Neurobiology and neurogenetics of anxiety and depression

Department of Clinical Neurosciences
Scientific Institute and University Vita
Salute San Raffaele
Milan, ITALY

Neurobiology and
neurogenetics of anxiety
and depression

by E. Smeraldi, Italy

Mood and anxiety disorders are characterized by a variety of alterations in brain morphology and activity and in neuroendocrine disruptions. Comorbidity among anxiety and depressive disorders is particularly common and has significant implications in terms of clinical presentation, assessment, treatment selection and effectiveness, as well as the course of illness, prognosis, and long-term outcome. Despite this high comorbidity, many distinguishing features support the continued classification of individual anxiety disorders that are distinct from each other and from mood disorders. The traditional neurobiological concept of the etiology of depressive and anxiety disorders has been the monoamine hypothesis; however, in recent years, researchers have turned their attention to glutamate. Moreover, it has become evident that factors other than imbalances between neurotransmitter systems must be taken into account when describing the neurobiological basis of major depression in particular, but also of anxiety disorders; it is now well accepted that these conditions are characterized by internal desynchronization of information processing inducing profound alterations in brain structure, function, and responsiveness. The subsequent alterations in neuroplasticity and in inflammatory mechanisms are thought to be involved in the pathogenesis of the disorders.

Medicographia. 2012;34:276-282 (see French abstract on page 282)

Anxiety disorders are the most prevalent psychiatric disorders both in the United States and in Europe. They include panic disorder, generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), agoraphobia, posttraumatic stress disorder (PTSD), and specific phobias.

Major depression is a severe disease with high prevalence, negative impact on social health, and serious consequences such as suicide. Core symptoms include depressed mood, anhedonia (reduced ability to experience pleasure from natural rewards), irritability, difficulties in concentrating, and abnormalities in appetite and sleep (neurovegetative symptoms). Major depressive disorder (MDD) accounts for 4.4% of the global burden of disease, which is in the same range as the total burden attributable to ischemic heart disease, or to the combined impact of asthma and chronic obstructive pulmonary disease.1

Mood and anxiety disorders are characterized by a variety of alterations in brain morphology and activity and in neuroendocrine disruptions. Comorbidity among the anx- iety and depressive disorders is particularly common and has significant implications in terms of clinical presentation, assessment, treatment selection and effectiveness, as well as the course of illness, prognosis, and long-term outcome.2

Despite this high comorbidity, many distinguishing features support the continued classification of individual anxiety disorders that are distinct from each other and from mood disorders (MDs).

The traditional neurobiological concept of the etiology of depressive and anxiety disorders has been the monoamine hypothesis, which proposes that MDs are caused by a deficiency in serotonin or noradrenaline at functionally important receptor sites in the brain. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of MDs. Studies employing in vivo magnetic resonance spectroscopy (MRS) have revealed altered cortical glutamate levels in depressed subjects and dysfunction of the predominant glutamatergic system. Malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/ morphological maladaptive changes in a number of brain areas mediating cognitive emotional behaviors have also been found. Consistent with a model of excessive glutamate induced excitation in MDs, several antiglutamatergic agents have demonstrated potential antidepressant efficacy3 and glutamatergic modulators are available as antidepressants.4 Concurrently, studies on animal models have shown that different types of environmental stress enhance glutamate release/ transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses, and possibly volumetric reductions resembling those observed in depressed patients.5 Considering anxiety disorders, drugs that reduce glutamate availability are hypothesized to possess anxiolytic properties. Elevated excitatory glutamatergic signaling associated with panicogenicity has been reported in patients affected by SAD who were shown to have a 13.2% higher glutamate/creatine ratio in the anterior cingulate cortex (ACC) as measured by MRS compared with healthy subjects. Moreover, as glutamate plays a critical role in hippocampal- dependent associative learning and in amygdala-dependent emotional processing in stressful conditions or following stress exposure, inappropriate glutamate signaling is believed to contribute to the processing distortion experienced by many patients who have PTSD. In support of the glutamate hypothesis of PTSD, the N-methyl-D-aspartic acid receptor antagonist ketamine is well-known for its ability to induce dissociative and perceptual distortions, similar to the processing distortion in patients affected by the disorder.6 There is growing evidence that disrupted neurotransmission of glutamate within cortico-striatal-thalamic-cortical circuitry plays a role in the pathogenesis of OCD. Candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 (the glutamate transporter gene). Furthermore, clinical studies using MRS found altered glutamate concentrations in the caudate and ACC of patients. Animal models also provided further indirect support for the role of glutamate dysfunction in OCD: in particular, the DLGAP3 (discs, large [drosophila] homolog associated protein 3) and Sltrk5 knockout mouse models in fact display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction.7

During recent years, it has become evident that factors other than imbalances between neurotransmitter systems must be taken into account when describing the neurobiological basis of major depression and it is now well accepted that this condition is characterized by profound alterations in brain structure, function, and responsiveness. Recent evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression, and suggest that disturbed neuroplasticity, including impaired adult hippocampal neurogenesis, might be implicated in the biological basis of the disorder. Antidepressant drugs have been suggested to act by inducing plastic changes in neuronal connectivity, which gradually lead to improvement in neuronal information processing, biological resynchronization of brain circuits, and recovery of mood.8 Several signaling pathways and targets have been implicated, including the neurotrophic factor Wnt and glycogen synthase kinase 3 (GSK3) pathways.9 Microarray studies demonstrate that antidepressants differentially regulate the expression of Wnts, Fz, and Dsh receptors, and downstream transcription partners in the rodent hippocampus. Moreover, viral expression ofWnt2 in the hippocampus produces an antidepressant response in the learned helplessness and sucrose preference tests.10 These pathways have not been studied in anxiety disorders.

Recent studies support the concept that inflammatory mechanisms play a crucial role in the pathomechanisms of major depression. Major depression has similarities with a chronic form of “sickness behavior,” a normal response to inflammatory cytokines. Elevations in proinflammatory cytokines and other inflammation-related proteins are a well-documented finding in major depression and contribute to the hypercortisolism and decreased sensitivity of the hypothalamic-pituitary- adrenal (HPA) axis found in the disorder, with adrenocorticotropin hormone (ACTH) responses being most attenuated in depressed patients with the most severe hypercortisolism.11 Moreover, roughly 30% of individuals treated with recombinant interferons develop depression as a side effect of treatment.12 Although administration of cytokines such as interferon-α or interleukin (IL)-6 was not found to cause consistent depression-like features in rodents, recent preclinical studies indicate that blocking proinflammatory cytokine-mediated signaling can produce antidepressant effects. Mice with targeted deletions of the gene encoding IL-6 or those encoding the tumor necrosis factor (TNF)–α receptors show antidepressant-like behavioral phenotypes, and a centrally administered antagonist of the IL-1β receptor reversed the behavioral and anti-neurogenic effects of chronic stress.13

Antidepressant treatments have been shown to normalize serum levels of inflammatory proteins and cytokines, including IL-1, IL-6, TNF-α and INF-agamma;.14 Wolkowitz et al postulated that inflammatory processes in major depression may be the underlying cause for early mortality, high rates of aging-related illnesses, as well as changes in leukocyte telomere length frequently found in major depression.15 There is evidence that abnormalities in HPA axis function may also characterize a subset of anxiety disorders, but the nature of these alterations differs from that seen in MDs (eg, hypercortisolemia and reduced negative feedback inhibition).16 Many studies have suggested that changes occur in HPA axis and sympathetic-adrenal- medullary system function in patients with PTSD who are known to have increased rates of comorbidity with somatic disorders that involve immune and inflammatory processes. Moreover, these patients have been found to exhibit a number of immune changes including increased circulating inflammatory markers, increased reactivity to antigen skin tests, lower natural killer cell activity, and lower total T lymphocyte counts.17 Although very few studies have specifically examined HPA axis reactivity in patients who have GAD, there is no evidence of hypercortisolism, dexamethasone non suppression, or increased cerebrospinal fluid corticotropin-releasing factor (CSF CRF) concentrations.18

Neuroimaging studies

The bulk of neuroimaging research about anxiety disorders has focused on the amygdala and its connections to the prefrontal cortex (PFC). The amygdala is the main brain region implicated in the processing of fear and its activity is believed to be regulated by the top-down governance of the medial PFC, including orbitofrontal cortex and subgenual ACC, as well as the hippocampus.19 Reciprocal connectivity between the amygdala and PFC is further implicated as a mechanism of fear extinction.20 Many researchers found an increased amygdalar reactivity to threat cues in patients affected by different anxiety disorders compared with healthy subjects; this alteration can also be observed in the very early stages of processing.21

Recent findings suggest the involvement of other brain regions in the pathogenesis of anxiety disorders. An emerging region of interest is the insula, which has been proposed to integrate information from the amygdala, nucleus accumbens, and orbitofrontal cortex and to be involved in the anticipation of aversive affective stimuli.22 In anxious subjects, this prediction signal might increase due to an exaggerated aversive expectation. Alteration in the activity of the insula has been demonstrated not only in patients affected by anxiety disorders (panic disorder, OCD, SAD, specific phobia, GAD, and PTSD), but also in subjects with an elevated anxiety trait.21

The number of brain imaging studies in patients with OCD has increased exponentially during recent years. Most of the studies using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or functional magnetic resonance imaging (fMRI) have shown a relationship between the disorder and overactivity in the orbitofrontal cortex, ACC, caudate nucleus, and thalamus. Moreover, some studies have found a positive correlation between frontal cortex hyperactivity during task performance and severity of symptomatology.23 Current knowledge from functional and structural neuroimaging emphasizes abnormalities of frontal-striatal thalamic-cortical circuits and orbitofronto-striatal-thalamic circuits in the pathophysiology of the disorder.24 Rauch25,26 suggested that at a neural circuitry level, primary striatal dysfunction in OCD leads to deficits in thalamic filtering, which in turn leads to exaggerated orbitofrontal cortex activity. Some have suggested that orbitofrontal-subcortical hyperactivity in OCD may be the result of abnormal neuroanatomic development of these structures or a failure of pruning of neuronal connections between them, as occurs in normal development.27 As the hippocampus-amygdala complex has strong connections with the orbitofrontal cortex, these complexes are included in the OCD circuit. Abnormalities in the regions of the hippocampus and amygdala have been emphasized in studies involving PET or fMRI, and these regions have been suggested to play an important role in the pathophysiology of OCD.28 Moreover, in patients affected by OCD, a loss of normal hemispheric asymmetry of the hippocampus-amygdala complex29 and differences in amygdala volumes30 were found.

Two recent magnetic resonance imaging (MRI) structural studies in patients affected by panic disorder showed a volume reduction in the ACC31 or a relative gray matter deficit in the right ACC, with a significant gray matter increase in the left insula, the left superior temporal gyrus, the midbrain, and the pons.32

Typically, neuroimaging and postmortem analyses of patients with depression reveal structural changes in limbic and forebrain regions, including the hippocampus, amygdala, and PFC.33,34 Probably the most reproduced finding in the imaging of MD is a small (10%-15%), but significant, reduction in hippocampal volume as documented in MRI studies, with a positive correlation between the duration of the depressive episode and the reduction in hippocampal volume.35 Variation in gray matter volume was associated with GSK3Β polymorphisms; the most significant associations were found for rs6438552, a putative functional intronic single nucleotide polymorphism (SNP) that showed 3 significant gray matter clusters in the right and left superior temporal gyri and the right hippocampus.36

Similarly, there are consistent reports of reduced PFC volumes in patients with depression, specifically in the dorsolateral PFC, orbitofrontal cortex, and subgenual PFC. Moreover, postmortem studies report a reduced size of pyramidal neurons and a decreased number of GABAergic interneurons and glia (both astrocytes and oligodendrocytes) in the PFC.37 Many of these effects also occur in response to chronic stress exposure in rodents and nonhuman primates, including atrophy of dendrites and spines in the PFC and hippocampus, and decreased glia numbers and neurogenesis in the adult hippocampus.38

Volumetric changes have also been found in the amygdala in patients affected by MDD; these changes, however, appear to be dynamic throughout the course of depressive illness, with an initial enlargement, followed by a volume reduction as the illness progresses.39

All the previously described regions are part of the limbic-cortico-thalamic circuit and are involved in the modulation of emotional and cognitive behavior. In patients affected by major depression, researchers have found morphological and functional alterations in these areas. Compared with healthy controls, patients affected by MDD have altered activation in the orbital and medial frontal cortex during exposure to emotionally charged stimuli and during performance of reward processing tasks.40 Moreover, one of the most consistent findings in the MD literature has been that patients with MDD show exaggerated activation in the amygdala when exposed to emotional stimuli.41

It is also possible that emotional dysregulation could result from a lack of inhibition by the PFC on limbic structures, as suggested by the observation of decreased glucose metabolism in the PFC with increased metabolism in subcortical structures42 and fMRI studies showing reduced activity and impaired signal communication in corticolimbic networks critical to processing emotional stimuli.43


ach anxiety disorder, as well as MDD, has both genetic and environmental contributions to vulnerability. When attempting to identify the genetic contribution toward susceptibility to psychopathology, the candidate genes are largely the same across diagnoses and tend to be genes whose products regulate the HPA axis and monoaminergic signaling. Ongoing research supports the hypothesis that a genetic predisposition may be shared among mood and anxiety disorders, with individual clinical manifestation being a product of both genetic and environmental influences. Some genetic factors are diagnosis specific; others are nonspecific, but influence the risk for psychopathology in general.

The most extensively studied variant in genetic studies of anxiety and MDs is an SNP in the promoter region of the serotonin transporter gene (5-HTTLPR). This transporter is the target of the most widely used pharmacotherapy for anxiety disorders and MDs, the selective serotonin reuptake inhibitors (SSRIs). The “short” allele of the 5-HTTLPR, lacking 44 base pairs of dinucleotide repeat sequence, confers reduced transcriptional activity to the serotonin transporter gene and has been associated with anxiety-related traits including neuroticism, harm avoidance, and, in some studies, anxiety disorders including social phobia, OCD, and PTSD.44 Regarding the association of the 5-HTTLPR polymorphism with depression, a gene-environment interaction was found. Short allele carriers seem to be more likely to develop depression after stressful life events than individuals homozygous for the long allele,45 and the same subjects seem to have an earlier age at onset, but a lower rate of illness recurrence.46 Moreover, a recent meta-analysis showed a significant association in MD between the long variant of the serotonin transporter gene-linked polymorphic region (SERTPR) and a better response to SSRI and chronobiological treatments.47,48 SERTPR was examined in OCD with regard to response to treatment: conflicting results were found, including evidence for a trend toward an association of poor response to SSRI in long-SERTPR as well as evidence for no association.48 The same polymorphism was found to influence brain morphometry in obsessive patients, with short-variant homozygotes having a smaller right oribito-frontal cortex than the long-variant homozygotes.49 In female patients affected by panic disorder, both homozygotes and heterozygotes for the SERTPR long variant were shown to have a better response to paroxetine than did homozygotes for the short variant.50

Another gene studied both in mood and anxiety disorders is that encoding for catechol-O-methyltransferase (COMT). The COMT enzyme inactivates catecholamines, and the COMT Val(108/158)Met polymorphism (rs4680) influences the enzyme activity with a trimodal distribution (high activity in Val/Val, intermediate activity in Val/Met, and low activity in Met/Met genotypes51). A significant association was found between the polymorphism and early onset MD, particularly for the COMT Val/Val genotype.52 In MD, the methionine allele in the COMT Val/Met variant has been associated with a worse response to mirtazapine,53 to paroxetine,54 and both a worse and better response to citalopram.55,56 Controversial results have been shown regarding the association of COMT gene polymorphism and OCD,57 while the same polymorphism has been implicated in susceptibility to panic disorder by several studies in independent samples. Moreover, in patients affected by panic disorder, Met homozygoteswere found to showa poorer response both to paroxetine and to cognitive behavioral therapy.58

The latest gene investigated both in mood and anxiety disorders is that encoding for the dopamine receptor D2 (DRD2). No association has been found with affective disorders, but DRD2 gene polymorphism has been shown to influence response to treatment in PTSD.59


Although the traditional neurobiological concept of the etiology of depressive and anxiety disorders has been the monoamine hypothesis, focusing on serotonin, noradrenaline, and dopamine, in recent years, researchers have turned their attention to glutamate, the most important amino acid neurotransmitter. The glutamatergic system is considered a primary mediator of psychiatric pathology and—potentially a final common pathway for the therapeutic action of antidepressant drugs— is also used in the treatment of anxiety disorders. Moreover, during recent years, it has become evident that factors other than imbalances between neurotransmitter systems must be taken into account when describing the neurobiological basis of major depression in particular, but also of anxiety disorders; it is now well accepted that these conditions are characterized by desynchronization of brain circuits, causing profound alterations in brain structure, function, and responsiveness. There has been a paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis, which focuses on glutamate. Recent evidence, in fact, indicates that problems in information processing within neural networks might underlie depression, and suggest that disturbed neuroplasticity, including impaired adult hippocampal neurogenesis, might be implicated in the biological basis of the disorder. Alteration in neuroplasticity has not been studied in anxiety disorders. Moreover, recent studies support the importance of inflammatory mechanism alteration in the pathomechanisms of both major depression and anxiety disorders. _

Acknowledgment. The author would like to thank Dr Sara Dallaspezia for her collaboration.

1. Chisholm D, Sanderson K, Ayuso-Mateos JL, Saxena S. Reducing the global burden of depression: population-level analysis of intervention cost-effectiveness in 14 world regions. Br J Psychiatry. 2004(184):393-403.
2. Belzer K, Schneier FR. Comorbidity of anxiety and depressive disorders: issues in conceptualization, assessment, and treatment. J Psychiatr Pract. 2004;10(5): 296-306.
3. Kugaya A, Sanacora G. Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 2005;10(10):808-819.
4. McEwen BS, Chattarji S, Diamond DM, et al. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010;15:237-249.
5. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2011;62(1):63-77.
6. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr Clin North Am. 2009;32(3):549-575.
7. Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav. 2012;100(4):726-735.
8. Castren E. Is mood chemistry? Nat Rev Neurosci. Mar 2005;6(3):241-246.
9. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62(1): 35-41.
10. Okamoto H, Voleti B, BanasrM, et al.Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biol Psychiatry. 2010;68(6): 521-527.
11. Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med. 1986;314(21):1329-1335.
12. Loftis JM, Hauser P. The phenomenology and treatment of interferon-induced depression. J Affect Disord. 2004;82(2):175-190.
13. Krishnan V, Nestler EJ. Themolecular neurobiology of depression. Nature. 2008; 455(7215):894-902.
14. De Berardis D, Conti CM, Serroni N, et al. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature. Int J Immunopathol Pharmacol. 2010;23(2):417-422.
15. Wolkowitz OM, Mellon SH, Epel ES, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress—preliminary findings. PLoS One. 2012;6(3):e17837.
16. Holsboer F. Corticotropin-releasing hormone modulators and depression. Curr Opin Investig Drugs. 2003;4(1):46-50.
17. Pace TW, Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011;25(1):6-13.
18. Nutt DJ. Neurobiological mechanisms in generalized anxiety disorder. J Clin Psychiatry. 2001;62(suppl 11):22-27;discussion 28.
19. Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci. 2007;10(9):1116- 1124.
20. Quirk GJ, Garcia R, Gonzalez-Lima F. Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry. 2006;60(4):337-343.
21. Mathew SJ, Price RB, Charney DS. Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am J Med Genet C Semin Med Genet. 2008;148C(2):89-98.
22. Simmons A, Matthews SC, Stein MB, Paulus MP. Anticipation of emotionally aversive visual stimuli activates right insula. Neuroreport. 2004;15(14):2261- 2265.
23. Lazaro L, Caldu X, Junque C, et al. Cerebral activation in children and adolescents with obsessive-compulsive disorder before and after treatment: a functional MRI study. J Psychiatr Res. 2008;42(13):1051-1059.
24. Atmaca M. Review of structural neuroimaging in patients with refractory obsessive- compulsive disorder. Neurosci Bull. 2011;27(3):215-220.
25. Rauch SL, Wedig MM, Wright CI, et al. Functional magnetic resonance imaging study of regional brain activation during implicit sequence learning in obsessive- compulsive disorder. Biol Psychiatry. 2007;61(3):330-336.
26. Rauch SL, Shin LM, Wright CI. Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci. 2003;985:389-410.
27. Rosenberg DR, Keshavan MS. A. E. Bennett Research Award. Toward a neurodevelopmental model of obsessive—compulsive disorder. Biol Psychiatry. 1998; 43(9):623-640.
28. McGuire PK, Bench CJ, Frith CD, Marks IM, Frackowiak RS, Dolan RJ. Functional anatomy of obsessive-compulsive phenomena. Br J Psychiatry. 1994; 164(4):459-468.
29. Szeszko PR, Robinson D, Alvir JM, et al. Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Arch Gen Psychiatry. 1999;56(10): 913-919.
30. Szeszko PR, MacMillan S, McMeniman M, et al. Amygdala volume reductions in pediatric patients with obsessive-compulsive disorder treated with paroxetine: preliminary findings. Neuropsychopharmacology. 2004;29(4):826-832.
31. Asami T, Hayano F, Nakamura M, et al. Anterior cingulate cortex volume reduction in patients with panic disorder. Psychiatry Clin Neurosci. 2008;62(3):322- 330.
32. Uchida RR, Del-Ben CM, Busatto GF, et al. Regional gray matter abnormalities in panic disorder: a voxel-based morphometry study. Psychiatry Res. 2008;163 (1):21-29.
33. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry. 2000; 48(8):813-829.
34. Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11(2):240-249.
35. MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100(3):1387-1392.
36. Inkster B, Nichols TE, Saemann PG, et al. Association of GSK3beta polymorphisms with brain structural changes in major depressive disorder. Arch Gen Psychiatry. 2009;66(7):721-728.
37. Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology. 2007;32(2): 471-482.
38. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116-1127.
39. Lorenzetti V, Allen NB, Fornito A, Yucel M. Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies. J Affect Disord. 2009;117(1-2):1-17.
40. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213(1-2):93-118.
41. Surguladze S, Brammer MJ, Keedwell P, et al. A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biol Psychiatry. 2005;57(3):201-209.
42. Ketter TA, Kimbrell TA, George MS, et al. Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder. Biol Psychiatry. 2001;49(2):97-109.
43. Benedetti F, Bernasconi A, Blasi V, et al. Neural and genetic correlates of antidepressant response to sleep deprivation: a functional magnetic resonance imaging study of moral valence decision in bipolar depression. Arch Gen Psychiatry. 2007;64(2):179-187.
44. Smoller JW, Block SR, Young MM. Genetics of anxiety disorders: the complex road from DSM to DNA. Depress Anxiety. 2009;26(11):965-975.
45. Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry. 2008;13(2):131-146.
46. Smeraldi E, Benedetti F, Zanardi R. Serotonin transporter promoter genotype and illness recurrence in mood disorders. Eur Neuropsychopharmacol. 2002; 12(1):73-75.
47. Benedetti F, Barbini B, Bernasconi A, et al. Lithium overcomes the influence of 5-HTTLPR gene polymorphism on antidepressant response to sleep deprivation. J Clin Psychopharmacol. 2008;28(2):249-251.
48. Serretti A, Chiesa A, Calati R, Perna G, Bellodi L, De Ronchi D. Common genetic, clinical, demographic and psychosocial predictors of response to pharmacotherapy in mood and anxiety disorders. Int Clin Psychopharmacol. 2009;24(1): 1-18.
49. Atmaca M, Onalan E, Yildirim H, et al. Serotonin transporter gene polymorphism implicates reduced orbito-frontal cortex in obsessive-compulsive disorder. J Anxiety Disord. 2011;25(5):680-685.
50. Perna G, Favaron E, Di Bella D, Bussi R, Bellodi L. Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology. 2005;30(12):2230-2235.
51. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243-250.
52. Massat I, Souery D, Del-Favero J, et al. Association between COMT (Val(158) Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry. 2005;10(6):598-605.
53. Szegedi A, Rujescu D, Tadic A, et al. The catechol-O-methyltransferase Val108/ 158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression. Pharmacogenomics J. 2005;5(1): 49-53.
54. Benedetti F, Colombo C, Pirovano A, Marino E, Smeraldi E. The catechol-Omethyltransferase Val(108/158)Met polymorphism affects antidepressant response to paroxetine in a naturalistic setting. Psychopharmacology (Berl). Mar 2009;203(1):155-160.
55. Arias B, Serretti A, Lorenzi C, Gasto C, Catalan R, Fananas L. Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin. J Affect Disord. 2006;90(2-3):251-256.
56. Yoshida K, Higuchi H, Takahashi H, et al. Influence of the tyrosine hydroxylase val81met polymorphism and catechol-O-methyltransferase val158met polymorphism on the antidepressant effect of milnacipran. Hum Psychopharmacol. 2008;23(2):121-128.
57. Erdal ME, Tot S, Yazici K, et al. Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder. Depress Anxiety. 2003;18(1):41-45.
58. Lonsdorf TB, Ruck C, Bergstrom J, et al. The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder. BMC Psychiatry. 2010;10:99.
59. Lawford BR, McD Young R, Noble EP, et al. D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder. Eur Neuropsychopharmacol. 2003;13(5):313-320.

Keywords: anxiety disorder; depression; gene polymorphism; glutamate; inflammatory mechanism; neuroimaging; neuroplasticity