Coral Xantia Giovacchini, MD

• Medical Instructor in the Department of Medicine

https://medicine.duke.edu/faculty/coral-xantia-giovacchini-md

As mentioned in Chapter 2 menstruation pronunciation purchase 5 mg aygestin with amex, the dopamine transporter protein is involved in reuptake of dopamine from the synaptic cleft following exocytosis thereby influencing the availability of dopamine in the synaptic cleft and in the terminal button women's health vancouver 5 mg aygestin sale. As discussed in Chapter 2 women's health clinic yuma arizona cheap aygestin 5 mg with visa, vesicular transporters are involved in the packaging of dopamine and other monoamines into vesicles that are released during exocytosis women's health center in salisbury md 5 mg aygestin order mastercard. These same polymorphisms have women's health center jobs discount 5 mg aygestin visa, however, been found in other clinical disorders. Meta-analyses exploring dopamine gene variants and schizophrenia have also produced conflicting results. More recently, Edward and colleagues (2016) focused on 11 genes directly related to the production and release of dopamine and did not find evidence supporting variation in genes that critically impact dopaminergic functioning and increased risk for schizophrenia. Schizophrenia 157 Serotonin and Glutamate Candidate Genes the role of gene variants affecting neurotransmitters serotonin and glutamate has also been investigated in schizophrenia. Similar to other studies that have found associations between schizophrenia drug response and interactions among genes, Bilic et al. A meta-analysis by de Medeiros Alves and colleagues (2015) reported that individuals with schizophrenia with a polymorphism of the serotonin transporter gene were significantly more likely to attempt suicide. These findings suggest that gene variants affecting the serotonergic system may be play a role in the etiology of schizophrenia, but additional studies are needed to address the specificities of this relationship. Concerning glutamate candidate genes, results suggest complex interactions among genes although results have also been conflicting across studies. For example, some genome-wide association studies focus on several single nucleotide polymorphisms covering one gene, others focus on numerous single nucleotide polymorphisms and numerous genes, and still others focus on major gene mutations and their impact on schizophrenia. Projects have also varied from single studies to large multi-site studies (Bergen & Petryshen, 2012; Sebat, Levy, & McCarthy, 2009). For example, some have supported strong associations between susceptibility genes and the development of schizophrenia, while other studies have failed to replicate these associations. However, Gejman, Sanders, and Duan (2010) reviewed 14 genes and a total of 789 single 158 Schizophrenia nucleotide polymorphisms previously reported as associated with schizophrenia and did not find a strong association with any of the 14 genes. It is possible that subgroups of individuals with schizophrenia are more susceptible to specific polymorphisms. Contrary to recent media headlines that read "Schizophrenia Gene" discovery sheds light on a possible cause (Scientific American, January 28, 2016); a gene was not discovered that caused schizophrenia. The study conducted by Sekar and colleagues (2016), however, did discover that polymorphisms of a gene (C4) that promote synaptic pruning in the brain were more strongly associated in patients with schizophrenia. The authors speculated that these findings might help to explain morphological findings, such as reduced gray matter and cortical thinning frequently observed in individuals with schizophrenia. Methodological factors are thought to play a major role as studies differ substantially in terms of participant characteristics, medication usage and history, heterogeneity, comorbidity of symptoms, and so on. Earlier studies, in particular, have been criticized for having small sample sizes, low statistical power, and unacceptably high Type I error rates. Clearly, additional research is needed to investigate the genetic complexities involved in conferring risk of developing schizophrenia, the role environmental factors, and the gene-environment interactions (epigenetics) of the disorder. Collaboration among scientists will certainly assist in unraveling the etiologic mystery of schizophrenia. To help foster communication and discovery, Jia, Han, Zhao, Lu, and Zhao (2016) recently established a schizophrenia resource base that serves as a central repository for thousands of genetic studies concerning schizophrenia and includes information concerning hundreds of candidate genes, gene variants, and their function and regulation. Structural Findings A large body of research exists concerning neuroanatomical brain differences of individuals with schizophrenia relative to individuals without the disorder. These studies have focused on anatomical size (whole brain and specific structures) and molecular morphological differences. In general, studies have found anatomical differences between individuals with schizophrenia relative to controls; however, the findings have varied among individuals with schizophrenia and across studies. In 1913, Emil Kraepelin was among the first to propose that individuals with schizophrenia follow a progressively deteriorating course in symptomatology. Current research suggests that the course can be highly variable, with some individuals showing chronic symptoms and others showing fewer symptoms that Schizophrenia 159 appear to remit. Whether these differences in symptomology are related to distinct brain differences is unclear; however, hundreds of studies have explored anatomical and molecular differences between patients with and without schizophrenia. The following discussion summarizes these results in terms of postmortem, brain imaging, and molecular findings. Postmortem and Imaging Findings Prior to the advancement of technology and neuroimaging techniques, researchers relied primarily on postmortem samples to investigate the brains of individuals with schizophrenia. Although many studies have found anatomical differences in individuals with schizophrenia relative to controls, to date there are no specific structural findings that are diagnostic of, or unique to , schizophrenia. Ventricular Size Perhaps the most common structural finding associated with schizophrenia is enlargement of the cerebral ventricles. Since that time, studies regarding ventricular size in schizophrenia have produced conflicting results with some studies finding differences while others have not. Meta-analytic studies, however, have estimated the increase in ventricle sized in patients with schizophrenia compared to controls to be about 26% and the reduction level is similar in males and females with schizophrenia (Harrison, Freemantle, & Geddes, 2003). To date, the precise cause of ventricular enlargement observed in many individuals with schizophrenia is largely speculative. It is also important to note that the extent of ventricular enlargement varies among individuals with schizophrenia, and ventricular size varies among healthy individuals. Weinberger (1995) reported that some patients with schizophrenia showed abnormally large ventricles while others showed ventricles resembling those of individuals without schizophrenia. Ventricular size difference has also been explored in monozygotic twins and Suddath et al. Results revealed, relative to controls, ventricular enlargement was observed in only 36% of individuals with schizophrenia and was not found in the other groups, suggesting that ventricular enlargement is not present in at-risk or early stages of the disorder. Results revealed that differences were not 160 Schizophrenia found between youth at risk for schizophrenia and controls in ventricular enlargement or cortical thickness at the onset of the study. Longitudinally, however, youth who developed psychosis showed accelerate gray matter reductions in widespread regions of the cortex that corresponded with ventricular enlargement. These changes were not observed in healthy controls and therefore suggest that ventricular enlargement occurs in tandem with loss of cortical gray matter and these changes begin to occur before the onset of psychosis (prodromal). These findings, do not, however, address underlying etiologic cause(s) of the observed cell loss and concomitant expansion of the ventricles (additional information regarding cell loss is discussed in the molecular section that appears later in this chapter). Enlarged Ventricles Sometimes Found in Individuals With Schizophrenia Copyright Blausen Medical Communications. Schizophrenia 161 Structural Differences Anatomical differences have also been reported between participants with and without schizophrenia with respect to overall brain volume and specific structures. For example, studies have reported a 3% or more decrease in total brain volume in patients with schizophrenia relative to healthy controls (Wright et al. This loss of brain tissue reportedly continues at twice the rate for individuals with the disorder relative to controls for 20 years or longer after initial symptoms (Hulsoff & Kahn, 2008). Several studies have found that the frontal and temporal lobes are most highly susceptible to volume loss. Based on recent meta-analytic findings, loss of brain tissue has been found to correlate with symptom severity and impaired neuropsychological functioning, with more severe symptoms associated with greater tissue loss, in some but not all studies (Hulsoff & Kahn, 2008; Kwon et al. Dose and years of antipsychotic usage have been found to be predictive of brain volume loss across several studies (Ho et al. Collectively, research supports a pattern of total brain volume loss in individuals with schizophrenia relative to healthy controls and long-term use of antipsychotic medication is association with this volume reduction. However, it is important to note that studies have also reported increased volume in some structures (basal ganglia) following antipsychotic treatment that corresponded with symptom improvement, and therefore it would be erroneous to conclude that antipsychotic medication only has deleterious effects on brain morphology (Huhtaniska et al. Volume loss of specific regions and structures are also implicated in schizophrenia. For example studies, albeit inconsistently, have reported volume reductions in the frontal and temporal lobes, and diverse structures, including the amygdala, corpus callosum, thalamus, hippocampus, caudate nucleus, cerebellum, and putamen. A number of studies have reported asymmetry of specific structures in patients with schizophrenia, although findings across studies have been inconsistent. The planum temporale is involved in the production and comprehension of language, and in right-handed people, the surface area of the left planum temporale is typically larger than the right. Results indicated that in all but one of the individuals with schizophrenia, a reversal of the expected asymmetry was found. The origin of these differences, whether prenatal or postnatal, is unclear but may support neurodevelopmental disturbances in schizophrenia that occurs as a result of genetic or environmental factors or the interaction of the two. Molecular Findings In addition to differences in size and volume of anatomical structures, researchers have investigated molecular differences between patients with schizophrenia relative to healthy 162 Schizophrenia controls in terms of cytoarchitecture, reduction and density of white and gray matter, white matter connectivity, and receptor availability. A number of studies have reported cytoarchitectural differences in participants with schizophrenia, including disorganized arrangements of neurons, misplacement of neurons, fewer dendritic branches and dendritic spines, and reduction in neuronal size and number in cortical and subcortical regions. Interestingly, neurodegenerative features, such as neurofibrillary tangles and plaques, have not been found to occur at the higher rate in schizophrenia, while levels of tau protein have been found to be significantly lower in patients with schizophrenia relative to healthy controls (Arnold et al. Review studies have estimated a 15% reduction in neuronal number in individuals with schizophrenia compared to healthy controls (Schmitt et al. In addition to neuronal number, Glantz and Lewis (2000) reported that synaptic connections are significantly altered in individuals with schizophrenia due to substantial dendritic spine reductions in the prefrontal cortex that directly compromises the number of excitatory inputs to neurons in this area. Interestingly, the prefrontal cortex does not fully mature until late adolescence or early adulthood, which is the period of onset for most individuals with schizophrenia. Therefore, it is plausible that problems that occur early in brain development (cell migration, proliferation, pruning) are cumulative and not observed until later late adolescence or young adulthood. Studies have also explored the density of neurons and glial cells, and have reported both increased and decreased density of neurons and glia depending on the locations examined. Increased density of neurons is thought represent areas where neurons have atrophied, have fewer dendritic branches, and fewer synaptic connections rather than reductions in numbers (Selemon and Goldman-Rakic, 1999). At the level of the cortex, studies have reported decreased and increased neuronal density, while others have reported increased and decreased neuronal density in subcortical structures (Chana et al. It is important to note that some studies have reported no differences in cell density in patients with schizophrenia compared to healthy controls. It is also possible that cell density may change over time and vary with age, medication usage, and other variables. Gray and White Matter Findings More recently studies have explored relationships between white and gray matter in participants with schizophrenia relative to healthy controls. A plethora of studies have explored gray matter volume in participants with schizophrenia and many have reported gray matter loss in cortical and subcortical regions, especially the frontal and temporal regions (see Torres et al. Specifically, meta-analytic studies have reported gray matter loss in participants with schizophrenia in the insula, thalamus, dorsolateral prefrontal cortex, medial frontal gyrus and posterior cingulate gyrus, superior temporal cortex, bilateral hippocampus, and bilateral amygdala. Some studies have found a significant relationship between reduced gray matter of the left temporal gyrus and severity of hallucinations (Dietsche, Kircher, & Falkenberg, 2017; Onitsuka et al. These findings were consistent with Dietsche (2017) who, in a systematic review, investigated gray matter in participants (a) at risk of developing psychosis, (b) patients with a first episode psychosis, and (c) participants with schizophrenia who were chronically ill. Results revealed that participants at risk who later developed psychosis had more pronounced cortical gray matter loss in the temporal and frontal regions, participants with a first episode psychosis showed decline in multiple gray matter regions over time, and they showed progressive cortical thinning in the frontal cortex. Findings also indicated that participants with chronic schizophrenia showed the most pronounced gray matter loss. Collectively, current findings suggest that gray matter loss is commonly found in patients with schizophrenia, and the loss tends to be greater and more widespread in individuals with chronic schizophrenia compared to first episode patients. In addition, gray matter loss appears to be more severe in early versus later onset cases, and loss is typically progressive. Antipsychotic medications are associated with global gray matter loss, although some subcortical structures appear to increase in volume with medication treatment. White matter (myelinated axons) findings appear to be less robust than gray matter findings in individuals with schizophrenia (Krakauer et al. For example, Selemon, Kleinman, Herman, and Goldman-Rakic (2002) compared the postmortem brains of 14 individuals with schizophrenia to 19 brains of healthy individuals. When total gray and white matter volumes of the cortex were measured, only the gray matter of the frontal lobes was found to differ between groups (12% smaller). Results were indicative of white matter integrity deficits in frontal, fronto-temporal, fronto-limbic connections, and the corpus callosom in individuals with schizophrenia, although questions remain regarding the effect of age, demographic and environmental variables, and antipsychotic medication on white matter integrity. Receptor Availability Stemming from the dopaminergic theory of schizophrenia research has sought to determine whether presynaptic and postsynaptic receptor availability may differ in individuals with schizophrenia relative to controls, using postmortem samples and neuroimaging techniques. Overall, findings are variable across studies with some reporting decreased availability of postsynaptic dopamine receptors, while others report increased availability (Farde et al. To investigate whether dopamine synapses were influenced by medication treatment, Roberts et al. Findings revealed dopamine synaptic density was 43% greater in participants with schizophrenia deemed treatment responders compared to controls, and 62% greater in treatment responders compared to treatment resistant cases. Meta-analytic studies, however, have reported discrepant findings with some reporting no postsynaptic receptor differences. However, studies have also found that participants with schizophrenia who have used antipsychotic medication 164 Schizophrenia over time show increased number of receptors relative to control participants, supporting Roberts et al. In summary, studies have produced conflicting results regarding availability of postsynaptic dopamine receptors in participants with schizophrenia relative to controls. Dopamine Transporters Research has also investigated density of presynaptic dopamine transporters in the striatum in patients with schizophrenia and results have been more consistent. Structural Findings: Schizophrenia Versus Other Disorders As noted throughout this textbook, structural and functional findings in isolation are correlational and do not reveal directionality or causality. Furthermore, although it is meaningful to establish that individuals with a particular disorder show structural (and/or functional) brain differences relative to healthy individuals, it is equally if not more important to demonstrate that structural and functional findings are uniquely characteristic of a particular disorder (or symptom). To that end, a substantial number of studies are available that have explored structural and functional differences between individuals with schizophrenia compared to other disorders. For example, researchers have compared participants with schizophrenia to bipolar disorder and findings have been variable across studies. Benes, Vincent, and Todtenkopf (2001) investigated whether the density of neurons in the anterior cingulate cortex differed between the postmortem brains of individuals with schizophrenia and those with bipolar disorder and controls.

This approach is very reasonable menstruation years aygestin 5 mg for sale, given its success in other immunocompromised groups women's health issues china purchase aygestin 5 mg online, but it has not been tested in a controlled trial pregnancy 6 weeks 1 day discount aygestin 5 mg without prescription. Immunization with pneumococcal vaccine is also recommended in situations where therapeutic splenectomy has been used or is being planned pregnancy hemorrhoids order 5 mg aygestin free shipping. Recent recommendations from an international working group recommend that a platelet count of <100 × 109/L be required for diagnosis breast cancer oakleys aygestin 5 mg purchase. Gestational thrombocytopenia develops in the late second or third trimester and is not associated with an increased incidence of pregnancy-related complications or the delivery of thrombocytopenic offspring. Platelet antibodies cause rapid clearance of transfused platelets and lead patients to become refractory to platelet transfusions. The drug-dependent antibodies bind to specific epitopes on platelet surface glycoproteins only in the presence of the sensitizing drug. Drug-dependent antibodies inducing thrombocytopenia typically develop 1­2 weeks after exposure to a drug; exceptions to this rule include eptifibatide, tirofiban, and abciximab, as naturally occurring antibodies to these drugs can cause thrombocytopenia within a few hours of the first exposure. Thrombocytopenia with platelet counts frequently below 20 × 109/L develops acutely, recovery occurs 1­2 days after discontinuation of the drug and is usually complete after 1 week, but rarely thrombocytopenia persists for several weeks. Treatment consists of discontinuing the offending drug; platelet transfusions are sometimes necessary. In the event of prior exposure, especially within the last 100 days, thrombocytopenia can occur within 1 day of heparin administration. Coumadin is generally used for long-term anticoagulation; it should be started concomitant with a heparin alternative because of the increased risk of thrombosis during the initial depletion of anticoagulant factors (proteins C and S) by warfarin (Coumadin). The role of direct oral anticoagulants that target thrombin or activated factor X remains to be defined. Bone marrow aspirate, biopsy, flow cytometry, and cytogenetics should be considered in patients older than 60 years of age and in patients with systemic symptoms. Pathogenesis In the majority of patients the underlying defects leading to autoantibody production remain unclear. Initial dosing of eltrombopag should be reduced by 50% in patients of Southeast Asian origin. Danazol is an attenuated androgen administered orally and has been used, with some success, as a steroid-sparing agent. Third-line therapy is reserved for patients who are unresponsive to or ineligible for first- and second-line therapies. These agents include cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, alemtuzumab, and vinca alkaloids. Routine testing for anticardiolipin antibodies is not recommended in the absence of symptoms of antiphospholipid syndrome. Blood group Rh(D) typing should be obtained if anti-D antiglobulin treatment is considered. In the absence of hemostatic comorbidity, trauma, or surgery, intracranial hemorrhage is rare in patients with a platelet count above 20 × 109/L. Intravascular hemolysis, disseminated intravascular coagulation, and renal failure have been reported with the use of anti-Rh(D). Several uncontrolled studies suggest that bolus oral therapy with oral dexamethasone for 1­4 cycles increases response rates and prolongs remission duration. Second-line therapy should be initiated if there is absence of a robust response at 1 month or once significant steroid related toxicity supervenes. Two-thirds of patients obtain a durable long-term remission following splenectomy, and these patients should receive immunizations with the pneumococcal, Haemophilus influenzae type b, and the quadrivalent meningococcal vaccines before splenectomy. Patients who relapse after an initial response usually respond to a second course. Obstetrical anesthesiologists recommend a minimum platelet count of 75 × 109/L to allow administration of spinal or epidural anesthesia. A platelet count of at least 50 × 109/L is generally considered adequate to allow a Cesarean section. Prednisone is initiated at a low dose (10­20 mg) and then adjusted to the minimum dose that produces a hemostatically effective platelet count. Corticosteroids may exacerbate hypertension, diabetes, and osteoporosis during pregnancy and are associated with weight gain and psychosis. Corticosteroid use in the first trimester has been associated with congenital anomalies, such as orofacial clefts, and low-dose corticosteroids have no impact on the fetal platelet count. Anti-Rh(D) is safe and effective for the mother and fetus in nonsplenectomized Rh(D)-positive patients. The risk of inducing premature labor is high during the first trimester, and the enlarged uterus renders the procedure difficult if not impossible during the third trimester. Vinca alkaloids, rituximab, danazol, thrombopoietin receptor agonists, and immunosuppressive drugs (other than azathioprine) should be avoided during pregnancy. The most reliable predictor of neonatal thrombocytopenia is a history of thrombocytopenia at delivery in a prior sibling. In a study of 61 patients, 66% of neonates had a further drop in platelets following delivery; the nadir occurred at day 2, and the counts stabilized or began to rise at day 7. The concurrent use of corticosteroids is controversial because of the risk of neonatal sepsis. Neonates with platelet counts below 50 × 109/L should have brain imaging performed to detect occult intracranial hemorrhage. Many investigators have sought to interrupt the interaction between immunoglobulin (Ig)­coated platelets and Fc receptors by use of monoclonal antibodies to the Fc receptor itself. However, the use of traditional murine monoclonal antibodies (mAbs) to Fc has been associated with adverse events, perhaps as a result of cross-linking of Fc receptors on the surface of macrophages, resulting in undesirable immune stimulation and even anaphylaxis. One strategy to circumvent these problems would be to use monovalent Fab fragments that would bind but not cross-link the Fc receptors. Further, in theory this approach could be applied to other diseases, such as autoimmune hemolytic anemia. Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and treatment. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Quantitative influence of antibody and complement coating of red cells on monocyte-mediated cell lysis. Neutrophil antibody specificity in different types of childhood autoimmune neutropenia. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Significance of the detection of anti-neutrophil antibodies in children with chronic neutropenia. Effect of leukocyte antibodies on the fate in vivo of indium-111-labelled granulocytes. Standardization of terminology, definitions of outcome criteria in immune thrombocytopenic purport of adults and children: report from an international working group. T-cell mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purport. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. Pregnancy in patients with idiopathic thrombocytopenic purpura: assessing the risks for the infant at delivery. Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes. Which is true of hemolysis caused by a "cold" antibody elicited by exposure to drugs Is more likely in a first pregnancy than subsequent pregnancies between the same two parents c. May be prevented by administration of RhoGam at week 28 of pregnancy when the parents are Rh incompatible d. These erosions are often persistent and shaggy; they can involve all areas of the oral mucosa and extend into the esophagus. In severe cases, the conjunctiva, nasal, anal, cervical, or urethral mucosae may be affected. Blisters can occur on any area of skin, most often beginning on the head, neck, or trunk. Generalized blistering is not uncommon, especially if diagnosis and/or treatment have been delayed. The characteristic lesions are plaques of hypertrophic granulation tissue with occasional pustules. Since the introduction of systemic glucocorticoids, the mortality rate has fallen to approximately 10%. The residual mortality is largely due to the side effects of the high doses of glucocorticoids required to treat the disease, particularly in debilitated or older patients. The most common agents that induce pemphigus are D-penicillamine and angiotensin-converting enzyme inhibitors. Patients with drug-induced pemphigus have autoantibodies directed against the keratinocyte cell surface; the mechanism(s) causing these antibodies are unknown, but reactive sulfhydryl or amide groups on the drugs are thought to be responsible. Skin biopsies from these patients revealed IgG bound to keratinocyte cell surfaces, and granular­linear deposits of IgG and C3 at the basement membrane. Serum contained circulating IgG antibodies, which bound to normal keratinocyte cell surfaces of squamous epithelium. Although initial reports suggested that these antibodies bound to stratified and nonstratified squamous epithelium, this is not always the case. Circulating IgA antibodies to intraepidermal structures are present in ~50% of cases. Patients of both types commonly present with flat pustules, often on a slightly erythematous base, which tend to coalesce to form annular patterns. Histology of lesional skin reveals subcorneal or intraepidermal blisters, with acantholytic cells and a neutrophilic infiltrate. This entity is also known as intraepidermal neutrophilic IgA dermatosis, intercellular IgA vesiculopustular dermatosis, and intercellular IgA dermatosis. Azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, and cyclosporine are the additional immunosuppressive agents most often utilized. Azathioprine and cyclosporine have steroid-sparing effects in long-term treatment, but adding these agents to steroids does not induce long-term remission any better than steroids alone. Other possible adjunctive therapies include parenteral gold, plasmapheresis, and extracorporeal photochemotherapy. Therapy for paraneoplastic pemphigus has been disappointing and usually unsuccessful. In a trial comparing infliximab plus prednisone versus prednisone alone, neither group achieved their primary endpoints,21 but at 26 weeks, three of 10 patients given infliximab showed positive responses, compared with none who received prednisone alone. Median anti-Dsg1 and anti-Dsg3 levels were lower in the infliximab group at 18 and 26 weeks. Three prospective studies of rituximab in pemphigus, alongside corticosteroids or other immunomodulatory agents, have reported dramatic improvement or total clearance in most patients. Healthy people living in endemic areas in South America have anti-Dsg1 IgG antibodies. Although autoantibodies are clearly important in pathogenesis, the mechanism by which they cause acantholysis is unknown. Complement components (C3, C1q) are often present in lesional skin, but autoantibodies can induce acantholysis in vitro and in neonatal mice without complement activation. Overall, it seems that complement may augment acantholysis, but pemphigus IgG on its own can bind keratinocytes and induce loss of cell­cell adhesion. It has been suggested that urokinase plasminogen activator is necessary for skin lesions to develop, but pemphigus antibodies remain pathogenic in plasminogen-activator knock-out mice. Pemphigus foliaceus presents with superficial intraepidermal blisters and antibodies directed against Dsg1 alone. Pemphigus vulgaris with only oral mucosal lesions most often has antibodies against Dsg3. Pemphigus vulgaris with skin and mucosal lesions most often has antibodies against both Dsg1 and Dsg3 Therapy Before the introduction of glucocorticoid therapy, pemphigus was uniformly fatal. Most blistering can be controlled with prednisone (1­2 mg/kg/ day, usually in divided doses). Blisters can occur anywhere on skin, but often on skin in the extremities, groin, and axillae. Higher mortality rates are reported in Europe, but the reasons for this difference are not currently understood. The classic finding is a subepidermal blister with a dermal inflammatory infiltrate, comprised predominantly of eosinophils with some lymphocytes, histiocytes, and neutrophils. The epidermis over this blister is often intact with minimal abnormality, whereas the blister cavity is filled with inflammatory cells. Sometimes neutrophils predominate, or there may be cell-poor lesions with very few inflammatory cells. Occasionally, there may only be mild epidermal edema, with eosinophil infiltration but no blister. Pathogenesis Immunofluorescence microscopy demonstrates IgG in the lamina lucida of the basement membrane. These are the major attachment sites of epidermal basal cells and where cytoskeletal proteins link through the plasma membrane to the dermis. These have been cloned and sequenced, confirming that they are distinct proteins, associated as a complex within the hemidesmosome. Passive transfer of this rabbit IgG to newborn mice resulted in blisters, an inflammatory infiltrate, and deposition of immunoreactants. In this model, complement activation, mast cell degranulation, and neutrophil infiltration are important in blister formation.

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Some studies have reported that antidepressants are associated with increased risk of suicide ideation in children and adolescents menopause young living essential oils purchase aygestin with a visa, although other studies have not replicated these findings menstruation occurs when discount aygestin 5 mg buy line. Heritability studies suggest that genes likely play a role in the susceptibility of major depression although no single gene has been found to confer a high degree of risk for the disorder menopause excessive bleeding discount aygestin 5 mg amex. The neuroplasticity theory of major depressive disorder proposes that the disorder is due in part to stress induced death of neurons and glial cells followed by decreased neurogenesis menstruation meaning order 5 mg aygestin overnight delivery, synaptogenesis women's health boutique houston tx 1960 discount 5 mg aygestin visa, and production of neurotrophic factors. The pathophysiology of major depressive disorder appears to be complex and likely involves interactions among genetic, cellular, morphological, neurochemical, psychological, and environmental factors. The distinguishing feature between major depressive disorder and bipolar disorder I is the presence of mania. A manic episode is characterized by an abnormally and persistently elevated, expansive, or irritable mood, along with increased energy or activity present daily for at least one week. Individuals with bipolar disorder are 15 times at greater risk for suicide than the general population (Pandey, 2013). Families of individuals with bipolar disorder compared to those without the disorder tend to have greater family conflict, less expressiveness of emotions, and less cohesiveness (Reinares et al. Information concerning cultural differences in the occurrence and expression of bipolar disorder are limited; however, recent findings have revealed marked disparities in treatment of Hispanic and non-Hispanic whites. Specifically, Salcedo, McMaster, and Johnson (2017) found Hispanics were less likely to receive medications for emotional problems, receive professional treatment for manic episodes, or participate in psychotherapy, and 0% compared to 21% of non-Hispanic whites were taking mood stabilizers at the time of the study. Similar inadequate treatment findings have been reported for African Americans compared to whites with bipolar disorder (Johnson & Johnson, 2014). Studies have also reported higher levels of stigmatizing experiences of individuals with bipolar disorder living in Canada and South Korea (Lee, Milev, & Paik, 2015) the disorder is often accompanied by associated problems, such as occupational failure, marital difficulties, school failure, neuropsychological impairment, substance use and abuse, anxiety disorders. Major Depressive Disorder 201 (2002) reported that more than a third of individuals with bipolar disorder or major depression had experienced at least one panic attack, and panic disorder was diagnosed more frequently in families of individuals with bipolar disorder relative to a control group. According to Yildiz and Sachs (2003), psychotic symptoms are also common in bipolar disorder. With respect to education, family, and occupational status, Kupfer and colleagues (2002) studied 2,839 patients with bipolar disorder and found that 85% were hospitalized at least once (43% for mania episodes and 69% for depressive episodes). Greater than 50% had attempted suicide and most attempts occurred during a depressed episode. One-third of the sample was married; one-third were never married; the remaining participants were divorced, widowed, or separated. More than 90% of the group had completed high school, and 11% had earned a graduate or professional degree. Nearly 65%, however, were unemployed at the time of the study and 40% were receiving public assistance or disability support. Over 50% of the sample reported that they did not receive any treatment during their first episode of depression or mania. Collectively, these findings are consistent with other studies that indicate that bipolar disorder has a relatively early onset and tends to run in families. Findings also suggest that most individuals with the disorder attain a high school education or above but do not maintain employment in adulthood and that bipolar disorder is a chronic condition characterized by social, interpersonal, and occupational struggles. Genetic Findings Family and Twin Studies Bipolar disorder tends to run in families and genetic studies have consistently reported a high heritability estimate for bipolar disorder. According to Smoller and Fin (2003), first-degree relatives of an individual with bipolar disorder have a tenfold risk of developing bipolar disorder compared to relatives of control participants. Heritability estimates vary slightly across studies and range from 85% to 93% (Craddock et al. Further support for a heritability component of bipolar disorder comes from twin studies; twin studies have reported consistently higher concordance rates for monozygotic twins with bipolar relative to dizygotic twin pairs. Adoption studies also support a heritability component for bipolar disorder; the incidence of the disorder is higher in biological parents compared to adoptive parents of children who later develop bipolar disorder (Smoller & Fin, 2003). Linkage and Association Studies Similar to major depressive disorder, linkage studies have focused on families with members with bipolar disorder in order to attempt to identify gene variants that confer a high degree 202 Major Depressive Disorder of risk of developing bipolar disorder. Results from linkage studies have produced a number of chromosomal regions of interest and meta-analyses have linked bipolar disorder in non-Hispanic whites and individuals of Latino ancestry to regions on several chromosomes including 1, 4, 8, 10, 11, 12, 13, 14, 16, 17, 18, and 22. However, none of the linkage studies have identified a region or loci that confers a high degree of risk for developing bipolar disorder. These findings support that the etiology of the disorder is currently poorly understood and likely genetically complex. Candidate Genes A large number have candidate genes have been identified a priori and studied for their potential role in the heritability of bipolar disorder. For example, due to pharmacological agents that target specific neurotransmitter systems and produce symptom improvement in patients with bipolar disorder, many studies have focused on genes that are specifically involved in neurotransmitter functioning. Although these findings are encouraging, it is important to note that these same polymorphisms have been implicated in other psychiatric disorders. Similar to other candidate genes, this particular polymorphism has been associated with other disorders such as obsessive-compulsive disorder (Geller et al. Genes that regulate the neurotransmitter serotonin have also been investigated in bipolar disorder, largely due to findings that suggest antidepressants can induce mania in 20% or more of individuals with bipolar disorder. Angst, 1985; Karlovi & Serretti, 2013; Kwok & Lim, 2017; Solomon, Rich, & Darko, 1990). Given that most antidepressants affect the serotonin system, researchers have speculated that abnormal serotonergic functioning may increase vulnerability to bipolar disorder. The gene that regulates the somatostatin receptor has also been explored in bipolar disorder for over a decade. Somatostatin functions as a neuropeptide in the brain and helps to modulate the release of neurotransmitters and other neuropeptides. Results supported a linkage between the somatostatin gene variant and bipolar disorder, and recently, Pantazopoulos et al. Additional candidate genes have been investigated, and although several chromosomal regions and candidate genes have generated intense interest and have been linked to bipolar disorder, to date, no robust, conclusive findings have yet emerged from the literature (Amare et al. For example, Bigdeli and colleagues (2013) studied 83 candidate genes and reported that no one gene was statistically associated with bipolar disorder. These findings are somewhat perplexing given that familial studies clearly support a strong heritability component for bipolar disorder. It is plausible that bipolar disorder involves multiple genes working singly or in combination, or that two or more gene variants. It is also possible that a single gene variant may play a role in multiple psychiatric disorders depending on environmental and physiologic factors. As Craddock and Sklar (2013) stated, the association between genotype and phenotype for psychiatric disorders is clearly complex. Reductionist thinking has no place and to think of any case as being either genetic or environmental, or to talk about a gene for bipolar disorder, makes no sense. Bipolar studies have explored a number of anatomical structures, including the hippocampus, thalamus, basal ganglia, amygdala, whole brain volume, and size of the ventricles. With respect to ventricular size, many studies, including meta-analyses, have found increased ventricular size in the right, left, or both right/left lateral ventricles, and in the third ventricle in participants with bipolar disorder relative to control participants 204 Major Depressive Disorder. In contrast, Lewine and colleagues found evidence of ventricular abnormalities only in males with schizophrenia relative to participants with depression, bipolar disorder, and controls. Collectively, these findings suggest that individuals with bipolar disorder are more likely to have enlarged cerebral ventricles compared to control participants and smaller ventricular size relative to individuals with schizophrenia; however, enlarged cerebral ventricles are characteristic of other psychiatric and medical disorders. Studies exploring other brain structures including whole brain, prefrontal regions, globus pallidus, amygdala, thalamus, and postmortem cellular morphology have also produced conflicting results (Z. Findings revealed very few structural differences between participants with bipolar disorder other than the lateral ventricles and increased lesions of the frontal and parietal lobes. Arnone and colleagues also noted that whole gray matter volume correlated with duration of bipolar disorder with and use of antipsychotic medication. These findings suggest that individuals with longer durations of bipolar disorder, particularly those who use antipsychotic medication, are more likely to have distinct anatomical brain differences compared to those without the disorder. Similar to structural findings in living individuals with bipolar disorder, postmortem studies have produced conflicting results with some studies reporting a decrease in neuronal and/or glial cell density in specific regions. In summary, a number of structural differences have been found in living and postmortem brains of individuals with bipolar disorder relative to those without the disorder. These findings have been inconsistent, however, and are likely influenced by a number of methodological and statistical factors. It is important to emphasize that when anatomical differences are found between participants with bipolar disorder relative to controls; it is unclear whether these differences occur before, during, or after onset of the disorder. Further, none Major Depressive Disorder 205 of the structural abnormalities found in individuals with bipolar disorder are unique to the disorder and are sometimes found in other psychiatric disorders and medical conditions. A crucial point is that current findings are inconclusive and are only correlational in nature-i. The etiology of structural abnormalities sometimes found in bipolar disorder is unknown but may reflect neurodevelopmental abnormalities or cellular degeneration over the course of the disorder due to environmental or physiologic factors. Most past and current studies employ a cross-sectional design and longitudinal studies are needed to clarify the emergence of structural differences. For example, postmortem studies have found reductions in serotonin metabolites in the frontal and parietal regions. With respect to serotonin transporters, Leake and colleagues (1991) reported fewer serotonin reuptake sites in postmortem samples of bipolar patients. Several studies have reported increased glutamate levels in the frontal regions of the brain and in the cerebral spinal fluid relative to control participants (Ehrlich et al. Recently researchers have reported on metabolome analysis-a method used to measure small molecules in blood plasma of patients with bipolar disorder. For example, Kageyama and colleagues (2017) found that levels of the amino acid citrulline were lower in participants with bipolar disorder relative to controls. Citrulline is purported to be a biomarker of mitochondria dysfunction, and molecular anomaly theories, including mitrochondria dysfunction, have recently proposed for bipolar disorder (Kim, Santos, et al. Ali and Milev (2003), for example, reported that abrupt antidepressant withdrawal, along with drugs that result in excessive levels of monoamines, are associated with the induction of manic symptoms. Bunney and Garland (1982) proposed that dopamine abnormalities may be implicated in bipolar disorder, given that dopamine agonists can induce manic like symptoms and antagonists can reduce mania and sometimes improve symptoms of depression (Goldberg, Burdick, & Endick, 2004). Overall, however, metabolite studies of patients with bipolar disorder have been inconsistent (Yildiz et al. Functional Studies With respect to functional neuroimaging studies, a plethora of studies have been conducted in an attempt to understand the underlying neurophysiological processes involved in bipolar disorder. Numerous glucose metabolism and blood flow studies are available concerning 206 Major Depressive Disorder the performance of individuals with bipolar disorder relative to those with other disorders and control groups during cognitive tasks or at rest. Similar to the neuroimaging findings with major depressive disorder, glucose metabolism and blood flow differences have been found between those with and without bipolar disorder-but the findings have been inconsistent. In addition, several studies have also reported blood flow and glucose abnormalities in the basal ganglia (an area rich in dopamine) of individuals with bipolar disorder (Caliguri et al. Given that bipolar disorder is characterized by episodes of major depression as well as mania, researchers have focused on regions and structures believed to underlie cognitive and emotional processes problematic in patients with bipolar disorder, including prefrontal regions and subcortical pathways involved in decision-making, planning, and emotional regulation (Smucny et al. Although findings are inconsistent across studies, some studies have reported increased activity (blood flow, glucose metabolism) in the left ventrolateral prefrontal cortex and orbitofrontal cortex during anticipation of rewards in patients with bipolar disorder, relative to control participants (Dutra et al. These findings suggest that individuals with bipolar disorder may have heightened reward sensitivity that may in turn predispose them to mania (Phillips & Swartz, 2014). Other studies have found increased activity in the amygdala and medial prefrontal cortex activity and decreased activity in frontal regions, as well as the amygdala during emotional recognition tasks (happy, sad, angry, etc. Phillips and Swartz (2014) interpreted the neuroimaging data as indicative of neural circuitry pathology in patients with bipolar disorder stating, Bipolar disorder can thus be conceptualized in neural circuitry terms as parallel dysfunction in bilateral prefrontal cortical (especially ventrolateral prefrontal cortex and orbitofrontal cortex)-hippocampal-amygdala emotion processing and emotion regulation neural circuitries, together with an "overactive" left-sided ventral striatalventrolateral prefrontal cortex reward processing circuitry, that may, together, result in the characteristic behavioral abnormalities associated with bipolar disorder: emotional lability, emotional dysregulation and reward sensitivity. Future research is clearly warranted to better understand potential functional brain differences between individuals with and without bipolar disorder. Ideally, future studies will involve well-designed, longitudinal studies with large sample sizes and control over demographic variables, such as age of onset, severity of symptoms, sex, ethnicity, and medication usage. In addition, corroboration across different types of neuroimaging techniques and cognitive tasks would help to establish the validity and reliability of neuroimaging findings. Abnormalities in signaling pathways have received considerable attention in bipolar disorder. For example, Bezchlibnyk and Young (2002) reviewed studies that used either blood samples or postmortem brain tissue of individuals with bipolar disorder and concluded that the disorder is likely due, at least in part, to abnormalities in signal transduction pathways. Specifically, altered levels of functioning of intracellular G-proteins, protein kinase A, and protein kinase C have been associated with bipolar disorder. Chang, Li, & Warsh, 2003) and lithium and anticonvulsants used to treat bipolar disorder are believed to target second-messenger systems (Stewart et al. As mentioned previously in this chapter, a current pathophysiologic theory of bipolar disorder relates to mitochondria, organelles that are critical for energy production and, consequently, normal cellular functioning (Iwamoto et al. Other researchers have focused on the role of autophagy in bipolar disorder, dysregulation of circadian rhythms, and density of neurons and glial cells in individuals with bipolar disorder. For example, in 2004 Uranova and colleagues found a 29% reduction of glial cells (oligodendroglia) in the prefrontal cortex of individuals with bipolar disorder relative to controls. Others have explored whether the normal process of autophagy (self-digestion of old or damaged parts of the cell including organelles) is dysfunctional in bipolar disorder. Interestingly, lithium, the most established long-term treatment for bipolar disorder, is thought to help enhance or regulate autophagy (Motoi et al. Although the role of molecular processes in bipolar disorder is inconclusive, in recent years, there has been a substantial shift in the literature from investigating levels of monoamines to exploring the molecular mechanisms of bipolar disorder (Kim, Santos, et al. Pharmacological Treatment of Bipolar Disorder Medications used in the treatment of bipolar disorder include (a) mood stabilizers. These classifications are based on the chemical structure of the drug as well as the effect of the drug. For example, anticonvulsants differ in their chemical structure from lithium, but they 208 Major Depressive Disorder have mood-stabilizing properties. Based on meta-analytic studies, lithium is considered the most effective long-term pharmacological treatment of bipolar disorder and is often prescribed in conjunction with antipsychotic medications (Bauer & Mitchner, 2004; Connolly & Thase, 2011; Goodwin et al. As discussed in Chapter 2, the precise mode of action of lithium is unknown but research suggests that it affects multiple signaling pathways and cellular processes and promotes neuroplasticity. The effectiveness of lithium and anticonvulsants varies among individuals depending on a number of factors including severity of symptoms, comorbidity, sex, and ethnicity (Connolly & Thase, 2011; Goodwin et al. Antipsychotic medications are recommended when symptoms persist despite treatment with a mood stabilizer.

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