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Principles of neuroreceptor pet imaging_Donald F. Smith

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for Advanced Course in Clinical Pharmacodynamics, Aarhus University, May 23, 2013

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Principles of neuroreceptor pet imaging_Donald F. Smith

  1. 1. Principles of Molecular Brain Imagingin Depressive DisordersDonald F. SmithTranslational Neuropsychiatry UnitClinical InstituteAarhus University
  2. 2. Parkinsonian patients and F-DOPA studies
  3. 3. Principles of Molecular Brain Imagingin Depressive Disorders• The Challenges• Principles of PET• Principles of Molecular Neuroimaging• Actions of Mirtazapine & Enantiomers• [11C]Mirtazapine PET in Pig• Requirements for Human PET• Initial [11C]Mirtazapine PET in Humans• Toward Evidence-based Neuropsychiatry
  4. 4. How might one go aboutdetermining whether a particularneurochemical and/orneurophysiological process is causallyinvolved in affective disorders?
  5. 5. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of molecular neuroimaging• Actions of mirtazapine & enantiomers• [11C]Mirtazapine PET in pig• Requirements for human PET• Initial [11C]Mirtazapine PET in humans• Toward Evidence-based Neuropsychiatry
  6. 6. Principle of PET signal
  7. 7. NHHO CH2CH2NH21OOONHF2N NNHO2N3N NNHO2NI4CH3NHCH3OO5ONCH3H6 NSCH3H7NNOCH3BrCH38ONCNH3C CH3F9NH3CICO2CH3HH10NHCO2CH3CH3HH3C11OHOCH3NCH3CH312HN CH3CH3CF313NCF3H3C14Structural drawings:1 = Serotonin, 2 = Paroxetine, 3 = Nitroquipazine,4 = 5-Iodo-6-nitro-quipazine, 5 = MDMA, 6 = Fluoxetine,7 = McN5652, 8 = LY257327, 9 = Citalopram, 10 = -CIT,11 = RTI-55, 12 = Venlafaxine, 13 = Fenfluramine, 14 = NS2381.
  8. 8. Brief account of compartmental kineticmodels used for PET.1. Reversible binding(2- or 3-compartments)a. with arterial input function (Logan)b. with reference region (Lammertsma)2. Irreversible binding (Gjedde-Patlak)
  9. 9. Radioactivity in bloodstream Radioactivity in brain
  10. 10. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of Molecular Neuroimaging• Actions of Mirtazapine & Enantiomers• [11C]Mirtazapine PET in Pig• Requirements for Human PET• Initial [11C]Mirtazapine PET in Humans• Toward Evidence-based Neuropsychiatry
  11. 11. Classes of cell-surfacereceptors
  12. 12. Receptor theoryFirst postulated by John Langley (1878)– Established after his experiments using nicotineand curare analogues on muscle contraction.Isolated muscle fibers: pilocarpine (contraction) andatropine (inhibition).Two compounds competing for a third, but unknownsubstrate.Furthered by Paul Ehrlich (1854-1915)– Demonstrated that stereoselectivity wasimperative in drug-receptor signaling.
  13. 13. Receptor occupancyActivation of membrane receptors andtarget cell responses are proportional tothe degree of receptor occupancy.
  14. 14. The amount of drug bound at any time issolely determined by:– the number of receptors– the concentration of ligand added– the affinity of the drug for its receptor.Binding of drug to receptor is essentially the sameas binding of drug to enzyme as defined by theMichelis-Menten equation.
  15. 15. Depressive DisordersSleepDisturbanceSexualDisturbanceMemoryDisturbanceThoughtDisordersSuicidalTendencyLow Self-EsteemEatingDisordersPsychomotorDisturbancePsychosomaticDisorders
  16. 16. Sequenced treatment alternatives to relieve depression(STAR*D): rationale and design.Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, SackeimHA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, KupferDJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group.Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9086, USA. john.rush@utsouthwestern.eduControl Clin Trials. 2004, Feb;25(1):119-42.
  17. 17. Treatment-Resistant Depression25 – 30% of patients suffering from depression show ”treatment-resistance”.Some patients never respond satisfactorily to antidepressanttherapies, and many of them commit suicide.Noone knows the neurobiological basis of treatment-resistantdepression.Few molecular tools are currently available for assessing causesand cures of treatment-resistant depression at neuroreceptors.The long-term aim of this project is to discover molecular tools forcorrectly diagnosing treatment-resistant depression and forselecting the most appropriate therapeutic procedures.
  18. 18. A major goal of modern biological psychiatryis discovering valid procedures for evaluatingneurochemical dysfunctions associated withneuropsychiatric disorders such asdepression.
  19. 19. Neuropsychosocial ModelSense of DangerCorticostriato- thalamic PathwaySymptoms of Depression5-HTSleep Disorders CognitiveDisordersEating DisordersACh NAGABAUnconditionedResponsesConditionedResponsesEmotional MemoryAmygdalothalamo-cortical PathwayVisceralLimbic Pathway5-HTAChCorticothalamicPathwayCortico-cortico PathwayCorticalLimbicPathway
  20. 20. Antidepressants (clinical and preclinical) that have been testedas PET radioligands• Paroxetine• Citalopram• Fluoxetine• Venlafaxine• Clomipramine• Nefopam• Mianserin• NS2381 & NS2456• McN5652• Mirtazapine
  21. 21. Blier, P. European Neuropsychopharmacology, 13: 57-66, 2003.
  22. 22. = NA neuron= 5-HT neuron= α2-autoreceptor= α2-heteroceptorNANANANANANANANA5-HT5-HTNoradrenaline (NA) exerts a tonic, inhibitory action on serotonin (5-HT) releasevia α2-heteroceptors, so antagonism of α2-heteroceptors enhances 5-HT release.NA binding at α2-autoreceptors reduces NA release, so antagonism ofα2-autoreceptors enhances NA release.
  23. 23. - antidepressant effect- anxiolytic effect- antidepressanteffect- anxiolytic effect- sleep improvementPrevents:- agitation- restlessness- sexual dysfunctionPrevents:- nausea- vomiting- headacheJ Clin Psych, 1997Remeron (mirtazepine)The NaSSA concept
  24. 24. • Mirtazapine’s antidepressantactions are related primarily toeffects at noradrenergicreceptors.• Mirtazapine has shown promisefor alleviating depression intreatment-resistant cases.
  25. 25. Fig. 2. Differences in the remission rate of mirtazapine and SSRIs from Montgomery et al. (2002). Datarepresent a meta-analysis of three clinical studies of mirtazapine versus fluoxetine, paroxetine and citalopram.A remission was defined as a score of 7 points or less on the HAMD-17, or 12 points or less on the MADRS. Thesample represented is an intent-to-treat sample; dropouts were handled by a last-observation carried forwardprocedure.
  26. 26. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of molecular neuroimaging• Actions of Mirtazapine & Enantiomers• [11C]Mirtazapine PET in pig• Requirements for human PET• Initial [11C]Mirtazapine PET in humans• Toward Evidence-based Neuropsychiatry
  27. 27. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of molecular neuroimaging• Actions of mirtazapine & enantiomers• [11C]Mirtazapine PET in Pig• Requirements for human PET• Initial [11C]Mirtazapine PET in humans• Toward Evidence-based Neuropsychiatry
  28. 28. Radiosynthesis of [11C]Mirtazapine
  29. 29. Metabolite analysis carried out by HPLC for plasma samples of pig bloodafter intravenous injection of [N-methyl-11C]mirtazapine.UV detectorRadiodetectorProduct + ColdReference - UVProduct + ColdReference -Radiodetector
  30. 30. Resolution of enantiomers:Enantiomer BEnantiomer ADaicel Chiralcel OD-H column 250 x 4,6 mm, n-hexane:ethanol (95:5),0,1% diethylamine, flow 0.5 ml/min, 232 nmEnantiomer BCa. 20 µg of each enantiomer resolved per injection
  31. 31. PigVervet monkey50 ml 75 mlAnimal model: Pig
  32. 32. [11C]Mirtazapine and ClonidineTotal 10-10 M 10-9 M10-8 M 10-7 M10-6 M10-5 M
  33. 33. [11C]Mirtazapine and Clonidine[11C]Mirtazapine - Clonidine10-1110-1010-910-810-710-610-510-410-3100125150175200Clonidine (M)PPL/mm2
  34. 34. Tomograph: Siemens ECAT HRAnimal model: Pig* (35 - 45 kg)Anaesthesia: Midazolam/ketamine HCl, followed byisoflurane in O2/N2OData acquisition over 90 minutes in 2 D modeArterial blood samples for metabolite correctionROI either using a neuroanatomical atlas of the pigbrain or by co-registration to a statistical MR atlas ofporcine brain.PET Procedure* Animal studies were performed in accordance with Danish AnimalExperimentation Act on a licence granted by the Danish Ministry of Justice
  35. 35. Time course of radioactivity derived from [N-methyl-11C]mirtazapine in selected regions of theliving porcine brain under baseline conditions.Frontal cortex (squares), Thalamus (triangles), Basal ganglia (filled circles), Cerebellum(triangles), Olfactory bulb (unfilled circles).0204060801000 10 20 30 40 50 60Radioactivity(MBq/cc)
  36. 36. pB2.1[11C]Mirtazapine pB maps (ERLiBiRD)Mean of seven baseline determinations
  37. 37. Vd ml g-1 (Logan)pB (ERLiBiRD)1.512[11C]mirtazapineExcess cold mirtazapine
  38. 38. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of molecular neuroimaging• Actions of mirtazapine & enantiomers• [11C]Mirtazapine PET in pig• Requirements for Human PET• Initial [11C]Mirtazapine PET in humans• Toward Evidence-based Neuropsychiatry
  39. 39. Steps for using aNew Radiopharmaceutical forHuman Research in Denmark1. Animal pharmacokinetic and pharmaco-dynamic evidence2. Animal Whole-Body Dosimetry3. Ethical Committee Application4. Good Clinical Practice Approval5. Human Whole-Body Dosimetry6. Lægemiddelstyrelsen Approval7. Ethical Committee Approval8. Good Clinical Practice Monitoring9. Recruitment of volunteers10. Screening of volunteers11. Scheduling of MRI and PET12. Completion of Case Report Forms13. Data Register Rule and Regulations14. Reporting to Lægemiddelstyrelsen15. Reporting to Good Clinical Practice Unit
  40. 40. [11C]Mirtazapine whole-body scans
  41. 41. [11C]Mirtazapine time-activity curves inhuman body organs
  42. 42. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of molecular neuroimaging• Actions of mirtazapine & enantiomers• [11C]Mirtazapine PET in pig• Requirements for human PET• Initial [11C]Mirtazapine PET in Humans• Toward Evidence-based Neuropsychiatry
  43. 43. 01020304050607080901000 10 20 30 40 50 60Time (min)C-11Mirtazapine(%unmetabolised)Figure 1. Percentage of [11C]-derived radioactivity correspondingto unmetabolised [N-methyl-11C]mirtazapine in the bloodstream offive humans at times after intravenous injection of theradioligand (dose of 175 – 413 MBq, specific activity of 13 – 67GBq/mol). An exponential function was used for curve-fitting.
  44. 44. 0246810120 10 20 30 40 50 60Time (min)Radioactivity(kBq/cc)CerebellumAmygdalaFrontal cortexThalamusStriatumHippocampusFigure 2. Time-course of radioactivity derived from[N-methyl-11C]mirtazapine in selected regions ofhuman brain.
  45. 45. 129631Figure 3. Parametric map ofVe’-values (Volume ofdistribution) of [N-methyl-11C]mirtazapine in the brain ofa healthy volunteer.The brain image is shown inTalairach coordinates (Talairachand Tournoux, 1988). The planesshown are transaxial (upper),coronal (lower left) andsagittal (lower right). The ‘ +’ mark in each image shows thelocation and orientation of theplanes of corresponding images.The color bar presents the scaleof Ve’-values.
  46. 46. Table 1. Kinetic parameters of [N-methyl-11C]mirtazapine inhuman brain regions (means ± s.d. of five subjects).Region Hemisphere K1 k2’’ Ve’_____________________________________________________Cerebellum Both 0.44 ± 0.07 0.067 ± 0.016 6.7 ± 1.3Hippocampus Right 0.40 ± 0.05 0.034 ± 0.006 11.8 ± 0.9Left 0.41 ± 0.07 0.034 ± 0.006 11.9 ± 0.8Frontal cortex Right 0.37 ± 0.07 0.040 ± 0.007 9.5 ± 1.0Left 0.38 ± 0.06 0.041 ± 0.006 9.3 ± 1.1Temporal cortex Right 0.35 ± 0.05 0.032 ± 0.007 10.9 ± 1.4Left 0.36 ± 0.06 0.034 ± 0.007 10.8 ± 1.5_________________________________________________
  47. 47. Properties of [11C]Mirtazapine asPET Radiotracer• Synthesized readily and obtained pure• Enters brain readily• Metabolized relatively slowly• Good target-to-noise ratio• Binds reversibly and competitively to certain cerebral sites• Low binding in cerebellum (O.K. as reference region)• Only antidepressant suitable for PET
  48. 48. The Golden OpportunityRelating TDM to Neuroreceptor OccupancyTherapeutic Drug Monitoring is used for determining whetherthe patient takes her medicine.There is often an inadequate therapeutic effect despitemeasureable amounts of antidepressant in plasma.Little is known concerning whether plasma levels ofantidepressants reflect drug actions at central sites.Combining TDM and PET neuroimaging could perhaps identifytreatment-resistant patients with abnormal neuroreceptors.
  49. 49. Principles of Molecular Neuroimagingin Depression Research.• The Challenges• Principles of PET• Principles of Molecular Neuroimaging• Actions of Mirtazapine & Enantiomers• [11C]Mirtazapine PET in Pig• Requirements for Human PET• Initial [11C]Mirtazapine PET in Humans• Toward Evidence-based Neuropsychiatry
  50. 50. The project aims to develop methods, based onneuroimaging, that can contribute to a reliable, evidence-basedselection of the most effective type of therapy for each patientsuffering from treatment-resistant depression.PET Neuroimaging with [11C]Mirtazapine forEvidence-based Psychiatry
  51. 51. Experimental Null Hypotheses• No reliable relationship between daily dose of mirtazapineand binding potential of radioactive PET tracer.• No reliable difference in receptor binding between (+)- og (-)-(11C)mirtazapin in brain regions.
  52. 52. • Klinisk ansvarlig• Prof. Raben Rosenberg, Center for Psykiatrisk Grundforskning, Psykiatrisk Hospital, 8240Risskov, DK (raben@dadlnet.dk)• Andre akademiske medarbejdere• Poul Videbech, Overlæge, Psykiatrisk Hospital, 8240 Risskov, DK• Dirk Bender, Chef Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Steen Jakobsen, Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Katalin Marthi, Kemiker, Hungarian Academy of Sciences, H-1111 Budapest, Hungary• Søren B. Hansen, Ledende Sektionsfysiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Ole L. Munk, Fysiker, Aarhus Sygehus, 8000 Aarhus C, DK• Paul Cumming, Neurofarmakolog, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Luciano Minuzzi, MD, PhD stud., PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Pompiliu Sorin Aburel, Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK• Håkan Hall, Assoc. Prof. Afd. Clinical Neuroscience, Karolinska Hospital, Stockholm, SEProject participants:
  53. 53. Study Design• Double-blind• Placebo-controlled• Randomized• 5 healthy males given each enantiomers• Blinded curve-fitting and kinetic analysis toestimate binding potentials
  54. 54. (S)(R)02550Whole-body scans of[11C]mirtazapineenantiomers. Decay-corrected image obtainedduring the first sequenceof PET scans.Color bar units in MBq/cc.
  55. 55. Organ (R)-[11C]Mirtazapine (S)-[11C]MirtazapineAdrenals 3.41 x 10-3 3.31 x 10-3Brain 6.40 x 10-3 7.98 x 10-3Breasts 2.16 x 10-3 2.14 x 10-3Gallbladder Wall 5.61 x 10-3 1.13 x 10-2LLI Wall 2.26 x 10-3 2.22 x 10-3Small Intestine 2.53 x 10-3 2.46 x 10-3Stomach Wall 2.64 x 10-3 2.56 x 10-3ULI Wall 2.65 x 10-3 2.58 x 10-3Heart Wall 9.96 x 10-3 9.06 x 10-3Kidneys 2.80 x 10-3 2.69 x 10-3Liver 1.67 x 10-2 1.52 x 10-2Lungs 1.30 x 10-2 1.57 x 10-2Muscle 2.20 x 10-3 2.15 x 10-3Ovaries 2.38 x 10-3 2.33 x 10-3Pancreas 3.30 x 10-3 3.21 x 10-3Red Marrow 2.16 x 10-3 2.13 x 10-3Osteogenic Cells 3.14 x 10-3 3.07 x 10-3Skin 1.75 x 10-3 1.71 x 10-3Spleen 2.43 x 10-3 2.38 x 10-3Testes 1.90 x 10-3 1.85 x 10-3Thymus 2.57 x 10-3 2.54 x 10-3Thyroid 2.17 x 10-3 2.15 x 10-3Urinary Bladder Wall 3.92 x 10-3 5.92 x 10-3Uterus 2.41 x 10-3 2.41 x 10-3Total Body 2.89 x 10-3 2.87 x 10-3Effective Dose (mSv/MBq) 4.33 x 10-3 4.65 x 10-3
  56. 56. 012345670 15 30 45 60 75 90Time (min)SUVAverage standard uptake values (SUV) of [11C]mirtazapine enantiomers in plasma,frontal cortex, and cerebellum studied by positron emission tomography in four healthymales.CerebellumFrontal cortexMetabolite-corrected plasma(R)-Mirtazapine(R)-Mirtazapine(S)-Mirtazapine(S)-Mirtazapine
  57. 57. Method Brain region (R)-[11C]Mirtazapine (S)-[11C]MirtazapineArterial Input 2-compartment modelBinding potential Binding PotentialK1k2k3k4 Frontal cortex 3.04 2.41 3.54 3.03Parietal cortex 2.91 2.39 3.65 2.65Temporal cortex 2.79 2.07 2.82 2.65Occipital cortex 2.51 1.80 3.93 3.31Hippocampus 2.65 1.61 2.62 1.86Amygdala 3.81 4.54 1.60 0.78Caudate 1.65 1.37 2.36 2.09Putamen 1.04 0.82 1.01 0.29Thalamus 1.00 0.85 1.86 1.86Cerebellum 0.94 0.68 1.05 0.81
  58. 58. (R)-[11C]mirtazapine (S)-[11C]mirtazapineDouble-blind, placebo-controlled, randomizedPET study of mirtazapineenantiomers in 4 healthymales.
  59. 59. Timeline for C-11 Mirtazapine Receptor Occupancy ProjectRecruit and screenhealthy subjectsBaselineC-11 Mirtazapine& O-15 H2O scanTreatment5 days of placeboor mirtazapine(7.5 mg or 15 mgDaily)PosttreatmentC-11 Mirtazapine& O-15 H2O scanVenous bloodFor HPLCVenous bloodFor HPLCDataanalysis
  60. 60. Radiosynthesis of [11C]Mirtazapine*** indicates chiral carbon
  61. 61. Properties of [11C]Mirtazapine as PETRadiotracer• Synthesized readily and obtained pure• Enters brain readily• Metabolized relatively slowly• Good target-to-noise ratio• Binds reversibly and competitively to certain cerebral sites• Low binding in cerebellum (O.K. as reference region)• Only antidepressant suitable for PET
  62. 62. •From Yasuno et al., Neuroimage, 16: 577-586, 2002Volume-of-Interest (VOI) Templates shown on axial slices
  63. 63. 0246810120 10 20 30 40 50 60Time (min)Radioactivity(kBq/cc)CerebellumAmygdalaFrontal cortexThalamusStriatumHippocampusTime-course of radioactivity derived from[N-methyl-11C]mirtazapine in selected regionsof human brain.
  64. 64. Region K1 k2 Vd Binding PotentialCerebellum 0.44 0.067 6.7Hippocampus 0.40 0.034 11.9 1.20Amygdala 0.32 0.028 11.6 1.09Frontal Cortex 0.37 0.041 9.4 1.48Thalamus 0.52 0.055 9.4 0.46Striatum 0.48 0.050 9.6 0.77The distribution volume (Vd) and binding potentialof rac-[N-methyl-11C]mirtazapine human brainregions.
  65. 65. Experimental Design• Baseline PET scans of 18 healthy, drug-free males and femalesfrom previous study using [11C]mirtazapine to determinereceptor occupancy.• PET scans using [11C]mirtazapine in drug-free men and womenwith treatment-resistant depression.• Brief description of recruitment procedure.
  66. 66. Table 1. Clinical characteristics of currently drug-free subjects withtreatment-resistant depression.I.D.Age Sex HDR BDI BAI Antidepressantdrug treatmentsAMP 43 F 25 37 23 2KJ 41 M 30 38 16 2IK 56 F 19 21 21 9 + ECTPA 54 F 25 26 12 4SLM 36 F 21 33 32 3KVS 43 M 20 23 12 6KA 43 F 24 28 16 7MLN 31 F 29 27 5 4KR 34 F 29 27 18 3JL 45 F 31 16 19 4JM 44 M 32 37 24 5VMH 52 M 34 30 23 9EPS 52 F 21 21 10 3AMGH 35 F 23 17 9 4BEKT 41 F 28 38 14 6HDR = 17-item Hamilton Depression Rating ScaleBDI = 21-item Beck Self-Rating Depression InventoryBAS = 14-item Beck Self-Rating Anxiety InventoryAntidepressant drug treatments had last at least 4 weeks.
  67. 67. Relationship between the amount of mirtazapine injected as abolus (µg) (natural logarithmic scale) and the binding potential(BPND) of [11C]mirtazapine in frontal cortex of drug-free subjectswith treatment-resistant depression and in healthy controls.
  68. 68. Regional binding potential of [11C]mirtazapine in drug-free, healthy subjects (unfilled bars) and in drug-freesubjects with treatment-resistant depression (filled bars).
  69. 69. 0.01.6
  70. 70. Main findingThe relationship between BPND of [11C]mirtazapine in brainregions differed significantly between drug-free, TRD subjectsand healthy controls (group x region interaction: p < 0.001).Inspection of the data shows that BPND values of[11C]mirtazapine were higher in cortical regions of healthysubjects than of TRD subjects, whereas no marked differenceswere found between the two groups for [11C]mirtazapine BPNDvalues in hippocampus, thalamus and putamen.
  71. 71. Main findings• The binding potential of [11C]mirtazapine depends heavily on theinjected dose of mirtazapine at levels as low as 2 µg.• Analysis of covariance is required to control for the strong inverserelationship between binding potential and injected dose ofmirtazapine.• Regional binding potentials of [11C]mirtazapine differbetween drug-free subjects with treatment-resistant depression andhealthy subjects.• Treatment-resistant depression is a heterogeneous disorder that can bestudied by PET.
  72. 72. Treatment-resistant depression is a heterogeneous disorderthat can be studied by PET.PET neuroimaging may eventually aid in the diagnosis ofdepression and in selection of the most appropriateantidepressant treatment.Main conclusions
  73. 73. Here’s a View of the Future in Pharmacodynamics!This slide shows the Treatment Evaluation Team (TET)of Aarhus University Hospital.The TET consists of specialists in pharmacodynamics, genetics, neuropsychiatry,neuroimaging, bioanalysis and biopsychology. They work at the newly constructed,high-tech Skejby Translational Neuropsychiatry Unit. They are evaluating thedigital molecular profiles of a treatment-resistant depressed person in order toselect the most appropriate, individualized, evidence-based therapy.

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