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Nemeroff  CB The neurobiology of depression.  Sci Am. 1998;27842- 49Google ScholarCrossref
Leonard  BE Evidence for a biochemical lesion in depression.  J Clin Psychiatry. 2000;6112- 17Google Scholar
Mayberg  HSBrannan  SKMahurin  RKJerabek  PABrickman  JSTekell  JLSilva  JAMcGinnis  SGlass  TGMartin  CCFox  PT Cingulate function in depression: a potential predictor of treatment response.  Neuroreport. 1997;81057- 1061Google ScholarCrossref
Drevets  WPrice  JSImpson  J  JrTodd  RDReich  TVannier  MRaichle  ME Subgenual prefrontal cortex abnormalities in mood disorders.  Nature. 1997;386824- 824Google ScholarCrossref
George  MSKetter  TAParekh  PIRosinsky  NRing  HAPazzaglia  PJMarangell  LBCallahan  AMPost  RM Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop).  J Neuropsychiatry Clin Neurosci. 1997;955- 63Google Scholar
Mayberg  HSLiotti  MBrannan  SKMcGinnis  SMahurin  RKJerabek  PASilva  JATekell  JLMartin  CCLancaster  JLFox  PT Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness.  Am J Psychiatry. 1999;156675- 682Google Scholar
Galynker  IICai  JOngseng  FFinestone  HDutta  ESerseni  D Hypofrontality and negative symptoms in major depressive disorder.  J Nucl Med. 1998;39608- 612Google Scholar
Rajkowska  GMiguel-Hidalgo  JJWei  JDilley  GPittman  SDMeltzer  HYOverholser  JCRoth  BLStyockmeier  CA Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression.  Biol Psychiatry. 1999;451085- 1098Google ScholarCrossref
Ongur  DDrevets  WCPrice  JL Glial reduction in the subgenual prefrontal cortex in mood disorders.  Proc Natl Acad Sci U S A. 1998;9513290- 13295Google ScholarCrossref
Schildkraut  JJ The catecholamine hypothesis of affective disorders: a review of supporting evidence.  Am J Psychiatry. 1965;122509- 522Google Scholar
Lapin  IPOxenkrug  GF Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect.  Lancet. 1969;1132- 136Google ScholarCrossref
Charney  DS Monoamine dysfunction and the pathophysiology and treatment of depression.  J Clin Psychiatry. 1998;5911- 14Google Scholar
Moller  H-J Are all antidepressants the same?  J Clin Psychiatry. 2000;6124- 28Google Scholar
Andreasen  NC Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology.  Science. 1997;2751586- 1591Google ScholarCrossref
Ongur  DPrice  JL The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans.  Cereb Cortex. 2000;10206- 219Google ScholarCrossref
Koob  GFLe Moal  M Drug addiction, dysregulation of reward and allostasis.  Neuropsychopharmacology. 2001;2497- 129Google ScholarCrossref
Wise  RA Drug-activation of brain reward pathways.  Drug Alcohol Depend. 1998;5113- 22Google ScholarCrossref
Olds  MEMilner  PM Positive reinforcement produced by electrical stimulation of the septal area and other regions of the rat brain.  J Comp Physiol Psychol. 1954;47419- 427Google ScholarCrossref
Wise  RA Addictive drugs and brain stimulation reward.  Annu Rev Neurosci. 1996;19319- 340Google ScholarCrossref
Leshner  AIKoob  GF Drugs of abuse and the brain.  Proc Assoc Am Physicians. 1999;11199- 108Google ScholarCrossref
Schultz  W Dopamine neurons and their role in reward mechanisms.  Curr Opin Neurobiol. 1997;7191- 197Google ScholarCrossref
Stein  EAPankiewicz  JHarsch  HHCho  JKFuller  SAHoffmann  RGHawkins  MRao  SMBandettini  PABloom  AS Nicotine-induced limbic cortical activation in the human brain: a functional MRI study.  Am J Psychiatry. 1998;1551009- 1015Google Scholar
Volkow  NDWang  GJFowler  JSLogan  JGatley  SJWong  CHitzemann  RPappas  NR Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2 receptors.  J Pharmacol Exp Ther. 1999;291409- 415Google Scholar
Laruelle  MAbi-Dargham  AVan Dyck  CRosenblatt  WZea-Ponce  YZoghbi  SSBaldwin  RMCharney  DSHoffer  PBKung  HFInnis  RB SPECT imaging of striatal dopamine release after amphetamine challenge.  J Nucl Med. 1995;361182- 1190Google Scholar
Drevets  WCGautier  CPrice  JCKupfer  KJKinahan  PEGrace  AAPrice  JLMathis  CA Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria.  Biol Psychiatry. 2001;4981- 96Google ScholarCrossref
Koob  GFLe Moal  M Drug abuse: hedonic homeostatic dysregulation.  Science. 1997;27852- 58Google ScholarCrossref
Naranjo  CATremblay  LKBusto  UE The role of the brain reward system in depression.  Prog Neuropsychopharmacol Biol Psychiatry. 2001;25781- 823Google ScholarCrossref
Shi  WXPun  CLZhang  XXJones  MDBunney  BS Dual effects of d-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors.  J Neurosci. 2000;203504- 3511Google Scholar
Hedou  GHomberg  JMartin  SWirth  KFeldon  JHeidbreder  CA Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex.  Eur J Pharmacol. 2000;390127- 136Google ScholarCrossref
Kuczenski  RSegal  DSCho  AKMelega  W Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.  J Neurosci. 1995;151308- 1317Google Scholar
Pifl  CDrobny  HReither  H Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter.  Mol Pharmacol. 1995;47368- 373Google Scholar
Seiden  LSSabol  KE Amphetamine: effects on catecholamine systems and behaviour.  Annu Rev Pharmacol Toxicol. 1993;33639- 677Google ScholarCrossref
Koob  GF Hedonic valence, dopamine and motivation.  Mol Psychiatry. 1996;1186- 189Google Scholar
Uhlenhuth  EHJohanson  CEKilgore  KKobasa  SC Drug preference and mood in humans: preference for d-amphetamine and subject characteristics.  Psychopharmacology. 74191- 194Google ScholarCrossref
Dommisse  CSSchulz  SCNarasimhachari  NBlackard  WGHamer  RM The neuroendocrine and behavioral response to dextroamphetamine in normal individuals.  Biol Psychiatry. 1984;191305- 1315Google Scholar
Klein  DF Endogenomorphic depression: a conceptual and terminological revision.  Arch Gen Psychiatry. 1974;31447- 454Google ScholarCrossref
Heinz  A Anhedonia: a general nosology surmounting correlate of a dysfunctional dopaminergic reward system?  Nervenarzt. 1999;70391- 398Google ScholarCrossref
Carroll  BJ Neurobiological dimensions of depression and mania. Angst  Jed.  The Origins of Depression: Current Concepts and Approaches. New York, NY Springer-Verlag1983;163- 186Google Scholar
Di Chiara  GLoddo  PTanda  G Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression.  Biol Psychiatry. 1999;461624- 1633Google ScholarCrossref
Willner  P Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.  Psychopharmacology. 1997;134319- 329Google ScholarCrossref
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;161- 198
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Dept, New York State Psychiatric Institute1994;
Hamilton  M A rating scale for depression.  J Neurol Neurosurg Psychiatry. 1960;2356- 62Google ScholarCrossref
Hill  HEHaertzen  CAWolbach  AB  JrMiner  EJ The Addiction Research Center Inventory: standardization of scales which evaluate subjective effects of morphine, amphetamine, pentobarbital, alcohol, LSD-25, pirahexl and chloropromazine.  Psychopharmacologia. 1963;4167- 183Google ScholarCrossref
Cole  JOOrzack  MHBeake  BBird  MBar-Tal  Y Assessment of the abuse liability of buspirone in recreational sedative users.  J Clin Psychiatry. 1982;4369- 75Google Scholar
Vogt  WJacob  KOhnesorge  A-BSchwertfeger  G Highly sensitive method for the quantitation of homovanillic acid in cerebrospinal fluid.  J Chromatogr. 1980;199191- 197Google ScholarCrossref
Midha  KKMcgilveray  IJCooper  JK Assay for simultaneous determination of fenfluramine and norfenfluramine in human plasma and urine.  Can J Pharm Sci. 1979;1418- 21Google Scholar
Kendall  PHollon  SBeck  AHammen  CLIngram  RE Issues and recommendations regarding use of the Beck Depression Inventory.  Cognit Ther Res. 1987;11289- 300Google ScholarCrossref
Snaith  RHamilton  MMorley  SHumayan  AHargreaves  DTrigwell  P A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale.  Br J Psychiatry. 1995;16799- 103Google ScholarCrossref
Glassman  SWestrich  NParker  KLevitt  A Psychomotor Function in Depression: Proceedings of the American Psychiatric Association Meeting, San Diego, CA.  Washington, DC American Psychiatric Association1997;
McNair  DMLorr  MDroppleman  LF Profile of Mood States (Manual).  San Diego, Calif Educational and Industrial Testing Service1971;
Johanson  CEUhlenhuth  EH Drug preference and mood in humans: d-amphetamine.  Psychopharmacology (Berl). 1980;71275- 279Google ScholarCrossref
Folstein  MFLuria  R Reliability, validity and clinical application of the Visual Analogue Mood Scale.  Psychol Med. 1973;3479- 486Google ScholarCrossref
Busto  UEKaplan  HLZawertailo  LASellers  EM Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans.  Clin Pharmacol Ther. 1994;55451- 463Google ScholarCrossref
Versiani  MAmin  MChouinard  G Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder.  J Clin Psychopharmacol. 2000;2028- 34Google ScholarCrossref
Kathiramalainathan  KKaplan  HLRomach  MKBusto  UELi  N-YSawe  JTyndale  RFSellers  EM Inhibition of P450 2D6 modifies codeine abuse liability.  J Clin Psychopharmacol. 2000;20435- 444Google ScholarCrossref
Ocampo  JABusto  UEKaplan  HLTyndale  RFOtton  SVNolte  HSymanzik  CSellers  EM Does extent of p-hydroxylation alter methamphetamine kinetics?  Clin Pharmacol Ther. 1996;59208- 212Google ScholarCrossref
Fabian  JESilverstone  PH Diltiazem, a calcium chanel antagonist, partly attenuates the effects of dextroamphetamine in healthy volunteers.  Int Clin Psychopharmacol. 1997;12113- 120Google ScholarCrossref
Nurnberger  JI  JrSimmons-Alling  SKessler  LJimerson  SSchreiber  JHollander  ETamminga  CANadi  NSGoldstein  DSGershon  ES Separate mechanisms for behavioral, cardiovascular, and hormonal responses to dextroamphetamine in man.  Psychopharmacology. 1984;84200- 204Google ScholarCrossref
Brauer  LHAmbre  JDe Wit  H Acute tolerance to subjective but not cardiovascular effects of d-amphetamine in normal, healthy men.  J Clin Psychopharmacol. 1996;1672- 76Google ScholarCrossref
Sofuoglu  MBrown  SBabb  DAPentel  PRHatsukami  DK Carvedilol affects the physiological and behavioral response to smoked cocaine in humans.  Drug Alcohol Depend. 2000;6069- 76Google ScholarCrossref
Pillay  SSRenshaw  PFBonello  CMLafer  BFava  MYurgelun-Todd  D A quantitative magnetic resonance imaging study of caudate and lenticular nucleus gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity.  Psychiatry Res. 1998;8461- 74Google ScholarCrossref
Laruelle  MAbi-Dargham  Avan Dyck  CGil  RD'Souza  DCKrystal  JSeibyl  JBaldwin  RInnis  R Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT.  Biol Psychiatry. 2000;47371- 379Google ScholarCrossref
Sofuoglu  MBrown  SDudish-Poulsen  SHatsukami  DK Individual differences in the subjective response to smoked cocaine in humans.  Am J Drug Alcohol Abuse. 2000;26591- 602Google ScholarCrossref
De Wit  HUhlenhuth  EHJohanson  CE The reinforcing properties of amphetamine in overweight subjects and subjects with depression.  Clin Pharmacol Ther. 1987;42127- 136Google ScholarCrossref
Little  KY Amphetamine, but not methylphenidate, predicts antidepressant efficacy.  J Clin Psychopharmacol. 1988;8177- 183Google ScholarCrossref
Gardner  ELAshby  CR  Jr Heterogeneity of mesotelencephalic dopamine fibers: physiology and pharmacology.  Neurosci Biobehav Rev. 2000;24115- 118Google ScholarCrossref
Volkow  NDFowler  JSWang  GJGur  RCWong  CFelder  CGatley  SJDing  YSHitzemann  RPappas  N Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism.  Am J Psychiatry. 200015775- 80Google Scholar
Hirsch  EC Nigrostriatal system plasticity in Parkinson's disease: effect of dopaminergic denervation and treatment.  Ann Neurol. 2000;47S115- S120Google Scholar
Miller  HLDelgado  PLSalomon  RMHeniner  GFCharney  DS Effects of alpha-methyl-paratyrosine (AMPT) in drug-free depressed patients.  Neuropsychopharmacology. 1996;141151- 157Google ScholarCrossref
D'haenen  HABossuyt  A Dopamine D2 receptors in depression measured with single photon emission computed tomography.  Biol Psychiatry. 1994;35128- 132Google ScholarCrossref
Shah  PJOgilvie  ADGoodwin  GMEbmeier  KP Clinical and psychometric correlates of dopamine D2 binding in depression.  Psychol Med. 1997;271247- 1256Google ScholarCrossref
Klimke  ALarisch  RJanz  AVosberg  HMullerGartner  HWGaebel  W Dopamine D2 receptor binding before and after treatment of major depression measured by [123I] IBZM SPECT.  Psychiatry Res. 1999;9091- 101Google ScholarCrossref
Ebert  DFeistel  HLoew  TPirner  A Dopamine and depression: striatal dopamine D2 receptor SPECT before and after antidepressant therapy.  Psychopharmacology. 1996;12691- 94Google ScholarCrossref
Lemke  MRPuhl  PKoethe  NWinkler  T Psychomotor retardation and anhedonia in depression.  Acta Psychiatr Scand. 1999;99252- 256Google ScholarCrossref
Martinot  M-L PBragulat  VArtiges  EDolle  FHinnen  FJouvent  RMartinot  J-L Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation.  Am J Psychiatry. 2001;158314- 316Google ScholarCrossref
Bardo  MT Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.  Crit Rev Neurobiol. 1998;1237- 67Google ScholarCrossref
Di Matteo  VDe Blasi  ADi Giulio  CEsposito  E Role of 5-HT(2C) receptors in the control of dopamine function.  Trends Pharmacol Sci. 2001;22229- 232Google ScholarCrossref
Linner  LEndersz  HOhman  DBengtsson  FSchalling  MSvensson  TH Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex.  J Pharmacol Exp Ther. 2001;297540- 546Google Scholar
West  WBVan Groll  BJAppel  JB Stimulus effects of d-amphetamine II: DA, NE, and 5-HT mechanisms.  Pharmacol Biochem Behav. 1995;5169- 76Google ScholarCrossref
Parker  GWilhelm  KMitchell  PRoy  KHadzi-Pavlovic  D Subtyping depression: testing algorithms and identification of a tiered model.  J Nerv Ment Dis. 1999;187610- 617Google ScholarCrossref
Meston  CMFrohlich  MA The neurobiology of sexual function.  Arch Gen Psychiatry. 2000;571012- 1030Google ScholarCrossref
Pani  LPorcella  AGessa  GL The role of stress in the pathophysiology of the dopaminergic system.  Mol Psychiatry. 2000;514- 21Google ScholarCrossref
Backman  LGinovart  NDixon  RAWahlin  TBWahlin  AHalldin  CFarde  L Age-related cognitive deficits mediated by changes in the striatal dopamine system.  Am J Psychiatry. 2000;157635- 637Google ScholarCrossref
Original Article
May 2002

Probing Brain Reward System Function in Major Depressive Disorder: Altered Response to Dextroamphetamine

Author Affiliations

From the Psychopharmacology Research Program, Sunnybrook & Women's College Health Sciences Centre–Sunnybrook Campus (Ms Tremblay and Drs Naranjo, Herrmann, and Busto), the Centre for Addiction and Mental Health, Addiction Research Centre Site (Drs Cardenas and Busto), and the Departments of Pharmacology (Drs Cardenas, Herrmann, and Busto), Psychiatry (Drs Naranjo and Herrmann), Medicine (Drs Naranjo and Herrmann), and Pharmaceutical Sciences(Ms Tremblay and Dr Busto), University of Toronto, Toronto, Ontario.

Arch Gen Psychiatry. 2002;59(5):409-416. doi:10.1001/archpsyc.59.5.409

Background  The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms.

Methods  In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure.

Results  Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R2 = 0.63; interaction P = .04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P = .02). Patients with severe symptoms reported rewarding effects3.4-fold greater than controls.

Conclusions  The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies.