Unipolar depression with bipolar family history: links with the bipolar spectrum

The aim of the present paper was to find if unipolar major depressive disorder (MDD) with bipolar family history could be included in the bipolar spectrum, by comparing it to unipolar MDD without bipolar family history, and to bipolar II disorder, on typical bipolar variables. A sample of 280 consecutive bipolar II outpatients, and a sample of 135 consecutive unipolar MDD outpatients, presenting for major depressive episode (MDE) treatment, were interviewed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (4th edn). Hypomanic symptoms during the MDE were systematically assessed. Clinical variables used to validate the inclusion of unipolar MDD with bipolar family history in the bipolar spectrum were young age of onset, many MDE recurrences, atypical features, and depressive mixed state (DMX; an MDE plus >2 concurrent hypomanic symptoms), following many previous studies reporting that these variables were typical features of bipolar disorders. Means were compared by t-test and frequencies by chi2 test (stata 7). Two-tailed P < 0.05 was chosen. Unipolar MDD with bipolar family history was present in 20% of MDD patients. Comparisons among unipolar MDD with bipolar family history (UP+BPFH), unipolar MDD without bipolar family history (UP-BPFH), and bipolar II (BPII), found that UP+BPFH versus UP-BPFH had a significantly lower age, lower age of onset, fewer recurrences, and more DMX; that UP+BPFH versus BPII had no significant differences (apart from recurrences); and that UP-BPFH versus BPII had significantly different age, age of onset, recurrences, atypical features, and DMX. Findings suggest that UP+BPFH shows many bipolar signs, and that it could therefore be included in the bipolar spectrum. Unipolar MDD with bipolar family history had a clinically significant 20.0% frequency in the unipolar MDD sample, supporting the clinical usefulness of this depression subtype. The subtyping of MDD based on bipolar family history could have treatment implications.     

Diagnosis of bipolar II disorder: a comparison of structured versus semistructured interviews

BACKGROUND: Reliability of bipolar II (BPII) disorder diagnosis is still a problem. Recent studies have shown that semistructured interviews by clinicians are better than structured interviews by nonclinicians for BPII diagnosis. The aim of the study was to find the degree of agreement in the diagnosis of BPII between the Structured Clinical Interview for DSM-IV (SCID) and a semistructured interview based on DSM-IV criteria done by an expert clinician. METHODS: One hundred eleven remitted major depressive episode (MDE) outpatients were interviewed first with the SCID and soon after that with a semistructured interview following DSM-IV criteria (based on clinical evaluation). Bipolar I (BPI) patients were excluded. RESULTS: By the SCID, 24 patients were diagnosed BPII (21.6%) and 30 were diagnosed BPI (27.0%). By the semistructured interview, 68 patients were diagnosed BPII (61.2% of the entire sample) and none BPI. Agreement between the SCID BPII diagnosis and the semistructured interview BPII diagnosis was 51.3% (meaning one in two missed). Sensitivity and specificity of the SCID BPII diagnosis for the semistructured BPII diagnosis were 29.4% and 90.7%, respectively. Overactivity (increased goal-directed activity) was the most common hypomanic symptom. In the group with overactivity (n=76), a semistructured interview BPII diagnosis was present in 77.6%, while a SCID BPII diagnosis was present in only 22.3%. Sensitivity and specificity of overactivity for BPII diagnosis were 86.7% and 60.4%, respectively, while elevated mood had sensitivity of 60.2% and specificity of 86.0%. CONCLUSIONS: Findings support a diagnosis of BPII based on a semistructured interview by an expert clinician versus a fully structured interview. Overactivity priority level for the diagnosis of hypomania is supported by the present findings.     

Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia

Learning in neuronal networks occurs by instructions to the neurons to change their synaptic weights (i.e., efficacies). According to the present model a molecular mechanism that can contribute to change synaptic weights may be represented by multiple interactions between membrane receptors forming aggregates (receptor mosaics) via oligomerization at both pre- and post-synaptic level. These assemblies of receptors together with inter alia single receptors, adapter proteins, G-proteins and ion channels form the membrane bound part of a complex three-dimensional (3D) molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. It is suggested that this molecular circuit has the capability to learn and store information. Thus, engram formation will depend on the resetting of 3D molecular circuits via the formation of new receptor mosaics capable of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins. Short-term memory occurs by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteromeric receptor complexes. The receptor mosaic hypothesis of the engram formation has been formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the pre-synaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at post-synaptic level and subsequently at pre-synaptic level with the formation of novel 3D molecular circuits leading to a different integration of chemical signals impinging on pre- and post-synaptic membranes hence leading to a new value of the synaptic weight. Engram retrieval is brought about by the scanning of the target networks by the highly divergent arousal systems. Hence, a continuous reverberating process occurs both at the level of the neural networks as well as at the level of the 3D molecular circuits within each neuron of the network until the appropriate tuning of the synaptic weights is obtained and, subsequently, the reappearance of the engram occurs. Learning and memory in the basal ganglia is discussed in the frame of the present hypothesis. It is proposed that formation of long-term memories (consolidated receptor mosaics) in the plasma membranes of the striosomal GABA neurons may play a major role in the motivational learning of motor skills of relevance for survival. In conclusion, long-lived heteromeric receptor complexes of high order may be crucial for learning, memory and retrieval processes, where extensive reciprocal feedback loops give rise to coherent synchronized neural activity (binding) essential for a sophisticated information handling by the central nervous system.     

Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment

Mitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheumatic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic. We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death. During a mean follow-up of 4.5 years, 1 systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, CI 0.01-2.3), and 1 minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI 0.01-2.3; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI 0.1-3.1; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment. These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF.     

Reproductive life milestones in women with Parkinson's disease

Reproductive life milestones were studied in 150 unselected women with idiopathic Parkinson's disease (PD) and in 300 postmenopausal healthy women (PM). Duration of reproductive life was found to be similar in the two groups. The women with PD reported significantly more premenstrual symptoms, fewer deliveries and abortions, and less use of contraception. Time and mode of menopause onset were similar in PD and PM, but the PD women reported significantly more hot flushes, less insomnia, depression, urinary incontinence and dyspareunia, and less recourse to hormone replacement therapy than the PM women. Women diagnosed with PD before the menopause reported more premenstrual symptoms and contraceptive use compared with those with postmenopausal PD onset, as well as a premenstrual worsening of PD symptoms in more than 50% of cases. Our data indicate poor adaptation of neuronal pathways to the hormonal fluctuations of reproductive life in women with PD, supporting the existence of a qualitative relationship between PD and reproductive events.     

Talking to patients about St. John's wort

St. John's wort, an unregulated herbal supplement widely used as a self-treatment for depression, can cause side effects and drug interactions. Physicians should ask their patients about use of over-the-counter products such as St. John's wort and discuss their use in a frank but nonjudgmental manner.     

Modeling the time dependence of the association between human papillomavirus infection and cervical cancer precursor lesions

The authors studied the time-dependent association between human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) among women enrolled in a cohort study in Brazil (1993-2002), using repeated Papanicolaou cytologic examination and HPV testing by polymerase chain reaction. Through simulation with conceivable alternative cohort designs, they investigated different regression modeling approaches using time-varying covariates, time-varying hazard ratio functions, and repeated events to assess the effect of delay in lesion detection. Associations between HPV and early SIL were of high magnitude. The age-adjusted hazard ratios for the association between HPV at enrollment and low-grade SIL decreased gradually with time until 72 months for both oncogenic types of HPV (hazard ratio = 3.96, 95% confidence interval (CI): 2.5, 6.4) and nononcogenic types (hazard ratio = 2.37, 95% CI: 1.3, 4.3). The hazard ratio for incident high-grade SIL remained constant, ranging from 7.15 (95% CI: 2.0, 25.1) at 12 months to 6.26 (95% CI: 2.7, 14.5) at 72 months for oncogenic types of HPV. With oncogenic HPV as the time-dependent predictor variable, the hazard ratios for incident SIL and high-grade SIL events were 14.2 (95% CI: 8.7, 23.1) and 32.7 (95% CI: 8.4, 127.3), respectively. Investigators may underestimate the prognostic value of HPV detection using designs that rely on HPV ascertainment at a single time point. The waning in hazard ratios should be considered in the implementation of HPV testing-based screening programs.     

Using claims data to examine mortality trends following hospitalization for heart attack in Medicare

OBJECTIVE: To see if changes in the demographics and illness burden of Medicare patients hospitalized for acute myocardial infarction (AMI) from 1995 through 1999 can explain an observed rise (from 32 percent to 34 percent) in one-year mortality over that period. DATA SOURCES: Utilization data from the Centers for Medicare and Medicaid Services (CMS) fee-for-service claims (MedPAR, Outpatient, and Carrier Standard Analytic Files); patient demographics and date of death from CMS Denominator and Vital Status files. For over 1.5 million AMI discharges in 1995-1999 we retain diagnoses from one year prior, and during, the case-defining admission. STUDY DESIGN: We fit logistic regression models to predict one-year mortality for the 1995 cases and apply them to 1996-1999 files. The CORE model uses age, sex, and original reason for Medicare entitlement to predict mortality. Three other models use the CORE variables plus morbidity indicators from well-known morbidity classification methods (Charlson, DCG, and AHRQ's CCS). Regressions were used as is--without pruning to eliminate clinical or statistical anomalies. Each model references the same diagnoses--those recorded during the pre- and index admission periods. We compare each model's ability to predict mortality and use each to calculate risk-adjusted mortality in 1996-1999. PRINCIPAL FINDINGS: The comprehensive morbidity classifications (DCG and CCS) led to more accurate predictions than the Charlson, which dominated the CORE model (validated C-statistics: 0.81, 0.82, 0.74, and 0.66, respectively). Using the CORE model for risk adjustment reduced, but did not eliminate, the mortality increase. In contrast, adjustment using any of the morbidity models produced essentially flat graphs. CONCLUSIONS: Prediction models based on claims-derived demographics and morbidity profiles can be extremely accurate. While one-year post-AMI mortality in Medicare may not be worsening, outcomes appear not to have continued to improve as they had in the prior decade. Rich morbidity information is available in claims data, especially when longitudinally tracked across multiple settings of care, and is important in setting performance targets and evaluating trends.