Youssef M.M.
        • Underwood M.D.
        • Huang Y.Y.
        • Hsiung S.C.
        • Liu Y.
        • Simpson N.R.
        • et al.
        Association of BDNF Val66Met polymorphism and brain BDNF levels with major depression and suicide.
        Int J Neuropsychopharmacol. 2018; 21: 528-538
        • Pandey G.N.
        • Ren X.
        • Rizavi H.S.
        • Conley R.R.
        • Roberts R.C.
        • Dwivedi Y.
        Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims.
        Int J Neuropsychopharmacol. 2008; 11: 1047-1061
        • Dwivedi Y.
        Brain-derived neurotrophic factor: Role in depression and suicide.
        Neuropsychiatr Dis Treat. 2009; 5: 433-449
        • Carlino D.
        • De Vanna M.
        • Tongiorgi E.
        Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions.
        Neuroscientist. 2013; 19: 345-353
        • Michalski B.
        • Corrada M.M.
        • Kawas C.H.
        • Fahnestock M.
        Brain-derived neurotrophic factor and TrkB expression in the “oldest-old,” the 90+ Study: Correlation with cognitive status and levels of soluble amyloid-beta.
        Neurobiol Aging. 2015; 36: 3130-3139
        • Roy B.
        • Shelton R.C.
        • Dwivedi Y.
        DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation.
        J Psychiatr Res. 2017; 89: 115-124
        • Kim J.M.
        • Kang H.J.
        • Bae K.Y.
        • Kim S.W.
        • Shin I.S.
        • Kim H.R.
        • et al.
        Association of BDNF promoter methylation and genotype with suicidal ideation in elderly Koreans.
        Am J Geriatr Psychiatry. 2014; 22: 989-996
        • Schroter K.
        • Brum M.
        • Brunkhorst-Kanaan N.
        • Tole F.
        • Ziegler C.
        • Domschke K.
        • et al.
        Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder.
        Eur Arch Psychiatry Clin Neurosci. 2020; 270: 169-181
        • Keller S.
        • Sarchiapone M.
        • Zarrilli F.
        • Videtic A.
        • Ferraro A.
        • Carli V.
        • et al.
        Increased BDNF promoter methylation in the Wernicke area of suicide subjects.
        Arch Gen Psychiatry. 2010; 67: 258-267
        • Tripp A.
        • Oh H.
        • Guilloux J.P.
        • Martinowich K.
        • Lewis D.A.
        • Sibille E.
        Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.
        Am J Psychiatry. 2012; 169: 1194-1202
        • Kohli M.A.
        • Salyakina D.
        • Pfennig A.
        • Lucae S.
        • Horstmann S.
        • Menke A.
        • et al.
        Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.
        Arch Gen Psychiatry. 2010; 67: 348-359
        • Egan M.F.
        • Kojima M.
        • Callicott J.H.
        • Goldberg T.E.
        • Kolachana B.S.
        • Bertolino A.
        • et al.
        The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.
        Cell. 2003; 112: 257-269
        • Shimizu E.
        • Hashimoto K.
        • Iyo M.
        Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: The possibility to explain ethnic mental traits.
        Am J Med Genet B Neuropsychiatr Genet. 2004; 126B: 122-123
        • Chen Z.Y.
        • Jing D.
        • Bath K.G.
        • Ieraci A.
        • Khan T.
        • Siao C.J.
        • et al.
        Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.
        Science. 2006; 314: 140-143
        • Baj G.
        • Carlino D.
        • Gardossi L.
        • Tongiorgi E.
        Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: A model of impaired dendritic mRNA trafficking.
        Front Neurosci. 2013; 7: 188
        • Bath K.G.
        • Lee F.S.
        Variant BDNF (Val66Met) impact on brain structure and function.
        Cogn Affect Behav Neurosci. 2006; 6: 79-85
        • Gyekis J.P.
        • Yu W.
        • Dong S.
        • Wang H.
        • Qian J.
        • Kota P.
        • et al.
        No association of genetic variants in BDNF with major depression: A meta- and gene-based analysis.
        Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 61-70
        • Li M.
        • Chang H.
        • Xiao X.
        BDNF Val66Met polymorphism and bipolar disorder in European populations: A risk association in case-control, family-based and GWAS studies.
        Neurosci Biobehav Rev. 2016; 68: 218-233
        • Verhagen M.
        • van der Meij A.
        • van Deurzen P.A.
        • Janzing J.G.
        • Arias-Vasquez A.
        • Buitelaar J.K.
        • et al.
        Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: Effects of gender and ethnicity.
        Mol Psychiatry. 2010; 15: 260-271
        • Licinio J.
        • Dong C.
        • Wong M.L.
        Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response.
        Arch Gen Psychiatry. 2009; 66: 488-497
        • Hing B.
        • Davidson S.
        • Lear M.
        • Breen G.
        • Quinn J.
        • McGuffin P.
        • et al.
        A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
        Biol Psychiatry. 2012; 71: 618-626
        • Juhasz G.
        • Dunham J.S.
        • McKie S.
        • Thomas E.
        • Downey D.
        • Chase D.
        • et al.
        The CREB1-BDNF-NTRK2 pathway in depression: Multiple gene-cognition-environment interactions.
        Biol Psychiatry. 2011; 69: 762-771
        • Kaufman J.
        • Yang B.Z.
        • Douglas-Palumberi H.
        • Grasso D.
        • Lipschitz D.
        • Houshyar S.
        • et al.
        Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children.
        Biol Psychiatry. 2006; 59: 673-680
        • Aguilera M.
        • Arias B.
        • Wichers M.
        • Barrantes-Vidal N.
        • Moya J.
        • Villa H.
        • et al.
        Early adversity and 5-HTT/BDNF genes: New evidence of gene-environment interactions on depressive symptoms in a general population.
        Psychol Med. 2009; 39: 1425-1432
        • Frodl T.
        • Skokauskas N.
        • Frey E.M.
        • Morris D.
        • M. Gill M
        • Carballedo A.
        BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields.
        Hum Brain Mapp. 2014; 35: 5776-5783
        • Carballedo A.
        • Morris D.
        • Zill P.
        • Fahey C.
        • Reinhold E.
        • Meisenzahl E.
        • et al.
        Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.
        Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 183-190
        • Hosang G.M.
        • Shiles C.
        • Tansey K.E.
        • McGuffin P.
        • Uher R.
        Interaction between stress and the BDNF Val66Met polymorphism in depression: A systematic review and meta-analysis.
        BMC Med. 2014; 12: 7
        • Zhao M.
        • Chen L.
        • Yang J.
        • Han D.
        • Fang D.
        • Qiu X.
        • et al.
        BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.
        J Affect Disord. 2018; 227: 226-235
        • Bath K.G.
        • Jing D.Q.
        • Dincheva I.
        • Neeb C.C.
        • Pattwell S.S.
        • Chao M.V.
        • et al.
        BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity.
        Neuropsychopharmacology. 2012; 37: 1297-1304
        • Liu R.J.
        • Lee F.S.
        • Li X.Y.
        • Bambico F.
        • Duman R.S.
        • Aghajanian G.K.
        Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex.
        Biol Psychiatry. 2012; 71: 996-1005
        • Fukumoto K.
        • Fogaca M.V.
        • Liu R.J.
        • Duman C.
        • Kato T.
        • Li X.Y.
        • et al.
        Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.
        Proc Natl Acad Sci U S A. 2019; 116: 297-302
        • Yan T.
        • Wang L.
        • Kuang W.
        • Xu J.
        • Li S.
        • Chen J.
        • et al.
        Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: A systematic review and meta-analysis.
        Asia Pac Psychiatry. 2014; 6: 241-251
        • Choi M.J.
        • Kang R.H.
        • Lim S.W.
        • Oh K.S.
        • Lee M.S.
        Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder.
        Brain Res. 2006; 1118: 176-182
        • Colle R.
        • Deflesselle E.
        • Martin S.
        • David D.J.
        • Hardy P.
        • Taranu A.
        • et al.
        BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients.
        Pharmacogenomics. 2015; 16: 997-1013
        • Domschke K.
        • Lawford B.
        • Laje G.
        • Berger K.
        • Young R.
        • Morris P.
        • et al.
        Brain-derived neurotrophic factor (BDNF) gene: No major impact on antidepressant treatment response.
        Int J Neuropsychopharmacol. 2010; 13: 93-101
        • Niitsu T.
        • Fabbri C.
        • Bentini F.
        • Serretti A.
        Pharmacogenetics in major depression: A comprehensive meta-analysis.
        Prog Neuropsychopharmacol Biol Psychiatry. 2013; 45: 183-194
        • Yamamoto H.
        • Gurney M.E.
        Human platelets contain brain-derived neurotrophic factor.
        J Neurosci. 1990; 10: 3469-3478
        • Radka S.F.
        • Holst P.A.
        • Fritsche M.
        • Altar C.A.
        Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay.
        Brain Res. 1996; 709: 122-301
        • Serra-Millas M.
        Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation.
        World J Psychiatry. 2016; 6: 84-101
        • Korhonen L.
        • Riikonen R.
        • Nawa H.
        • Lindholm D.
        Brain derived neurotrophic factor is increased in cerebrospinal fluid of children suffering from asphyxia.
        Neurosci Lett. 1998; 240: 151-154
        • Naegelin Y.
        • Dingsdale H.
        • Sauberli K.
        • Schadelin S.
        • Kappos L.
        • Barde Y.A.
        Measuring and validating the levels of brain-derived neurotrophic factor in human serum.
        eNeuro. 2018; 5 (ENEURO.0419-17.2018)
        • Lommatzsch M.
        • Zingler D.
        • Schuhbaeck K.
        • Schloetcke K.
        • Zingler C.
        • Schuff-Werner P.
        • et al.
        The impact of age, weight and gender on BDNF levels in human platelets and plasma.
        Neurobiol Aging. 2005; 26: 115-123
        • Fujimura H.
        • Altar C.A.
        • Chen R.
        • Nakamura T.
        • Nakahashi T.
        • Kambayashi J.
        • et al.
        Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation.
        Thromb Haemost. 2002; 87: 728-734
        • Seifert T.
        • Brassard P.
        • Wissenberg M.
        • Rasmussen P.
        • Nordby P.
        • Stallknecht B.
        • et al.
        Endurance training enhances BDNF release from the human brain.
        Am J Physiol Regul Integr Comp Physiol. 2010; 298: R372-R377
        • Tamura S.
        • Suzuki H.
        • Hirowatari Y.
        • Hatase M.
        • Nagasawa A.
        • Matsuno K.
        • et al.
        Release reaction of brain-derived neurotrophic factor (BDNF) through PAR1 activation and its two distinct pools in human platelets.
        Thromb Res. 2011; 128: e55-e61
        • Tamura S.
        • Nagasawa A.
        • Masuda Y.
        • Tsunematsu T.
        • Hayasaka K.
        • Matsuno K.
        • et al.
        BDNF, produced by a TPO-stimulated megakaryocytic cell line, regulates autocrine proliferation.
        Biochem Biophys Res Commun. 2012; 427: 542-546
        • Chacón-Fernández P.
        • Säuberli K.
        • Colzani M.
        • Moreau T.
        • Ghevaert C.
        • Barde Y.A.
        Brain-derived neurotrophic factor in megakaryocytes.
        J Biol Chem. 2016; 291: 9872-9881
        • Karege F.
        • Perret G.
        • Bondolfi G.
        • Schwald M.
        • Bertschy G.
        • Aubry J.M.
        Decreased serum brain-derived neurotrophic factor levels in major depressed patients.
        Psychiatry Res. 2002; 109: 143-148
        • Shimizu E.
        • Hashimoto K.
        • Okamura N.
        • Koike K.
        • Komatsu N.
        • Kumakiri C.
        • et al.
        Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.
        Biol Psychiatry. 2003; 54: 70-75
        • Sen S.
        • Duman R.
        • Sanacora G.
        Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications.
        Biol Psychiatry. 2008; 64: 527-532
        • Karege F.
        • Bondolfi G.
        • Gervasoni N.
        • Schwald M.
        • Aubry J.M.
        • Bertschy G.
        Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.
        Biol Psychiatry. 2005; 57: 1068-1072
        • Bocchio-Chiavetto L.
        • Bagnardi V.
        • Zanardini R.
        • Molteni R.
        • Nielsen M.G.
        • Placentino A.
        • et al.
        Serum and plasma BDNF levels in major depression: A replication study and meta-analyses.
        World J Biol Psychiatry. 2010; 11: 763-773
        • Gonul A.S.
        • Akdeniz F.
        • Taneli F.
        • Donat O.
        • Eker C.
        • Vahip S.
        Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients.
        Eur Arch Psychiatry Clin Neurosci. 2005; 255: 381-386
        • Piccinni A.
        • Marazziti D.
        • Catena M.
        • Domenici L.
        • Del Debbio A.
        • Bianchi C.
        • et al.
        Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments.
        J Affect Disord. 2008; 105: 279-283
        • Matrisciano F.
        • Bonaccorso S.
        • Ricciardi A.
        • Scaccianoce S.
        • Panaccione I.
        • Wang L.
        • et al.
        Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine.
        J Psychiatr Res. 2009; 43: 247-254
        • Yoshimura R.
        • Mitoma M.
        • Sugita A.
        • Hori H.
        • Okamoto T.
        • Umene W.
        • et al.
        Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients.
        Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 1034-1037
        • Hellweg R.
        • Ziegenhorn A.
        • Heuser I.
        • Deuschle M.
        Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.
        Pharmacopsychiatry. 2008; 41: 66-71
        • Molendijk M.L.
        • Bus B.A.
        • Spinhoven P.
        • Penninx B.W.
        • Kenis G.
        • Prickaerts J.
        • et al.
        Serum levels of brain-derived neurotrophic factor in major depressive disorder: State-trait issues, clinical features and pharmacological treatment.
        Mol Psychiatry. 2011; 16: 1088-1095
        • Bocchio-Chiavetto L.
        • Zanardini R.
        • Bortolomasi M.
        • Abate M.
        • Segala M.
        • Giacopuzzi M.
        • et al.
        Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients.
        Eur Neuropsychopharmacol. 2006; 16: 620-624
        • Rocha R.B.
        • Dondossola E.R.
        • Grande A.J.
        • Colonetti T.
        • Ceretta L.B.
        • Passos I.C.
        • et al.
        Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: A meta-analysis study.
        J Psychiatr Res. 2016; 83: 47-53
        • Lang U.E.
        • Bajbouj M.
        • Gallinat J.
        • Hellweg R.
        Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation.
        Psychopharmacology (Berl). 2006; 187: 56-59
        • Molendijk M.L.
        • Spinhoven P.
        • Polak M.
        • Bus B.A.
        • Penninx B.W.
        • Elzinga B.M.
        Serum BDNF concentrations as peripheral manifestations of depression: Evidence from a systematic review and meta-analyses on 179 associations (N=9484).
        Mol Psychiatry. 2014; 19: 791-800
        • Polacchini A.
        • Metelli G.
        • Francavilla R.
        • Baj G.
        • Florean M.
        • Mascaretti L.G.
        • et al.
        A method for reproducible measurements of serum BDNF: Comparison of the performance of six commercial assays.
        Sci Rep. 2015; 5: 17989
        • Yoshida T.
        • Ishikawa M.
        • Niitsu T.
        • Nakazato M.
        • Watanabe H.
        • Shiraishi T.
        • et al.
        Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder.
        PLoS One. 2012; 7e42676
        • Sodersten K.
        • Palsson E.
        • Ishima T.
        • Funa K.
        • Landen M.
        • Hashimoto K.
        • et al.
        Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: A study of two independent cohorts.
        J Affect Disord. 2014; 160: 1-9
        • Zhao G.
        • Zhang C.
        • Chen J.
        • Su Y.
        • Zhou R.
        • Wang F.
        • et al.
        Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression.
        Mol Neurobiol. 2017; 54: 5573-5582
        • Toyooka K.
        • Asama K.
        • Watanabe Y.
        • Muratake T.
        • Takahashi M.
        • Someya T.
        • et al.
        Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients.
        Psychiatry Res. 2002; 110: 249-257
        • Fernandes B.S.
        • Steiner J.
        • Berk M.
        • Molendijk M.L.
        • Gonzalez-Pinto A.
        • Turck C.W.
        • et al.
        Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: Meta-analysis and implications.
        Mol Psychiatry. 2015; 20: 1108-1119
        • Kimhy D.
        • Vakhrusheva J.
        • Bartels M.N.
        • Armstrong H.F.
        • Ballon J.S.
        • Khan S.
        • et al.
        The impact of aerobic exercise on brain-derived neurotrophic factor and neurocognition in individuals with schizophrenia: A single-blind, randomized clinical trial.
        Schizophr Bull. 2015; 41: 859-868
        • Hashimoto K.
        • Iwata Y.
        • Nakamura K.
        • Tsujii M.
        • Tsuchiya K.J.
        • Sekine Y.
        • et al.
        Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism.
        Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30: 1529-1531
        • Katoh-Semba R.
        • Wakako R.
        • Komori T.
        • Shigemi H.
        • Miyazaki N.
        • Ito H.
        • et al.
        Age-related changes in BDNF protein levels in human serum: Differences between autism cases and normal controls.
        Int J Dev Neurosci. 2007; 25: 367-372
        • Tuomisto J.
        • Tukiainen E.
        Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients.
        Nature. 1976; 262: 596-598
        • Blair P.
        • Flaumenhaft R.
        Platelet alpha-granules: Basic biology and clinical correlates.
        Blood Rev. 2009; 23: 177-189
        • Girgenti M.J.
        • Pothula S.
        • Newton S.S.
        Stress and its impact on the transcriptome.
        Biol Psychiatry. 2021; 90: 102-108
        • Ploski J.E.
        • Vaidya V.A.
        The neurocircuitry of posttraumatic stress disorder and major depression: Insights into overlapping and distinct circuit dysfunction—A tribute to Ron Duman.
        Biol Psychiatry. 2021; 90: 109-117
        • Autry A.E.
        • Monteggia L.M.
        Brain-derived neurotrophic factor and neuropsychiatric disorders.
        Pharmacol Rev. 2012; 64: 238-258
        • Saarelainen T.
        • Hendolin P.
        • Lucas G.
        • Koponen E.
        • Sairanen M.
        • MacDonald E.
        • et al.
        Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.
        J Neurosci. 2003; 23: 349-357
        • Rantamäki T.
        • Hendolin P.
        • Kankaanpaa A.
        • Mijatovic J.
        • Piepponen P.
        • Domenici E.
        • et al.
        Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-C gamma signaling pathways in mouse brain.
        Neuropsychopharmacology. 2007; 32: 2152-2162
        • Casarotto P.C.
        • Girych M.
        • Fred S.M.
        • Kovaleva V.
        • Moliner R.
        • Enkavi G.
        • et al.
        Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
        Cell. 2021; 184: 1299-1313.e19
        • Karson C.N.
        • Newton J.E.
        • Livingston R.
        • Jolly J.B.
        • Cooper T.B.
        • Sprigg J.
        • et al.
        Human brain fluoxetine concentrations.
        J Neuropsychiatry Clin Neurosci. 1993; 5: 322-329
        • Monteggia L.M.
        • Barrot M.
        • Powell C.M.
        • Berton O.
        • Galanis V.
        • Gemelli T.
        • et al.
        Essential role of brain-derived neurotrophic factor in adult hippocampal function.
        Proc Natl Acad Sci U S A. 2004; 101: 10827-10832
        • Adachi M.
        • Barrot M.
        • Autry A.E.
        • Theobald D.
        • Monteggia L.M.
        Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy.
        Biol Psychiatry. 2008; 63: 642-649
        • Li Y.
        • Luikart B.W.
        • Birnbaum S.
        • Chen J.
        • Kwon C.H.
        • Kernie S.G.
        • et al.
        TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment.
        Neuron. 2008; 59: 399-412
        • Guirado R.
        • Perez-Rando M.
        • Sanchez-Matarredona D.
        • Castrén E.
        • Nacher J.
        Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons.
        Int J Neuropsychopharmacol. 2014; 17: 1635-1646
        • Gerhard D.M.
        • Pothula S.
        • Liu R.J.
        • Wu M.
        • Li X.Y.
        • Girgenti M.J.
        • et al.
        GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions.
        J Clin Invest. 2020; 130: 1336-1349
        • Wohleb E.S.
        • Wu M.
        • Gerhard D.M.
        • Taylor S.R.
        • Picciotto M.R.
        • Alreja M.
        • et al.
        GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.
        J Clin Invest. 2016; 126: 2482-2494
        • Yang C.
        • Shirayama Y.
        • Zhang J.C.
        • Ren Q.
        • Yao W.
        • Ma M.
        • et al.
        R-ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects.
        Transl Psychiatry. 2015; 5e632
        • Ohira K.
        • Takeuchi R.
        • Iwanaga T.
        • Miyakawa T.
        Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice.
        Mol Brain. 2013; 6: 43
        • Sagi Y.
        • Medrihan L.
        • George K.
        • Barney M.
        • McCabe K.A.
        • Greengard P.
        Emergence of 5-HT5A signaling in parvalbumin neurons mediates delayed antidepressant action.
        Mol Psychiatry. 2020; 25: 1191-1201
        • Donegan J.J.
        • Lodge D.J.
        Hippocampal perineuronal nets are required for the sustained antidepressant effect of ketamine.
        Int J Neuropsychopharmacol. 2017; 20: 354-358
        • Umemori J.
        • Winkel F.
        • Castren E.
        • Karpova N.N.
        Distinct effects of perinatal exposure to fluoxetine or methylmercury on parvalbumin and perineuronal nets, the markers of critical periods in brain development.
        Int J Dev Neurosci. 2015; 44: 55-64
        • Pozzi L.
        • Pollak Dorocic I.
        • Wang X.
        • Carlen M.
        • Meletis K.
        Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.
        PLoS One. 2014; 9e83879
      1. Winkel F, Ryazantseva M, Voigt MB, Didio G, Lilja A, Pou ML, et al. (In press): Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulates intrinsic states to orchestrate cortical plasticity. Mol Psychiatry.

        • Lesnikova A.
        • Casarotto P.C.
        • Fred S.M.
        • Voipio M.
        • Winkel F.
        • Steinzeig A.
        • et al.
        Chondroitinase and antidepressants promote plasticity by releasing TRKB from dephosphorylating control of PTPσ in parvalbumin neurons.
        J Neurosci. 2021; 41: 972-980
        • Carceller H.
        • Perez-Rando M.
        • Castren E.
        • Nacher J.
        • Guirado R.
        Effects of the antidepressant fluoxetine on the somatostatin interneurons in the basolateral amygdala.
        Neuroscience. 2018; 386: 205-213
        • Siuciak J.A.
        • Lewis D.R.
        • Wiegand S.J.
        • Lindsay R.M.
        Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).
        Pharmacol Biochem Behav. 1997; 56: 131-137
        • Adachi M.
        • Autry A.E.
        • Mahgoub M.
        • Suzuki K.
        • Monteggia L.M.
        TrkB signaling in dorsal raphe nucleus is essential for antidepressant efficacy and normal aggression behavior.
        Neuropsychopharmacology. 2017; 42: 886-894
        • Sahu M.P.
        • Pazos-Boubeta Y.
        • Steinzeig A.
        • Kaurinkoski K.
        • Palmisano M.
        • Borowecki O.
        • et al.
        Depletion of TrkB receptors from adult serotonergic neurons increases brain serotonin levels, enhances energy metabolism and impairs learning and memory.
        Front Mol Neurosci. 2021; 14: 616178
        • Cao L.
        • Jiao X.
        • Zuzga D.S.
        • Liu Y.
        • Fong D.M.
        • Young D.
        • et al.
        VEGF links hippocampal activity with neurogenesis, learning and memory.
        Nat Genet. 2004; 36: 827-835
        • Greene J.
        • Banasr M.
        • Lee B.
        • Warner-Schmidt J.
        • Duman R.S.
        Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: Pharmacological and cellular characterization.
        Neuropsychopharmacology. 2009; 34: 2459-2468
        • Warner-Schmidt J.L.
        • Duman R.S.
        VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.
        Proc Natl Acad Sci U S A. 2007; 104: 4647-4652
        • Kiuchi T.
        • Lee H.
        • Mikami T.
        Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice.
        Neuroscience. 2012; 207: 208-217
        • Deyama S.
        • Bang E.
        • Kato T.
        • Li X.Y.
        • Duman R.S.
        Neurotrophic and antidepressant actions of brain-derived neurotrophic factor require vascular endothelial growth factor.
        Biol Psychiatry. 2019; 86: 143-152
        • Widman A.J.
        • McMahon L.L.
        Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy.
        Proc Natl Acad Sci U S A. 2018; 115: E3007-E3016
        • Fuchs T.
        • Jefferson S.J.
        • Hooper A.
        • Yee P.H.
        • Maguire J.
        • Luscher B.
        Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.
        Mol Psychiatry. 2017; 22: 920-930
        • Pothula S.
        • Kato T.
        • Liu R.-J.
        • Wu M.
        • Gerhard D.
        • Shinohara R.
        • et al.
        Cell-type specific modulation of NMDA receptors triggers antidepressant actions [published online ahead of print Jun 2].
        Mol Psychiatry. 2020;
        • Picard N.
        • Takesian A.E.
        • Fagiolini M.
        • Hensch T.K.
        NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity.
        Mol Psychiatry. 2019; 24: 828-838
        • Li N.
        • Lee B.
        • Liu R.J.
        • Banasr M.
        • Dwyer J.M.
        • Iwata M.
        • et al.
        mTOR-Dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
        Science. 2010; 329: 959-964
        • Abdallah C.G.
        • Averill L.A.
        • Gueorguieva R.
        • Goktas S.
        • Purohit P.
        • Ranganathan M.
        • et al.
        Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.
        Neuropsychopharmacology. 2020; 45: 990-997
        • Zanos P.
        • Moaddel R.
        • Morris P.J.
        • Georgiou P.
        • Fischell J.
        • Elmer G.I.
        • et al.
        NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
        Nature. 2016; 533: 481-486
        • Suzuki K.
        • Nosyreva E.
        • Hunt K.W.
        • Kavalali E.T.
        • Monteggia L.M.
        Effects of a ketamine metabolite on synaptic NMDAR function.
        Nature. 2017; 546: E1-E3
        • Nosyreva E.
        • Autry A.E.
        • Kavalali E.T.
        • Monteggia L.M.
        Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade.
        Front Mol Neurosci. 2014; 7: 94
        • Zhou W.
        • Wang N.
        • Yang C.
        • Li X.M.
        • Zhou Z.Q.
        • Yang J.J.
        Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.
        Eur Psychiatry. 2014; 29: 419-423
        • Yang C.
        • Hu Y.M.
        • Zhou Z.Q.
        • Zhang G.F.
        • Yang J.J.
        Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.
        Ups J Med Sci. 2013; 118: 3-8
        • Antila H.
        • Ryazantseva M.
        • Popova D.
        • Sipila P.
        • Guirado R.
        • Kohtala S.
        • et al.
        Isoflurane produces antidepressant effects and induces TrkB signaling in rodents.
        Sci Rep. 2017; 7: 7811
        • Rantamaki T.
        • Kohtala S.
        Encoding, consolidation, and renormalization in depression: Synaptic homeostasis, plasticity, and sleep integrate rapid antidepressant effects.
        Pharmacol Rev. 2020; 72: 439-465
        • Laje G.
        • Lally N.
        • Mathews D.
        • Brutsche N.
        • Chemerinski A.
        • Akula N.
        • et al.
        Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients.
        Biol Psychiatry. 2012; 72: e27-e28
        • Su T.P.
        • Chen M.H.
        • Li C.T.
        • Lin W.C.
        • Hong C.J.
        • Gueorguieva R.
        • et al.
        Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression.
        Neuropsychopharmacology. 2017; 42: 2482-2492
        • Kim J.W.
        • Monteggia L.M.
        Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways.
        Behav Brain Res. 2020; 380: 112378
        • Lenze E.J.
        • Skidmore E.R.
        • Begley A.E.
        • Newcomer J.W.
        • Butters M.A.
        • Whyte E.M.
        Memantine for late-life depression and apathy after a disabling medical event: A 12-week, double-blind placebo-controlled pilot study.
        Int J Geriatr Psychiatry. 2012; 27: 974-980
        • Ferguson J.M.
        • Shingleton R.N.
        An open-label, flexible-dose study of memantine in major depressive disorder.
        Clin Neuropharmacol. 2007; 30: 136-144
        • Zarate C.A.J.
        • Singh J.B.
        • Quiroz J.A.
        • De Jesus G.
        • Denicoff K.K.
        • Luckenbaugh D.A.
        • et al.
        A double-blind, placebo-controlled study of memantine in the treatment of major depression.
        Am J Psychiatry. 2006; 163: 153-155
        • Maya Vetencourt J.F.
        • Sale A.
        • Viegi A.
        • Baroncelli L.
        • De Pasquale R.
        • O’Leary O.F.
        • et al.
        The antidepressant fluoxetine restores plasticity in the adult visual cortex.
        Science. 2008; 320: 385-388
        • Castrén E.
        Neuronal network plasticity and recovery from depression.
        JAMA Psychiatry. 2013; 70: 983-989