The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology.

Anxiety disorders are highly comorbid with each other and with major depressive disorder. As syndromes, anxiety and mood disorders share many symptoms, and several treatments are effective for both. Despite this overlap, there exist many distinguishing features that support the continued classification of individual anxiety disorders that are distinct from each other and from major depression. The goal of this article is to describe the key biological similarities and differences between anxiety disorders.

[1]  C. Nemeroff,et al.  Long-term behavioral and neuroendocrine adaptations to adverse early experience. , 2000, Progress in brain research.

[2]  J. Armony,et al.  An fMRI investigation of memory encoding in PTSD: Influence of symptom severity , 2008, Neuropsychologia.

[3]  F. Zitman,et al.  Elevated alpha-amylase but not cortisol in generalized social anxiety disorder , 2008, Psychoneuroendocrinology.

[4]  H. Sackeim,et al.  Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. , 2004, The American journal of psychiatry.

[5]  J. Ballenger,et al.  Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder. , 1997, The American journal of psychiatry.

[6]  R. Yehuda,et al.  The ACTH response to dexamethasone in PTSD. , 2004, The American journal of psychiatry.

[7]  R. Yehuda.  Biology of posttraumatic stress disorder. , 2001, The Journal of clinical psychiatry.

[8]  T. Bártfai,et al.  Galanin--10 years with a neuroendocrine peptide. , 1995, The international journal of biochemistry & cell biology.

[9]  Suzanne R. Best,et al.  Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. , 2008, Psychological bulletin.

[10]  J. Krystal,et al.  Riluzole in the Treatment of Mood and Anxiety Disorders , 2008, CNS drugs.

[11]  R Plomin,et al.  Gene–environment interaction analysis of serotonin system markers with adolescent depression , 2004, Molecular Psychiatry.

[12]  R. Yehuda,et al.  Childhood trauma and risk for PTSD: Relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion , 2001, Development and Psychopathology.

[13]  D. M. Lyons,et al.  Salivary cortisol levels in socially phobic adolescent girls , 1999, Depression and anxiety.

[14]  Richard J. Davidson,et al.  A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder , 2008, Biological Psychiatry.

[15]  P. Sawchenko,et al.  Neurotransmitter Regulation of Cellular Activation and Neuropeptide Gene Expression in the Paraventricular Nucleus of the Hypothalamus , 2002, The Journal of Neuroscience.

[16]  S. Southwick,et al.  Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. , 2000, The American journal of psychiatry.

[17]  S. Argyropoulos,et al.  Dopaminergic challenges in social anxiety disorder: evidence for dopamine D3 desensitisation following successful treatment with serotonergic antidepressants , 2010, Journal of psychopharmacology.

[18]  C. Kilts,et al.  The Neural Correlates of Social Anxiety Disorder and Response to Pharmacotherapy , 2006, Neuropsychopharmacology.

[19]  S. Galea,et al.  The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. , 2007, The American journal of psychiatry.

[20]  Steven M. Southwick,et al.  Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder , 2001, Biological Psychiatry.

[21]  A. Lüthi,et al.  Switching on and off fear by distinct neuronal circuits , 2008, Nature.

[22]  K. Felmingham,et al.  Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour therapy for post-traumatic stress disorder , 2007, Psychological Medicine.

[23]  George P. Chrousos,et al.  Plasma and Cerebrospinal Fluid Interleukin-6 Concentrations in Posttraumatic Stress Disorder , 2002, Neuroimmunomodulation.

[24]  F. Holsboer,et al.  FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells* , 2005, Journal of Biological Chemistry.

[25]  J. Gorman,et al.  Molecular targets in the treatment of anxiety , 2002, Biological Psychiatry.

[26]  M C Neale,et al.  A review and meta-analysis of the genetic epidemiology of anxiety disorders. , 2001, The American journal of psychiatry.

[27]  J. Davidson,et al.  The corticotropin-releasing hormone test in patients with posttraumatic stress disorder , 1989, Biological Psychiatry.

[28]  S. Southwick,et al.  Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder. , 2003, Journal of the American Academy of Child and Adolescent Psychiatry.

[29]  H Völzke,et al.  Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden , 2005, Molecular Psychiatry.

[30]  R. Yehuda,et al.  Plasma Neuropeptide Y Concentrations in Combat Exposed Veterans: Relationship to Trauma Exposure, Recovery from PTSD, and Coping , 2006, Biological Psychiatry.

[31]  Lisa M Shin,et al.  Neuroimaging Studies of Amygdala Function in Anxiety Disorders , 2003, Annals of the New York Academy of Sciences.

[32]  Amit Anand,et al.  Brain Imaging Studies in Mood and Anxiety Disorders , 2003, Annals of the New York Academy of Sciences.

[33]  K. Felmingham,et al.  Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder. , 2008, Journal of psychiatry & neuroscience : JPN.

[34]  X. Langlois,et al.  Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450. , 2004, European journal of pharmacology.

[35]  T. Hökfelt,et al.  Colocalization of peptide and glucocorticoid receptor immunoreactivities in rat central amygdaloid nucleus. , 1992, Neuroendocrinology.

[36]  S. Arneric,et al.  Anxiolytic-Like Effects of the Corticotropin-Releasing Factor1 (CRF1) Antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] Administered Acutely or Chronically at Doses Occupying Central CRF1 Receptors in Rats , 2004, Journal of Pharmacology and Experimental Therapeutics.

[37]  R. Yehuda,et al.  Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring. , 2001, Journal of psychiatric research.

[38]  Anthony K. P. Jones,et al.  The cortical representation of pain , 1999, PAIN.

[39]  S. Hodge,et al.  Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR) , 2010, Molecular Psychiatry.

[40]  Matcheri S Keshavan,et al.  Superior temporal gyrus volumes in pediatric generalized anxiety disorder , 2002, Biological Psychiatry.

[41]  Thomas Meitinger,et al.  Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment , 2004, Nature Genetics.

[42]  B. Kofler,et al.  The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. , 2007, Pharmacology & therapeutics.

[43]  G. Gimpl,et al.  The oxytocin receptor system: structure, function, and regulation. , 2001, Physiological reviews.

[44]  Henk J Groenewegen,et al.  Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. , 2005, Archives of general psychiatry.

[45]  W. Kaschka,et al.  Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. , 1995, Journal of psychiatric research.

[46]  M. Liebowitz,et al.  An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder. , 1998, Journal of clinical psychopharmacology.

[47]  J. Krystal,et al.  Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder. , 2004, The American journal of psychiatry.

[48]  J. Smoller,et al.  The genetics of panic disorder , 2001, Current psychiatry reports.

[49]  Alan G. Watts,et al.  The Impact of Physiological Stimuli on the Expression of Corticotropin-Releasing Hormone (CRH) and Other Neuropeptide Genes , 1996, Frontiers in Neuroendocrinology.

[50]  Monique Ernst,et al.  Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. , 2006, The American journal of psychiatry.

[51]  F. Rijsdijk,et al.  Phenotypic and genetic differentiation of anxiety‐related behaviors in middle childhood , 2009, Depression and anxiety.

[52]  C. Olson,et al.  Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. , 1992, Cerebral cortex.

[53]  T. Hökfelt,et al.  The participation of galanin in pain processing at the spinal level. , 2002, Trends in pharmacological sciences.

[54]  V. Arolt,et al.  fMRI amygdala activation during a spontaneous panic attack in a patient with panic disorder , 2007, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[55]  M. Stein,et al.  Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. , 2002, The American journal of psychiatry.

[56]  R. Yehuda,et al.  The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder , 2002, Biological Psychiatry.

[57]  J. Tiihonen,et al.  SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder , 2004, European Archives of Psychiatry and Clinical Neuroscience.

[58]  M. Vaswani,et al.  Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[59]  K. Gysling,et al.  Corticotropin-releasing hormone and urocortin: redundant or distinctive functions? , 2004, Brain Research Reviews.

[60]  A. Neumeister,et al.  Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter , 2004, Psychopharmacology.

[61]  Linda Carpenter,et al.  Reduced brain serotonin transporter availability in major depression as measured by [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography , 1998, Biological Psychiatry.

[62]  R. Hurlemann.  Noradrenergic–glucocorticoid mechanisms in emotion-induced amnesia: from adaptation to disease , 2008, Psychopharmacology.

[63]  Steven C. R. Williams,et al.  The Neural Correlates of Anhedonia in Major Depressive Disorder , 2005, Biological Psychiatry.

[64]  K. Kendler,et al.  A Population-Based Twin Study of Generalized Anxiety Disorder in Men and Women , 2001, The Journal of nervous and mental disease.

[65]  A. Shalev,et al.  Genetics of Posttraumatic Stress Disorder , 2003, CNS Spectrums.

[66]  J. Krystal,et al.  Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children , 2006, Biological Psychiatry.

[67]  Philip Spinhoven,et al.  Hypothalamus–Pituitary–Adrenal Axis Hyperresponsiveness Is Associated with Increased Social Avoidance Behavior in Social Phobia , 2009, Biological Psychiatry.

[68]  Oliver Gruber,et al.  Neuroimaging in anxiety disorders , 2008, Journal of Neural Transmission.

[69]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[70]  Michael Davis,et al.  Role of the Amygdala in Fear Extinction Measured with Potentiated Startle , 2003, Annals of the New York Academy of Sciences.

[71]  Takeshi Inoue,et al.  Changes in amygdala neural activity that occur with the extinction of context-dependent conditioned fear stress , 2008, Pharmacology Biochemistry and Behavior.

[72]  I. Liberzon,et al.  HPA axis activity in patients with panic disorder: review and synthesis of four studies , 2007, Depression and anxiety.

[73]  I. Lyoo,et al.  Decreased blood flow of temporal regions of the brain in subjects with panic disorder. , 2006, Journal of psychiatric research.

[74]  Monique Ernst,et al.  fMRI predictors of treatment outcome in pediatric anxiety disorders , 2007, Psychopharmacology.

[75]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.

[76]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[77]  S. Galea,et al.  RGS2 and generalized anxiety disorder in an epidemiologic sample of hurricane‐exposed adults , 2009, Depression and anxiety.

[78]  J. Smoller,et al.  Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children , 2005, Molecular Psychiatry.

[79]  H. Westenberg,et al.  Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. , 2006, Journal of psychiatric research.

[80]  M. Heilig.  The NPY system in stress, anxiety and depression , 2004, Neuropeptides.

[81]  P. Pervanidou.  Biology of Post‐Traumatic Stress Disorder in Childhood and Adolescence , 2008, Journal of neuroendocrinology.

[82]  J. Smoller,et al.  The genetic basis of panic and phobic anxiety disorders , 2008, American journal of medical genetics. Part C, Seminars in medical genetics.

[83]  M. Tsuang,et al.  A High Risk Twin Study of Combat-Related PTSD Comorbidity , 2003, Twin Research.

[84]  D. Yurgelun-Todd,et al.  fMRI of fearful facial affect recognition in panic disorder: the cingulate gyrus-amygdala connection. , 2006, Journal of affective disorders.

[85]  A. Shekhar,et al.  Interactions between NPY and CRF in the amygdala to regulate emotionality , 2004, Neuropeptides.

[86]  D. Morilak,et al.  One for all or one for one: does co-transmission unify the concept of a brain galanin “system” or clarify any consistent role in anxiety? , 2005, Neuropeptides.

[87]  G. Edwards.  Textbook of psychopharmacology , 1975, Nature.

[88]  Monique Ernst,et al.  Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. , 2008, Archives of general psychiatry.

[89]  C. Nemeroff,et al.  The role of GABA in the pathophysiology and treatment of anxiety disorders. , 2003, Psychopharmacology bulletin.

[90]  John H Krystal,et al.  Social supports and serotonin transporter gene moderate depression in maltreated children. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  J. Davidson,et al.  The DST and posttraumatic stress disorder. , 1987, The American journal of psychiatry.

[92]  A. Shalev,et al.  Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors , 2005, Molecular Psychiatry.

[93]  G. Tsujimoto,et al.  Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice , 2007, Behavioural Brain Research.

[94]  N. Martin,et al.  The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression , 2005, Psychological Medicine.

[95]  M. Palkovits,et al.  Stress-induced expression of co-localized neuropeptides in hypothalamic and amygdaloid neurons. , 2000, European journal of pharmacology.

[96]  Andrew H. Miller,et al.  When Not Enough Is Too Much: The Role of Insufficient Glucocorticoid Signaling in the Pathophysiology of Stress-Related Disorders , 2003 .

[97]  Mark B. Powers,et al.  Functional MRI changes during panic anticipation and imagery exposure , 2001, Neuroreport.

[98]  S. Southwick,et al.  Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. , 1997, The American journal of psychiatry.

[99]  Cortese,et al.  The Role of Glutamate in Anxiety and Related Disorders , 2005, CNS Spectrums.

[100]  Dan J Stein,et al.  Social anxiety disorder , 2008, The Lancet.

[101]  G. Griebel,et al.  Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. , 2003, Trends in pharmacological sciences.

[102]  C. Nemeroff,et al.  Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects , 1996, Biological Psychiatry.

[103]  M. Stein,et al.  Role of corticotropin releasing factor in anxiety disorders: A translational research perspective , 2006, Hormones and Behavior.

[104]  C. Pull,et al.  Pharmacotherapy of panic disorder , 2008, Neuropsychiatric disease and treatment.

[105]  Florian Holsboer,et al.  Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. , 2008, European journal of pharmacology.

[106]  Jonathan M. Amiel,et al.  Open-label trial of riluzole in generalized anxiety disorder. , 2005, The American journal of psychiatry.

[107]  K. Ressler,et al.  Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. , 2008, Archives of general psychiatry.

[108]  David Silbersweig,et al.  SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder , 2000, Biological Psychiatry.

[109]  D. Nutt.  Neurobiological mechanisms in generalized anxiety disorder. , 2001, The Journal of clinical psychiatry.

[110]  Michael C Neale,et al.  The structure of genetic and environmental risk factors for anxiety disorders in men and women. , 2005, Archives of general psychiatry.

[111]  D. Rujescu,et al.  Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[112]  E. R. Sánchez,et al.  A New First Step in Activation of Steroid Receptors , 2002, The Journal of Biological Chemistry.

[113]  P. Lichtenstein,et al.  A developmental twin study of symptoms of anxiety and depression: evidence for genetic innovation and attenuation , 2008, Psychological Medicine.

[114]  V J Cunningham,et al.  Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. , 1998, Archives of general psychiatry.

[115]  F. Holsboer,et al.  Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder , 2008 .

[116]  C. Nemeroff,et al.  Long-Term Consequences of Neonatal Rearing on Central Corticotropin-Releasing Factor Systems in Adult Male Rat Offspring , 2005, Neuropsychopharmacology.

[117]  M. Millan,et al.  Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695: A Comparison to Other Classes of Anxiolytic Agent , 2001, Neuropsychopharmacology.

[118]  G. McCarthy,et al.  Neural systems for executive and emotional processing are modulated by symptoms of posttraumatic stress disorder in Iraq War veterans , 2008, Psychiatry Research: Neuroimaging.

[119]  J. Thakore,et al.  HPA axis response to a psychological stressor in generalised social phobia , 2002, Psychoneuroendocrinology.

[120]  S. Southwick,et al.  Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder , 1991, Biological Psychiatry.

[121]  Sui-yu Hu,et al.  Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder , 2005, Psychiatric genetics.

[122]  K. Ressler,et al.  Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. , 2008, JAMA.

[123]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[124]  D. Schoepp,et al.  Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. , 1998, The Journal of pharmacology and experimental therapeutics.

[125]  K. Felmingham,et al.  The neural networks of inhibitory control in posttraumatic stress disorder. , 2008, Journal of psychiatry & neuroscience : JPN.

[126]  S. Hodge,et al.  A Third-Pass Genome Scan in Panic Disorder: Evidence for Multiple Susceptibility Loci , 2006, Biological Psychiatry.

[127]  S. Southwick,et al.  Low Urinary Cortisol Excretion in Patients with Posttraumatic Stress Disorder , 1990, The Journal of nervous and mental disease.

[128]  Namkug Kim,et al.  Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: A proton magnetic resonance spectroscopy (1H-MRS) study , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[129]  R. Lydiard,et al.  Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder , 1999, Biological Psychiatry.

[130]  R. Bonsall,et al.  Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse , 2004, Biological Psychiatry.

[131]  M. Weissman,et al.  Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[132]  Miranda Olff,et al.  HPA- and HPT-axis alterations in chronic posttraumatic stress disorder , 2006, Psychoneuroendocrinology.

[133]  W. Drevets.  Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders , 2001, Current Opinion in Neurobiology.

[134]  W. Maier,et al.  Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[135]  David F. Smith,et al.  Printed in U.S.A. Copyright © 2000 by The Endocrine Society Squirrel Monkey Immunophilin FKBP51 Is a Potent Inhibitor of Glucocorticoid Receptor Binding* , 2000 .

[136]  F. DuBois Bowman,et al.  Erratum: The neural correlates of social anxiety disorder and response to pharmacotherapy (Neuropsychopharmacology (2006) 31 (2243-2253) DOI: 10.1038/sj.npp.1301053) , 2006 .

[137]  P. Ninan.  Recent perspectives on the diagnosis and treatment of generalized anxiety disorder. , 2001, The American journal of managed care.

[138]  A. Meyer-Lindenberg.  Impact of prosocial neuropeptides on human brain function. , 2008, Progress in brain research.

[139]  J. Strawn,et al.  Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder , 2008, Depression and anxiety.

[140]  M. Buonocore,et al.  Brain regions showing increased activation by threat-related words in panic disorder , 2003, Neuroreport.