Anxiety Disorders: Savitz J

Savitz J, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health/NIH, Bethesda, MD 20892, USA. · Neurosci Biobehav Rev. · Pubmed #19428491 No free full text.

Abstract: Both major depressive disorder and bipolar disorder are the subject of a voluminous imaging and genetics literature. Here, we attempt a comprehensive review of MRI and metabolic PET studies conducted to date on these two disorders, and interpret our findings from the perspective of developmental and degenerative models of illness. Elevated activity and volume loss of the hippocampus, orbital and ventral prefrontal cortex are recurrent themes in the literature. In contrast, dorsal aspects of the PFC tend to display hypometabolism. Ventriculomegaly and white matter hyperintensities are intimately associated with depression in elderly populations and likely have a vascular origin. Important confounding influences are medication, phenotypic and genetic heterogeneity, and technological limitations. We suggest that environmental stress and genetic risk variants interact with each other in a complex manner to alter neural circuitry and precipitate illness. Imaging genetic approaches hold out promise for advancing our understanding of affective illness.

Drevets WC, Savitz J, Trimble M. · Section on Neuroimaging in Mood and Anxiety Disorders, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. · CNS Spectr. · Pubmed #18704022 links to  free full text

Abstract: The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

Savitz J, Lucki I, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, NIH/NIMH, Bethesda, MD 20892, United States. · Prog Neurobiol. · Pubmed #19428959 No free full text.

Abstract: Dysfunction of the serotonin 1A receptor (5-HT(1A)) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT(1A) receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT(1A) receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT(1A) receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT(1A) receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT(1A) receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT(1A) receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT(1A) receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.

Savitz J, van der Merwe L, Ramesar R. · Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, USA. <> · J Affect Disord. · Pubmed #18192025 No free full text.

Abstract: Anxious and dysthymic personality traits were measured in a euthymic, familial sample of bipolar (BPD) individuals and their affectively ill and unaffected relatives. According to the quantitative genetic model of bipolar spectrum illness [Evans, L., Akiskal, H.S., Keck, Jr., P.E., McElroy, S.L., Sadovnick, A.D., Remick, R.A., Kelsoe, J.R., 2005. Familiality of temperament in bipolar disorder: support for a genetic spectrum. J. Affect. Disord. 85, 153-168], these traits should be normally distributed with the bipolar disorder I (BPD I) group showing the highest and the unaffected relatives the least "pathological" scores. Three hundred individuals from 47 bipolar disorder families were administered a battery of personality questionnaires (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego; Temperament and Character Inventory; Affective Neuroscience Personality Scale) as well as a self-rating depression (Beck Depression Inventory) and mania (Altman Self-Rating Mania) scale. Out of the 300 participants, 58 were diagnosed with BPD I, 27 with bipolar disorder II (BPD II), 58 with recurrent major depression (MDE-R), 45 had one previous depressive episode (MDE-S), and 88 were unaffected. The BPD I group scored significantly higher than their unaffected relatives on the Harm Avoidance and Sadness scales of the TCI and ANPS, respectively, while the MDE-R but not the BPD samples scored significantly higher than unaffected relatives on the Anxious Temperament (AT) subscale of the TEMPS-A. In general, the mean dysthymic personality scores were highest in the BPD sample, followed by the MDE-R, MDE-S, and unaffected relative groups. Nevertheless, no significant personality differences were found between the psychiatrically-ill groups. While dysthymic temperament traits conform relatively well to the quantitative genetic model of affective illness, anxious traits as defined by the AT scale, are equally salient in BPD and unipolar depression.

Stein DJ, Newman TK, Savitz J, Ramesar R. · Department of Mental Health and Psychiatry, University of Cape Town, South Africa. · CNS Spectr. · Pubmed #17008817 links to  free full text

Abstract: Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.