By M. Volkar. University of South Florida. 2018.
MERIKANGAS DANIEL PINE Despite dramatic advances in our understanding of genetics First generic lamictal 25mg visa medications versed, although studies through the early 1990s often em- and neurobiology buy lamictal 50 mg on-line medications kidney damage, the etiology of the anxiety disorders is phasized the role of one or another particular risk factor, still relatively unknown. To date, there remain no pathog- more recent studies emphasize the manner in which multi- nomonic markers with which a presumptive diagnosis of ple risk factors might interact to cause mental syndromes, an anxiety disorder may be made. This highlights the impor- including anxiety, as part of a mechanistic pathway. For tance of the empirical epidemiologic approach to investigat- example, although dysregulation in fear conditioning has ing the definitions and risk factors for the expression of been linked to anxiety for more than two decades (3), such anxiety across the life course. Anxiety disorders are develop- dysregulation is now viewed as part of a larger chain of mental conditions that often emerge during childhood and intrinsic and extrinsic events that may ultimately culminate follow varied developmental trajectories (1,2). Second, as a corollary to this early-life vulnerability factors that predict the trajectory of view, vulnerability markers are now conceptualized as tied anxiety symptoms across development holds promise for to families of anxiety disorders, as opposed to specific condi- elucidating mechanistic pathways in anxiety. This change in perspective follows the observation In evaluating the risk factors for the development of anxi- that validators of individual mental syndromes related to ety disorders, there are several issues requiring considera- differential course, familial aggregation, or psychophysiol- tion. First, there is substantial overlap between the anxiety ogy relate more closely to families of disorders than to partic- disorders and other psychiatric disorders both concomi- ular disorders. Third, marked advances over the past 20 tantly and longitudinally. Second, manifestations of anxiety years in neuroscience have stimulated a closer integration of change substantially across the life course, particularly dur- basic and clinical work on vulnerability markers in anxiety ing childhood and adolescence. Progress in elucidating neural circuits related to perspective is essential in evaluating links between risk fac- anxiety has facilitated research on vulnerability markers for tors and anxiety disorders. Third, the assessment of anxiety anxiety disorders that integrates data from basic and clinical requires evaluation of the context in which the individual science. As such, anxiety becomes a disorder velopment of anxiety disorders across the life span. Particu- when there is a mismatch between inherent threat posed lar attention is paid to the specificity of vulnerability factors by a particular stimulus or situation and the cognitive or and to developmental differences in expression of the disor- somatic response. Research on vulnerability factors has undergone a rela- tively marked transformation in recent years, due to concep- tual changes in causal theories of mental disorders. Such MAGNITUDE AND DEMOGRAPHIC RISK conceptual changes are reflected in three major themes that FACTORS organize current research on vulnerability factors in anxiety. Magnitude of Anxiety in General Population Kathleen R. Merikangas and Daniel Pine: National Institute of Mental The anxiety disorders are the most common psychiatric dis- Health, Bethesda, Md. The 868 Neuropsychopharmacology: The Fifth Generation of Progress results of the two large-scale community-based surveys of ability according to specific subtypes. Although tional Comorbidity Study (NCS) (5), reveal that the total the magnitude of the rates of anxiety disorders varies sub- prevalence rates of anxiety disorders are greater than those stantially between the two studies, the sex ratio is strikingly of the affective disorders, behavior disorders, and substance similar: women have an approximately twofold elevation in use disorders. Phobias tend to be the most common anxiety lifetime rates of panic, generalized anxiety disorder, agora- disorder, whereas panic disorder is fairly rare in the general phobia, and simple phobia than men in both studies. There is substantial overlap both cross-section- contrast, there is a nearly equal sex ratio for the lifetime ally and longitudinally between the anxiety disorders and prevalence of social phobia. On average, there is a threefold studies that anxiety symptoms and disorders are also the increased risk of having a second disorder compared to that most common problems in childhood and adolescence as of manifesting an anxiety disorder alone across the lifetime. The rates of anxiety disorders in community or school- Comorbidity between anxiety disorders and other psy- based surveys of children and adolescents as defined by con- chiatric disorders has been demonstrated in both clinical temporary diagnostic criteria range from 0. Similar to the sex strongly associated with affective disorders and with sub- ratio for adults, girls tend to have more of all subtypes of stance use disorders (6), though they are generally associated anxiety disorders, irrespective of the age composition of the with all other major classes of disorders including depres- sample. For example, in a recent epidemiologic study, fe- sion, disruptive behaviors, eating disorders, and substance males compared to males had greater rates of current anxiety use. Comorbidity between anxiety disorders and other dis- disorders (i. Nevertheless, or -IV) may be even more common in adolescents than in Lewinsohn et al. A review of comorbidity of anxiety and depres- of anxiety in girls across all ages, there was no difference sion by Brady and Kendall (8) suggests that anxiety and between boys and girls in the average age at onset of anxiety depression may be part of a developmental sequence in (mean for girls 8.
Genome Res 1998;8: of a locus on chromosome 5q31 contributing to susceptibility 1273–1288 for schizophrenia in German and Israeli families by multipoint 114 generic lamictal 100 mg medicine ball exercises. Positive association be- affected sib-pair linkage analysis discount lamictal 100 mg with amex symptoms quitting smoking. Mol Psychiatry 1997;2: tween a DNA sequence variant in the serotonin 2A receptor 156–160, gene and schizophrenia. Association between schizophrenia vulnerability locus in region 5q22-31 in Irish schizophrenia and T102C polymorphism of the 5-hydroxytryp- families. A family-based associa- some 18p locus conferring susceptibility to functional psychoses tion study of T102C polymorphism in 5-HT2Aand schizophre- in families with schizophrenia, by association and linkage analy- nia plus identification of new polymorphisms in the promoter. Results of the NIMH association between the 5-HT2a receptor T102C polymor- Genetics Initiative and Millennium Consortium. Mol Brain Res 1998;59:90–92 may be located in region 10p15-p11. A meta-analysis and confirmation in an independent series of pedigrees. Genomics transmission disequilibrium study of association between the 1997;43:1–8. The molecular genetics of schizo- major susceptibility locus for familial schizophrenia on chromo- phrenia. Am bipolar disorder are associated with expanded CAG/CTG re- J Med Genet 1992;44:261–268. CAG repeat expan- involving cleft palate, cardiac anomalies, typical facies and learn- sions and schizophrenia—association with disease in females ing disabilities: velo-cardio-facial syndrome. Bipolar spectrum disorders association between expanded CAG/CTG repeats and both in patients diagnosed with velo-cardio-facial syndrome: does a schizophrenia and bipolar disorder. Psychol Med 1996;26: hemizygous deletion of chromosome 22q11 result in bipolar 1145–1153. Late-onset wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizo- psychosis in the velo-cardio-facial syndrome. Am J Med Genet phrenia and bipolar affective disorder. Anticipation in schizo- in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry phrenia: no evidence of expanded CAG/CTG repeat sequences 1999;56:940–945. Velo-cardio-facial syn- novel potassium channel gene hSKCa3 containing a polymor- drome associated with chromosome 22 deletions encompassing phic CAG repeat: a candidate for schizophrenia and bipolar the DiGeorge locus. Schizophrenia tissues and localization to chromosome 1q21. Mol Psychiatry susceptibility associated with interstitial deletions of chromo- 1999;4:254–260. Velocardiofacial manifes- association between a polymorphic CAG repeat in the hKCa3 tations and microdeletions in schizophrenic patients. Am J Med Genet 1998; equilibrium test in 193 offspring parents trios. Transmission disequilibrium of potential linkage on chromosome 22q12-q13. Am analysis of a triplet repeat within the hKCa3 gene using family J Med Genet 1994;54:36–43. A genome wide search for repeat polymorphism to schizophrenia. Mol Psychiatry 1999;4: 261–266 schizophrenia susceptibility genes. Possible role for COMT channel (KCNN3) gene and schizophrenia among the chinese in psychosis associated with velo-cardio-facial syndrome.
This finding is consis- tent with the negative correlation between cortisol and tes- tosterone concentrations (102) in volunteer subjects under Opiates controlled conditions cheap 25 mg lamictal fast delivery symptoms 6 days after iui. Correlations have been found among Although opiate withdrawal may precipitate aggressive be- plasma PRL purchase lamictal 100 mg medicine 54 543, testosterone, and aggression, but not with cor- havior, there has been little study of the relationship of tisol, although cortisol and PRL concentrations were corre- aggression with endogenous opiates. In one study, a CSF lated with each other in their day-to-day changes in one opioid-binding protein was positively correlated with 'as- study (103). In children, increases in cortisol during the saultiveness' in healthy male volunteers (110). Circulating day were correlated with increased aggression (104). Alow levels of metenkephalins have been associated with self-inju- concentration of salivary cortisol was associated with persis- rious behaviors in a limited number of studies (111). Post- tent aggression in boys referred because of disruptive behav- mortem brain studies of violent suicide victims have also ior (105). In criminal offender or antisocial populations, found greater numbers of -opioid receptors as well (112). Plasma cortisol has also been re- induced than the placebo conditions (113), whereas naltrex- ported to be reduced in persons with alcoholism and a his- one, an opiate blocker, attenuated self-injurious behavior tory of repeated domestic violence (95) but increased after (114). These studies suggested that increased opioid activity cessation of drinking in incarcerated persons with alcohol- may increase the likelihood of aggressive behavior. However, the data in both animals and man are inconsistent because a positive correlation has been observed between plasma ACTH and aggression in nonhuman pri- Cholesterol and Fatty Acids mates (19), and cortisol rises during competition for domi- Some studies, both from persons who attempted suicide nance in vervet monkey males (107). The relationship be- and from healthy persons, suggested that reduced serum tween cortisol and aggression is thus likely to be complex cholesterol may be associated with aggressive behavior (115, and dependent on social context and stress. Male monkeys randomized to a low-fat and low-cho- lesterol diet displayed more aggressive behavior and less pro- Neuropeptides social behaviors than those randomized to a high-cholesterol diet (117,118). In humans, pharmacologic reduction of Among peptides neurotransmitters and modulators, limited cholesterol may increase the risk of non–illness-related mor- data suggest a positive relationship between aggression and tality such as death by suicide or trauma related to aggression central vasopressin and central opioid activity. Naturally occurring reduced cholesterol may also be associated with non–illness-related mortality (116, 120–123), largely attributable to suicide (116,122). Low Vasopressin serum cholesterol has been reported in psychiatric inpatients Whereas Virkkunen et al. Reduced serum vasopressin concentrations among impulsive and nonim- cholesterol has also been related to the severity of borderline pulsive violent offenders (8), Coccaro et al. It is also found in male forensic patients (130), aggres- sons, particularly men (108). Despite a significant inverse sive conduct-disordered children and adolescents with at- correlation between CSF vasopressin and PRL[d-FEN] re- tention deficit disorder (131), and suicidal adolescents sponse, the positive relationship between aggression and (132). CSF vasopressin remained even after the influence of PRL[d-FEN] response on the aggression score was taken into account. These data are consistent with those from MOLECULAR GENETICS animal studies in which vasopressin antagonists reduced ag- gression in golden hamsters, whereas 5-HT uptake inhibi- An understanding of the molecular genetics of impulsive tors increased central 5-HT activity and reduced central aggression is currently emerging with the rise of association vasopressin concentration and levels of aggressive behavior studies involving various DNApolymorphisms of candidate in the same species (109). One of the first notable studies in this area was that human studies may be accounted for by significant differ- of Brunner et al. The presence of this mutation function also contributed to failures to inhibit responses to was associated with evidence of altered catecholamine me- stimuli associated with punishment on a 'go/no-go' learn- tabolism (i. Al- cerebral dysfunction has also been related to increased hos- though no other families with this specific MAO A point tility. Verbal signal decoding and P300 amplitudes in an mutation have been reported, this report highlighted the evoked potential paradigm predicted impulsiveness and potential of the candidate gene approach to the molecular anger in prison inmates (147). In terms of regional localiza- genetics of aggression. At about the same time, Nielson et tion, neuropsychological tasks sensitive to frontal and tem- al. Thus, neuropsychological and associated with a reduction of CSF 5-HIAA concentration cognitive studies do suggest that abnormalities of higher in impulsive violent offenders (nearly all with DSM-III integrative functions, consistent with reduced cortical in- IED) (134). In the same study, the presence of the L allele hibitory influences on aggression, result in more disinhibi- was also associated with history of suicide attempts in all tion of aggressive behaviors. Although this finding was not replicated laboratory paradigms may discriminate aggressive individu- by Abbar et al. The PSAP has been externally validated in violent offenders and more specifically for severe suicide attempts.
Several studies order lamictal 100 mg with amex symptoms of flu, particularly in mice with effects in other systems purchase lamictal 100 mg online treatment zone lasik, such as insulin-like growth factors engineered deletions of NTs or their receptors, have shown or tumor-derived factors, have now clearly been found also significant complexity to these interactions. These have been grouped into work falls beyond the scope of this review. Perhaps the best understood and most widely expressed in TRK DOCKING PROTEINS the brain of these families are the neurotrophins (NTs) (2, 15). NGF is the prototype of the NT family, which also On binding of an NT, the Trk receptor tyrosine kinase now includes brain-derived neurotrophic factor (BDNF), becomes activated. The most critical substrate of this activ- NT-3, and NT-4 (or NT-4/5). NGF has the most restricted ity appears to be the receptor itself. NGF in the brain acts specifically rapidly autophosphorylated, and this is critical to receptor on cholinergic neurons. The receptor autophosphorylation sites form it also acts on sympathetic and sensory neurons. BDNF docking sites for the interaction of downstream signaling and NT-3 are widely and highly expressed, particularly in molecules (Fig. Many signaling proteins contain do- cortical and neocortical structures. NT-4 is also widely ex- mains that specifically bind to tyrosine residues when they pressed, although generally at lower levels in the adult than are phosphorylated. Further binding specificity is mediated are the others. The NTs are small, secreted proteins of about by the amino acids surrounding the autophosphorylated ty- 12 kd that contain characteristic intramolecular disulfide rosine. The domains of the signaling molecules that are used bonds. Each has been cloned and expressed in active recom- Most proteins that bind to phosphorylated tyrosines fall binant forms. The most common phosphotyrosine binding motif is the src-homology domain 2, or SH-2 domain. SH-2 domains are typically identified based on their homol- TRK RECEPTORS ogy to other SH-2 domain–containing proteins. Some of these have been shown directly to possess specificity for Generally better conserved than their ligands, the neuro- phosphorylated tyrosines in the appropriate amino acid con- trophic factor receptors also form families of related proteins text. The SH-2 domain–containing proteins also often con- (16,17). These receptors can be found in many different tain, or interact with proteins containing, an src-homology forms, from single, active proteins to large heteromeric com- domain 3, or SH-3 (20). Common to these are an extracellular ligand-binding motif that directs a separate type of specific protein–protein portion, a mechanism to transduce this signal across the interaction has been termed, appropriately, a phosphotyrosine membrane, and at least one intracellular signaling appara- binding domain, or PTB domain. These may be contained in single proteins or distributed domain bind to a distinct set of phosphorylated tyrosine among several interacting proteins. Most, if not all, of the residues from those with SH-2 domains (21). In addition, specific tyrosine phosphatases are acti- vated that modulate these responses and may contain path- way-activating properties of their own. NEUROTROPHIC FACTOR INTRACELLULAR SIGNALING PATHWAYS: RAS/ERK (MAPK) CASCADE The Ras/ERK pathway is regulated by the activity of the Ras proteins. Ras is a small, membrane-associated protein that serves as a transducer of signal from tyrosine kinase activity to ERK proteins, among other activities (25). The activity of Ras depends on the type of the guanine nucleo- tide it is bound to. Hence, Ras is a G protein, although distinct from the heterotrimeric G proteins coupled to many neurotransmitter receptors. Ras is active when binding gua- nosine triphosphate (GTP), but at rest it is inactive and bound to guanosine diphosphate (GDP).