Erika F.H. Saunders

Intermediate: Cognitive phenotypes in bipolar disorder

BACKGROUND Intermediate cognitive phenotypes (ICPs) are measurable and quantifiable states that may be objectively assessed in a standardized method, and can be integrated into association studies, including genetic, biochemical, clinical, and imaging based correlates. The present study used neuropsychological measures as ICPs, with factor scores in executive functioning, attention, memory, fine motor function, and emotion processing, similar to prior work in schizophrenia. METHODS Healthy control subjects (HC, n=34) and euthymic (E, n=66), depressed (D, n=43), or hypomanic/mixed (HM, n=13) patients with bipolar disorder (BD) were assessed with neuropsychological tests. These were from eight domains consistent with previous literature; auditory memory, visual memory, processing speed with interference resolution, verbal fluency and processing speed, conceptual reasoning and set-shifting, inhibitory control, emotion processing, and fine motor dexterity. RESULTS Of the eight factor scores, the HC group outperformed the E group in three (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity), the D group in seven (all except Inhibitory Control), and the HM group in four (Inhibitory Control, Processing Speed with Interference Resolution, Fine Motor Dexterity, and Auditory Memory). LIMITATIONS The HM group was relatively small, thus effects of this phase of illness may have been underestimated. Effects of medication could not be fully controlled without a randomized, double-blind, placebo-controlled study. CONCLUSIONS Use of the factor scores can assist in determining ICPs for BD and related disorders, and may provide more specific targets for development of new treatments. We highlight strong ICPs (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity) for further study, consistent with the existing literature.

Lithium Therapy and Hyperparathyroidism: An Evidence-Based Assessment

BackgroundProlonged therapeutic exposure to lithium compounds can have adverse consequences on calcium homeostasis. A unique form of hyperparathyroidism appears to be causally linked to chronic lithium exposure. We provide a comprehensive review of relevant literature using a structured, evidence-based approach.MethodsPublished data were identified from systematic electronic literature searches. References are assigned a level of evidence according to a validated classification schema.ResultsLevel III and V evidence supports an etiologic link between sustained lithium therapy and both hypercalcemia and hyperparathormonemia (grade C recommendation). Level V evidence supports the use of preoperative parathyroid imaging if a focused exploration is planned (grade C recommendation). Level V evidence supports the use of intraoperative parathyroid hormone monitoring to guide appropriate surgical therapy (grade C recommendation). There is conflicting and equally weighted level V evidence supporting a routine preoperative plan of bilateral neck exploration versus selective unilateral exploration (no recommendation). There may be a role for calcimimetic drug therapy as an alternate, nonsurgical means of controlling lithium-associated hyperparathyroidism (grade C recommendation).ConclusionsEvidence-based recommendations support screening of patients on chronic lithium therapy for hypercalcemia. Appropriate surgical therapy may consist of either a bilateral or a unilateral approach when performed by an experienced endocrine surgeon. Focused approaches should be guided by preoperative imaging and intraoperative hormone monitoring. Calcimimetic therapy is a potential alternative to parathyroidectomy.

Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder

BACKGROUND Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol. METHOD Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined. RESULTS A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups. LIMITATIONS The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account. CONCLUSIONS Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.

Depression and anxiety in patients with hereditary angioedema.

BACKGROUND Hereditary angioedema (HAE) is characterized by edematous swelling attacks of the face, extremities, abdomen, genitalia, and upper airway. The potential for laryngeal swelling makes the disease life-threatening, and the swelling elsewhere contributes to the significant burden of illness. The increased risk for mental health disorders in HAE is due to the burden of disease and possibly associated activation of the immune system. OBJECTIVE To determine the prevalence of depression and anxiety in HAE patients and the most high-yield features of depression to target in a clinical encounter. METHODS Depression and anxiety symptoms were evaluated using the 29 items of the Hamilton Depression Rating Scale along with the 14-item Hamilton Anxiety Rating Scale. The sample size was 26 participants with a diagnosis of type 1 or 2 HAE drawn from a cohort of 60 adult patients. In addition, a literature search was performed regarding how immune modulation affects depression and anxiety. RESULTS A total of 39% of participants were identified as experiencing depression of mild (50%), moderate (40%), or severe (10%) levels. Fifteen percent of participants displayed prominent anxiety, half of whom had mild anxiety, 25% moderate anxiety, and 25% severe anxiety. The literature on inflammation and depression suggests a possible link between HAE and depression. CONCLUSION Our data and the literature support that depression and anxiety symptoms are common in patients with HAE and may be secondary to chronic disease burden, associated pathophysiologic features, or both. Treatment that addresses the psychosocial and mental health of HAE patients is critical for best practice.

Modeling gene-by-environment interaction in comorbid depression with alcohol use disorders via an integrated bioinformatics approach

BackgroundComorbidity of Major Depressive Disorder (depression) and Alcohol Use Disorders (AUD) is well documented. Depression, AUD, and the comorbidity of depression with AUD show evidence of genetic and environmental influences on susceptibility. We used an integrated bioinformatics approach, mining available data in multiple databases, to develop and refine a model of gene-by-environment interaction consistent with this comorbidity.MethodsWe established the validity of a genetic model via queries against NCBI databases, identifying and validating TNF (Tumor Necrosis Factor) and MTHFR (Methylenetetrahydrofolate Reductase) as candidate genes. We used the PDG-ACE algorithm (Prioritizing Disease Genes by Analysis of Common Elements) to show that TNF and MTHFR share significant commonality and that this commonality is consistent with a response to environmental exposure to ethanol. Finally, we used MetaCore from GeneGo, Inc. to model a gene-by-environment interaction consistent with the data.ResultsTNF Alpha Converting Enzyme (TACE) activity is suppressed by ethanol exposure, resulting in reduced TNF signaling. TNF binds to TNF receptors, initiating signal transduction pathways that activate MTHFR expression. MTHFR is an essential enzyme in folate metabolism and reduced folate levels are associated with both AUD and depression. Integrating these pieces of information our model shows how excessive alcohol use would be expected to lead to reduced TNF signaling, reduced MTHFR expression, and increased susceptibility to depression.ConclusionThe proposed model provides a novel hypothesis on the genetic etiology of comorbid depression with AUD, consistent with established clinical and biochemical data. This analysis also provides an example of how an integrated bioinformatics approach can maximize the use of available biomedical data to improve our understanding of complex disease.

Gender differences, clinical correlates, and longitudinal outcome of bipolar disorder with comorbid migraine.

OBJECTIVE Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. METHOD A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM-IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005-2010. Informed consent was obtained from all participants. RESULTS Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1-5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3-41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0-11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (β = .13, P = .03), and more frequent depression longitudinally (β = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 × 10⁻³), emotional neglect (P = .01), and high neuroticism (P = 2 × 10⁻³). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). CONCLUSIONS Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders.

Modality-specific alterations in the perception of emotional stimuli in Bipolar Disorder compared to Healthy Controls and Major Depressive Disorder

OBJECTIVES Affect identification accuracy paradigms have increasingly been utilized to understand psychiatric illness including Bipolar Disorder (BD) and Major Depressive Disorder (MDD). This investigation focused on perceptual accuracy in affect identification in both visual and auditory domains among patients with BD, relative to Healthy Controls (HC) and patients with MDD. Demographic and clinical variables, in addition to medications were also investigated. METHOD The visual Facial Emotion Perception Test (FEPT) and auditory Emotional Perception Test (EPT) were administered to adults with BD (n=119) and MDD (n=78) as well as HC (n=66). RESULTS Performance on the FEPT was significantly stronger than on the EPT irrespective of group. Performance on the EPT did not significantly differentiate the groups. On the FEPT, BD samples had the greatest difficulty relative to HC in identification of sad and fearful faces. BD participants also had greater difficulty identifying sad faces relative to MDD participants though not after controlling for severity of illness factors. For the BD (but not MDD) sample several clinical variables were also correlated with FEPT performance. CONCLUSIONS The findings suggest that disruptions in identification of negative emotions such as sadness and fear may be a characteristic trait of BD. However, this effect may be moderated by greater illness severity found in our BD sample.

Personality Trait Dimensions and the Pharmacological Treatment of Borderline Personality Disorder

The number of well-designed placebo-controlled studies on pharmacological treatment of borderline personality disorder has been small. We present a breakdown of results of placebo-controlled pharmacological studies, sorting target symptoms into the trait dimensions of affective instability, anxiety inhibition, cognitive-perceptual disturbances, and impulsivity-aggression. Twenty randomized placebo-controlled pharmacological trials studying typical and atypical antipsychotics, selective serotonin reuptake and monoamine oxidase inhibitors, tricyclic antidepressants, mood stabilizers, and benzodiazepines were included. A relative measure of the weight of an outcome was determined by (1) dividing the number of positive comparisons for a drug class by the total number of comparisons of all drugs of all classes for each dimension and (2) dividing the number of positive comparisons for a drug class by the total number of comparisons for that particular drug class for that trait dimension. Antipsychotics (neuroleptics and atypicals) had the most evidence for each of the traits with both methods. Our results are compared with the results of 2 meta-analyses, 1 guideline set, and 1 other systematic review. We found little concordance across these studies. We propose a consortium to discuss guidelines for future studies, including agreement as to what should be measured to determine the outcome and adoption of standardized instruments to measure that outcome.

The effect of poor sleep quality on mood outcome differs between men and women: A longitudinal study of bipolar disorder

BACKGROUND Sleep disturbance is bi-directionally related to mood de-stabilization in bipolar disorder (BD), and sleep quality differs in men and women. We aimed to determine whether perception of poor sleep quality would have a different effect on mood outcome in men versus women. METHODS We assessed association between sleep quality (Pittsburgh Sleep Quality Index (PSQI)) at study intake and mood outcome over 2 years in subjects from the Prechter Longitudinal Study of Bipolar Disorder (N=216; 29.6% males). The main outcome measure was the severity, variability, and frequency of mood episodes measured by self-report over 2 years of follow-up. Multivariable linear regression models stratified by sex examined the relationship between PSQI with mood outcomes, while age, stressful life events, mood state and neuroticism at baseline were controlled. RESULTS In women, poor sleep quality at baseline predicted increased severity (B=0.28, p<0.001) and frequency of episodes (B=0.32, p<0.001) of depression, and poor sleep quality was a stronger predictor than baseline depression; poor sleep quality predicted increased severity (B=0.19, p<0.05) and variability (B=0.20, p<0.05) of mania, and frequency of mixed episodes (B=0.27, p<0.01). In men, baseline depression and neuroticism were stronger predictors of mood outcome compared to poor sleep quality. LIMITATIONS We measured perception of sleep quality, but not objective changes in sleep. CONCLUSIONS In a longitudinal study of BD, women reported poorer perceived sleep quality than men, and poor sleep quality predicted worse mood outcome in BD. Clinicians should be sensitive to addressing sleep complaints in women with BD early in treatment to improve outcome in BD.

Greater executive and visual memory dysfunction in comorbid bipolar disorder and substance use disorder

Measures of cognitive dysfunction in Bipolar Disorder (BD) have identified state and trait dependent metrics. An influence of substance abuse (SUD) on BD has been suggested. This study investigates potential differential, additive, or interactive cognitive dysfunction in bipolar patients with or without a history of SUD. Two hundred fifty-six individuals with BD, 98 without SUD and 158 with SUD, and 97 Healthy Controls (HC) completed diagnostic interviews, neuropsychological testing, and symptom severity scales. The BD groups exhibited poorer performance than the HC group on most cognitive factors. The BD with SUD exhibited significantly poorer performance than BD without SUD in visual memory and conceptual reasoning/set-shifting. In addition, a significant interaction effect between substance use and depressive symptoms was found for auditory memory and emotion processing. BD patients with a history of SUD demonstrated worse visual memory and conceptual reasoning skills above and beyond the dysfunction observed in these domains among individuals with BD without SUD, suggesting greater impact on integrative, gestalt-driven processing domains. Future research might address longitudinal outcome as a function of BD, SUD, and combined BD/SUD to evaluate neural systems involved in risk for, and effects of, these illnesses.